Airborne Diseases Some Common Airborne Diseases Contents

Home , Pneumoparotitis, Timeline of influenza

1 Airborne disease 1 1.1 Overview ...... 1 1.2 Causes ...... 1 1.3 Transmission ...... 1 1.4 Prevention ...... 2 1.5 See also ...... 3 1.6 References ...... 3

2 Influenza A virus 4 2.1 Variants and subtypes ...... 4 2.2 Annual flu ...... 5 2.2.1 FI6 antibody ...... 5 2.3 Structure and genetics ...... 5 2.4 Multiplicity Reactivation ...... 6 2.5 In Non-humans ...... 6 2.6 Human influenza virus ...... 7 2.6.1 Evolution ...... 9 2.7 See also ...... 10 2.8 Notes ...... 10 2.9 Further reading ...... 13 2.10 External links ...... 13

3 Hand, foot, and mouth disease 14 3.1 Signs and symptoms ...... 14 3.2 Cause ...... 15 3.2.1 Transmission ...... 15 3.3 Diagnosis ...... 15 3.4 Prevention ...... 15 3.4.1 Vaccine ...... 15 3.5 Treatment ...... 15 3.6 Complications ...... 15 3.7 Epidemiology ...... 15 3.7.1 Major outbreaks ...... 16

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3.8 History ...... 16 3.9 Research ...... 16 3.10 References ...... 16 3.11 External links ...... 18

4 Tuberculosis 19 4.1 Signs and symptoms ...... 19 4.1.1 Pulmonary ...... 20 4.1.2 Extrapulmonary ...... 20 4.2 Causes ...... 20 4.2.1 Mycobacteria ...... 20 4.2.2 Risk factors ...... 21 4.3 Mechanism ...... 21 4.3.1 Transmission ...... 21 4.3.2 Pathogenesis ...... 21 4.4 Diagnosis ...... 22 4.4.1 Active tuberculosis ...... 23 4.4.2 Latent tuberculosis ...... 23 4.5 Prevention ...... 23 4.5.1 Vaccines ...... 23 4.5.2 Public health ...... 24 4.6 Management ...... 24 4.6.1 New onset ...... 24 4.6.2 Recurrent disease ...... 24 4.6.3 Medication resistance ...... 24 4.7 Prognosis ...... 24 4.8 Epidemiology ...... 25 4.9 History ...... 25 4.10 Society and culture ...... 27 4.10.1 Names ...... 27 4.10.2 Public health eﬀorts ...... 27 4.10.3 Stigma ...... 27 4.11 Research ...... 28 4.12 Other animals ...... 28 4.13 References ...... 28 4.14 External links ...... 35

5 Measles 36 5.1 Signs and symptoms ...... 36 5.1.1 Complications ...... 37 5.2 Cause ...... 37 5.3 Diagnosis ...... 38 CONTENTS iii

5.3.1 Laboratory testing ...... 38 5.4 Prevention ...... 38 5.5 Treatment ...... 38 5.6 Prognosis ...... 39 5.7 Epidemiology ...... 39 5.8 History ...... 40 5.9 Society and culture ...... 41 5.10 Research ...... 41 5.11 References ...... 41 5.12 External links ...... 45

6 Parotitis 46 6.1 Causes ...... 46 6.1.1 Dehydration ...... 46 6.1.2 Infectious parotitis ...... 46 6.1.3 Autoimmune causes ...... 46 6.1.4 Blockage ...... 46 6.1.5 Diseases of uncertain cause ...... 46 6.2 Notes ...... 47 6.3 References ...... 47 6.4 External links ...... 47

7 Inﬂuenza 48 7.1 Signs and symptoms ...... 48 7.2 Virology ...... 49 7.2.1 Types of virus ...... 49 7.2.2 Structure, properties, and subtype nomenclature ...... 50 7.2.3 Replication ...... 51 7.3 Mechanism ...... 51 7.3.1 Transmission ...... 51 7.3.2 Pathophysiology ...... 52 7.4 Prevention ...... 53 7.4.1 Vaccination ...... 53 7.4.2 Infection control ...... 53 7.5 Treatment ...... 54 7.5.1 Antivirals ...... 54 7.6 Prognosis ...... 54 7.7 Epidemiology ...... 55 7.7.1 Seasonal variations ...... 55 7.7.2 Epidemic and pandemic spread ...... 55 7.8 History ...... 56 7.8.1 Etymology ...... 56 iv CONTENTS

7.8.2 Pandemics ...... 56 7.9 Society and culture ...... 58 7.10 Research ...... 58 7.11 Other animals ...... 59 7.11.1 Bird ﬂu ...... 59 7.11.2 Swine ﬂu ...... 60 7.12 References ...... 60 7.13 Further reading ...... 70 7.14 External links ...... 70

8 Chickenpox 71 8.1 Signs and symptoms ...... 71 8.1.1 Pregnancy and neonates ...... 72 8.2 Diagnosis ...... 73 8.3 Pathophysiology ...... 73 8.3.1 Shingles ...... 73 8.4 Prevention ...... 74 8.4.1 Hygiene measures ...... 74 8.4.2 Vaccine ...... 74 8.5 Treatment ...... 74 8.5.1 Children ...... 74 8.5.2 Adults ...... 74 8.6 Prognosis ...... 75 8.7 Epidemiology ...... 75 8.8 Etymology ...... 75 8.9 Society and culture ...... 76 8.10 Other animals ...... 76 8.11 References ...... 76 8.12 External links ...... 78

9 Meningitis 80 9.1 Signs and symptoms ...... 80 9.1.1 Clinical features ...... 80 9.1.2 Early complications ...... 81 9.2 Causes ...... 82 9.2.1 Bacterial ...... 82 9.2.2 Viral ...... 82 9.2.3 Fungal ...... 82 9.2.4 Parasitic ...... 83 9.2.5 Non-infectious ...... 83 9.3 Mechanism ...... 83 9.4 Diagnosis ...... 83 CONTENTS v

9.4.1 Blood tests and imaging ...... 83 9.4.2 Lumbar puncture ...... 84 9.4.3 Postmortem ...... 85 9.5 Prevention ...... 85 9.5.1 Behavioral ...... 85 9.5.2 Vaccination ...... 85 9.5.3 Antibiotics ...... 86 9.6 Management ...... 86 9.6.1 Bacterial meningitis ...... 86 9.6.2 Viral meningitis ...... 87 9.6.3 Fungal meningitis ...... 87 9.7 Prognosis ...... 87 9.8 Epidemiology ...... 87 9.9 History ...... 88 9.10 References ...... 89 9.11 External links ...... 92

10 Pneumonia 93 10.1 Signs and symptoms ...... 93 10.2 Cause ...... 94 10.2.1 Bacteria ...... 94 10.2.2 Viruses ...... 95 10.2.3 Fungi ...... 95 10.2.4 Parasites ...... 95 10.2.5 Noninfectious ...... 95 10.3 Mechanisms ...... 95 10.3.1 Viral ...... 96 10.3.2 Bacterial ...... 96 10.4 Diagnosis ...... 96 10.4.1 Physical exam ...... 96 10.4.2 Imaging ...... 96 10.4.3 Microbiology ...... 97 10.4.4 Classiﬁcation ...... 97 10.4.5 Diﬀerential diagnosis ...... 98 10.5 Prevention ...... 98 10.5.1 Vaccination ...... 98 10.5.2 Medications ...... 98 10.5.3 Other ...... 98 10.6 Management ...... 99 10.6.1 Bacterial ...... 99 10.6.2 Viral ...... 99 10.6.3 Aspiration ...... 99 vi CONTENTS

10.7 Prognosis ...... 99 10.7.1 Clinical prediction rules ...... 100 10.7.2 Pleural eﬀusion, empyema, and abscess ...... 100 10.7.3 Respiratory and circulatory failure ...... 100 10.8 Epidemiology ...... 100 10.8.1 Children ...... 101 10.9 History ...... 101 10.10Society and culture ...... 102 10.10.1 Awareness ...... 102 10.10.2 Costs ...... 102 10.11Research ...... 102 10.12References ...... 102 10.13External links ...... 107

11 Rubella virus 108 11.1 Taxonomy ...... 108 11.2 Structure ...... 108 11.3 Genome ...... 108 11.4 Replication ...... 108 11.5 Capsid protein ...... 109 11.6 Epidemiology ...... 109 11.7 Literature ...... 109 11.8 References ...... 109 11.9 External links ...... 110 11.10Text and image sources, contributors, and licenses ...... 111 11.10.1 Text ...... 111 11.10.2 Images ...... 119 11.10.3 Content license ...... 123 Chapter 1

Airborne disease

by the inhalation of these pathogens that affect a person’s respiratory system or even the rest of the body. Sinus congestion, coughing and sore throats are examples of inflammation of the upper respiratory air way due to these airborne agents. Air pollution plays a significant role in airborne diseases which is linked to asthma. Pollutants are said to influence lung function by increasing air way inflammation.[1] Many common infections can spread by airborne transmission at least in some cases, including: Anthrax (in- halational), Chickenpox, Influenza, Measles, Smallpox, Cryptococcosis, and Tuberculosis. Airborne diseases can be spread via respiratory droplets expelled Airborne diseases can also affect non-humans. For ex- from the mouth and nose. ample, Newcastle disease is an avian disease that affects many types of domestic poultry worldwide which An airborne disease is any disease that is caused by is transmitted via airborne contamination.[2] Often, air- pathogens and transmitted through the air. Such diseases borne pathogens or allergens cause inflammation in the include many that are of considerable importance both in nose, throat, sinuses, and the upper airway lungs. Up- human and veterinary medicine. The relevant pathogens per airway inflammation causes coughing congestion,and may be viruses, bacteria, or fungi, and they may be spread sore throat. This is caused by the inhalation of these through coughing, sneezing, raising of dust, spraying of pathogens that affect a person’s respiratory system or liquids, or similar activities likely to generate aerosol par- even the rest of the body. Sinus congestion, coughing ticles or droplets. Strictly speaking airborne diseases do and sore throats are examples of inflammation of the up- not include conditions caused simply by air pollution such per respiratory air way due to these airborne agents. as dusts and poisons, though their study and prevention may be related. 1.2 Causes 1.1 Overview An airborne disease can be caused by exposure to a source: an infected patient or animal, by being trans- Airborne diseases include any that are caused and transferred from the infected person or animal’s mouth, nose, mitted through the air. Some are of great medical im- cut, or needle puncture. People receive the disease portance. The pathogens transmitted may be any kind of through a portal of entry: mouth, nose, cut, or needle microbe, and they may be spread in aerosols, dust or liq- puncture. uids. The aerosols might be generated from sources of infection such as the bodily secretions of an infected animal or person, or biological wastes such as accumulate in lofts, caves, garbage and the like. Such infected aerosols 1.3 Transmission may stay suspended in air currents long enough to travel for considerable distances, though the rate of infection Airborne transmission of disease depends on several decreases sharply with the distance between the source physical variables endemic to the infectious particle. En- and the organism infected. vironmental factors influence the efficacy of airborne dis- Airborne pathogens or allergens often cause inflammation ease transmission; the most evident environmental con- in the nose, throat, sinuses and the lungs. This is caused ditions are temperature and relative humidity. The sum

1 2 CHAPTER 1. AIRBORNE DISEASE of all the factors that influence temperature and humid- Nearness to large sources of water as rivers ity, either meteorological (outdoor) or human (indoor), and lakes can be a cause of some outbreaks as well as other circumstances influencing the spread of of airborne diseases, after changes in local the droplets containing the infectious particles, as winds, watershed.[7] Poor sewage systems are usually or human behavior, sum up the factors influencing the found in poor countries, especially in the rural transmission of airborne diseases. areas, and can determine the proliferation of infectious bacteria, that once infecting animal • Climate and living area. Rainfall (number of or humans can be transmitted throughout the rainy days[3] being more important than total air. precipitation[4][5]), mean of sunshine daily hours,[6] latitude, altitude[4] are characteristic agents to take Working conditions, can also settle infectious in account when assessing the possibility of spread airborne diseases. At indoor environments, of any airborne infection. Furthermore, some in- temperature and relative humidity are mainly frequent or exceptional extreme events also influ- affected by HVAC systems (heating, ventila- ence the dissemination of airborne diseases, as trop- tion and air conditioning).[10] Inadequate ven- ical storms, hurricanes, typhoons, or monsoons.[7] tilation is implicated in the airborne trans- Climate conditions determine temperature, winds mission of respiratory viruses.[3] Poor mainte- and relative humidity in any territory, either all year nance or defects on those systems can foster around or at isolated moments (days or weeks). the conditions for airborne infections.[11] For Those are the main factors affecting the spread, instance, a poor maintenance of air condition- duration and infectiousness of droplets containing ing systems, can lead to an outbreak of Le- infectious particles. For instance, influenza virus, gionella (mainly Legionella pneumophila), that is spread easily in northern countries (north hemi- will spread among the population of the build- sphere), because of climate conditions which favour ing (workers), before the finding of the focal the infectiousness of the virus but on the other hand, point.[12] In hospitals, isolation of patients sick in those countries, lots of bacterial infections cannot of infectious diseases has to be added as a fac- spread outdoor most of the year, keeping in a latent tor, which is noticeable in poor regions, where stage. lack of resources facilitates the spread of infectious diseases.[13] UV is harmful to both viruses and bacteria. UV incidence can determine the survival of the infectious particles, so that in those terri- 1.4 Prevention tories with a higher average of sunshine daily hours, and closer to the equator, some particles Some ways to prevent airborne diseases include washing lose their infectious ability. Infectious particles hands, using appropriate hand disinfection, getting reg- show and increased survival in the presence of ular immunizations against diseases believed to be lo- UV light at higher relative humidity levels. It cally present, wearing a respirator and limiting time spent is thought to be due to the protective effect of in the presence of any patient likely to be a source of larger particle sizes, as evaporation would be infection.[14] Exposure to a patient or animal with an air- less at these higher RH levels, showing a pro- borne disease does not guarantee receiving the disease. tective effect of a thicker water coat.[8] Because of the changes in host immunity and how much the host was exposed to the particles in the air makes a After isolated events, as tropical storms, has difference to how the disease affects the body.[14] been determined that firstly the quantity of fungal spores is decreased, but a few days later, With few exceptions, antibiotics are not prescribed for an exponentially increased number of spores is patients to control viral infections. They may however found, compared to normal conditions.[9] be prescribed to a flu patient for instance, to control or prevent bacterial secondary infections. They also may be • used in dealing with air-borne bacterial primary infec- Socioeconomics and living conditions. They have [15] a minor role in airborne diseases transmission, but tions, such as pneumonic plague. they also have to be taken in consideration. Dwelling Additionally the Centers for Disease Control and Preven- is an important aspect. In cities the spread of dis- tion (CDC) has told consumers about vaccination and fol- eases is faster than in rural areas and outskirts. Nor- lowing careful hygiene and sanitation protocols for air- mally, cities enclose quarters of buildings, in which borne disease prevention.[16] Consumers also have access the transmission of the viral and bacterial diseases to preventive measures like UV Air purification devices among the neighborhoods is uncomplicated. How- that FDA and EPA-certified laboratory test data has ver- ever, suburban areas are generally more favourable ified as effective in inactivating a broad array of airborne for higher airborne fungal spores[8] infectious diseases.[17] 1.6. REFERENCES 3

1.5 See also [12] “Legionnaire disease”. Retrieved 12 April 2015. [13] “Legionnaires Disease”. legionellacontrol.com. • Vector (epidemiology) [14] American Academy of Orthopaedic Surgeons (AAOS) • Waterborne diseases (2011). Bloodborne and Airborne Pathogens. Jones & • Zoonosis Barlett Publishers. p. 2. Retrieved 21 May 2013. [15] Laura Ester Ziady; Nico Small (2006). Prevent and Con- trol Infection: Application Made Easy. Juta and Company 1.6 References Ltd. pp. 119–120. Retrieved 21 May 2013. [16] “Redirect - Vaccines: VPD-VAC/VPD menu page”. [1] “Airborne diseases”. Retrieved 21 May 2013. [17] “Chamber Test Analysis on Eco-RX Inc. Model 400 Air [2] Mitchell, Bailey W.; King, Daniel J. (October–December Puriﬁer” (PDF). Retrieved 4 May 2007. 1994). “Eﬀect of Negative Air Ionization on Airborne Transmission of Newcastle Disease Virus”. Avian Dis- eases. 38 (4). JSTOR 1592107. Retrieved 21 May 2013.

[3] Pica N, Bouvier NM (2012). “Environmental Factors Aﬀecting the Transmission of Respi- ratory Viruses”. Curr Opin Virol. 2 (1): 90–5. doi:10.1016/j.coviro.2011.12.003. PMC 3311988 . PMID 22440971.

[4] Rodríguez-Rajo FJ, Iglesias I, Jato V. “Variation assessment of airborne Alternaria and Cladosporium spores at diﬀerent bioclimatical conditions.”. Mycol Res. 109: 497–507. doi:10.1017/s0953756204001777. PMID 15912938.

[5] Peternel R, Culig J, Hrga I. “Atmospheric concentrations of Cladosporium spp. and Alternaria spp. spores in Za- greb (Croatia) and eﬀects of some meteorological factors.”. Ann Agric Environ Med. 11: 303–7. PMID 15627341.

[6] Sabariego S, Díaz , de la Guardia C, Alba F. “The eﬀect of meteorological factors on the daily variation of airborne fungal spores in Granada (southern Spain).”. Int J Biome- teorol. 44: 1–5. doi:10.1007/s004840050131. PMID 10879421.

[7] Hedlund C, Blomstedt Y, Schumann B (2014). “Association of climatic factors with infectious diseases in the Arctic and subarctic region – a systematic review”. Glob Health Action. 7: 24161. doi:10.3402/gha.v7.24161. PMC 4079933 . PMID 24990685.

[8] Tang JW (2009). “The eﬀect of environmental parameters on the survival of airborne infectious agents”. J R Soc Interface. 6 Suppl 6: S737–46. doi:10.1098/rsif.2009.0227.focus. PMC 2843949 . PMID 19773291.

[9] Khan NN, Wilson BL. “An environmental assessment of mold concentrations and potential mycotoxin exposures in the greater Southeast Texas area.”. J Environ Sci Health A Tox Hazard Subst Environ Eng. 38: 2759–72. PMID 14672314.

[10] “Aerobiology and Its Role in the Transmission of Infec- tious Diseases”. Retrieved 12 April 2015.

[11] “Aerosolization 's Roll in Transmission of Healthcare Ac- quired Conditions”. Retrieved 12 April 2015. Chapter 2

Inﬂuenza A virus

Influenza A virus causes influenza in birds and some Different influenza viruses encode for different hemag- mammals, and is the only species of influenza virus A. glutinin and neuraminidase proteins. For example, the Influenza virus A is a genus of the Orthomyxoviridae fam- H5N1 virus designates an influenza A subtype that has ily of viruses. Strains of all subtypes of influenza A virus a type 5 hemagglutinin (H) protein and a type 1 neu- have been isolated from wild birds, although disease is un- raminidase (N) protein. There are 18 known types of common. Some isolates of influenza A virus cause severe hemagglutinin and 11 known types of neuraminidase, so, disease both in domestic poultry and, rarely, in humans.[1] in theory, 198 different combinations of these proteins Occasionally, viruses are transmitted from wild aquatic are possible.[4][5] birds to domestic poultry, and this may cause an outbreak [2][3] Some variants are identified and named according to the or give rise to human influenza pandemics. isolate they resemble, thus are presumed to share lineage Influenza A viruses are negative-sense, single-stranded, (example Fujian flu virus-like); according to their typ- segmented RNA viruses. The several subtypes are ical host (example human flu virus); according to their labeled according to an H number (for the type of subtype (example H3N2); and according to their deadli- hemagglutinin) and an N number (for the type of ness (example LP, low pathogenic). So a flu from a virus neuraminidase). There are 18 different known H antigens similar to the isolate A/Fujian/411/2002(H3N2) is called (H1 to H18) and 11 different known N antigens (N1 to Fujian flu, human flu, and H3N2 flu. N11).[4][5] H17 was isolated from fruit bats in 2012.[6][7] [5] Variants are sometimes named according to the species H18N11 was discovered in a Peruvian bat in 2013. (host) in which the strain is endemic or to which it is Each virus subtype has mutated into a variety of strains adapted. The main variants named using this convention with differing pathogenic profiles; some are pathogenic to are: one species but not others, some are pathogenic to multiple species. • Bird flu A filtered and purified influenza A vaccine for humans has been developed, and many countries have stockpiled • Human flu it to allow a quick administration to the population in the event of an avian influenza pandemic. Avian influenza is • Swine influenza sometimes called avian flu, and colloquially, bird flu. In 2011, researchers reported the discovery of an antibody • Equine influenza effective against all types of the influenza A virus.[8] • Canine influenza

2.1 Variants and subtypes Variants have also sometimes been named according to their deadliness in poultry, especially chickens: Influenza type A viruses are categorized into subtypes based on the type of two proteins on the surface of the • Low pathogenic avian influenza (LPAI) viral envelope: • Highly pathogenic avian influenza (HPAI), also H = hemagglutinin, a protein that causes red called deadly flu or death flu blood cells to agglutinate. N = neuraminidase, an enzyme that cleaves Most known strains are extinct strains. For example, the the glycosidic bonds of the monosaccharide, annual flu subtype H3N2 no longer contains the strain that neuraminic acid caused the Hong Kong flu.

4 2.3. STRUCTURE AND GENETICS 5

2.2 Annual flu only H 1, 2 and 3, and N 1 and 2 are commonly found in humans.[19] Main article: Flu season The central core of a virion contains the viral genome and other viral proteins that package and protect the genetic The annual flu (also called “seasonal flu” or “human flu”) material. Unlike the genomes of most organisms (in- in the U.S. “results in approximately 36,000 deaths and cluding humans, animals, plants, and bacteria) which are more than 200,000 hospitalizations each year. In addition made up of double-stranded DNA, many viral genomes to this human toll, influenza is annually responsible for a are made up of a different, single-stranded nucleic acid total cost of over $10 billion in the U.S.”[9] called RNA. Unusually for a virus, though, the influenza type A virus genome is not a single piece of RNA; instead, The annually updated, trivalent influenza vaccine consists it consists of segmented pieces of negative-sense RNA, of hemagglutinin (HA) surface glycoprotein components each piece containing either one or two genes which code [10] from influenza H3N2, H1N1, and B influenza viruses. for a gene product (protein).[16] The term negative-sense Measured resistance to the standard antiviral drugs RNA just implies that the RNA genome cannot be trans- amantadine and rimantadine in H3N2 has increased from lated into protein directly; it must first be transcribed to 1% in 1994 to 12% in 2003 to 91% in 2005. positive-sense RNA before it can be translated into protein products. The segmented nature of the genome al- “Contemporary human H3N2 influenza viruses are now lows for the exchange of entire genes between different endemic in pigs in southern China and can reassort with viral strains.[16] avian H5N1 viruses in this intermediate host.”[11] The entire Influenza A virus genome is 13,588 bases long and is contained on eight RNA segments that code for 11 2.2.1 FI6 antibody proteins:[16]

FI6, an antibody that targets the hemagglutinin protein, • Segment 1 encodes RNA polymerase subunit was discovered in 2011. FI6 is the only known anti- (PB2). body effective against all 16 subtypes of the influenza A virus.[12][13][14] • Segment 2 encodes RNA polymerase subunit (PB1) and the PB1-F2 protein, which induces cell death, by using different reading frames from the same 2.3 Structure and genetics RNA segment. • Segment 3 encodes RNA polymerase subunit (PA); See also: H5N1 genetic structure an alternate form of this polymerase can sometimes be made with a change to the reading frame. Influenza type A viruses are very similar in structure to • Segment 4 encodes for HA (hemagglutinin). About influenza viruses types B and C. The virus particle (also 500 molecules of hemagglutinin are needed to make called the virion) is 80–120 nanometers in diameter and one virion. HA determines the extent and severity of usually roughly spherical, although some rare filamentous a viral infection in a host organism. forms can occur.[15] According to researchers, there are more filamentous particles in clinical isolates, whereas • Segment 5 encodes NP, which is a nucleoprotein. laboratory strains consist of more spherical virions.[16] • Segment 6 encodes NA (neuraminidase). About Despite these varied shapes, the virions of all influenza 100 molecules of neuraminidase are needed to make type A viruses are similar in composition. They are all one virion. made up of a viral envelope containing two main types of • proteins, wrapped around a central core.[16] Segment 7 encodes two matrix proteins (M1 and M2) by using different reading frames from the The two large proteins found on the outside of viral parti- same RNA segment. About 3000 matrix protein cles are hemagglutinin (HA) and neuraminidase (NA). molecules are needed to make one virion. HA is a protein that mediates binding of the virion to target cells and entry of the viral genome into the target cell, • Segment 8 encodes two distinct non-structural pro- while NA is involved in the release of progeny virions teins (NS1 and NEP) by using different reading from infected cells.[17] These proteins are usually the tar- frames from the same RNA segment. gets for antiviral drugs.[18] Furthermore, they are also the antigen proteins to which a host’s antibodies can bind and The RNA segments of the viral genome have comple- trigger an immune response. Influenza type A viruses are mentary base sequences at the terminal ends, allowing categorized into subtypes based on the type of these two them to bond to each other with hydrogen bonds.[17] After proteins on the surface of the viral envelope. There are transcription from negative-sense to positive-sense RNA 16 subtypes of HA and 9 subtypes of NA known, but takes place, the positive-sense RNA strands are capped 6 CHAPTER 2. INFLUENZA A VIRUS

on the 5’ end by a process called cap snatching. This in- Fowl act as natural asymptomatic carriers of influenza volves the viral protein NS1 binding to the host cell’s early A viruses. Prior to the current H5N1 epizootic, strains messenger RNA transcripts. A second viral protein, PA, of influenza A virus had been demonstrated to be trans- cleaves the cap from the host’s RNA. The short cap is then mitted from wild fowl to only birds, pigs, horses, seals, added to the influenza positive-sense RNA strands, allow- whales and humans; and only between humans and pigs ing it to be processed by ribosomes and translated into its and between humans and domestic fowl; and not other protein products.[16] The positive-sense RNA strands also pathways such as domestic fowl to horse.[26] serve for synthesis of negative-sense RNA strands for new Wild aquatic birds are the natural hosts for a large variety virions.[16] of influenza A viruses. Occasionally, viruses are trans- The RNA synthesis takes place in the cell nucleus, while mitted from these birds to other species and may then the synthesis of proteins takes place in the cytoplasm. cause devastating outbreaks in domestic poultry or give Once the viral proteins are assembled into virions, the as- rise to human influenza pandemics.[2][3] sembled virions leave the nucleus and migrate towards the [20] H5N1 has been shown to be transmitted to tigers, leop- cell membrane. The host cell membrane has patches of ards, and domestic cats that were fed uncooked domestic viral transmembrane proteins (HA, NA, and M2) and an fowl (chickens) with the virus. H3N8 viruses from horses underlying layer of the M1 protein which assist the assem- have crossed over and caused outbreaks in dogs. Labora- bled virions to budding through the membrane, releasing [20] tory mice have been infected successfully with a variety finished enveloped viruses into the extracellular fluid. of avian flu genotypes.[27] Influenza A viruses spread in the air and in manure, and 2.4 Multiplicity Reactivation survives longer in cold weather. It can also be transmitted by contaminated feed, water, equipment and cloth- ing; however, there is no evidence the virus can survive Influenza virus is able to undergo multiplicity reactivation [21][22] in well-cooked meat. Symptoms in animals vary, but vir- after inactivation by UV radiation, or by ionizing ulent strains can cause death within a few days. radiation.[23] If any of the eight RNA strands that make up the genome contains damage that prevents replication “Highly pathogenic avian influenza virus is on every or expression of an essential gene, the virus is not viable top ten list available for potential agricultural bioweapon [28] when it alone infects a cell (a single infection). However, agents”. when two or more damaged viruses infect the same cell Avian influenza viruses that the OIE and others test for (multiple infection), viable progeny viruses can be pro- to control poultry disease include: H5N1, H7N2, H1N7, duced provided each of the eight genomic segments is H7N3, H13N6, H5N9, H11N6, H3N8, H9N2, H5N2, present in at least one undamaged copy. That is, multi- H4N8, H10N7, H2N2, H8N4, H14N5, H6N5, H12N5 plicity reactivation can occur. and others. Upon infection, influenza virus induces a host re- Known outbreaks of highly pathogenic flu in poultry sponse involving increased production of reactive oxy- 1959–2003[29] gen species, and this can damage the virus genome.[24] If, under natural conditions, virus survival is ordinarily vulnerable to the challenge of oxidative damage, then mul- *Outbreaks with significant spread to numerous farms, resulting tiplicity reactivation is likely selectively advantageous as in great economic losses. Most other outbreaks involved little or a kind of genomic repair process. It has been suggested no spread from the initially infected farms. that multiplicity reactivation involving segmented RNA 1979: “More than 400 harbor seals, most of them im- genomes may be similar to the earliest evolved form of mature, died along the New England coast between sexual interaction in the RNA world that likely preceded December 1979 and October 1980 of acute pneumo- the DNA world.[25] (Also see RNA world hypothesis.) nia associated with influenza virus, A/Seal/Mass/1/180 (H7N7).”[30] 2.5 In Non-humans 1995: "[V]accinated birds can develop asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive surveillance is re- See H5N1 for the current epizootic (an epidemic quired to detect these “silent epidemics” in time to cur- in nonhumans) and panzootic (a disease affect- tail them. In Mexico, for example, mass vaccination of ing animals of many species especially over a chickens against epidemic H5N2 influenza in 1995 has wide area) of H5N1 influenza had to continue in order to control a persistent and evolving virus (Lee et al., 2004).”[31] Avian influenza 1997: “Influenza A viruses normally seen in one species Main article: Avian influenza sometimes can cross over and cause illness in another species. For example, until 1997, only H1N1 viruses 2.6. HUMAN INFLUENZA VIRUS 7 circulated widely in the U.S. pig population. However, Main article: Canine influenza in 1997, H3N2 viruses from humans were introduced into the pig population and caused widespread disease among pigs. Most recently, H3N8 viruses from horses Dog flu (or “canine influenza”) refers to vari- have crossed over and caused outbreaks in dogs.”[32] eties of influenza A virus that affect dogs. The 2000: “In California, poultry producers kept their knowl- equine influenza virus H3N8 was found to in- edge of a recent H6N2 avian influenza outbreak to them- fect and kill – with respiratory illness – grey- selves due to their fear of public rejection of poultry prod- hound race dogs at a Florida racetrack in Jan- ucts; meanwhile, the disease spread across the western uary 2004. United States and has since become endemic.”[33] H3N8 2003: In Netherlands H7N7 influenza virus infection broke out in poultry on several farms.[34] Main article: Influenza A virus subtype H3N8 2004: In North America, the presence of avian influenza strain H7N3 was confirmed at several poultry farms in British Columbia in February 2004. As of April 2004, H3N8 is now endemic in birds, horses and 18 farms had been quarantined to halt the spread of the dogs. virus.[35] 2005: Tens of millions of birds died of H5N1 influenza and hundreds of millions of birds were culled to protect 2.6 Human influenza virus humans from H5N1. H5N1 is endemic in birds in southeast Asia and represents a long-term pandemic threat. “Human influenza virus” usually refers to those subtypes 2006: H5N1 spreads across the globe, killing hundreds that spread widely among humans. H1N1, H1N2, and of millions of birds and over 100 people, and causing a H3N2 are the only known influenza A virus subtypes cur- significant H5N1 impact from both actual deaths and pre- rently circulating among humans.[36] dicted possible deaths. Genetic factors in distinguishing between “human flu viruses” and “avian influenza viruses” include: Swine flu PB2: (RNA polymerase): Amino acid (or Main article: Swine influenza residue) position 627 in the PB2 protein en- coded by the PB2 RNA gene. Until H5N1, all known avian influenza viruses had a Glu at po- Swine influenza (or “pig influenza”) refers to sition 627, while all human influenza viruses a subset of Orthomyxoviridae that create in- had a lysine. fluenza and are endemic in pigs. The species of Orthomyxoviridae that can cause flu in pigs HA: (hemagglutinin): Avian influenza HA are influenza A virus and influenza C virus, but binds alpha 2–3 sialic acid receptors, while hu- not all genotypes of these two species infect man influenza HA binds alpha 2–6 sialic acid pigs. The known subtypes of influenza A virus receptors. Swine influenza viruses have the that create influenza and are endemic in pigs ability to bind both types of sialic acid recep- are H1N1, H1N2, H3N1 and H3N2. tors.

Horse flu “About 52 key genetic changes distinguish avian influenza strains from those that spread easily among people, according to researchers in Taiwan, who analyzed the genes Main article: Equine influenza of more than 400 A type flu viruses.”[37] “How many mutations would make an avian virus capable of infecting humans efficiently, or how many mutations would render Horse flu (or “equine influenza”) refers to va- an influenza virus a pandemic strain, is difficult to pre- rieties of influenza A virus that affect horses. dict. We have examined sequences from the 1918 strain, Horse flu viruses were only isolated in 1956. which is the only pandemic influenza virus that could be The two main types of virus are called equine- entirely derived from avian strains. Of the 52 species- 1 (H7N7), which commonly affects horse heart associated positions, 16 have residues typical for human muscle, and equine-2 (H3N8), which is usually strains; the others remained as avian signatures. The re- more severe. sult supports the hypothesis that the 1918 pandemic virus is more closely related to the avian influenza A virus than Dog flu are other human influenza viruses.”[38] 8 CHAPTER 2. INFLUENZA A VIRUS

Human flu symptoms usually include fever, cough, sore H3N2 throat, muscle aches, conjunctivitis and, in severe cases, severe breathing problems and pneumonia that may be Main article: Influenza A virus subtype H3N2 fatal. The severity of the infection will depend in large part on the state of the infected person’s immune system and if the victim has been exposed to the strain before, H3N2 is currently endemic in both human and and is therefore partially immune. pig populations. It evolved from H2N2 by Highly pathogenic H5N1 avian influenza in a human is antigenic shift and caused the Hong Kong flu far worse, killing 50% of humans who catch it. In one pandemic of 1968 and 1969 that killed up case, a boy with H5N1 experienced diarrhea followed to 750,000.[41] “An early-onset, severe form rapidly by a coma without developing respiratory or flu- of influenza A H3N2 made headlines when like symptoms.[39] it claimed the lives of several children in the [42] The influenza A virus subtypes that have been confirmed United States in late 2003.” in humans, ordered by the number of known human pandemic deaths, are: The dominant strain of annual flu in January 2006 was H3N2. Measured resistance to the • H1N1 caused "Spanish flu" and the 2009 swine flu standard antiviral drugs amantadine and riman- outbreak tadine in H3N2 increased from 1% in 1994 to 12% in 2003 to 91% in 2005.[43] • H2N2 caused "Asian flu" in the late 1950s • H3N2 caused "Hong Kong flu" in the late 1960s "[C]ontemporary human H3N2 influenza viruses are now endemic in pigs in southern • H5N1 considered a global influenza pandemic threat China and can reassort with avian H5N1 through its spread in the mid-2000s viruses in this intermediate host.”[11] • H7N7 has unusual zoonotic potential H5N1 • H1N2 is currently endemic in humans and pigs • H9N2, H7N2, H7N3, H5N2, and H10N7. Main article: Influenza A virus subtype H5N1

H1N1 H5N1 is the world’s major inﬂuenza pandemic Main article: Inﬂuenza A virus subtype H1N1 threat.

H1N1 is currently pandemic in both human “When he compared the 1918 virus with to- and pig populations. A variant of H1N1 was day’s human flu viruses, Dr. Taubenberger no- responsible for the Spanish flu pandemic that ticed that it had alterations in just 25 to 30 killed some 50 million to 100 million peo- of the virus’s 4,400 amino acids. Those few ple worldwide over about a year in 1918 and changes turned a bird virus into a killer that [44] 1919.[40] Another variant was named a pan- could spread from person to person.” demic threat in the 2009 flu pandemic. Contro- versy arose in October, 2005, after the H1N1 H7N7 genome was published in the journal, Science, because of fears that this information could be Main article: Influenza A virus subtype H7N7 used for bioterrorism.

H2N2 H7N7 has unusual zoonotic potential. In 2003 in Netherlands, 89 people were confirmed to Main article: Influenza A virus subtype H2N2 have H7N7 influenza virus infection following an outbreak in poultry on several farms. One death was recorded. The Asian flu, a pandemic outbreak of H2N2 avian influenza, originated in China in 1957, spread worldwide that same year during which H7N9 a influenza vaccine was developed, lasted until 1958 and caused between one and four million Main article: Influenza A virus subtype H7N9 deaths. 2.6. HUMAN INFLUENZA VIRUS 9

On 2 April 2013, the Centre for Health Pro- H5N2 tection (CHP) of the Department of Health of Hong Kong confirmed four more cases in Main article: Influenza A virus subtype H5N2 Jiangsu province in addition to the three cases initially reported on 31 March 2013.[45] Japan’s Health Ministry said January 2006 that H1N2 poultry farm workers in Ibaraki prefecture may have been exposed to H5N2 in 2005.[47] The Main article: Influenza A virus subtype H1N2 H5N2 antibody titers of paired sera of 13 subjects increased fourfold or more.[48]

H1N2 is currently endemic in both human and H10N7 pig populations. The new H1N2 strain appears to have resulted from the reassortment of Main article: Influenza A virus subtype H10N7 the genes of the currently circulating influenza H1N1 and H3N2 subtypes. The hemagglutinin protein of the H1N2 virus is similar to that of In 2004 in Egypt, H10N7 was reported for the the currently circulating H1N1 viruses, and the first time in humans. It caused illness in two in- neuraminidase protein is similar to that of the fants in Egypt. One child’s father was a poultry current H3N2 viruses. merchant.[49]

H9N2 2.6.1 Evolution Main article: Inﬂuenza A virus subtype H9N2 Taubenberger says:

Low pathogenic avian influenza A (H9N2) in- “All influenza A pandemics since [the Span- fection was confirmed in 1999, in China and ish flu pandemic], and indeed almost all cases Hong Kong in two children, and in 2003 in of influenza A worldwide (excepting human Hong Kong in one child. All three fully infections from avian viruses such as H5N1 recovered.[46] and H7N7), have been caused by descen- dants of the 1918 virus, including “drifted” H1N1 viruses and reassorted H2N2 and H3N2 H7N2 viruses. The latter are composed of key genes from the 1918 virus, updated by sub- Main article: Influenza A virus subtype H7N2 sequently incorporated avian influenza genes that code for novel surface proteins, making the 1918 virus indeed the “mother” of all One person in New York in 2003 and one per- pandemics.”[50] son in Virginia in 2002 were found to have serologic evidence of infection with H7N2. Researchers from the National Institutes of Health used [46] Both fully recovered. data from the Influenza Genome Sequencing Project and concluded that during the ten-year period examined, most H7N3 of the time the hemagglutinin gene in H3N2 showed no significant excess of mutations in the antigenic regions Main article: Influenza A virus subtype H7N3 while an increasing variety of strains accumulated. This resulted in one of the variants eventually achieving higher fitness, becoming dominant, and in a brief interval of rapid evolution, rapidly sweeping through the population In North America, the presence of avian in- [51] fluenza strain H7N3 was confirmed at several and eliminating most other variants. poultry farms in British Columbia in Febru- Short-term Evolution In the short-term evolution of in- ary 2004. As of April 2004, 18 farms had fluenza A virus, a 2006 study found that stochastic, or been quarantined to halt the spread of the virus. random, processes are key factors.[52] Influenza A virus Two cases of humans with avian influenza have HA antigenic evolution appears to be characterized more been confirmed in that region. “Symptoms in- by punctuated, sporadic jumps as opposed to a constant cluded conjunctivitis and mild influenza-like rate of antigenic change.[53] Using phylogenetic analysis illness.”[35] Both fully recovered. of 413 complete genomes of human influenza A viruses 10 CHAPTER 2. INFLUENZA A VIRUS that were collected throughout the state of New York, the Donis RO (2012). “A distinct lineage of influenza A authors of Nelson et al. 2006 were able to show that ge- virus from bats”. Proc. Natl. Acad. Sci. U.S.A. 109 netic diversity, and not antigenic drift, shaped the short- (11): 4269–74. doi:10.1073/pnas.1116200109. PMC term evolution of influenza A via random migration and 3306675 . PMID 22371588. reassortment. The evolution of these viruses is dominated more by the random importation of genetically different [8] Gallagher, James (29 July 2011). "'Super antibody' fights off flu”. BBC News. Retrieved 29 July 2011. viral strains from other geographic locations and less by natural selection. Within a given season, adaptive evolu- [9] whitehouse.gov National Strategy for Pandemic Influenza tion is infrequent and had an overall weak effect as ev- — Introduction — “Although remarkable advances have idenced from the data gathered from the 413 genomes. been made in science and medicine during the past cen- Phylogenetic analysis revealed the different strains were tury, we are constantly reminded that we live in a universe derived from newly imported genetic material as opposed of microbes – viruses, bacteria, protozoa and fungi that to isolates that had been circulating in New York in pre- are forever changing and adapting themselves to the hu- vious seasons. Therefore, the gene flow in and out of this man host and the defenses that humans create. Influenza population, and not natural selection, was more important viruses are notable for their resilience and adaptability. in the short term. While science has been able to develop highly effective vaccines and treatments for many infectious diseases that threaten public health, acquiring these tools is an ongoing challenge with the influenza virus. Changes in the genetic 2.7 See also makeup of the virus require us to develop new vaccines on an annual basis and forecast which strains are likely to • FI6 (antibody) predominate. As a result, and despite annual vaccinations, the U.S. faces a burden of influenza that results in approx- • Animal virology imately 36,000 deaths and more than 200,000 hospitalizations each year. In addition to this human toll, influenza • ACAM-FLU- is annually responsible for a total cost of over $10 billion in the U.S. A pandemic, or worldwide outbreak of a new influenza virus, could dwarf this impact by overwhelming our health and medical capabilities, potentially resulting 2.8 Notes in hundreds of thousands of deaths, millions of hospitalizations, and hundreds of billions of dollars in direct and [1] “Avian influenza (" bird flu”) — Fact sheet”. WHO. indirect costs. This Strategy will guide our preparedness and response activities to mitigate that impact.” [2] Klenk, Hans-Dieter; Matrosovich, Mikhail; Stech, Jür- gen (2008). “Avian Influenza: Molecular Mechanisms of [10] Daum LT, Shaw MW, Klimov AI, Canas LC, Macias Pathogenesis and Host Range”. In Mettenleiter, Thomas EA, Niemeyer D, Chambers JP, Renthal R, Shrestha C.; Sobrino, Francisco. Animal Viruses: Molecular Biol- SK, Acharya RP, Huzdar SP, Rimal N, Myint KS, ogy. Caister Academic Press. ISBN 978-1-904455-22-6. Gould P (August 2005). “Influenza A (H3N2) outbreak, Nepal”. Emerging Infect. Dis. 11 (8): 1186–91. [3] Kawaoka Y, ed. (2006). Influenza Virology: Current Top- doi:10.3201/eid1108.050302. PMC 3320503 . PMID ics. Caister Academic Press. ISBN 1-904455-06-9. 16102305. [4] “Influenza Type A Viruses and Subtypes”. Centers for “The 2003–2004 influenza season was severe in terms of Disease Control and Prevention. 2 April 2013. Retrieved its impact on illness because of widespread circulation 13 June 2013. of antigenically distinct influenza A (H3N2) Fujian-like viruses. These viruses first appeared late during the 2002– [5] Tong S, Zhu X, Li Y, Shi M, Zhang J, Bourgeois M, 2003 influenza season and continued to persist as the dom- Yang H, Chen X, Recuenco S, Gomez J, Chen LM, John- inant circulating strain throughout the subsequent 2003– son A, Tao Y, Dreyfus C, Yu W, McBride R, Carney 2004 influenza season, replacing the A/Panama/2007/99- PJ, Gilbert AT, Chang J, Guo Z, Davis CT, Paulson JC, like H3N2 viruses (1). Of the 172 H3N2 viruses ge- Stevens J, Rupprecht CE, Holmes EC, Wilson IA, Do- netically characterized by the Department of Defense in nis RO (October 2013). “New World Bats Harbor Di- 2003–2004, only one isolate (from Thailand) belonged to verse Influenza A Viruses”. PLoS Pathogens. 9 (10): the A/Panama-like lineage. In February 2003, the World e1003657. doi:10.1371/journal.ppat.1003657. PMC Health Organization (WHO) changed the H3N2 compo- 3794996 . PMID 24130481. nent for the 2004–2005 influenza vaccine to afford protection against the widespread emergence of Fujian-like [6] “Unique new flu virus found in bats”. NHS Choices. 1 viruses (2). The annually updated trivalent vaccine con- March 2012. Retrieved 16 May 2012. sists of hemagglutinin (HA) surface glycoprotein components from influenza H3N2, H1N1, and B viruses.” [7] Tong S, Li Y, Rivailler P, Conrardy C, Castillo DA, Chen LM, Recuenco S, Ellison JA, Davis CT, York IA, [11] Mahmoud 2005, p. 126 Turmelle AS, Moran D, Rogers S, Shi M, Tao Y, Weil “H5N1 virus is now endemic in poultry in Asia (Table 2-1) MR, Tang K, Rowe LA, Sammons S, Xu X, Frace M, and has gained an entrenched ecological niche from which Lindblade KA, Cox NJ, Anderson LJ, Rupprecht CE, to present a long-term pandemic threat to humans. At 2.8. NOTES 11

present, these viruses are poorly transmitted from poultry [23] Gilker JC, Pavilanis V, Ghys R (June 1967). “Multiplic- to humans, and there is no conclusive evidence of human- ity reactivation in gamma irradiated influenza viruses”. to-human transmission. However, continued, extensive Nature. 214 (5094): 1235–7. doi:10.1038/2141235a0. exposure of the human population to H5N1 viruses in- PMID 6066111. creases the likelihood that the viruses will acquire the necessary characteristics for efficient human-to-human trans- [24] Peterhans E (May 1997). “Oxidants and antioxidants in mission through genetic mutation or reassortment with a viral diseases: disease mechanisms and metabolic reg- prevailing human influenza A virus. Furthermore, con- ulation”. J. Nutr. 127 (5 Suppl): 962S–965S. PMID temporary human H3N2 influenza viruses are now en- 9164274. demic in pigs in southern China (Peiris et al., 2001) and [25] Bernstein H, Byerly HC, Hopf FA, Michod RE (October can reassort with avian H5N1 viruses in this 'intermediate 1984). “Origin of sex”. J. Theor. Biol. 110 (3): 323–51. host.' Therefore, it is imperative that outbreaks of H5N1 doi:10.1016/S0022-5193(84)80178-2. PMID 6209512. disease in poultry in Asia are rapidly and sustainably con- trolled. The seasonality of the disease in poultry, together [26] Mahmoud 2005, p. 30 with the control measures already implemented, are likely [27] Mahmoud 2005, p. 82 to reduce temporarily the frequency of H5N1 influenza “Interestingly, recombinant influenza viruses containing outbreaks and the probability of human infection.” the 1918 HA and NA and up to three additional genes [12] BBC: 'Super antibody' fights off flu derived from the 1918 virus (the other genes being derived from the A/WSN/33 virus) were all highly viru- [13] Independent: Scientists hail the prospect of a universal lent in mice (Tumpey et al., 2004). Furthermore, ex- vaccine for flu pression microarray analysis performed on whole lung tissue of mice infected with the 1918 HA/ NA recombinant [14] Huffington Post: Universal Flu Vaccine On The Horizon: showed increased upregulation of genes involved in apop- Researchers Find 'Super Antibody' tosis, tissue injury, and oxidative damage (Kash et al., 2004). These findings were unusual because the viruses [15] Lamb, R.A & Choppin, P.W. The gene structure and with the 1918 genes had not been adapted to mice. The replication of influenza virus. Annu. Rev. Biochem. 52, completion of the sequence of the entire genome of the 467–506 (1985) 1918 virus and the reconstruction and characterization of viruses with 1918 genes under appropriate biosafety con- [16] Bouvier NM, Palese P (2008). “The biology of in- ditions will shed more light on these findings and should fluenza viruses”. Vaccine. 26 Suppl 4: D49–53. allow a definitive examination of this explanation. Anti- doi:10.1016/j.vaccine.2008.07.039. PMC 3074182 . genic analysis of recombinant viruses possessing the 1918 PMID 19230160. HA and NA by hemagglutination inhibition tests using ferret and chicken antisera suggested a close relationship with [17] Suzuki Y (2005). “Sialobiology of influenza: molec- the A/swine/Iowa/30 virus and H1N1 viruses isolated in ular mechanism of host range variation of influenza the 1930s (Tumpey et al., 2004), further supporting data viruses”. Biol. Pharm. Bull. 28 (3): 399–408. of Shope from the 1930s (Shope, 1936). Interestingly, doi:10.1248/bpb.28.399. PMID 15744059. when mice were immunized with different H1N1 virus strains, challenge studies using the 1918-like viruses re- [18] Wilson JC, von Itzstein M (2003). “Recent strate- vealed partial protection by this treatment, suggesting that gies in the search for new anti-influenza ther- current vaccination strategies are adequate against a 1918- apies”. Curr Drug Targets. 4 (5): 389–408. like virus (Tumpey et al., 2004).” doi:10.2174/1389450033491019. PMID 12816348. [28] Mahmoud 2005, p. 285 [19] Lynch JP, Walsh EE (2007). “Influenza: evolving strate- “As of October 2001, the potential for use of infectious gies in treatment and prevention”. Semin Respir Crit agents, such as anthrax, as weapons has been firmly es- Care Med. 28 (2): 144–58. doi:10.1055/s-2007-976487. tablished. It has been suggested that attacks on a na- PMID 17458769. tion’s agriculture might be a preferred form of terrorism or economic disruption that would not have the attendant [20] Smith AE, Helenius A (2004). “How viruses en- stigma of infecting and causing disease in humans. Highly ter animal cells”. Science. 304 (5668): 237–42. pathogenic avian influenza virus is on every top ten list doi:10.1126/science.1094823. PMID 15073366. available for potential agricultural bioweapon agents, generally following foot and mouth disease virus and Newcas- [21] Barry RD (August 1961). “The multiplication of influenza tle disease virus at or near the top of the list. Rapid detec- virus. II. Multiplicity reactivation of ultraviolet irradiated tion techniques for bioweapon agents are a critical need for virus”. Virology. 14 (4): 398–405. doi:10.1016/0042- the first-responder community, on a par with vaccine and 6822(61)90330-0. PMID 13687359. antiviral development in preventing spread of disease.” [22] Henle W, Liu OC (October 1951). “Studies on host- [29] “Avian influenza A(H5N1)- update 31: Situation (poul- virus interactions in the chick embryo-influenza virus try) in Asia: need for a long-term response, comparison system. VI. Evidence for multiplicity reactivation of with previous outbreaks”. Epidemic and Pandemic Alert inactivated virus”. J. Exp. Med. 94 (4): 305–22. and Response (EPR). WHO. 2004. doi:10.1084/jem.94.4.305. PMC 2136114 . PMID Known outbreaks of highly pathogenic flu in poultry 14888814. 1959–2003. 12 CHAPTER 2. INFLUENZA A VIRUS

[30] Geraci JR, St Aubin DJ, Barker IK, Webster RG, Hin- Tran TH, Do QH, Farrar J (February 2005). “Fatal avian shaw VS, Bean WJ, Ruhnke HL, Prescott JH, Early G, influenza A (H5N1) in a child presenting with diarrhea Baker AS, Madoff S, Schooley RT (February 1982). followed by coma”. N. Engl. J. Med. 352 (7): 686–91. “Mass mortality of harbor seals: pneumonia associated doi:10.1056/NEJMoa044307. PMID 15716562. with influenza A virus”. Science. 215 (4536): 1129–31. doi:10.1126/science.7063847. PMID 7063847. More [40] Mahmoud 2005, p. 7 than 400 harbor seals, most of them immature, died along the New England coast between December 1979 [41] Detailed chart of its evolution here at PDF called Ecology and October 1980 of acute pneumonia associated with in- and Evolution of the Flu fluenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, [42] Mahmoud 2005, p. 115 and causes mild respiratory disease in experimentally in- “There is particular pressure to recognize and heed the fected seals. Concurrent infection with a previously un- lessons of past influenza pandemics in the shadow of the described mycoplasma or adverse environmental condi- worrisome 2003–2004 flu season. An early-onset, se- tions may have triggered the epizootic. The similarities vere form of influenza A H3N2 made headlines when it between this epizootic and other seal mortalities in the claimed the lives of several children in the United States past suggest that these events may be linked by common in late 2003. As a result, stronger than usual demand for biological and environmental factors. annual flu inactivated vaccine outstripped the vaccine supply, of which 10 to 20 percent typically goes unused. Be- [31] Mahmoud 2005, p. 15 cause statistics on pediatric flu deaths had not been col- “Unlike most other affected countries, Indonesia also in- lected previously, it is unknown if the 2003–2004 season stituted mass vaccination of healthy domestic birds against witnessed a significant change in mortality patterns.” H5N1, followed by routine vaccination (China has a similar policy; other Asian countries are considering it [43] Reason New York Times This Season’s Flu Virus Is Resis- [ProMED-mail, 2004j]) (Soebandrio, 2004). This is tant to 2 Standard Drugs By Altman Published: 15 January a risky strategy, because vaccinated birds can develop 2006 asymptomatic infections that allow virus to spread, mutate, and recombine (ProMED-mail, 2004j). Intensive [44] New York Times Published: 8 November 2005 — Hazard surveillance is required to detect these “silent epidemics” in Hunt for New Flu: Looking for Bugs in All the Wrong in time to curtail them. In Mexico, for example, mass vac- Places cination of chickens against epidemic H5N2 influenza in [45] Schnirring, Lisa (2 April 2013). “China reports 4 more 1995 has had to continue in order to control a persistent H7N9 infections”. CIDRAP News. and evolving virus (Lee et al., 2004).”

[32] CDC Centers for Disease Control and Prevention — [46] CDC Avian Influenza Infection in Humans Transmission of Influenza A Viruses Between Animals and [47] CBS News article Dozens In Japan May Have Mild Bird People Flu January 2006. [33] Mahmoud 2005, p. 27 [48] Ogata T, Yamazaki Y, Okabe N, Nakamura Y, Tashiro [34] BBC News Early bird flu warning for Dutch — 6 Novem- M, Nagata N, Itamura S, Yasui Y, Nakashima K, Doi ber 2005 M, Izumi Y, Fujieda T, Yamato S, Kawada Y (July 2008). “Human H5N2 Avian Influenza Infection in Japan [35] Tweed SA, Skowronski DM, David ST, Larder A, Petric and the Factors Associated with High H5N2-Neutralizing M, Lees W, Li Y, Katz J, Krajden M, Tellier R, Halpert Antibody Titer” (PDF). J Epidemiol. 18 (4): 160–6. C, Hirst M, Astell C, Lawrence D, Mak A (Decem- doi:10.2188/jea.JE2007446. PMID 18603824. ber 2004). “Human illness from avian influenza H7N3, British Columbia”. Emerging Infect. Dis. 10 (12): [49] niaid.nih.gov Timeline of Human Flu Pandemics 2196–9. doi:10.3201/eid1012.040961. PMC 3323407 . PMID 15663860. [50] Taubenberger JK, Morens DM (January 2006). “1918 In- fluenza: the mother of all pandemics”. Emerging Infect. [36] CDC Key Facts About Avian Influenza (Bird Flu) and Dis. 12 (1): 15–22. doi:10.3201/eid1201.050979. PMC Avian Influenza A (H5N1) Virus 3291398 . PMID 16494711. [37] Bloomberg News article Scientists Move Closer to Under- [51] Science Daily article New Study Has Important Implica- standing Flu Virus Evolution published 28 August 2006 tions For Flu Surveillance published 27 October 2006 [38] Chen GW, Chang SC, Mok CK, Lo YL, Kung YN, Huang JH, Shih YH, Wang JY, Chiang C, Chen CJ, Shih SR [52] Nelson MI, Simonsen L, Viboud C, Miller MA, Taylor (September 2006). “Genomic signatures of human ver- J, George KS, Griesemer SB, Ghedin E, Ghedi E, Sen- sus avian influenza A viruses”. Emerging Infect. Dis. gamalay NA, Spiro DJ, Volkov I, Grenfell BT, Lipman 12 (9): 1353–60. doi:10.3201/eid1209.060276. PMC DJ, Taubenberger JK, Holmes EC (2006). “Stochastic processes are key determinants of short-term evolution 3294750 . PMID 17073083. in influenza a virus”. PLoS Pathog. 2 (12): e125. [39] de Jong MD, Bach VC, Phan TQ, Vo MH, Tran TT, doi:10.1371/journal.ppat.0020125. PMC 1665651 . Nguyen BH, Beld M, Le TP, Truong HK, Nguyen VV, PMID 17140286. 2.10. EXTERNAL LINKS 13

[53] Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, • A Variety of Avian Flu Images and Pictures Rimmelzwaan GF, Osterhaus AD, Fouchier RA (July 2004). “Mapping the Antigenic and Genetic Evolution • Mahmoud 2005, p. 285 “Highly pathogenic avian of Influenza Virus”. Science. 305 (5682): 371–376. influenza virus is on every top ten list available for doi:10.1126/science.1097211. PMID 15218094. potential agricultural bioweapon agents” • Mahmoud, Adel A. F; Institute of Medicine; Kno- bler, Stacey; Mack, Alison (2005). The Threat of 2.9 Further reading Pandemic Influenza: Are We Ready?: Workshop Summary. Washington, D.C: National Academies Official sources Press. ISBN 0-309-09504-2. • Further information: H5N1 'The Threat of Bird Flu': HealthPolitics.com • Is a Global Flu Pandemic Imminent? from Infection Control Today. • Avian influenza and Influenza Pandemics from the Centers for Disease Control and Prevention • Bird Flu is a Real Pandemic Threat to Humans by Leonard Crane, author of Ninth Day of Creation. • Avian influenza FAQ from the World Health Orga- nization • Links to Bird Flu pictures (Hardin MD/Univ of Iowa) • Avian influenza information from the Food and Agriculture Organization • Yoshihiro Kawaoka (2006). Influenza Virology: Current Topics. Caister Academic Pr. ISBN 1- • U.S. Government’s avian influenza information 904455-06-9. website • Francisco Sobrino; Thomas Mettenleiter (2008). • European Centre for Disease Prevention and Con- Animal Viruses: Molecular Biology. Caister Aca- trol (ECDC) Stockholm, Sweden demic Pr. ISBN 1-904455-22-0.

General information 2.10 External links Further information: Flu • Influenza Research Database – Database of influenza genomic sequences and related information. • “The Bird Flu and You” Full-color poster provided by the Center for Technology and National Security • Health-EU portal European Union response to in- Policy at the National Defense University, in col- fluenza laboration with the National Security Health Policy Center • Influenza Report 2006 Online book. Research level quality information. Highly recommended. • Special issue on avian flu from Nature • Nature Reports: Homepage: Avian Flu • Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY (September 2005). “Avian influenza A (H5N1) infection in humans”. N. Engl. J. Med. 353 (13): 1374–85. doi:10.1056/NEJMra052211. PMID 16192482. • Pandemic Influenza: Domestic Preparedness Ef- forts Congressional Research Service Report on Pandemic Preparedness. • A guide to bird flu and its symptoms from BBC Health Chapter 3

Hand, foot, and mouth disease

Not to be confused with Foot-and-mouth disease or 3.1 Signs and symptoms Hand-foot syndrome.

Hand, foot and mouth disease (HFMD) is a common infection caused by a group of viruses.[1] It typically begins with a fever and feeling generally unwell.[1] This is followed a day or two later by flat discolored spots or bumps that may blister, on the hands, feet, and mouth, and occasionally buttocks and groin.[2][3][4] Signs and symptoms normally appear 3–6 days after exposure to the virus.[5] The rash generally goes away on its own in about a week.[6] Fingernail and toenail loss may occur a few weeks later and these then regrow.[7] The viruses that cause HFMD are spread through close personal contact, through the air from coughing, and Rash on palms of the hands. the feces of an infected person. Contaminated objects can also spread the disease.[8] Coxsackievirus A16 is the most common cause and Enterovirus 71 is the second- most common cause.[9] Other strains of coxsackievirus and enterovirus can also be responsible.[9][10] Some people may carry and pass on the virus despite having no symptoms of disease.[1] Other animals are not involved.[8] Diagnosis can often be made based on symptoms. Oc- casionally throat or stool sample may be tested for the virus.[11] Handwashing may prevent spread and those infected should not go to work, daycare, or school.[8] No antiviral medication or vaccine is available, but development efforts are underway.[12] Most cases require no specific treatment.[6] Simple pain medication such as ibuprofen or numbing mouth gel may be used. Occasionally in- Rash on hand and feet of a 36-year-old man travenous fluids are given to children who are unable to drink enough.[13] Rarely viral meningitis or encephalitis Common constitutional signs and symptoms of the may complicate the disease.[7] HFMD include fever, nausea, vomiting, feeling tired, HFMD occurs in all areas of the world.[14] It often occurs generalized discomfort, loss of appetite, and irritability in small outbreaks in nursery schools or kindergartens.[4] in infants and toddlers. Skin lesions frequently develop Large outbreaks have been occurring in Asia since 1997. in the form of a rash of flat discolored spots and bumps It usually occurs during the spring, summer, and fall which may be followed by vesicular sores with blisters [14] on palms of the hands, soles of the feet, buttocks, and months. Typically it occurs in children less than five [16] [1][4] sometimes on the lips. The rash is rarely itchy for years old, but can occasionally occur in adults. [5] HFMD should not be confused with foot-and-mouth children, but can be extremely itchy for adults. Painful facial ulcers, blisters, or lesions may also develop in or disease (also known as hoof-and-mouth disease) which [4][17][18] mostly affects livestock.[15] around the nose or mouth. HFMD usually resolves on its own after 7–10 days.[17]

14 3.5. TREATMENT 15

3.4.1 Vaccine

A vaccine known as the EV71 vaccine is available to prevent HFMD in China as of December 2015.[20] No vaccine is currently available in the United States.[19]

3.5 Treatment

Medications are usually not needed as hand, foot and mouth disease is a viral disease that typically gets better on its own. Currently, there is no specific curative treatment for hand, foot and mouth disease.[17] Disease management typically focuses on achieving symptomatic relief. Pain from the sores may be eased with the use of analgesic medications. Infection in older children, adolescents, and adults is typically mild and lasts approxi- Rash on the soles of a child’s feet mately 1 week, but may occasionally run a longer course. Fever reducers and lukewarm baths can help decrease 3.2 Cause body temperature. A minority of individuals with hand, foot and mouth disease may require hospital admission due to complications The viruses that cause the disease are of the such as inflammation of the brain, inflammation of the Picornaviridae family. Coxsackievirus A16 is the meninges, or acute flaccid paralysis.[10] Non-neurologic most common cause of HFMD.[9] Enterovirus 71 complications such as inflammation of the heart, fluid in (EV-71) is the second-most common cause.[9] Many the lungs, or bleeding into the lungs may also occur.[10] other strains of coxsackievirus and enterovirus can also be responsible.[9][10] 3.6 Complications 3.2.1 Transmission Complications from the viral infections that cause HFMD HFMD is highly contagious and is transmitted by are rare, but require immediate medical treatment if nasopharyngeal secretions such as saliva or nasal mucus, present. HFMD infections caused by Enterovirus 71 tend by direct contact, or by fecal-oral transmission. to be more severe and are more likely to have neurologic or cardiac complications including death than infections caused by Coxsackievirus A16.[17] Viral or aseptic 3.3 Diagnosis meningitis can occur with HFMD in rare cases and is characterized by fever, headache, stiff neck, or back pain.[10][17] The condition is usually mild and clears with- A diagnosis usually can be made by the presenting signs out treatment; however, hospitalization for a short time and symptoms alone.[17] If the diagnosis is unclear, a may be needed. Other serious complications of HFMD throat swab or stool specimen may be taken to identify the include encephalitis (swelling of the brain), or flaccid virus by culture.[17] The common incubation period (the paralysis in rare circumstances.[16][17] time between infection and onset of symptoms) ranges from three to six days.[5] Fingernail and toenail loss have been reported in children 4–8 weeks after having HFMD.[5] The relationship between HFMD and the reported nail loss is unclear; however, it is temporary and nail growth resumes without 3.4 Prevention treatment.[5][21]

Preventive measures include avoiding direct contact with infected individuals (including keeping infected children home from school), proper cleaning of shared utensils, 3.7 Epidemiology disinfecting contaminated surfaces, and proper hand hygiene. These measures have been shown to be eﬀective Hand, foot and mouth disease most commonly occurs in in decreasing the transmission of the viruses responsible children under the age of 10[5][17] and tends to occur in for HFMD.[17][19] outbreaks during the spring, summer, and fall seasons.[9] 16 CHAPTER 3. HAND, FOOT, AND MOUTH DISEASE

HFMD is most commonly caused by infection with Cox- 71 (EV-71), which causes hand foot and mouth dis- sackievirus A16.[9] ease (HFMD). The EV-71 virus has been known to generally cause severe complications amongst some patients.”[36] 3.7.1 Major outbreaks • HFMD infected 1,520,274 people with up to 431 • In 1998, there was an outbreak in Taiwan, aﬀecting deaths reported at the end of July in 2012 in mainly children.[22] There were 405 severe compli- China.[37] cations, and 78 children died.[23] The total number of cases in that epidemic is estimated to have been • The governorate of Daraa in Syria reported over 200 1.5 million.[9] cases of HFMD there in early 2015.[38] These were due to the central Syrian government denying the re- • In 2008 an outbreak in China, beginning in March gion water chlorination. in Fuyang, Anhui, led to 25,000 infections, and 42 deaths, by May 13.[9] Similar outbreaks were reported in Singapore (more than 2,600 cases as of April 20, 2008),[24] Vietnam (2,300 cases, 11 3.8 History deaths),[25] Mongolia (1,600 cases),[26] and Brunei (1053 cases from June–August 2008)[27] HFMD cases were ﬁrst described in New Zealand in 1957.[17] • In 2009 17 children died in an outbreak during March and April 2009 in China’s eastern Shandong Province, and 18 children died in the neighboring Henan Province.[28] Out of 115,000 reported cases 3.9 Research in China from January to April, 773 were severe and 50 were fatal.[29] Novel antiviral agents to prevent and treat infection with the viruses responsible for HFMD are currently under de- • In 2010 in China, an outbreak occurred in south- velopment. Preliminary studies have shown inhibitors of ern China’s Guangxi Autonomous Region as well as the EV-71 viral capsid to have potent antiviral activity.[12] Guangdong, Henan, Hebei and Shandong provinces. Until March 70,756 children were infected and 40 died from the disease. By June, the peak season for 3.10 References the disease, 537 had died.[30]

• The World Health Organization reporting between [1] “Hand Foot and Mouth Disease”. CDC. August 18, 2015. January to October 2011 (1,340,259) states the Retrieved 14 May 2016. number of cases in China had dropped by approx 300,000 from 2010 (1,654,866) cases, with new [2] Frydenberg, A; Starr, M (August 2003). “Hand, foot and cases peaking in June. There were 437 deaths, down mouth disease.”. Australian family physician. 32 (8): 594–5. PMID 12973865. from 2010 (537 deaths).[31] [3] Ooi, MH; Wong, SC; Lewthwaite, P; Cardosa, MJ; • In December 2011, the California Department of Solomon, T (2010). “Clinical features, diagnosis, and Public Health identiﬁed a strong form of the virus, management of enterovirus 71”. Lancet Neurology. 9 coxsackievirus A6 (CVA6), where nail loss in chil- (11): 1097–1105. doi:10.1016/S1474-4422(10)70209- [32] dren is common. X. PMID 20965438.

• In 2012 in Alabama, United States there was an [4] Kaminska, K; Martinetti, G; Lucchini, R; Kaya, G; outbreak of an unusual type of the disease. It oc- Mainetti, C (2013). “Coxsackievirus A6 and Hand, curred in a season when it is not usually seen and af- Foot, and Mouth Disease: Three Case Reports of Famil- fected teenagers and older adults. There were some ial Child-to-Immunocompetent Adult Transmission and a hospitalizations due to the disease but no reported Literature Review”. Case Reports in Dermatology. 5 (2): deaths.[33] 203–209. doi:10.1159/000354533. PMID 24019771.

• In 2012 in Cambodia, 52 of 59 reviewed cases of [5] Hoy, NY; Leung, AK; Metelitsa, AI; Adams, S (2012). children reportedly[34] dead (as of July 9, 2012) due “New concepts in median nail dystrophy, onychomy- to a mysterious disease were diagnosed to be caused cosis, and hand, foot and mouth disease nail pathology”. ISRN Dermatology. 2012 (680163): 680163. by a virulent form of HFMD.[35] Although a signiﬁ- doi:10.5402/2012/680163. PMID 22462009. cant degree of uncertainty exists with reference to the diagnosis, the WHO report states, “Based on [6] Longo, Dan L. (2012). Harrison’s principles of internal the latest laboratory results, a signiﬁcant propor- medicine. (18th ed.). New York: McGraw-Hill. ISBN tion of the samples tested positive for enterovirus 978-0-07174889-6. 3.10. REFERENCES 17

[7] “Hand, Foot, and Mouth Disease (HFMD) Complica- [22] Centers for Disease Control and Prevention (CDC) tions”. CDC. August 18, 2015. Retrieved 14 May 2016. (1998). “Deaths among children during an outbreak of hand, foot, and mouth disease--Taiwan, Republic of [8] “Causes & Transmission”. CDC. August 18, 2015. Re- China, April–July 1998”. MMWR Morb. Mortal. Wkly. trieved 15 May 2016. Rep. 47 (30): 629–32. PMID 9704628.

[9] Repass GL, Palmer WC, Stancampiano FF (September [23] Ho M, Chen ER, Hsu KH, et al. (1999). “An epidemic 2014). “Hand, foot, and mouth disease: Identifying and of enterovirus 71 infection in Taiwan. Taiwan Enterovirus managing an acute viral syndrome”. Cleve Clin J Med. Epidemic Working Group”. N. Engl. J. Med. 341 (13): 81 (9): 537–43. doi:10.3949/ccjm.81a.13132. PMID 929–35. doi:10.1056/NEJM199909233411301. PMID 25183845. 10498487. [10] Li, Y; Zhu, R; Qian, Y; Deng, J (2012). “The char- [24] Suhaimi, Nur Dianah (April 20, 2008). “HFMD: 1,000 acteristics of blood glucose and WBC counts in periph- cases a week is unusual, says doc”. Singapore: The Sun- eral blood of cases of hand foot and mouth disease in day Times (Straits Times). pp. 1–2. China: a systematic review”. PLOS ONE. 7 (1): e29003. doi:10.1371/journal.pone.0029003. PMC 3250408 . [25] Viet Nam News: HFMD cases prompt tighter health PMID 22235257. screening at airport(accessed May 15, 2008)

[11] “Diagnosis”. CDC. August 18, 2015. Retrieved 15 May [26] EV-71 Virus Continues Dramatic Rise (accessed May 23, 2016. 2008)

[12] Pourianfar HR, Grollo L (February 2014). “Devel- [27] Bandar Seri Begawan (7 November 2008). “1,053 HFD opment of antiviral agents toward enterovirus 71 in- cases recorded”. The Birmingham News. Retrieved May fection”. J Microbiol Immunol Infect. 48: 1–8. 11, 2012. doi:10.1016/j.jmii.2013.11.011. PMID 24560700. [28] “Hand-foot-mouth disease death toll rises to 17 in East [13] “Prevention & Treatment”. CDC. August 18, 2015. Re- China’s Shandong Province”. China View. April 9, 2009. trieved 15 May 2016. Retrieved September 29, 2009.

[14] “Outbreaks”. CDC. August 18, 2015. Retrieved 15 May [29] “Health Ministry: Hand-foot-mouth disease claims 50 2016. lives this year”. China View. 10 April 2009. Retrieved 29 September 2009. [15] “Foot and Mouth Disease update: further temporary control zone established in Surrey”. Defra. 2007-08-14. [30] http://news.xinhuanet.com/english2010/china/2010-06/ Archived from the original on 2007-09-27. Retrieved 24/c_13367598.htm 2007-08-14. [31] “China reports 537 deaths from hand-foot-mouth disease [16] Huang, CC; Liu, CC; Chang, YC; Chen, CY; Wang, ST; this year”. People’s Daily Online. 2010. Retrieved 16 Yeh, TF (23 September 1999). “Neurologic complica- October 2013. tions in children with enterovirus 71 infection.”. The New England Journal of Medicine. 341 (13): 936–42. [32] “Coxsackievirus A6 (CVA6)". California Department of doi:10.1056/nejm199909233411302. PMID 10498488. Public Health. 2013. Retrieved 16 October 2013.

[17] Sarma, N (March–April 2013). “Hand, foot and mouth [33] Hannah Wolfson (February 13, 2012). “Outbreak of disease: current scenario and Indian perspective”. Indian hand, foot and mouth disease severe in Alabama”. The Journal of Dermatology, Venereology, and Leprology. 79 Birmingham News. Retrieved May 11, 2012. (2): 165–175. doi:10.4103/0378-6323.107631. PMID 23442455. [34] CBS News Staﬀ (2012). “Joint Press Release Between The Ministry of Health Kingdom of Cambodia and the [18] “Hand, Foot and Mouth Disease: Signs & Symptoms”. World Health Organization” (PDF). CBS News. Re- mayoclinic.com. The Mayo Clinic. Retrieved May 5, trieved 16 October 2013. 2008. [35] “Mysterious deadly illness in Cambodian children tied to [19] “Hand, Foot and Mouth Disease”. Prevention and Treat- hand, foot and mouth disease”. Hand, Foot and Mouth ment. Centers for Disease Control and Prevention. 2013. Disease. World Health Organization. 2012. Retrieved 16 Retrieved 18 October 2013. October 2013.

[20] Mao, QY; Wang, Y; Bian, L; Xu, M; Liang, Z [36] “Global Alert and Response (GAR)". Undiagnosed illness (May 2016). “EV71 vaccine, a new tool to con- in Cambodia-update. World Health Organization. 2012. trol outbreaks of hand, foot and mouth disease Retrieved 16 October 2013. (HFMD).”. Expert review of vaccines. 15 (5): 599– 606. doi:10.1586/14760584.2016.1138862. PMID [37] “Emerging disease surveillance and response”. Hand, 26732723. Foot and Mouth Disease. World Health Organization. 2013. Retrieved 16 October 2013. [21] “Hand, Foot and Mouth Disease”. Complications. Centers for Disease Control and Prevention. 2011. Retrieved 14 [38] Sparrow, Annie (2015), “Syria: Death from Assad’s Chlo- October 2013. rine”, The New York Review of Books, (7 May issue). 18 CHAPTER 3. HAND, FOOT, AND MOUTH DISEASE

3.11 External links

Media related to Hand, foot and mouth disease at Wiki- media Commons News related to Highly contagious Hand, foot and mouth disease killing China’s children at Wikinews Chapter 4

Tuberculosis

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis (MTB).[1] Tuber- culosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, in which case it is known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those infected. The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss.[1] The historical term "consumption" came about due to the weight loss.[3] Infection of other organs can cause a wide range of symptoms.[4] Video explanation Tuberculosis is spread through the air when people who have active TB in their lungs cough, spit, speak, or 4.1 Signs and symptoms sneeze.[1][5] People with latent TB do not spread the disease. Active infection occurs more often in people with HIV/AIDS and in those who smoke.[1] Diagnosis of ac- Symptoms of Tuberculosis Grey lines = More specific tive TB is based on chest X-rays, as well as microscopic Colored lines = Overlapping Poor appetite examination and culture of body fluids. Diagnosis of la- (Established) Miliary tuberculosis pulmonary tuberculosis tent TB relies on the tuberculin skin test (TST) or blood Productive cough tests.[6] Return of dormant Prevention of TB involves screening those at high risk, Night sweats tuberculosis early detection and treatment of cases, and vaccination Cough with Weakness [7][8][9] Primary increasing mucus with the bacillus Calmette-Guérin vaccine. Those pulmonary Fever Coughing at high risk include household, workplace, and social con- tuberculosis up blood Structural [9] Dry cough tacts of people with active TB. Treatment requires the abnormalities use of multiple antibiotics over a long period of time.[1] Weight loss Extrapulmonary tuberculosis Antibiotic resistance is a growing problem with increas- Common sites: Tuberculous Meninges ing rates of multiple drug-resistant tuberculosis (MDR- pleuritis Lymph nodes [1] Chest pain Gastrointestinal symptoms Bone and joint sites TB). Genitourinary tract One-third of the world’s population is thought to be infected with TB.[1] New infections occur in about 1% [10] The main symptoms of variants and stages of tuberculosis are of the population each year. In 2014, there were 9.6 given,[13] with many symptoms overlapping with other variants, million cases of active TB which resulted in 1.5 million while others are more (but not entirely) specific for certain vari- deaths. More than 95% of deaths occurred in developing ants. Multiple variants may be present simultaneously. countries. The number of new cases each year has decreased since 2000.[1] About 80% of people in many Tuberculosis may infect any part of the body, but most Asian and African countries test positive while 5–10% commonly occurs in the lungs (known as pulmonary of people in the United States population tests positive tuberculosis).[4] Extrapulmonary TB occurs when tuber- by the tuberculin test.[11] Tuberculosis has been present culosis develops outside of the lungs, although extrapul- in humans since ancient times.[12] monary TB may coexist with pulmonary TB.[4] General signs and symptoms include fever, chills, night sweats, loss of appetite, weight loss, and fatigue.[4] Sig- nificant nail clubbing may also occur.[14]

19 20 CHAPTER 4. TUBERCULOSIS

4.1.1 Pulmonary

If a tuberculosis infection does become active, it most commonly involves the lungs (in about 90% of cases).[12][15] Symptoms may include chest pain and a prolonged cough producing sputum. About 25% of people may not have any symptoms (i.e. they remain “asymptomatic”).[12] Occasionally, people may cough up blood in small amounts, and in very rare cases, the infection may erode into the pulmonary artery or a Rasmussen’s aneurysm, resulting in massive bleeding.[4][16] Tuberculosis may become a chronic illness and cause extensive scarring in the upper lobes of the lungs. The upper lung lobes are more frequently affected by tuberculosis than the lower ones.[4] The reason for this diﬀerence is not clear.[11] It may be due to either better air ﬂow,[11] or poor lymph drainage within the upper lungs.[4] Scanning electron micrograph of M. tuberculosis

4.1.2 Extrapulmonary than an hour.[24] Mycobacteria have an outer membrane In 15–20% of active cases, the infection spreads [25] [17] lipid bilayer. If a Gram stain is performed, MTB either outside the lungs, causing other kinds of TB. stains very weakly “Gram-positive” or does not retain dye These are collectively denoted as “extrapulmonary [18] as a result of the high lipid and mycolic acid content of its tuberculosis”. Extrapulmonary TB occurs more com- cell wall.[26] MTB can withstand weak disinfectants and monly in immunosuppressed persons and young children. survive in a dry state for weeks. In nature, the bacterium In those with HIV, this occurs in more than 50% of [18] can grow only within the cells of a host organism, but M. cases. Notable extrapulmonary infection sites include tuberculosis can be cultured in the laboratory.[27] the pleura (in tuberculous pleurisy), the central nervous system (in tuberculous meningitis), the lymphatic system Using histological stains on expectorated samples from (in scrofula of the neck), the genitourinary system (in phlegm (also called “sputum”), scientists can identify urogenital tuberculosis), and the bones and joints (in Pott MTB under a microscope. Since MTB retains certain disease of the spine), among others. stains even after being treated with acidic solution, it is [11][26] [19] classified as an acid-fast bacillus. The most com- Spread to lymph nodes is the most common. An ulcer mon acid-fast staining techniques are the Ziehl–Neelsen originating from nearby infected lymph nodes may occur stain[28] and the Kinyoun stain, which dye acid-fast bacilli and is painless, slowly enlarging and has an appearance [29] [20] a bright red that stands out against a blue background. of “wash leather”. Auramine-rhodamine staining[30] and fluorescence mi- When it spreads to the bones, it is known as “osseous croscopy[31] are also used. [21] [11] tuberculosis”, a form of osteomyelitis. A poten- The M. tuberculosis complex (MTBC) includes four tially more serious, widespread form of TB is called “dis- other TB-causing mycobacteria: M. bovis, M. africanum, seminated tuberculosis”, also known as miliary tubercu- M. canetti, and M. microti.[32] M. africanum is not losis.[4] Miliary TB currently makes up about 10% of ex- [22] widespread, but it is a significant cause of tuberculosis in trapulmonary cases. parts of Africa.[33][34] M. bovis was once a common cause of tuberculosis, but the introduction of pasteurized milk has almost completely eliminated this as a public health 4.2 Causes problem in developed countries.[11][35] M. canetti is rare and seems to be limited to the Horn of Africa, although a [36][37] 4.2.1 Mycobacteria few cases have been seen in African emigrants. M. microti is also rare and is seen almost only in immunodeficient people, although its prevalence may be significantly Main article: Mycobacterium tuberculosis [38] The main cause of TB is Mycobacterium tuberculo- underestimated. sis (MTB), a small, aerobic, nonmotile bacillus.[4] The Other known pathogenic mycobacteria include M. lep- high lipid content of this pathogen accounts for many rae, M. avium, and M. kansasii. The latter two species of its unique clinical characteristics.[23] It divides every are classified as "nontuberculous mycobacteria" (NTM). 16 to 20 hours, which is an extremely slow rate com- NTM cause neither TB nor leprosy, but they do cause pared with other bacteria, which usually divide in less pulmonary diseases that resemble TB.[39] 4.3. MECHANISM 21

4.2.2 Risk factors

Main article: Risk factors for tuberculosis

A number of factors make people more susceptible to TB infections. The most important risk factor globally is HIV; 13% of all people with TB are infected by the virus.[40] This is a particular problem in sub-Saharan Africa, where rates of HIV are high.[41][42] Of people without HIV who are infected with tuberculosis, about 5–10% develop active disease during their lifetimes;[14] in contrast, 30% of those coinfected with HIV develop the active disease.[14] Tuberculosis is closely linked to both overcrowding and malnutrition, making it one of the principal diseases of poverty.[12] Those at high risk thus include: people who inject illicit drugs, inhabitants and employees of locales where vulnerable people gather (e.g. prisons and homeless shelters), medically underprivileged and resource- poor communities, high-risk ethnic minorities, children in close contact with high-risk category patients, and health-care providers serving these patients.[43] Chronic lung disease is another signiﬁcant risk factor. Silicosis increases the risk about 30-fold.[44] Those who smoke cigarettes have nearly twice the risk of TB compared to nonsmokers.[45]

Other disease states can also increase the risk of de- Public health campaigns in the 1920s tried to halt the spread of [12] veloping tuberculosis. These include alcoholism and TB. diabetes mellitus (three-fold increase).[46] Certain medications, such as corticosteroids and The probability of transmission from one person to an- infliximab (an anti-αTNF monoclonal antibody), are other depends upon several factors, including the num- becoming increasingly important risk factors, especially ber of infectious droplets expelled by the carrier, the ef- [12] in the developed world. fectiveness of ventilation, the duration of exposure, the Genetic susceptibility also exists,[47] for which the overall virulence of the M. tuberculosis strain, the level of immu- importance remains undefined.[12] nity in the uninfected person, and others.[52] The cascade of person-to-person spread can be circumvented by seg- regating those with active (“overt”) TB and putting them 4.3 Mechanism on anti-TB drug regimens. After about two weeks of effective treatment, subjects with nonresistant active infections generally do not remain contagious to others.[50] If 4.3.1 Transmission someone does become infected, it typically takes three to four weeks before the newly infected person becomes When people with active pulmonary TB cough, sneeze, infectious enough to transmit the disease to others.[53] speak, sing, or spit, they expel infectious aerosol droplets 0.5 to 5.0 µm in diameter. A single sneeze can release up to 40,000 droplets.[48] Each one of these droplets may 4.3.2 Pathogenesis transmit the disease, since the infectious dose of tuberculosis is very small (the inhalation of fewer than 10 bacteria About 90% of those infected with M. tuberculosis have may cause an infection).[49] asymptomatic, latent TB infections (sometimes called [54] People with prolonged, frequent, or close contact with LTBI), with only a 10% lifetime chance that the latent infection will progress to overt, active tuberculous people with TB are at particularly high risk of becom- [55] [50] disease. In those with HIV, the risk of developing ac- ing infected, with an estimated 22% infection rate. A [55] person with active but untreated tuberculosis may infect tive TB increases to nearly 10% a year. If effective [51] treatment is not given, the death rate for active TB cases 10–15 (or more) other people per year. Transmission [51] should occur from only people with active TB – those is up to 66%. with latent infection are not thought to be contagious.[11] TB infection begins when the mycobacteria reach the 22 CHAPTER 4. TUBERCULOSIS

Microscopy of tuberculous epididymitis. H&E stain

pulmonary alveoli, where they invade and replicate within endosomes of alveolar macrophages.[11][56] Macrophages identify the bacterium as foreign and attempt to eliminate it by phagocytosis. During this process, the bacterium is enveloped by the macrophage and stored temporarily in a membrane-bound vesicle called a phagosome. The phagosome then combines with a lysosome [60] to create a phagolysosome. In the phagolysosome, the Robert Carswell's illustration of tubercle cell attempts to use reactive oxygen species and acid to kill the bacterium. However, M. tuberculosis has a thick, waxy mycolic acid capsule that protects it from these toxic sulting in latent infection. Another feature of the granulo- substances. M. tuberculosis is able to reproduce inside the mas is the development of abnormal cell death (necrosis) macrophage and will eventually kill the immune cell. in the center of tubercles. To the naked eye, this has the texture of soft, white cheese and is termed caseous necro- The primary site of infection in the lungs, known as the sis.[61] "Ghon focus", is generally located in either the upper part of the lower lobe, or the lower part of the upper If TB bacteria gain entry to the blood stream from an area lobe.[11] Tuberculosis of the lungs may also occur via in- of damaged tissue, they can spread throughout the body fection from the blood stream. This is known as a Simon and set up many foci of infection, all appearing as tiny, [63] focus and is typically found in the top of the lung.[57] white tubercles in the tissues. This severe form of TB This hematogenous transmission can also spread infec- disease, most common in young children and those with [64] tion to more distant sites, such as peripheral lymph nodes, HIV, is called miliary tuberculosis. People with this the kidneys, the brain, and the bones.[11][58] All parts of disseminated TB have a high fatality rate even with treat- [22][65] the body can be affected by the disease, though for un- ment (about 30%). known reasons it rarely affects the heart, skeletal muscles, In many people, the infection waxes and wanes. Tissue pancreas, or thyroid.[59] destruction and necrosis are often balanced by healing [61] Tuberculosis is classified as one of the granulomatous and fibrosis. Affected tissue is replaced by scarring inflammatory diseases. Macrophages, T lymphocytes, and cavities filled with caseous necrotic material. Dur- B lymphocytes, and fibroblasts aggregate to form ing active disease, some of these cavities are joined to granulomas, with lymphocytes surrounding the infected the air passages bronchi and this material can be coughed macrophages. When other macrophages attack the in- up. It contains living bacteria, so can spread the infection. fected macrophage, they fuse together to form a giant Treatment with appropriate antibiotics kills bacteria and multinucleated cell in the alveolar lumen. The granuloma allows healing to take place. Upon cure, affected areas [61] may prevent dissemination of the mycobacteria and pro- are eventually replaced by scar tissue. vide a local environment for interaction of cells of the immune system.[61] However, more recent evidence suggests that the bacteria use the granulomas to avoid destruction by the host’s immune system. Macrophages and dendritic 4.4 Diagnosis cells in the granulomas are unable to present antigen to lymphocytes; thus the immune response is suppressed.[62] Main article: Tuberculosis diagnosis Bacteria inside the granuloma can become dormant, re- 4.5. PREVENTION 23

Mantoux tuberculin skin test

who are positive to the Mantoux test.[72] These are not affected by immunization or most environmental mycobacteria, so they generate fewer false-positive results.[75] M. tuberculosis (stained red) in sputum However, they are aﬀected by M. szulgai, M. marinum, and M. kansasii.[76] IGRAs may increase sensitivity when used in addition to the skin test, but may be less sensitive 4.4.1 Active tuberculosis than the skin test when used alone.[77]

Diagnosing active tuberculosis based only on signs and symptoms is difficult,[66] as is diagnosing the disease in those who are immunosuppressed.[67] A diagnosis of TB 4.5 Prevention should, however, be considered in those with signs of lung disease or constitutional symptoms lasting longer than Tuberculosis prevention and control efforts rely primar- two weeks.[67] A chest X-ray and multiple sputum cul- ily on the vaccination of infants and the detection and tures for acid-fast bacilli are typically part of the initial appropriate treatment of active cases.[12] The World evaluation.[67] Interferon-γ release assays and tuberculin Health Organization has achieved some success with im- skin tests are of little use in the developing world.[68][69] proved treatment regimens, and a small decrease in case IGRA have similar limitations in those with HIV.[69][70] numbers.[12] The US Preventive Services Task Force A definitive diagnosis of TB is made by identifying M. (USPSTF) recommends screening people who are at high tuberculosis in a clinical sample (e.g., sputum, pus, or a risk for latent tuberculosis with either tuberculin skin tests tissue biopsy). However, the difficult culture process for or interferon-gamma release assays.[78] this slow-growing organism can take two to six weeks for blood or sputum culture.[71] Thus, treatment is often be- gun before cultures are confirmed.[72] 4.5.1 Vaccines Nucleic acid amplification tests and adenosine deaminase testing may allow rapid diagnosis of TB.[66] These tests, Main articles: Tuberculosis vaccines and BCG vaccine however, are not routinely recommended, as they rarely alter how a person is treated.[72] Blood tests to detect antibodies are not specific or sensitive, so they are not The only available vaccine as of 2011 is Bacillus recommended.[73] Calmette-Guérin (BCG).[79] In children it decreases the risk of getting the infection by 20% and the risk of infection turning into disease by nearly 60%.[80] 4.4.2 Latent tuberculosis It is the most widely used vaccine worldwide, with more than 90% of all children being vaccinated.[12] The im- Main article: Latent tuberculosis munity it induces decreases after about ten years.[12] As The Mantoux tuberculin skin test is often used to screen tuberculosis is uncommon in most of Canada, the United people at high risk for TB.[67] Those who have been previ- Kingdom, and the United States, BCG is administered to ously immunized may have a false-positive test result.[74] only those people at high risk.[81][82][83] Part of the rea- The test may be falsely negative in those with sarcoidosis, soning against the use of the vaccine is that it makes the Hodgkin’s lymphoma, malnutrition, and most notably, tuberculin skin test falsely positive, reducing the test’s use active tuberculosis.[11] Interferon gamma release assays in screening.[83] A number of new vaccines are currently (IGRAs), on a blood sample, are recommended in those in development.[12] 24 CHAPTER 4. TUBERCULOSIS

4.5.2 Public health detected, treatment with at least four effective antibiotics for 18 to 24 months is recommended.[12] The World Health Organization declared TB a “global health emergency” in 1993,[12] and in 2006, the Stop TB Partnership developed a Global Plan to Stop Tuberculosis 4.6.3 Medication resistance that aimed to save 14 million lives between its launch and 2015.[84] A number of targets they set were not achieved Primary resistance occurs when a person becomes in- by 2015, mostly due to the increase in HIV-associated tu- fected with a resistant strain of TB. A person with fully berculosis and the emergence of multiple drug-resistant susceptible MTB may develop secondary (acquired) re- tuberculosis.[12] A tuberculosis classification system de- sistance during therapy because of inadequate treatment, veloped by the American Thoracic Society is used pri- not taking the prescribed regimen appropriately (lack of marily in public health programs.[85] compliance), or using low-quality medication.[91] Drug- resistant TB is a serious public health issue in many developing countries, as its treatment is longer and requires more expensive drugs. MDR-TB is defined as resistance 4.6 Management to the two most effective first-line TB drugs: rifampicin and isoniazid. Extensively drug-resistant TB is also re- Main article: Tuberculosis management sistant to three or more of the six classes of second-line drugs.[92] Totally drug-resistant TB is resistant to all cur- [93] Treatment of TB uses antibiotics to kill the bacteria. Ef- rently used drugs. It was first observed in 2003 in [94] [93][95] fective TB treatment is difficult, due to the unusual struc- Italy, but not widely reported until 2012, and [96][97] ture and chemical composition of the mycobacterial cell has also been found in Iran and India. Bedaquiline wall, which hinders the entry of drugs and makes many is tentatively supported for use in multiple drug-resistant [98] antibiotics ineffective.[86] The two antibiotics most com- TB. monly used are isoniazid and rifampicin, and treatments XDR-TB is a term sometimes used to define extensively can be prolonged, taking several months.[52] Latent TB resistant TB, and constitutes one in ten cases of MDR- treatment usually employs a single antibiotic,[87] while ac- TB. Cases of XDR TB have been identified in more than tive TB disease is best treated with combinations of sev- 90% of countries.[96] eral antibiotics to reduce the risk of the bacteria developing antibiotic resistance.[12] People with latent infections are also treated to prevent them from progressing to active 4.7 Prognosis TB disease later in life.[87] Directly observed therapy, i.e., having a health care provider watch the person take their medications, is recommended by the WHO in an effort to reduce the number of people not appropriately taking antibiotics.[88] The evidence to support this practice over people simply taking their medications independently is poor.[89] Methods to remind people of the importance of treatment do, however, appear effective.[90]

4.6.1 New onset Age-standardized disability-adjusted life years caused by The recommended treatment of new-onset pulmonary tuberculosis per 100,000 inhabitants in 2004.[99] tuberculosis, as of 2010, is six months of a combination of antibiotics containing rifampicin, isoniazid, pyrazinamide, and ethambutol for the ﬁrst two months, Progression from TB infection to overt TB disease oc- and only rifampicin and isoniazid for the last four curs when the bacilli overcome the immune system de- months.[12] Where resistance to isoniazid is high, etham- fenses and begin to multiply. In primary TB disease butol may be added for the last four months as an (some 1–5% of cases), this occurs soon after the initial [11] alternative.[12] infection. However, in the majority of cases, a latent infection occurs with no obvious symptoms.[11] These dormant bacilli produce active tuberculosis in 5–10% of [14] 4.6.2 Recurrent disease these latent cases, often many years after infection. The risk of reactivation increases with immunosuppres- If tuberculosis recurs, testing to determine to which an- sion, such as that caused by infection with HIV. In peo- tibiotics it is sensitive is important before determining ple coinfected with M. tuberculosis and HIV, the risk of treatment.[12] If multiple drug-resistant TB (MDR-TB) is reactivation increases to 10% per year.[11] Studies using 4.9. HISTORY 25

DNA fingerprinting of M. tuberculosis strains have shown Tuberculosis is the second-most common cause of death reinfection contributes more substantially to recurrent TB from infectious disease (after those due to HIV/AIDS).[4] than previously thought,[100] with estimates that it might The total number of tuberculosis cases has been de- account for more than 50% of reactivated cases in areas creasing since 2005, while new cases have decreased where TB is common.[101] The chance of death from a since 2002.[40] China has achieved particularly dramatic case of tuberculosis is about 4% as of 2008, down from progress, with about an 80% reduction in its TB mortal- 8% in 1995.[12] ity rate between 1990 and 2010.[106] The number of new cases has declined by 17% between 2004 and 2014.[96] Tuberculosis is more common in developing countries; 4.8 Epidemiology about 80% of the population in many Asian and African countries test positive in tuberculin tests, while only 5– 10% of the US population test positive.[11] Hopes of Main article: Epidemiology of tuberculosis totally controlling the disease have been dramatically Roughly one-third of the world’s population has been in- dampened because of a number of factors, including the difficulty of developing an effective vaccine, the expensive and time-consuming diagnostic process, the ne- 1000 cessity of many months of treatment, the increase in HIV-associated tuberculosis, and the emergence of drug- 100 resistant cases in the 1980s.[12]

10 In 2007, the country with the highest estimated incidence rate of TB was Swaziland, with 1,200 cases per 100,000 0 people. India had the largest total incidence, with an estimated 2.0 million new cases.[107] In developed countries, In 2007, the number of cases of TB per 100,000 people was tuberculosis is less common and is found mainly in ur- highest in sub-Saharan Africa, and was also relatively high in ban areas. Rates per 100,000 people in different areas [102] Asia. of the world were: globally 178, Africa 332, the Amer- icas 36, Eastern Mediterranean 173, Europe 63, South- east Asia 278, and Western Pacific 139 in 2010.[106] In Canada and Australia, tuberculosis is many times more common among the aboriginal peoples, especially in remote areas.[108][109] In the United States Native Ameri- cans have a fivefold greater mortality from TB,[110] and racial and ethnic minorities accounted for 84% of all reported TB cases.[111] The rates of TB varies with age. In Africa, it primarily affects adolescents and young adults.[112] However, in Tuberculosis deaths per million persons in 2012 countries where incidence rates have declined dramati- 0–3 cally (such as the United States), TB is mainly a disease of 4–7 older people and the immunocompromised (risk factors 8–16 are listed above).[11][113] Worldwide, 22 “high-burden” 17–26 27–45 states or countries together experience 80% of cases as [96] 46–83 well as 83% of deaths. 84–137 138–215 216–443 4.9 History 444-1,359

Main articles: History of tuberculosis and Timeline of tu- fected with M. tuberculosis,[51] with new infections oc- berculosis curring in about 1% of the population each year.[10] Tuberculosis has been present in humans since However, most infections with M. tuberculosis do not antiquity.[12] The earliest unambiguous detection of M. cause TB disease,[103] and 90–95% of infections re- tuberculosis involves evidence of the disease in the remain asymptomatic.[54] In 2012, an estimated 8.6 mil- mains of bison in Wyoming dated to around 17,000 years lion chronic cases were active.[104] In 2010, 8.8 million ago.[114] However, whether tuberculosis originated in new cases of TB were diagnosed, and 1.20–1.45 million bovines, then was transferred to humans, or whether it di- deaths occurred, most of these occurring in developing verged from a common ancestor, is currently unclear.[115] countries.[40][105] Of these 1.45 million deaths, about 0.35 A comparison of the genes of M. tuberculosis complex million occur in those also infected with HIV.[106] (MTBC) in humans to MTBC in animals suggests humans 26 CHAPTER 4. TUBERCULOSIS

Egyptian mummy in the British Museum – tubercular decay has been found in the spine

did not acquire MTBC from animals during animal do- mestication, as was previously believed. Both strains of the tuberculosis bacteria share a common ancestor, which could have infected humans even before the Neolithic Revolution.[116] Skeletal remains show prehistoric humans (4000 BC) had TB, and researchers have found tubercular decay in the spines of Egyptian mummies dating from 3000–2400 BC.[117] Genetic studies suggest TB was present in the Americas from about 100 AD.[118] Robert Koch discovered the tuberculosis bacillus. Before the Industrial Revolution, folklore often associated tuberculosis with vampires. When one member of

a family died from it, the other infected members would [126] lose their health slowly. People believed this was caused tuberculosis. The World Tuberculosis Day was estab- by the original person with TB draining the life from the lished on 24 March for this reason. other family members.[119] Albert Calmette and Camille Guérin achieved the first Although the pulmonary form associated with tubercles genuine success in immunization against tuberculosis in was established as a pathology by Richard Morton in 1906, using attenuated bovine-strain tuberculosis. It was [120][121] called bacille Calmette–Guérin (BCG). The BCG vac- 1689, due to the variety of its symptoms, TB [127] was not identified as a single disease until the 1820s. It cine was first used on humans in 1921 in France, but received widespread acceptance in the US, Great Britain, was not named “tuberculosis” until 1839, by J. L. Schön- [128] lein.[122] During 1838–1845, Dr. John Croghan, the and Germany only after World War II. owner of Mammoth Cave, brought a number of people Tuberculosis caused widespread public concern in the with tuberculosis into the cave in the hope of curing the 19th and early 20th centuries as the disease became com- disease with the constant temperature and purity of the mon among the urban poor. In 1815, one in four deaths cave air; they died within a year.[123] Hermann Brehmer in England was due to “consumption”. By 1918, one in opened the first TB sanatorium in 1859 in Görbersdorf six deaths in France was still caused by TB. After TB (now Sokołowsko), Silesia.[124] was determined to be contagious, in the 1880s, it was The bacillus causing tuberculosis, M. tuberculosis, was put on a notifiable disease list in Britain; campaigns were identified and described on 24 March 1882 by Robert started to stop people from spitting in public places, and Koch. He received the Nobel Prize in physiology or the infected poor were “encouraged” to enter sanatoria medicine in 1905 for this discovery.[125] Koch did not be- that resembled prisons (the sanatoria for the middle and upper classes offered excellent care and constant med- lieve the bovine (cattle) and human tuberculosis diseases [124] were similar, which delayed the recognition of infected ical attention). Whatever the benefits of the “fresh milk as a source of infection. Later, the risk of transmis- air” and labor in the sanatoria, even under the best conditions, 50% of those who entered died within five years sion from this source was dramatically reduced by the in- [124] vention of the pasteurization process. Koch announced (c. 1916). When the Medical Research Council was formed in Britain in 1913, its initial focus was tuberculo- a glycerine extract of the tubercle bacilli as a “remedy” [129] for tuberculosis in 1890, calling it “tuberculin”. While sis research. it was not effective, it was later successfully adapted In Europe, rates of tuberculosis began to rise in the early as a screening test for the presence of pre-symptomatic 1600s to a peak level in the 1800s, when it caused nearly 4.10. SOCIETY AND CULTURE 27

25% of all deaths.[130] By the 1950s, mortality in Europe Program are working to reduce TB levels amongst people had decreased about 90%.[131] Improvements in sanita- receiving public health care.[144][145] tion, vaccination, and other public health measures began A 2014 the EIU-healthcare report that the need to address signiﬁcantly reducing rates of tuberculosis even before apathy and urging for increased funding. The report cites the arrival of streptomycin and other antibiotics, although [131] among others Lucica Ditui "[TB] is like an orphan. It has the disease remained a signiﬁcant threat. In 1946, been neglected even in countries with a high burden and the development of the antibiotic streptomycin made ef- often forgotten by donors and those investing in health fective treatment and cure of TB a reality. Prior to the interventions.”[96] introduction of this medication, the only treatment was surgical intervention, including the "pneumothorax tech- Slow progress has led to frustration, expressed by the ex- nique”, which involved collapsing an infected lung to ecutive director of the Global Fund to Fight AIDS, Tu- “rest” it and allow tuberculous lesions to heal.[132] berculosis and Malaria – Mark Dybul: “we have the tools to end TB as a pandemic and public health threat on the Because of the emergence of MDR-TB, surgery has been planet, but we are not doing it.”[96] Several international re-introduced for certain cases of TB infections. It in- organizations are pushing for more transparency in treat- volves removal of infected chest cavities (“bullae”) in ment, and more countries are implementing mandatory the lungs to reduce the number of bacteria and to in- reporting of cases to the government, although adher- crease exposure of the remaining bacteria to antibiotics [133] ence is often sketchy. Commercial treatment providers in the bloodstream. Hopes of completely eliminating may at times overprescribe second-line drugs as well as TB were ended with the rise of drug-resistant strains in supplementary treatment, promoting demands for fur- the 1980s. The subsequent resurgence of tuberculosis re- ther regulations.[96] The government of Brazil provides sulted in the declaration of a global health emergency by [96] [134] universal TB-care, which reduces this problem. Con- the World Health Organization in 1993. versely, falling rates of TB-infection may not relate to the number of programs directed at reducing infection rates but may be tied to increased level of education, income, 4.10 Society and culture and health of the population.[96] Costs of the disease, as calculated by the World Bank in 2009 may exceed 150 4.10.1 Names billion USD per year in “high burden” countries.[96] Lack of progress eradicating the disease may also be due to lack Phthisis (Φθισις) is a Greek word for consumption, of patient follow-up – as among the 250M rural migrants an old term for pulmonary tuberculosis;[3] around 460 in China.[96] BCE, Hippocrates described phthisis as a disease of dry seasons.[135] The abbreviation “TB” is short for tubercle bacillus. 4.10.3 Stigma

“Consumption” was the most common nineteenth century Slow progress in preventing the disease may in part be due English word for the disease. The Latin root “con” mean- to stigma associated with TB.[96] Stigma may be due to ing “completely” is linked to “sumere” meaning “to take the fear of transmission from affected individuals. This [136] up from under.” In The Life and Death of Mr. Bad- stigma may additionally arise due to links between TB man by John Bunyan, the author calls consumption “the and poverty, and in Africa, AIDS.[96] Such stigmatization [137] captain of all these men of death.” may be both real and perceived; for example, in Ghana individuals with TB are banned from attending public [146] 4.10.2 Public health efforts gatherings. Stigma towards TB may result in delays in seeking The World Health Organization, Bill and Melinda Gates treatment,[96] lower treatment compliance, and family Foundation, and US government are subsidizing a fast- members keeping cause of death secret[146] – allow- acting diagnostic tuberculosis test for use in low- and ing the disease to spread further.[96] At odds is Russia, middle-income countries.[138][139][140] In addition to be- where stigma was associated with increased treatment ing fast-acting, the test can determine if there is resis- compliance.[146] TB stigma also affects socially marginal- tance to the antibiotic rifampicin which may indicate ized individuals to a greater degree and varies between multi-drug resistant tuberculosis and is accurate in those regions.[146] [138][141] who are also infected with HIV. Many resource- One way to decrease stigma may be through the promo- poor places as of 2011 have access to only sputum [142] tion of “TB clubs”, where those infected may share ex- microscopy. periences and offer support, or through counseling.[146] India had the highest total number of TB cases world- Some studies have shown TB education programs to be wide in 2010, in part due to poor disease management effective in decreasing stigma, and may thus be effec- within the private and public health care sector.[143] Pro- tive in increasing treatment adherence.[146] Despite this, grams such as the Revised National Tuberculosis Control studies on the relationship between reduced stigma and 28 CHAPTER 4. TUBERCULOSIS mortality are lacking as of 2010, and similar efforts to Mycobacterium tuberculosis, though, is rarely present in decrease stigma surrounding AIDS have been minimally wild animals.[165] An effort to eradicate bovine tuber- effective.[146] Some have claimed the stigma to be worse culosis caused by Mycobacterium bovis from the cat- than the disease, and healthcare providers may uninten- tle and deer herds of New Zealand has been relatively tionally reinforce stigma, as those with TB are often per- successful.[166] Efforts in Great Britain have been less ceived as difficult or otherwise undesirable.[96] A greater successful.[167][168] understanding of the social and cultural dimensions of tu- [147] As of 2015, tuberculosis appears to be widespread among berculosis may also help with stigma reduction. captive elephants in the US. It is believed that the animals originally acquired the disease from humans, a process called reverse zoonosis. Because the disease can 4.11 Research spread through the air to infect both humans and other animals, it is a public health concern affecting circuses and zoos.[169][170] The BCG vaccine has limitations, and research to develop new TB vaccines is ongoing.[148] A number of potential candidates are currently in phase I and II clinical trials.[148] Two main approaches are being used to attempt 4.13 References to improve the efficacy of available vaccines. One approach involves adding a subunit vaccine to BCG, while [1] “Tuberculosis Fact sheet N°104”. WHO. October 2015. the other strategy is attempting to create new and better Retrieved 11 February 2016. [148] live vaccines. MVA85A, an example of a subunit vac- [2] GBD 2015 Mortality and Causes of Death, Collaborators. cine, currently in trials in South Africa, is based on a ge- (8 October 2016). “Global, regional, and national life ex- netically modified vaccinia virus.[149] Vaccines are hoped pectancy, all-cause mortality, and cause-specific mortality to play a significant role in treatment of both latent and for 249 causes of death, 1980-2015: a systematic analysis active disease.[150] for the Global Burden of Disease Study 2015.”. Lancet (London, England). 388 (10053): 1459–1544. PMID To encourage further discovery, researchers and pol- 27733281. icymakers are promoting new economic models of vaccine development, including prizes, tax incentives, [3] The Chambers Dictionary. New Delhi: Allied Chambers and advance market commitments.[151][152] A number India Ltd. 1998. p. 352. ISBN 978-81-86062-25-8. [153] of groups, including the Stop TB Partnership, the [4] Dolin, [edited by] Gerald L. Mandell, John E. Bennett, South African Tuberculosis Vaccine Initiative, and the Raphael (2010). Mandell, Douglas, and Bennett’s princi- Aeras Global TB Vaccine Foundation, are involved with ples and practice of infectious diseases (7th ed.). Philadel- research.[154] Among these, the Aeras Global TB Vac- phia, PA: Churchill Livingstone/Elsevier. pp. Chapter cine Foundation received a gift of more than $280 mil- 250. ISBN 978-0-443-06839-3. lion (US) from the Bill and Melinda Gates Foundation to [5] “Basic TB Facts”. CDC. March 13, 2012. Retrieved 11 develop and license an improved vaccine against tubercu- February 2016. losis for use in high burden countries.[155][156] [6] Konstantinos A (2010). “Testing for tuberculosis”. Aus- A number of medications are being studied for tralian Prescriber. 33 (1): 12–18. multidrug-resistant tuberculosis, including bedaquiline and delamanid.[157] Bedaquiline received U.S. Food and [7] Hawn, TR; Day, TA; Scriba, TJ; Hatherill, M; Hanekom, Drug Administration (FDA) approval in late 2012.[158] WA; Evans, TG; Churchyard, GJ; Kublin, JG; Bekker, The safety and effectiveness of these new agents are still LG; Self, SG (December 2014). “Tuberculosis vaccines and prevention of infection.”. Microbiology and uncertain, because they are based on the results of a rel- molecular biology reviews: MMBR. 78 (4): 650–71. atively small studies.[157][159] However, existing data sug- doi:10.1128/MMBR.00021-14. PMC 4248657 . PMID gest that patients taking bedaquiline in addition to stan- 25428938. dard TB therapy are five times more likely to die than those without the new drug,[160] which has resulted in [8] Harris, Randall E. (2013). Epidemiology of chronic dis- medical journal articles raising health policy questions ease: global perspectives. Burlington, MA: Jones & about why the FDA approved the drug and whether finan- Bartlett Learning. p. 682. ISBN 9780763780470. cial ties to the company making bedaquiline influenced [9] Organization, World Health (2008). Implementing the [159][161] physicians’ support for its use WHO Stop TB Strategy: a handbook for national TB control programmes. Geneva: World Health Organization. p. 179. ISBN 9789241546676. 4.12 Other animals [10] “Tuberculosis”. World Health Organization. 2002. [11] Kumar V, Abbas AK, Fausto N, Mitchell RN (2007). Mycobacteria infect many different animals, including Robbins Basic Pathology (8th ed.). Saunders Elsevier. pp. birds,[162] rodents,[163] and reptiles.[164] The subspecies 516–522. ISBN 978-1-4160-2973-1. 4.13. REFERENCES 29

[12] Lawn, SD; Zumla, AI (2 July 2011). “Tuberculo- [27] Parish T.; Stoker N. (1999). “Mycobacteria: bugs and sis”. Lancet. 378 (9785): 57–72. doi:10.1016/S0140- bugbears (two steps forward and one step back)". Molec- 6736(10)62173-3. PMID 21420161. ular Biotechnology. 13 (3): 191–200. doi:10.1385/MB: 13:3:191. PMID 10934532. [13] Schiﬀman G (15 January 2009). “Tuberculosis Symp- toms”. eMedicineHealth. [28] Medical Laboratory Science: Theory and Practice. New Delhi: Tata McGraw-Hill. 2000. p. 473. ISBN 0-07- [14] Gibson, Peter G. (ed.); Abramson, Michael (ed.); Wood- 463223-X. Baker, Richard (ed.); Volmink, Jimmy (ed.); Hensley, Michael (ed.); Costabel, Ulrich (ed.) (2005). Evidence- [29] “Acid-Fast Stain Protocols”. 21 August 2013. Retrieved Based Respiratory Medicine (1st ed.). BMJ Books. p. 26 March 2016. 321. ISBN 978-0-7279-1605-1. [30] Kommareddi S.; Abramowsky C.; Swinehart G.; Hrabak [15] Behera, D. (2010). Textbook of Pulmonary Medicine (2nd L. (1984). “Nontuberculous mycobacterial infections: ed.). New Delhi: Jaypee Brothers Medical Publishers. p. comparison of the ﬂuorescent auramine-O and Ziehl- 457. ISBN 978-81-8448-749-7. Neelsen techniques in tissue diagnosis”. Human Pathol- ogy. 15 (11): 1085–1089. doi:10.1016/S0046- [16] Halezeroğlu, S; Okur, E (March 2014). “Thoracic surgery 8177(84)80253-1. PMID 6208117. for haemoptysis in the context of tuberculosis: what is the best management approach?". Journal of Tho- [31] van Lettow, Monique; Whalen, Christopher (2008). racic Disease. 6 (3): 182–5. doi:10.3978/j.issn.2072- Nutrition and health in developing countries (2nd ed.). To- 1439.2013.12.25. PMID 24624281. towa, N.J. (Richard D. Semba and Martin W. Bloem, eds.): Humana Press. p. 291. ISBN 978-1-934115-24-4. [17] Jindal, editor-in-chief SK (2011). Textbook of Pulmonary and Critical Care Medicine. New Delhi: Jaypee Brothers [32] van Soolingen D., et al. (1997). “A novel pathogenic Medical Publishers. p. 549. ISBN 978-93-5025-073-0. taxon of the Mycobacterium tuberculosis complex, Canetti: characterization of an exceptional isolate from [18] Golden MP, Vikram HR (2005). “Extrapulmonary tuber- Africa”. International Journal of Systematic Bacteriol- culosis: an overview”. American Family Physician. 72 (9): ogy. 47 (4): 1236–45. doi:10.1099/00207713-47-4- 1761–8. PMID 16300038. 1236. PMID 9336935.

[19] Rockwood, RR (August 2007). “Extrapulmonary TB: [33] Niemann S., et al. (2002). “Mycobacterium africanum what you need to know.”. The Nurse practitioner. 32 Subtype II Is Associated with Two Distinct Genotypes (8): 44–9. doi:10.1097/01.npr.0000282802.12314.dc. and Is a Major Cause of Human Tuberculosis in Kam- PMID 17667766. pala, Uganda”. Journal of Clinical Microbiology. 40 (9): 3398–405. doi:10.1128/JCM.40.9.3398-3405.2002. [20] Burkitt, H. George (2007). Essential Surgery: Prob- lems, Diagnosis & Management 4th ed. p. 34. ISBN PMC 130701 . PMID 12202584. 9780443103452. [34] Niobe-Eyangoh S.N., et al. (2003). “Genetic Biodiver- [21] Kabra, [edited by] Vimlesh Seth, S.K. (2006). Essentials sity of Mycobacterium tuberculosis Complex Strains from of tuberculosis in children (3rd ed.). New Delhi: Jaypee Patients with Pulmonary Tuberculosis in Cameroon”. Bros. Medical Publishers. p. 249. ISBN 978-81-8061- Journal of Clinical Microbiology. 41 (6): 2547– 709-6. 53. doi:10.1128/JCM.41.6.2547-2553.2003. PMC 156567 . PMID 12791879. [22] Ghosh, editors-in-chief, Thomas M. Habermann, Amit K. (2008). Mayo Clinic internal medicine: concise textbook. [35] Thoen C, Lobue P, de Kantor I (2006). “The Rochester, MN: Mayo Clinic Scientiﬁc Press. p. 789. importance of Mycobacterium bovis as a zoono- ISBN 978-1-4200-6749-1. sis”. Veterinary Microbiology. 112 (2–4): 339–45. doi:10.1016/j.vetmic.2005.11.047. PMID 16387455. [23] Southwick F (10 December 2007). “Chapter 4: Pul- monary Infections”. Infectious Diseases: A Clinical Short [36] Acton, Q. Ashton (2011). Mycobacterium Infections: New Course, 2nd ed. McGraw-Hill Medical Publishing Divi- Insights for the Healthcare Professional. ScholarlyEdi- sion. pp. 104, 313–4. ISBN 0-07-147722-5. tions. p. 1968. ISBN 978-1-4649-0122-5.

[24] Jindal, editor-in-chief SK (2011). Textbook of Pulmonary [37] Pfyffer, GE; Auckenthaler, R; van Embden, JD; van and Critical Care Medicine. New Delhi: Jaypee Brothers Soolingen, D (Oct–Dec 1998). “Mycobacterium canet- Medical Publishers. p. 525. ISBN 978-93-5025-073-0. tii, the smooth variant of M. tuberculosis, isolated from a Swiss patient exposed in Africa”. Emerging Infectious Dis- [25] Niederweis M, Danilchanka O, Huff J, Hoffmann C, En- eases. 4 (4): 631–4. doi:10.3201/eid0404.980414. PMC gelhardt H (March 2010). “Mycobacterial outer mem- 2640258 . PMID 9866740. branes: in search of proteins”. Trends in Microbiology. 18 (3): 109–16. doi:10.1016/j.tim.2009.12.005. PMC [38] Panteix, G; Gutierrez, MC; Boschiroli, ML; Rouviere, 2931330 . PMID 20060722. M; Plaidy, A; Pressac, D; Porcheret, H; Chyderiotis, G; Ponsada, M; Van Oortegem, K; Salloum, S; Cabuzel, [26] Madison B (2001). “Application of stains in clinical mi- S; Bañuls, AL; Van de Perre, P; Godreuil, S (Au- crobiology”. Biotechnic & Histochemistry. 76 (3): 119– gust 2010). “Pulmonary tuberculosis due to Mycobac- 25. doi:10.1080/714028138. PMID 11475314. terium microti: a study of six recent cases in France”. 30 CHAPTER 4. TUBERCULOSIS

Journal of Medical Microbiology. 59 (Pt 8): 984–9. [49] Nicas M, Nazaroff WW, Hubbard A (2005). “Toward doi:10.1099/jmm.0.019372-0. PMID 20488936. understanding the risk of secondary airborne infection: emission of respirable pathogens”. J Occup Environ [39] American Thoracic Society (1997). “Diagnosis and treat- Hyg. 2 (3): 143–54. doi:10.1080/15459620590918466. ment of disease caused by nontuberculous mycobac- PMID 15764538. teria. This official statement of the American Tho- racic Society was approved by the Board of Direc- [50] Ahmed N, Hasnain S (2011). “Molecular epidemiol- tors, March 1997. Medical Section of the Ameri- ogy of tuberculosis in India: Moving forward with a sys- can Lung Association”. American Journal of Respira- tems biology approach”. Tuberculosis. 91 (5): 407–3. tory and Critical Care Medicine. 156 (2 Pt 2): S1–25. doi:10.1016/j.tube.2011.03.006. PMID 21514230. doi:10.1164/ajrccm.156.2.atsstatement. PMID 9279284. [51] “Tuberculosis Fact sheet N°104”. World Health Organi- zation. November 2010. Retrieved 26 July 2011. [40] World Health Organization (2011). “The sixteenth global report on tuberculosis” (PDF). [52] “Core Curriculum on Tuberculosis: What the Clinician Should Know” (PDF) (5th ed.). Centers for Disease [41] World Health Organization. “Global tuberculosis control– Control and Prevention (CDC), Division of Tuberculosis surveillance, planning, financing WHO Report 2006”. Elimination. 2011. p. 24. Retrieved 13 October 2006. [53] “Causes of Tuberculosis”. Mayo Clinic. 21 December [42] Chaisson, RE; Martinson, NA (13 March 2008). “Tuber- 2006. Retrieved 19 October 2007. culosis in Africa—combating an HIV-driven crisis”. The [54] Skolnik, Richard (2011). Global health 101 (2nd ed.). New England Journal of Medicine. 358 (11): 1089–92. Burlington, MA: Jones & Bartlett Learning. p. 253. doi:10.1056/NEJMp0800809. PMID 18337598. ISBN 978-0-7637-9751-5.

[43] Griﬃth D, Kerr C (1996). “Tuberculosis: disease of [55] editors, Arch G. Mainous III, Claire Pomeroy, (2009). the past, disease of the present”. Journal of Perianes- Management of antimicrobials in infectious diseases: im- thesia Nursing. 11 (4): 240–5. doi:10.1016/S1089- pact of antibiotic resistance. (2nd rev. ed.). Totowa, N.J.: 9472(96)80023-2. PMID 8964016. Humana Press. p. 74. ISBN 978-1-60327-238-4.

[44] ATS/CDC Statement Committee on Latent Tuberculosis [56] Houben E, Nguyen L, Pieters J (2006). “Interac- Infection (June 2000). “Targeted tuberculin testing and tion of pathogenic mycobacteria with the host im- treatment of latent tuberculosis infection. American Tho- mune system”. Curr Opin Microbiol. 9 (1): 76–85. racic Society”. MMWR. Recommendations and Reports. doi:10.1016/j.mib.2005.12.014. PMID 16406837. 49 (RR–6): 1–51. PMID 10881762. [57] Khan (2011). Essence Of Paediatrics. Elsevier India. p. 401. ISBN 978-81-312-2804-3. [45] van Zyl Smit, RN; Pai, M; Yew, WW; Leung, CC; Zumla, A; Bateman, ED; Dheda, K (January 2010). “Global lung [58] Herrmann J, Lagrange P (2005). “Dendritic cells health: the colliding epidemics of tuberculosis, tobacco and Mycobacterium tuberculosis: which is the Tro- smoking, HIV and COPD”. European Respiratory Jour- jan horse?". Pathol Biol (Paris). 53 (1): 35–40. nal. 35 (1): 27–33. doi:10.1183/09031936.00072909. doi:10.1016/j.patbio.2004.01.004. PMID 15620608. PMID 20044459. These analyses indicate that smokers are almost twice as likely to be infected with TB and to [59] Agarwal R, Malhotra P, Awasthi A, Kakkar N, Gupta progress to active disease (RR of about 1.5 for latent TB D (2005). “Tuberculous dilated cardiomyopathy: an infection (LTBI) and RR of ∼2.0 for TB disease). Smok- under-recognized entity?". BMC Infect Dis. 5 (1): 29. ers are also twice as likely to die from TB (RR of about doi:10.1186/1471-2334-5-29. PMC 1090580 . PMID 2.0 for TB mortality), but data are difficult to interpret 15857515. because of heterogeneity in the results across studies. [60] John Mason Good; Samuel Cooper; Augustus Sidney [46] Restrepo, BI (15 August 2007). “Convergence of the Doane (1835). The Study of Medicine. Harper. p. 32. tuberculosis and diabetes epidemics: renewal of old ac- [61] Grosset J (2003). “Mycobacterium tuberculosis in the quaintances”. Clinical Infectious Diseases. 45 (4): 436– Extracellular Compartment: an Underestimated Adver- 8. doi:10.1086/519939. PMC 2900315 . PMID sary”. Antimicrob Agents Chemother. 47 (3): 833–6. 17638190. doi:10.1128/AAC.47.3.833-836.2003. PMC 149338 . PMID 12604509. [47] Möller, M; Hoal, EG (March 2010). “Current findings, challenges and novel approaches in human genetic sus- [62] Bozzano F (2014). “Immunology of tuberculosis”. ceptibility to tuberculosis”. Tuberculosis. 90 (2): 71–83. Mediterr J Hematol Infect Dis. 6 (1): e2014027. doi:10.1016/j.tube.2010.02.002. PMID 20206579. doi:10.4084/MJHID.2014.027. PMC 4010607 . PMID 24804000. [48] Cole E, Cook C (1998). “Characterization of infectious aerosols in health care facilities: an aid to effec- [63] Crowley, Leonard V. (2010). An introduction to human tive engineering controls and preventive strategies”. Am disease: pathology and pathophysiology correlations (8th J Infect Control. 26 (4): 453–64. doi:10.1016/S0196- ed.). Sudbury, Mass.: Jones and Bartlett. p. 374. ISBN 6553(98)70046-X. PMID 9721404. 978-0-7637-6591-0. 4.13. REFERENCES 31

[64] Anthony, Harries (2005). TB/HIV a Clinical Manual. Mantoux test imminent?". Expert Rev Anti Infect Ther. (2nd ed.). Geneva: World Health Organization. p. 75. 3 (6): 981–93. doi:10.1586/14787210.3.6.981. PMID ISBN 978-92-4-154634-8. 16307510.

[65] Jacob, JT; Mehta, AK; Leonard, MK (January [75] Pai M, Zwerling A, Menzies D (2008). “Systematic 2009). “Acute forms of tuberculosis in adults”. Review: T-Cell–based Assays for the Diagnosis of La- The American Journal of Medicine. 122 (1): 12–7. tent Tuberculosis Infection: An Update”. Ann. Intern. doi:10.1016/j.amjmed.2008.09.018. PMID 19114163. Med. 149 (3): 1–9. doi:10.7326/0003-4819-149-3- 200808050-00241. PMC 2951987 . PMID 18593687. [66] Bento, J; Silva, AS; Rodrigues, F; Duarte, R (Jan–Feb 2011). "[Diagnostic tools in tuberculosis]". Acta Médica [76] Jindal, editor-in-chief SK (2011). Textbook of Pulmonary Portuguesa. 24 (1): 145–54. PMID 21672452. and Critical Care Medicine. New Delhi: Jaypee Brothers Medical Publishers. p. 544. ISBN 978-93-5025-073-0. [67] Escalante, P (2 June 2009). “In the clinic. Tuberculosis”. Annals of Internal Medicine. 150 (11): ITC61–614; quiz [77] Amicosante, M; Ciccozzi, M; Markova, R (April 2010). ITV616. doi:10.7326/0003-4819-150-11-200906020- “Rational use of immunodiagnostic tools for tuberculosis 01006. PMID 19487708. infection: guidelines and cost eﬀectiveness studies”. The new microbiologica. 33 (2): 93–107. PMID 20518271. [68] Metcalfe, JZ; Everett, CK; Steingart, KR; Cattamanchi, A; Huang, L; Hopewell, PC; Pai, M (15 November 2011). [78] Bibbins-Domingo, Kirsten; Grossman, David C.; Curry, “Interferon-γ release assays for active pulmonary tubercu- Susan J.; Bauman, Linda; Davidson, Karina W.; Epling, losis diagnosis in adults in low- and middle-income coun- John W.; García, Francisco A.R.; Herzstein, Jessica; tries: systematic review and meta-analysis”. The Journal Kemper, Alex R.; Krist, Alex H.; Kurth, Ann E.; of Infectious Diseases. 204 Suppl 4 (suppl_4): S1120– Landefeld, C. Seth; Mangione, Carol M.; Phillips, 9. doi:10.1093/infdis/jir410. PMC 3192542 . PMID William R.; Phipps, Maureen G.; Pignone, Michael 21996694. P. (6 September 2016). “Screening for Latent Tuber- culosis Infection in Adults”. JAMA. 316 (9): 962. [69] Sester, M; Sotgiu, G; Lange, C; Giehl, C; Girardi, doi:10.1001/jama.2016.11046. E; Migliori, GB; Bossink, A; Dheda, K; Diel, R; Dominguez, J; Lipman, M; Nemeth, J; Ravn, P; Win- [79] McShane, H (12 October 2011). “Tuberculosis vac- kler, S; Huitric, E; Sandgren, A; Manissero, D (January cines: beyond bacille Calmette–Guérin”. Philosophi- 2011). “Interferon-γ release assays for the diagnosis of ac- cal transactions of the Royal Society of London. Se- tive tuberculosis: a systematic review and meta-analysis”. ries B, Biological sciences. 366 (1579): 2782–9. The European Respiratory Journal. 37 (1): 100–11. doi:10.1098/rstb.2011.0097. PMC 3146779 . PMID doi:10.1183/09031936.00114810. PMID 20847080. 21893541.

[70] Chen, J; Zhang, R; Wang, J; Liu, L; Zheng, Y; Shen, Y; [80] Roy, A; Eisenhut, M; Harris, RJ; Rodrigues, LC; Srid- Qi, T; Lu, H (2011). Vermund, Sten H, ed. “Interferon- har, S; Habermann, S; Snell, L; Mangtani, P; Adetifa, gamma release assays for the diagnosis of active tu- I; Lalvani, A; Abubakar, I (Aug 5, 2014). “Eﬀect berculosis in HIV-infected patients: a systematic re- of BCG vaccination against Mycobacterium tuberculo- view and meta-analysis”. PLoS ONE. 6 (11): e26827. sis infection in children: systematic review and meta- doi:10.1371/journal.pone.0026827. PMC 3206065 . analysis.”. BMJ (Clinical research ed.). 349: g4643. PMID 22069472. doi:10.1136/bmj.g4643. PMC 4122754 . PMID 25097193. [71] Diseases, Special Programme for Research & Training in Tropical (2006). Diagnostics for tuberculosis: global de- [81] “Vaccine and Immunizations: TB Vaccine (BCG)". Cen- mand and market potential. Geneva: World Health Orga- ters for Disease Control and Prevention. 2011. Retrieved nization on behalf of the Special Programme for Research 26 July 2011. and Training in Tropical Diseases. p. 36. ISBN 978-92- [82] “BCG Vaccine Usage in Canada – Current and Histori- 4-156330-7. cal”. Public Health Agency of Canada. September 2010. [72] National Institute for Health and Clinical Excellence. Retrieved 30 December 2011. Clinical guideline 117: Tuberculosis. London, 2011. [83] Teo, SS; Shingadia, DV (June 2006). “Does BCG have a role in tuberculosis control and prevention in the [73] Steingart, KR; Flores, LL; Dendukuri, N; Schiller, I; United Kingdom?". Archives of Disease in Childhood. Laal, S; Ramsay, A; Hopewell, PC; Pai, M (August 91 (6): 529–31. doi:10.1136/adc.2005.085043. PMC 2011). Evans, Carlton, ed. “Commercial serological tests for the diagnosis of active pulmonary and extra- 2082765 . PMID 16714729. pulmonary tuberculosis: an updated systematic review [84] “The Global Plan to Stop TB”. World Health Organiza- and meta-analysis”. PLOS Medicine. 8 (8): e1001062. tion. 2011. Retrieved 13 June 2011. doi:10.1371/journal.pmed.1001062. PMC 3153457 . PMID 21857806. [85] Warrell, ed. by D. J. Weatherall ... [4. + 5. ed.] ed. by David A. (2005). Sections 1 – 10. (4. ed., paperback. [74] Rothel J, Andersen P (2005). “Diagnosis of latent My- ed.). Oxford [u.a.]: Oxford Univ. Press. p. 560. ISBN cobacterium tuberculosis infection: is the demise of the 978-0-19-857014-1. 32 CHAPTER 4. TUBERCULOSIS

[86] Brennan PJ, Nikaido H (1995). “The envelope of [99] “WHO Disease and injury country estimates”. World mycobacteria”. Annu. Rev. Biochem. 64: 29– Health Organization. 2004. Retrieved 11 November 63. doi:10.1146/annurev.bi.64.070195.000333. PMID 2009. 7574484. [100] Lambert M, et al. (2003). “Recurrence in tuberculosis: [87] Menzies, D; Al Jahdali, H; Al Otaibi, B (March 2011). relapse or reinfection?". Lancet Infect Dis. 3 (5): 282–7. “Recent developments in treatment of latent tuberculosis doi:10.1016/S1473-3099(03)00607-8. PMID 12726976. infection”. The Indian journal of medical research. 133 (3): 257–66. PMC 3103149 . PMID 21441678. [101] Wang, JY; Lee, LN; Lai, HC; Hsu, HL; Liaw, YS; Hsueh, PR; Yang, PC (15 July 2007). “Prediction of the tuber- [88] Arch G.; III Mainous (2010). Management of Antimi- culosis reinfection proportion from the local incidence”. crobials in Infectious Diseases: Impact of Antibiotic Re- The Journal of Infectious Diseases. 196 (2): 281–8. sistance. Totowa, N.J.: Humana Press. p. 69. ISBN 1- doi:10.1086/518898. PMID 17570116. 60327-238-0. [102] World Health Organization (2009). “The Stop TB Strat- [89] Volmink J, Garner P (2007). Volmink, Jimmy, ed. egy, case reports, treatment outcomes and estimates of TB “Directly observed therapy for treating tuberculo- burden”. Global tuberculosis control: epidemiology, strat- sis”. Cochrane Database Syst Rev (4): CD003343. egy, financing. pp. 187–300. ISBN 978-92-4-156380-2. doi:10.1002/14651858.CD003343.pub3. PMID Retrieved 14 November 2009. 17943789. [103] “Fact Sheets: The Difference Between Latent TB Infec- [90] Liu, Q; Abba, K; Alejandria, MM; Balanag, VM; tion and Active TB Disease”. Centers for Disease Control. Berba, RP; Lansang, MA (8 October 2008). Liu, 20 June 2011. Retrieved 26 July 2011. Qin, ed. “Reminder systems and late patient trac- ers in the diagnosis and management of tuberculosis”. [104] “Global tuberculosis report 2013”. World Health Organi- Cochrane database of systematic reviews (Online) (4): zation. 2013. CD006594. doi:10.1002/14651858.CD006594.pub2. PMID 18843723. [105] Lozano, R (15 December 2012). “Global and regional mortality from 235 causes of death for 20 age [91] O'Brien R (1994). “Drug-resistant tuberculosis: etiology, groups in 1990 and 2010: a systematic analysis for the management and prevention”. Semin Respir Infect. 9 (2): Global Burden of Disease Study 2010”. Lancet. 380 104–12. PMID 7973169. (9859): 2095–128. doi:10.1016/S0140-6736(12)61728- [92] Centers for Disease Control and Prevention (CDC) 0. PMID 23245604. (2006). “Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs—worldwide, [106] “Global Tuberculosis Control 2011” (PDF). World Health 2000–2004”. MMWR Morb Mortal Wkly Rep. 55 (11): Organization. Retrieved 15 April 2012. 301–5. PMID 16557213. [107] World Health Organization (2009). “Epidemiology” [93] Maryn McKenna (12 January 2012). “Totally Resistant (PDF). Global tuberculosis control: epidemiology, strategy, TB: Earliest Cases in Italy”. Wired. Retrieved 12 January financing. pp. 6–33. ISBN 978-92-4-156380-2. 2012. [108] FitzGerald, JM; Wang, L; Elwood, RK (8 February 2000). [94] Migliori, G.B.; De Iaco, G.; Besozzi, G.; Centis, R.; Cir- “Tuberculosis: 13. Control of the disease among abo- illo, D.M. (May 17, 2007). “First tuberculosis cases in riginal people in Canada”. Canadian Medical Associa- Italy resistant to all tested drugs”. Euro Surveillance. 12 tion Journal. 162 (3): 351–5. PMC 1231016 . PMID (5): E070517.1. PMID 17868596. 10693593. [95] “Totally Drug-Resistant TB: a WHO consultation on [109] Quah, Stella R.; Carrin, Guy; Buse, Kent; Kristian the diagnostic definition and treatment options” (PDF). Heggenhougen (2009). Health Systems Policy, Finance, who.int. World Health Organization. Retrieved 25 March and Organization. Boston: Academic Press. p. 424. 2016. ISBN 0-12-375087-3. [96] Paul Kielstra (30 June 2014). Zoe Tabary, ed. “Ancient enemy, modern imperative – A time for greater action [110] Anne-Emanuelle Birn (2009). Textbook of International against tuberculosis”. Economist Insights. The Economist Health: Global Health in a Dynamic World. p. 261. ISBN Group. Retrieved 1 August 2014. 9780199885213. [97] Velayati, A.A.; Masjedi, M.R.; Farnia, P.; Tabarsi, P.; [111] Centers for Disease Control and Prevention. “CDC Ghanavi, J.; Ziazarifi, A.H.; Hoffner, S.E. (August 2009). Surveillance Slides 2012 – TB”. “Emergence of new forms of totally drug-resistant tuberculosis bacilli: super extensively drug-resistant tuberculo- [112] World Health Organization. “Global Tuberculosis Con- sis or totally drug-resistant strains in Iran”. Chest. 136 (2): trol Report, 2006 – Annex 1 Profiles of high-burden coun- 420–425. doi:10.1378/chest.08-2427. PMID 19349380. tries” (PDF). Retrieved 13 October 2006. [98] “Provisional CDC Guidelines for the Use and Safety Mon- [113] Centers for Disease Control and Prevention (12 Septem- itoring of Bedaquiline Fumarate (Sirturo) for the Treat- ber 2006). “2005 Surveillance Slide Set”. Retrieved 13 ment of Multidrug-Resistant Tuberculosis”. October 2006. 4.13. REFERENCES 33

[114] Rothschild BM, Martin LD, Lev G, et al. (August 2001). [127] Bonah C (2005). “The 'experimental stable' of the BCG “Mycobacterium tuberculosis complex DNA from an ex- vaccine: safety, eﬃcacy, proof, and standards, 1921– tinct bison dated 17,000 years before the present”. Clin. 1933”. Stud Hist Philos Biol Biomed Sci. 36 (4): 696–721. Infect. Dis. 33 (3): 305–11. doi:10.1086/321886. PMID doi:10.1016/j.shpsc.2005.09.003. PMID 16337557. 11438894. [128] Comstock G (1994). “The International Tuberculo- [115] Pearce-Duvet J (2006). “The origin of human pathogens: sis Campaign: a pioneering venture in mass vaccina- evaluating the role of agriculture and domestic animals in tion and research”. Clin Infect Dis. 19 (3): 528–40. the evolution of human disease”. Biol Rev Camb Philos doi:10.1093/clinids/19.3.528. PMID 7811874. Soc. 81 (3): 369–82. doi:10.1017/S1464793106007020. PMID 16672105. [129] editor, Caroline Hannaway, (2008). Biomedicine in the twentieth century: practices, policies, and politics. Ams- [116] Comas, I; Gagneux, S (October 2009). Manchester, terdam: IOS Press. p. 233. ISBN 978-1-58603-832-8. Marianne, ed. “The past and future of tuberculosis research”. PLoS Pathogens. 5 (10): e1000600. [130] Bloom, editor, Barry R. (1994). Tuberculosis: pathogen- doi:10.1371/journal.ppat.1000600. PMC 2745564 . esis, protection, and control. Washington, D.C.: ASM PMID 19855821. Press. ISBN 978-1-55581-072-6.

[117] Zink A, Sola C, Reischl U, Grabner W, Rastogi N, Wolf [131] Persson, Sheryl (2010). Smallpox, Syphilis and Salvation: H, Nerlich A (2003). “Characterization of Mycobac- Medical Breakthroughs That Changed the World. Read- terium tuberculosis Complex DNAs from Egyptian Mum- HowYouWant.com. p. 141. ISBN 978-1-4587-6712-7. mies by Spoligotyping”. J Clin Microbiol. 41 (1): 359–67. [132] Shields, Thomas (2009). General thoracic surgery (7th doi:10.1128/JCM.41.1.359-367.2003. PMC 149558 . ed.). Philadelphia: Wolters Kluwer Health/Lippincott PMID 12517873. Williams & Wilkins. p. 792. ISBN 978-0-7817-7982- 1. [118] Konomi N, Lebwohl E, Mowbray K, Tattersall I, Zhang D (2002). “Detection of Mycobacterial DNA in An- [133] Lalloo UG, Naidoo R, Ambaram A (May 2006). “Recent dean Mummies”. J Clin Microbiol. 40 (12): 4738– advances in the medical and surgical treatment of multi- 40. doi:10.1128/JCM.40.12.4738-4740.2002. PMC drug resistant tuberculosis”. Curr Opin Pulm Med. 12 (3): 154635 . PMID 12454182. 179–85. doi:10.1097/01.mcp.0000219266.27439.52. PMID 16582672. [119] Sledzik, Paul S.; Nicholas Bellantoni (June 1994). “Bioarcheological and biocultural evidence for the New [134] “Frequently asked questions about TB and HIV”. World England vampire folk belief” (PDF). American Jour- Health Organization. Archived from the original on 11 nal of Physical Anthropology. 94 (2): 269–274. August 2011. Retrieved 15 April 2012. doi:10.1002/ajpa.1330940210. PMID 8085617. [135] “Hippocrates 3.16 Classics, MIT”. Archived from the [120] Léon Charles Albert Calmette at Who Named It? original on 11 February 2005. Retrieved 15 December 2015. [121] Trail RR (April 1970). “Richard Morton (1637–1698)". Med Hist. 14 (2): 166–74. [136] Caldwell, Mark (1988). The Last Crusade. New York: doi:10.1017/S0025727300015350. PMC 1034037 . Macmillan. p. 21. ISBN 0689118104. PMID 4914685. [137] Bunyan, John. “The Life and Death of Mr. Badman”. [122] Zur Pathogenie der Impetigines. Auszug aus einer Google Books. Google. Retrieved 28 September 2016. brieﬂichen Mitteilung an den Herausgeber. [Müller’s] Archiv für Anatomie, Physiologie und wissenschaftliche [138] “Public-Private Partnership Announces Immediate 40 Medicin. 1839, page 82. Percent Cost Reduction for Rapid TB Test” (pdf). World Health Organization. 6 August 2012. [123] Kentucky: Mammoth Cave long on history. CNN. 27 February 2004. Accessed 8 October 2006. [139] Lawn, SD; Nicol, MP (September 2011). “Xpert® MTB/RIF assay: development, evaluation and implemen- [124] McCarthy OR (August 2001). “The key to the sanatoria”. tation of a new rapid molecular diagnostic for tubercu- J R Soc Med. 94 (8): 413–7. PMC 1281640 . PMID losis and rifampicin resistance”. Future microbiology. 6 11461990. (9): 1067–82. doi:10.2217/fmb.11.84. PMC 3252681 . PMID 21958145. [125] Nobel Foundation. The Nobel Prize in Physiology or Medicine 1905. Accessed 7 October 2006. [140] “WHO says Cepheid rapid test will transform TB care”. Reuters. 8 December 2010. [126] Waddington K (January 2004). “To stamp out “So Terri- ble a Malady": bovine tuberculosis and tuberculin test- [141] STOPTB (5 April 2013). “The Stop TB Partnership, ing in Britain, 1890–1939”. Med Hist. 48 (1): 29– which operates through a secretariat hosted by the World 48. doi:10.1017/S0025727300007043. PMC 546294 . Health Organization (WHO) in Geneva, Switzerland.” PMID 14968644. (pdf). 34 CHAPTER 4. TUBERCULOSIS

[142] Lienhardt, C; Espinal, M; Pai, M; Maher, D; Rav- [155] Bill and Melinda Gates Foundation Announcement (12 iglione, MC (November 2011). “What research is February 2004). “Gates Foundation Commits $82.9 Mil- needed to stop TB? Introducing the TB Research lion to Develop New Tuberculosis Vaccines”. Movement”. PLOS Medicine. 8 (11): e1001135. [156] Nightingale, Katherine (19 September 2007). “Gates doi:10.1371/journal.pmed.1001135. PMC 3226454 . foundation gives US$280 million to ﬁght TB”. PMID 22140369. [157] Zumla, A; Hafner, R; Lienhardt, C; Hoelscher, M; Nunn, [143] Mishra, G (2013). “Tuberculosis Prescription Practices In A (1 March 2012). “Advancing the development of tu- Private And Public Sector In India”. NJIRM. 4 (2): 71–78. berculosis therapy”. Nature reviews. Drug discovery. 11 (3): 171–2. doi:10.1038/nrd3694. PMID 22378254. [144] Anurag Bhargava; Lancelot Pinto; Madhukar Pai (2011). “Mismanagement of tuberculosis in India: Causes, con- [158] “J&J Sirturo Wins FDA Approval to Treat Drug-Resistant sequences, and the way forward”. Hypothesis. 9 (1): e7. TB”. Bloombeg. 31 December 2012. Retrieved 1 January doi:10.5779/hypothesis.v9i1.214. 2013.

[145] Amdekar, Y (July 2009). “Changes in the management of [159] Avorn, J (April 2013). “Approval of a tuberculosis drug tuberculosis”. Indian journal of pediatrics. 76 (7): 739– based on a paradoxical surrogate measure”. JAMA. 309 42. doi:10.1007/s12098-009-0164-4. PMID 19693453. (13): 1349–1350. doi:10.1001/jama.2013.623. PMID 23430122. [146] Courtwright, A; Turner, AN (Jul–Aug 2010). “Tuber- culosis and stigmatization: pathways and interventions”. [160] US Food and Drug Administration. “Briefing Package: Public Health Reports. 125 Suppl 4: 34–42. PMID NDA 204–384: Sirturo” (PDF). 20626191. [161] Zuckerman, Diana; Jennifer Yttri (January 2013). [147] Mason, PH; Roy, A; Spillane, J; Singh, P (22 May 2015). “Antibiotics: When science and wishful thinking collide”. “SOCIAL, HISTORICAL AND CULTURAL DIMEN- Health Affairs. SIONS OF TUBERCULOSIS.”. Journal of biosocial sci- [162] Shivaprasad, H.L.; Palmieri, C. (January 2012). “Pathol- ence: 1–27. doi:10.1017/S0021932015000115. PMID ogy of mycobacteriosis in birds”. The Veterinary Clin- 25997539. ics of North America. Exotic Animal Practice. 15 (1): [148] Martín Montañés, C.; Gicquel, B. (March 2011). 41–55, v–vi. doi:10.1016/j.cvex.2011.11.004. PMID “New tuberculosis vaccines”. Enfermedades infec- 22244112. ciosas y microbiologia clinica. 29 Suppl 1: 57– [163] Reavill, D.R.; Schmidt, R.E. (January 2012). “My- 62. doi:10.1016/S0213-005X(11)70019-2. PMID cobacterial lesions in fish, amphibians, reptiles, ro- 21420568. dents, lagomorphs, and ferrets with reference to ani- [149] Ibanga H.; Brookes R.; Hill P.; Owiafe P.; Fletcher mal models”. The Veterinary Clinics of North Amer- H.; Lienhardt C.; Hill A.; Adegbola R.; McShane H. ica. Exotic Animal Practice. 15 (1): 25–40, v. (2006). “Early clinical trials with a new tuberculosis vac- doi:10.1016/j.cvex.2011.10.001. PMID 22244111. cine, MVA85A, in tuberculosis-endemic countries: issues [164] Mitchell, M.A. (January 2012). “Mycobacterial infec- in study design”. Lancet Infectious Diseases. 6 (8): 522–8. tions in reptiles”. The Veterinary Clinics of North Amer- doi:10.1016/S1473-3099(06)70552-7. PMID 16870530. ica. Exotic Animal Practice. 15 (1): 101–11, vii. doi:10.1016/j.cvex.2011.10.002. PMID 22244116. [150] Kaufmann S.H. (2010). “Future vaccination strategies against tuberculosis: Thinking out- [165] Wobeser, Gary A. (2006). Essentials of disease in wild an- side the box”. Immunity. 33 (4): 567–77. imals (1st ed.). Ames, Iowa [u.a.]: Blackwell Publishing. doi:10.1016/j.immuni.2010.09.015. PMID 21029966. p. 170. ISBN 978-0-8138-0589-4.

[151] Webber D.; Kremer M. (2001). “Stimulating Industrial [166] Ryan, T.J.; Livingstone, P.G.; Ramsey, D.S.; de Lisle, R&D for Neglected Infectious Diseases: Economic Per- G.W.; Nugent, G.; Collins, D.M.; Buddle, B.M. (25 spectives” (PDF). Bulletin of the World Health Organiza- February 2006). “Advances in understanding disease epi- tion. 79 (8): 693–801. demiology and implications for control and eradication of tuberculosis in livestock: the experience from New [152] Barder O.; Kremer M.; Williams H. (2006). “Advance Zealand”. Veterinary Microbiology. 112 (2–4): 211–9. Market Commitments: A Policy to Stimulate Investment doi:10.1016/j.vetmic.2005.11.025. PMID 16330161. in Vaccines for Neglected Diseases”. The Economists’ Voice. 3 (3). doi:10.2202/1553-3832.1144. [167] White, P.C.; Böhm, M.; Marion, G.; Hutchings, M.R. (September 2008). “Control of bovine tuber- [153] Economic, Department of; Aﬀairs, Social (2009). culosis in British livestock: there is no 'silver bul- Achieving the global public health agenda: dialogues at the let'". Trends in Microbiology. 16 (9): 420–7. Economic and Social Council. New York: United Nations. doi:10.1016/j.tim.2008.06.005. PMID 18706814. p. 103. ISBN 978-92-1-104596-3. [168] Ward, A.I.; Judge, J.; Delahay, R.J. (1 January 2010). [154] Jong, [edited by] Jane N. Zuckerman, Elaine C. (2010). “Farm husbandry and badger behaviour: opportunities Travelers’ vaccines (2nd ed.). Shelton, CT: People’s Medi- to manage badger to cattle transmission of Mycobac- cal Publishing House. p. 319. ISBN 978-1-60795-045-5. terium bovis?". Preventive veterinary medicine. 93 (1): 4.14. EXTERNAL LINKS 35

2–10. doi:10.1016/j.prevetmed.2009.09.014. PMID 19846226.

[169] Holt, Nathalia (24 March 2015). “The Infected Elephant in the Room”. Slate. Retrieved 2016-04-05.

[170] Mikota, Susan K. “A Brief History of TB in Elephants” (PDF). APHIS. US Department of Agriculture. Retrieved 2016-04-05.

4.14 External links

Wikipedia’s health care articles can be viewed oﬄine with the Medical Wikipedia app.

• Tuberculosis at DMOZ • “Tuberculosis (TB)". Centers for Disease Control.

• “Tuberculosis (TB)". UK Health Protection Agency. Chapter 5

Measles

Warning: Page using Template:Infobox medical condi- Measles affects about 20 million people a year,[1] primar- tion with unknown parameter “Image” (this message is ily in the developing areas of Africa and Asia.[3] It causes shown only in preview). the most vaccine-preventable deaths of any disease.[9] Warning: Page using Template:Infobox medical condi- It resulted in about 73,000 deaths in 2014, down from tion with unknown parameter “Caption” (this message is 545,000 deaths in 1990.[5][10] In 1980, the disease was shown only in preview). estimated to have caused 2.6 million deaths per year.[3] Warning: Page using Template:Infobox medical condi- Most of those who are infected and who die are less tion with unknown parameter “Name” (this message is than five years old.[3] The risk of death among those in- shown only in preview). fected is usually 0.2%,[7] but may be up to 10% in those who have malnutrition.[3] It is not believed to affect other animals.[3] Before immunization in the United States, be- Measles is a highly contagious infection caused by the [7] measles virus.[1][6] Initial signs and symptoms typically tween three and four million cases occurred each year. As a result of widespread vaccination, the disease was include fever, often greater than 40 °C (104.0 °F), cough, [11] runny nose, and inflamed eyes.[1][2] Two or three days af- eliminated from the Americas by 2016. ter the start of symptoms, small white spots may form inside the mouth, known as Koplik’s spots. A red, flat rash which usually starts on the face and then spreads to the rest of the body typically begins three to five days after the start of symptoms.[2] Symptoms usually develop 10– 12 days after exposure to an infected person and last 7–10 days.[3][4] Complications occur in about 30% and may include diarrhea, blindness, inflammation of the brain, and pneumonia among others.[3][7] Rubella (German measles) and roseola are different diseases.[8] Measles is an airborne disease which spreads easily through the coughs and sneezes of those infected. It Video explanation may also be spread through contact with saliva or nasal secretions.[3] Nine out of ten people who are not immune and share living space with an infected person will catch it. People are infectious to others from four days before 5.1 Signs and symptoms to four days after the start of the rash.[7] People usually do not get the disease more than once.[3] Testing for the virus [7] The classic signs and symptoms of measles include four- in suspected cases is important for public health efforts. day fevers (the 4 D’s) and the three C’s — cough, coryza The measles vaccine is effective at preventing the disease. (head cold, fever, sneezing), and conjunctivitis (red eyes) Vaccination has resulted in a 75% decrease in deaths — along with fever and rashes.[12] Fever is common and from measles between 2000 and 2013 with about 85% typically lasts for about one week; the fever seen with of children globally being currently vaccinated. No spe- measles is often as high as 40 °C (104 °F).[13] Koplik’s cific treatment is available. Supportive care may improve spots seen inside the mouth are pathognomonic (diagnos- outcomes.[3] This may include giving oral rehydration so- tic) for measles, but are temporary and therefore rarely lution (slightly sweet and salty fluids), healthy food, and seen.[12] Recognizing these spots before a person reaches medications to control the fever.[3][4] Antibiotics may be their maximum infectiousness can help physicians reduce used if a secondary bacterial infection such as pneumonia the spread of the disease.[14] occurs. Vitamin A supplementation is also recommended [3] The characteristic measles rash is classically described as in the developing world. a generalized red maculopapular rash that begins several

36 5.2. CAUSE 37

5.1.1 Complications

Complications with measles are relatively common, ranging from mild complications such as diarrhea to serious complications such as pneumonia (either direct viral pneumonia or secondary bacterial pneumonia), bronchitis (either direct viral bronchitis or secondary bacterial bronchitis), otitis media,[16] acute brain inflammation[17] (and very rarely SSPE — subacute sclerosing panencephalitis),[18] and corneal ulceration (leading to corneal scarring).[19] Complications are usually more severe in adults who catch the virus.[20] The death rate in the 1920s was around 30% for measles pneumonia.[21] People that are Skin of a person after 3 days of measles infection at high risk for complications are: Infants and children aged <5 years, adults aged >20 years, pregnant women, and people with compromised immune systems, such as from leukemia and HIV infection.[22] Between 1987 and 2000, the case fatality rate across the United States was three measles-attributable deaths per 1000 cases, or 0.3%.[23] In underdeveloped nations with high rates of malnutrition and poor healthcare, fatality rates have been as high as 28%.[23] In immunocompromised persons (e.g., people with AIDS) the fatality rate is approximately 30%.[24] Risk factors for severe measles and its complications include malnutrition,[25] underlying immunodeficiency,[25] pregnancy,[25] and vitamin A deficiency.[25][26] Even in previously healthy children, measles can cause serious Koplik’s spots on the third pre-eruptive day illness requiring hospitalization.[27] One out of every 1,000 measles cases will develop acute encephalitis, which often results in permanent brain damage.[27] One days after the fever starts. It starts on the back of the or two out of every 1,000 children who become infected ears and, after a few hours, spreads to the head and neck with measles will die from respiratory and neurologic before spreading to cover most of the body, often caus- complications.[22] ing itching. The measles rash appears two to four days after the initial symptoms and lasts for up to eight days. The rash is said to “stain”, changing color from red to dark brown, before disappearing.[15] Overall, the disease 5.2 Cause from infection with the measles virus usually resolves after about three weeks.[13] Measles is caused by the measles virus, a single-stranded, negative-sense, enveloped RNA virus of the genus Morbillivirus within the family Paramyxoviridae.[28] The virus was first isolated in 1954 by Nobel Laureate John F. Enders and Thomas Peebles, who were careful to point out that the isolations were made from patients who had Koplik’s spots.[29] Humans are the only natural hosts of the virus, and no other animal reservoirs are known to exist. This highly contagious virus is spread by coughing and sneezing via close personal contact or direct contact with secretions. Risk factors for measles virus infection include immunodeficiency caused by HIV or AIDS,[30] immunosuppression following re- ceipt of an organ or a stem cell transplant,[31] alkylating agents, or corticosteroid therapy, regardless of immunization status;[25] travel to areas where measles is endemic or contact with travelers to endemic areas;[25] and the loss A child with measles of passive, inherited antibodies before the age of routine immunization.[32] 38 CHAPTER 5. MEASLES

<50% 50-79% 80-89% ≧90% no data

Rates of measles vaccination worldwide

six months or less.[32] Infants under one year of age whose maternal anti-measles antibodies have disappeared become susceptible to infection with the measles virus.[32] A second dose of the vaccine is usually given to children between the ages of four and five, to increase rates of immunity. Vaccination rates have been high enough to An electron micrograph of the measles virus. make measles relatively uncommon. Adverse reactions to vaccination are rare, with fever and pain at the injection site being the most common. Life-threatening adverse 5.3 Diagnosis reactions occur in less than one per million vaccinations (<0.0001%).[37] Clinical diagnosis of measles requires a history of fever In developing countries where measles is highly endemic, of at least three days, with at least one of the three C’s WHO doctors recommend two doses of vaccine be given (cough, coryza, conjunctivitis). Observation of Koplik’s at six and nine months of age. The vaccine should be spots is also diagnostic of measles.[14][33][34] given whether the child is HIV-infected or not.[38] The vaccine is less effective in HIV-infected infants than in the general population, but early treatment with antiretro- 5.3.1 Laboratory testing viral drugs can increase its effectiveness.[39] Measles vaccination programs are often used to deliver other child Alternatively, laboratory diagnosis of measles can be health interventions, as well, such as bed nets to pro- done with confirmation of positive measles IgM anti- tect against malaria, antiparasite medicine and vitamin A bodies or isolation of measles virus RNA from respi- supplements, and so contribute to the reduction of child ratory specimens.[35] For people unable to have their deaths from other causes.[40] blood drawn, saliva can be collected for salivary measles- specific IgA testing.[36] Positive contact with other patients known to have measles adds strong epidemiological evidence to the diagnosis. Any contact with an infected 5.5 Treatment person, including semen through sex, saliva, or mucus, can cause infection.[34] There is no specific treatment for measles. Most people with uncomplicated measles will recover with rest and supportive treatment. 5.4 Prevention Patients who become sicker may be developing medical complications. Some people will develop pneumonia Further information: Measles vaccine, MMR vaccine, as a consequence of infection with the measles virus. MMRV vaccine, and MMR vaccine controversy Other complications include ear infections, bronchitis (either viral bronchitis or secondary bacterial bronchi- In developed countries, children are immunized against [41] measles at 12 months, generally as part of a three-part tis), and brain inflammation. Brain inflammation from MMR vaccine (measles, mumps, and rubella). The vac- measles has a mortality rate of 15%. While there is no cination is generally not given before this age because specific treatment for brain inflammation from measles, such infants respond inadequately to the vaccine due to antibiotics are required for bacterial pneumonia, sinusitis, an immature immune system.[32] Anti-measles antibod- and bronchitis that can follow measles. ies are transferred from mothers who have been vacci- All other treatment addresses symptoms, with ibuprofen nated against measles or have been previously infected or paracetamol to reduce fever and pain and, if required, a with measles to their newborn children.[32] However, such fast-acting medication to dilate the airways for cough. As antibodies are transferred in low amounts and usually last for aspirin, some research has suggested a correlation be- 5.7. EPIDEMIOLOGY 39 tween children who take aspirin and the development of Reye syndrome.[42] Some research has shown aspirin may not be the only medication associated with Reye, and even antiemetics have been implicated.[43] The link between aspirin use in children and Reye syndrome development is weak at best, if not actually nonexistent.[44] Neverthe- less, most health authorities still caution against the use of aspirin for any fevers in children under 16.[45][46][47][48]

The use of vitamin A during treatment is recommended Disability-adjusted life year for measles per 100,000 inhabitants by the World Health Organization to decrease the risk in 2004. of blindness.[49] A systematic review of trials into its no data use found no significant reduction in overall mortality, ≤ 10 but it did reduce mortality in children aged under two 10–25 years.[50][51][52] 25–50 50–75 It is unclear if zinc supplementation in children with 75–100 [53] measles affects outcomes. 100–250 250–500 500–750 750–1000 5.6 Prognosis 1000–1500 1500–2000 The majority of people survive measles, though in ≥ 2000 some cases, complications may occur. Possible consequences of measles virus infection include bronchitis, sensorineural hearing loss,[28] and — in about 1 in 10,000 to 1 in 300,000 cases[54] — panencephalitis, which is usu- lation in a community depends on the generation of sus- ally fatal.[55] Acute measles encephalitis is another serious ceptible hosts by birth of children. In communities which risk of measles virus infection. It typically occurs two generate insufficient new hosts the disease will die out. days to one week after the breakout of the measles rash This concept was first recognized in measles by Bartlett in and begins with very high fever, severe headache, con- 1957, who referred to the minimum number supporting vulsions and altered mentation. A person with measles measles as the critical community size (CCS).[57] Anal- encephalitis may become comatose, and death or brain ysis of outbreaks in island communities suggested that injury may occur.[56] the CCS for measles is around 250,000.[58] To achieve herd immunity, more than 95% of the community must be vaccinated due to the ease with which measles is trans- 5.7 Epidemiology mitted from person to person.[13] The disease was eliminated from the Americas in 2016.[11] Main article: Epidemiology of measles In 2011, the WHO estimated that 158,000 deaths were Measles is extremely infectious and its continued circu- caused by measles. This is down from 630,000 deaths in 1990.[59] As of 2013, measles remains the leading cause of vaccine-preventable deaths in the world.[9] In developed countries, death occurs in 1 to 2 cases out of every 1,000 (0.1% - 0.2%).[60] In populations with high levels of malnutrition and a lack of adequate healthcare, mortality can be as high as 10%. In cases with complications, the rate may rise to 20–30%.[61] In 2012, the number of deaths due to measles was 78% lower than in 2000 due to increased rates of immunization among UN member states.[13] Deaths from measles per million persons in 2012 Even in countries where vaccination has been introduced, 0-0 1-8 rates may remain high. Measles is a leading cause of 9-26 vaccine-preventable childhood mortality. Worldwide, the 27-38 fatality rate has been significantly reduced by a vacci- 39-73 nation campaign led by partners in the Measles Initia- 74-850 tive: the American Red Cross, the United States’ Centers for Disease Control and Prevention (CDC), the United Nations Foundation, UNICEF and the WHO. Globally, 40 CHAPTER 5. MEASLES

measles fell 60% from an estimated 873,000 deaths in infrastructure.[79][80] 1999 to 345,000 in 2005.[68] Estimates for 2008 indicate deaths fell further to 164,000 globally, with 77% of the remaining measles deaths in 2008 occurring within the 5.8 History Southeast Asian region.[69] In 2013–14 there were almost 10,000 cases in 30 Euro- See also: Timeline of measles pean countries. Most cases occurred in unvaccinated in- Estimates based on modern molecular biology place the dividuals and over 90% of cases occurred in the five Euro- pean nations: Germany, Italy, the Netherlands, Romania, and the United Kingdom.[13] In the Vietnamese measles epidemic in spring of 2014, an estimated 8,500 measles cases were reported as of April 19, with 114 fatalities;[70] as of May 30, 21,639 suspected measles cases had been reported, with 142 measles-related fatalities.[71] Five out of six WHO regions have set goals to eliminate measles, and at the 63rd World Health Assembly in May 2010, delegates agreed on a global target of a 95% reduction in measles mortality by 2015 from the level seen in 2000, as well as to move towards eventual eradication. 16th-century Aztec drawing of someone with measles However, no specific global target date for eradication has emergence of measles as a human disease sometime af- yet been agreed to as of May 2010.[72][73] ter 500 AD[81] (the former speculation that the Antonine In 2014, a review by the Centers for Disease Control Plague of 165–180 AD was caused by measles is now reported a total of 911 cases of measles from 2001 to discounted). The first systematic description of measles, 2011, with an annual median number of 61 cases and con- and its distinction from smallpox and chickenpox, is cred- cluded that “the elimination of endemic measles, rubella, ited to the Persian physician Rhazes (860–932), who pub- and CRS has been sustained in the United States.”[74] lished The Book of Smallpox and Measles.[82] Given what However, in 2015, a measles outbreak occurred in the is now known about the evolution of measles, Rhazes’ ac- U.S. and spread rather farther than it should have, be- count is remarkably timely, as recent work that examined cause misguided ideas about anti-vaccination and vacci- the mutation rate of the virus indicates the measles virus nation delaying have decreased the community immunity emerged from rinderpest (cattle plague) as a zoonotic dis- afforded by proper public health programs. In 2015, a ease between 1100 and 1200 AD, a period that may have U.S. woman died of pneumonia, as a result of measles. been preceded by limited outbreaks involving a virus not She was the first fatality in the USA from measles since yet fully acclimated to humans.[81] This agrees with the 2003.[75] The woman had been vaccinated for measles observation that measles requires a susceptible population and was taking immune suppression drugs for another of >500,000 to sustain an epidemic, a situation that oc- condition. The drugs suppressed the measles immunity, curred in historic times following the growth of medieval the woman became infected with measles, did not de- European cities.[83] velop a rash, and contracted pneumonia which caused her Measles is an endemic disease, meaning it has been con- death.[76] tinually present in a community, and many people de- Between October 2014 and March 2015, a measles out- velop resistance. In populations not exposed to measles, break in the German capital of Berlin resulted in at least exposure to the new disease can be devastating. In 1529, 782 cases.[77] a measles outbreak in Cuba killed two-thirds of those na- From January 4 to April 2, 2015, there were 159 reported tives who had previously survived smallpox. Two years cases of measles to the CDC. Of those 159 cases, 111 later, measles was responsible for the deaths of half the population of Honduras, and it had ravaged Mexico, (70%) were determined to have come from an earlier ex- [85] posure in late December 2014. This outbreak was be- Central America, and the Inca civilization. lieved to have originated from the Disney theme parks in Between roughly 1855 and 2005, measles has been California. The initial exposure to the virus was never estimated to have killed about 200 million people found. There have been cases associated with this out- worldwide.[86] Measles killed 20 percent of Hawaii's break in seven states, Mexico, and Canada. Of the cases population in the 1850s.[87] In 1875, measles killed 48% were unvaccinated and 38% were unsure of their over 40,000 Fijians, approximately one-third of the vaccination status.[78] population.[88] In the 19th century, the disease killed 50% [89] In the Naga Self-Administered Zone in a remote north- of the Andamanese population. Seven to eight million children are thought to have died from measles each year ern region of Myanmar, at least 40 children died dur- [13] ing a measles outbreak in August 2016 that was probably before the vaccine was introduced. caused by lack of vaccination in an area of poor health In 1954, the virus causing the disease was isolated from 5.10. RESEARCH 41

erage that prompted many to comment on it, including clinical neurologist, well-known skeptic and science- based medicine advocate Dr. Steven Novella, who called Lanka “a crank”.[98]

5.10 Research

In May 2015, the journal Science, published a report in which researchers found that the measles infection can leave a population at increased risk for mortality from other diseases for 2 to 3 years.[99][100] A speciﬁc drug treatment for measles ERDRP-0519 has shown promising results in animal studies, but has not yet been tested in humans.[101][102][103]

5.11 References

[1] Caserta, MT, ed. (September 2013). “Measles”. Merck Manual Professional. Merck Sharp & Dohme Corp. Re- trieved 23 March 2014.

[2] “Measles (Rubeola) Signs and Symptoms”. cdc.gov. November 3, 2014. Retrieved 5 February 2015.

[3] “Measles Fact sheet N°286”. who.int. November 2014. Retrieved 4 February 2015. Maurice Hilleman's measles vaccine is estimated to prevent 1 million deaths per year.[84] [4] Conn’s Current Therapy 2015: Expert Consult - On- line. Elsevier Health Sciences. 2014. p. 153. ISBN 9780323319560. a 13-year-old boy from the United States, David Ed- monston, and adapted and propagated on chick embryo [5] GBD 2015 Mortality and Causes of Death, Collaborators. tissue culture.[90] To date, 21 strains of the measles (8 October 2016). “Global, regional, and national life ex- pectancy, all-cause mortality, and cause-specific mortality virus have been identified.[91] While at Merck, Maurice [92] for 249 causes of death, 1980-2015: a systematic analysis Hilleman developed the first successful vaccine. Li- for the Global Burden of Disease Study 2015.”. Lancet censed vaccines to prevent the disease became avail- (London, England). 388 (10053): 1459–1544. PMID [93] able in 1963. An improved measles vaccine became 27733281. available in 1968.[94] Measles as an endemic disease was eliminated from the United States in 2000, but continues [6] “Measles (Red Measles, Rubeola)". Dept of Health, to be reintroduced by international travelers. Saskatchewan. Retrieved 10 February 2015. [7] Atkinson, William (2011). Epidemiology and Prevention of Vaccine-Preventable Diseases (12 ed.). Public Health Foundation. pp. 301–323. ISBN 9780983263135. Re- 5.9 Society and culture trieved 5 February 2015.

German anti-vaccination campaigner and HIV/AIDS de- [8] Marx, John A. (2010). Rosen’s emergency medicine : concepts and clinical practice (7th ed.). Philadelphia: nialist[95] Stefan Lanka posed a challenge on his website Mosby/Elsevier. p. 1541. ISBN 9780323054720. in 2011, offering a sum of €100,000 for anyone who could scientifically prove that measles is caused by a virus [9] Kabra, SK; Lodhra, R (14 August 2013). “An- and determine the diameter of the virus.[96] He posits that tibiotics for preventing complications in children with the illness is psychosomatic and that the measles virus measles”. Cochrane Database of Systematic Reviews. does not exist. When provided with overwhelming sci- 8: CD001477. doi:10.1002/14651858.CD001477.pub4. entific evidence from various medical studies by Ger- PMID 23943263. man physician David Barden, Lanka did not accept the [10] GBD 2013 Mortality and Causes of Death, Collaborators findings, forcing Barden to appeal in court. The legal (17 December 2014). “Global, regional, and national age- case ended with the ruling that Lanka was to pay the sex specific all-cause and cause-specific mortality for 240 prize.[77][97] The case received wide international cov- causes of death, 1990-2013: a systematic analysis for the 42 CHAPTER 5. MEASLES

Global Burden of Disease Study 2013.”. Lancet. 385: with human immunodeﬁciency virus”. American Jour- 117–171. doi:10.1016/S0140-6736(14)61682-2. PMC nal of Diseases of Children (1960). 142 (12): 1271– 4340604 . PMID 25530442. 2. doi:10.1001/archpedi.1988.02150120025021. PMID 3195521. [11] “Region of the Americas is declared free of measles”. PAHO. 29 September 2016. Retrieved 30 September [25] Chen S.S.P. (October 3, 2011). Measles (Report). Med- 2016. scape.

[12] Biesbroeck L, Sidbury R (November 2013). “Viral exan- [26] National Institutes of Health Oﬃce of Dietary Supple- thems: an update”. Dermatologic therapy. 26 (6): 433–8. ments (2013). “Vitamin A”. U.S. Department of Health doi:10.1111/dth.12107. PMID 24552405. & Human Services. Retrieved 11 March 2015.

[13] Ludlow M, McQuaid S, Milner D, de Swart RL, Duprex [27] “Measles | For Healthcare Professionals | CDC”. www. WP (January 2015). “Pathological consequences of sys- cdc.gov. temic measles virus infection”. The Journal of pathology. 235 (2): 253–65. doi:10.1002/path.4457. PMID [28] Cohen BE, Durstenfeld A, Roehm PC (July 2014). 25294240. “Viral causes of hearing loss: a review for hearing health professionals”. Trends in Hearing. 18: [14] Baxby D (1997). “Classic Paper: Henry Koplik. 2331216514541361. doi:10.1177/2331216514541361. The diagnosis of the invasion of measles from a study PMC 4222184 . PMID 25080364. of the exanthema as it appears on the buccal membrane”. Reviews in Medical Virology. 7 (2): 71– [29] Enders JF, Peebles TC (1954). “Propagation in tis- 4. doi:10.1002/(SICI)1099-1654(199707)7:2<71::AID- sue culture of cytopathogenic agents from patients with RMV185>3.0.CO;2-S. PMID 10398471. measles”. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biol- [15] NHS UK: Symptoms of measles. Last reviewed: ogy and Medicine (New York, N.Y.). 86 (2): 277–86. 26/01/2010. doi:10.3181/00379727-86-21073. PMID 13177653.

[16] Gardiner, W. T. (2007). “Otitis Media in Measles”. The [30] Gowda VK, Sukanya V (2012). “Acquired Immun- Journal of Laryngology & Otology. 39 (11): 614–617. odeficiency Syndrome with Subacute Sclerosing Pa- doi:10.1017/S0022215100026712. nencephalitis”. Pediatric Neurology. 47 (5): 379– 381. doi:10.1016/j.pediatrneurol.2012.06.020. PMID [17] Fisher DL, Defres S, Solomon T (2014). “Measles- 23044024. induced encephalitis”. QJM. 108: 177–182. doi:10.1093/qjmed/hcu113. PMID 24865261. [31] Waggoner JJ, Soda EA, Deresinski S (October 2013). [18] Anlar B (2013). “Subacute sclerosing panencephalitis and “Rare and emerging viral infections in transplant recip- chronic viral encephalitis”. Handbook of Clinical Neurol- ients”. Clinical Infectious Diseases. 57 (8): 1182–8. ogy. 112: 1183–1189. doi:10.1016/B978-0-444-52910- doi:10.1093/cid/cit456. PMID 23839998. 7.00039-8. PMID 23622327. [32] Leuridan E, Sabbe M, Van Damme P (September 2012). [19] Semba RD, Bloem MW (March 2004). “Measles “Measles outbreak in Europe: susceptibility of infants too blindness”. Survey of Ophthalmology. 49 (2): 243– young to be immunized”. Vaccine. 30 (41): 5905–13. 55. doi:10.1016/j.survophthal.2003.12.005. PMID doi:10.1016/j.vaccine.2012.07.035. PMID 22841972. 14998696. [33] “Bug of the Month—Measles”. Banner Gateway Medical [20] Sabella C (2010). “Measles: Not just a childhood rash”. Center. April 2012. Retrieved May 3, 2013. Cleveland Clinic Journal of Medicine. 77 (3): 207–213. doi:10.3949/ccjm.77a.09123. PMID 20200172. [34] Total Health (May 5, 2010). “Actual Confirmed Measles Cases in UK”. totalhealth. Retrieved May 4, 2013. [21] Ellison, J.B (1931). “Pneumonia in Measles”. 1931 Archives of Disease in Childhood. 6 (31): 37–52. [35] Durrheim DN, Kelly H, Ferson MJ, Featherstone D (Au- doi:10.1136/adc.6.31.37. PMC 1975146 . PMID gust 2007). “Remaining measles challenges in Australia”. 21031836. The Medical journal of Australia. 187 (3): 181–4. PMID 17680748. [22] “Measles | For Healthcare Professionals | CDC”. www. cdc.gov. Retrieved 22 October 2016. [36] Friedman M, Hadari I, Goldstein V, Sarov I (1983). “Virus-specific secretory IgA antibodies as a means of [23] Perry RT, Halsey NA (May 1, 2004). “The Clinical Sig- rapid diagnosis of measles and mumps infection”. Israel nificance of Measles: A Review”. The Journal of Infec- Journal of Medical Sciences. 19 (10): 881–884. PMID tious Diseases. 189 (S1): S4–16. doi:10.1086/377712. 6662670. PMID 15106083. [37] Galindo BM, Concepción D, Galindo MA, Pérez A, Saiz [24] Sension MG, Quinn TC, Markowitz LE, Linnan MJ, J (2012). “Vaccine-related adverse events in Cuban chil- Jones TS, Francis HL, Nzilambi N, Duma MN, Ryder dren, 1999–2008”. MEDICC Review. 14 (1): 38–43. RW (1988). “Measles in hospitalized African children PMID 22334111. 5.11. REFERENCES 43

[38] Helfand RF, Witte D, Fowlkes A, Garcia P, Yang C, [48] Reye’s Syndrome at NINDS “Epidemiologic evidence in- Fudzulani R, Walls L, Bae S, Strebel P, Broadhead R, dicates that aspirin (salicylate) is the major preventable Bellini WJ, Cutts F (2008). “Evaluation of the immune risk factor for Reye’s syndrome. The mechanism by which response to a 2-dose measles vaccination schedule admin- aspirin and other salicylates trigger Reye’s syndrome is not istered at 6 and 9 months of age to HIV-infected and HIV- completely understood.” uninfected children in Malawi”. The Journal of Infec- tious Diseases. 198 (10): 1457–65. doi:10.1086/592756. [49] “Measles vaccines: WHO position paper.” (PDF). Weekly PMID 18828743. epidemiological record. 84 (35): 349–60. 28 August 2009. PMID 19714924. [39] Ołdakowska A, Marczyńska M (2008). “Measles vaccination in HIV-infected children”. Medycyna Wieku Roz- [50] Huiming Y, Chaomin W, Meng M (2005). Yang wojowego. 12 (2 Pt 2): 675–680. PMID 19418943. H, ed. “Vitamin A for treating measles in children”. The Cochrane Database of Systematic Reviews (4): [40] UNICEF (2007). “Global goal to reduce measles deaths CD001479. doi:10.1002/14651858.CD001479.pub3. in children surpassed”. Joint press release. Retrieved 11 PMID 16235283. March 2015. [51] D'Souza RM, D'Souza R (2002). “Vitamin A [41] “Complications of Measles”. Centers for Disease Control for treating measles in children”. The Cochrane and Prevention (CDC). Database of Systematic Reviews (1): CD001479. [42] Starko KM, Ray CG, Dominguez LB, Stromberg WL, doi:10.1002/14651858.CD001479. PMID 11869601. Woodall DF (6 Dec 1980). “Reye’s Syndrome and Sal- [52] D'Souza RM, D'Souza R (April 2002). “Vitamin A icylate Use”. Pediatrics. 66 (6): 859–64. PMID for preventing secondary infections in children with 7454476. Retrieved 2011-03-17. It is postulated that sali- measles—a systematic review”. Journal of Tropical Pedi- cylate [taken by school-age children], operating in a dose- atrics. 48 (2): 72–7. doi:10.1093/tropej/48.2.72. PMID dependent manner, possibly potentiated by fever, repre- 12022432. sents a primary causative agent of Reye’s syndrome. [53] Awotiwon, AA; Oduwole, O; Sinha, A; Okwundu, [43] Casteels-Van Daele M, Van Geet C, Wouters C, Egger- CI (20 March 2015). “Zinc supplementation for the mont E (April 2000). “Reye syndrome revisited: a de- treatment of measles in children.”. The Cochrane scriptive term covering a group of heterogeneous disor- database of systematic reviews. 3: CD011177. ders”. European Journal of Pediatrics. 159 (9): 641–8. doi:10.1002/14651858.CD011177.pub2. PMID doi:10.1007/PL00008399. PMID 11014461. Retrieved 25794053. 2011-03-17. Reye syndrome is a non-specific descriptive term covering a group of heterogeneous disorders. More- [54] Noyce RS, Richardson CD (September 2012). over, not only the use of acetylsalicylic acid but also of “Nectin 4 is the epithelial cell receptor for measles antiemetics is statistically significant in Reye syndrome virus”. Trends in Microbiology. 20 (9): 429–39. cases. Both facts weaken the validity of the epidemio- doi:10.1016/j.tim.2012.05.006. PMID 22721863. logical surveys suggesting a link with acetylsalicylic acid. [55] “NINDS Subacute Sclerosing Panencephalitis Informa- [44] Schrör K (2007). “Aspirin and Reye Syndrome: A Re- tion Page” view of the Evidence”. Paediatric Drugs. 9 (3): 195– 204. doi:10.2165/00148581-200709030-00008. PMID [56] 14-193b. at Merck Manual of Diagnosis and Therapy 17523700. Retrieved 2011-03-17. The suggestion of a Professional Edition defined cause-effect relationship between aspirin intake [57] Bartlett, M.S. (1957). “Measles periodicity and commu- and Reye syndrome in children is not supported by suf- nity size”. J. Roy. Stat. Soc. Ser. A (120): 48–70. ficient facts. Clearly, no drug treatment is without side effects. Thus, a balanced view of whether treatment with [58] Black FL (1966). “Measles endemicity in insular popula- a certain drug is justified in terms of the benefit/risk ratio tions; critical community size and its evolutionary impli- is always necessary. Aspirin is no exception. cations”. Journal of Theoretical Biology. 11 (2): 207–11. [45] Macdonald S (2002). “Aspirin use to be banned in un- doi:10.1016/0022-5193(66)90161-5. PMID 5965486. der 16 year olds”. BMJ (Clinical Research Ed.). 325 [59] Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, (7371): 988. doi:10.1136/bmj.325.7371.988/c. PMC Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, 1169585 . PMID 12411346. Professor Alasdair Breck- et al. (Dec 15, 2012). “Global and regional mortal- enridge, said, “There are plenty of analgesic products con- ity from 235 causes of death for 20 age groups in 1990 taining paracetamol and ibuprofen for this age group not and 2010: a systematic analysis for the Global Burden of associated with Reye’s syndrome. There is simply no need Disease Study 2010”. Lancet. 380 (9859): 2095–128. to expose those under 16 to the risk—however small.” doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.

[46] “Aspirin and Reye’s Syndrome”. MHRA. October 2003. [60] “Complications of measles”. CDC. November 3, 2014. Retrieved 2011-03-17. Retrieved November 7, 2014.

[47] “Surgeon General’s advisory on the use of salicylates [61] Measles, World Health Organization Fact sheet N°286. and Reye syndrome”. MMWR. Morbidity and Mortality Retrieved June 28, 2012. Updated February 2014 Weekly Report. 31 (22): 289–90. June 1982. PMID 6810083. [62] WHO: Global summary on measles, 2006 44 CHAPTER 5. MEASLES

[63] Measles Surveillance Data after WHO, last updated 2014- [82] Cohen SG (February 2008). “Measles and immunomod- 3-6 ulation”. The Journal of allergy and clinical immunology. 121 (2): 543–4. doi:10.1016/j.jaci.2007.12.1152. PMID [64] Measles reported cases by WHO in 2014 18269930.

[65] Số người chết và mắc bệnh theo quốc gia, last update [83] Black, Francis L. (July 1966). “Measles endemicity in in- 2014-4-7 by WHO sular populations: Critical community size and its evolutionary implication”. Journal of Theoretical Biology. [66] “Measles---United States, 2005”. Centers for Disease 11 (2): 207–211. doi:10.1016/0022-5193(66)90161-5. Control and Prevention. December 22, 2006. Retrieved ISSN 0022-5193. PMID 5965486. Retrieved 2014-10- 30 March 2015. 15. [67] Reported Measles Cases by WHO region 2014, 2015, as [84] "Maurice R. Hilleman Dies; Created Vaccines". The of 07 July 201, WHO Washington Post. April 13, 2005. [68] UNICEF Joint Press Release [85] Byrne, Joseph Patrick (2008). Encyclopedia of Pestilence, [69] WHO Weekly Epidemiology Record, 4th December 2009 Pandemics, and Plagues: A–M. ABC-CLIO. p. 413. WHO.int ISBN 0-313-34102-8.

[70] “Vietnam minister calls for calm in face of 8,500 measles [86] Torrey EF and Yolken RH. 2005. Their bugs are worse cases, 114 fatalities | Health | Thanh Nien Daily”. than their bite. Washington Post, April 3, p. B01. Thanhniennews.com. Retrieved 2014-04-19. [87] Migration and Disease. Digital History. [71] “Bộ Y tế: “VN đã phản ứng rất nhanh đối với dịch sởi"". [88] Fiji School of Medicine Archived from the original on 2014-05-31. [89] Measles hits rare Andaman tribe. BBC News. May 16, [72] “Sixty-third World Health Assembly Agenda provisional 2006. agenda item 11.15 Global eradication of measles” (PDF). Retrieved 2 June 2010. [90] “Live attenuated measles vaccine”. EPI Newsletter / C Ex- panded Program on Immunization in the Americas. 2 (1): [73] “Sixty-third World Health Assembly notes from day four”. 6. 1980. PMID 12314356. Retrieved 2 June 2010. [91] Rima BK, Earle JA, Yeo RP, Herlihy L, Baczko K, [74] Papania, Mark (Feb 2014). “Elimination of Endemic ter Meulen V, Carabaña J, Caballero M, Celma ML, Measles, Rubella, and Congenital Rubella Syndrome Fernandez-Muñoz R (1995). “Temporal and geographical From the Western Hemisphere The US Experience”. distribution of measles virus genotypes”. The Journal of JAMA Pediatrics. General Virology. 76 (5): 1173–80. doi:10.1099/0022- [75] “Measles kills ﬁrst patient in 12 years”. USA Today. 2 1317-76-5-1173. PMID 7730801. July 2015. Retrieved 2 July 2015. [92] Oﬃt PA (2007). Vaccinated: One Man’s Quest to Defeat [76] “First Measles Death in US Since 2003 Highlights the the World’s Deadliest Diseases. Washington, DC: Smith- Unknown Vulnerables – Phenomena: Germination”. Re- sonian. ISBN 0-06-122796-X. trieved 2015-07-03. [93] "Measles Prevention: Recommendations of the Immu- [77] Elizabeth Whitman (2015-03-13). “Who Is Stefan nization Practices Advisory Committee (ACIP)". Centers Lanka? Court Orders German Measles Denier To Pay for Disease Control and Prevention (CDC). 100,000 Euros”. International Business Times. Retrieved [94] Measles: Questions and Answers, Immunization Action 2015-03-31. Coalition. [78] Clemmons, Nakia. “Measles - United States, January 4 - [95] Stefan Lanka (April 1995). “HIV; Reality or artefact?". April 2, 2015”. cdc.gov. Virusmyth.com. Retrieved 2015-03-31. [79] “WHO doctors in Myanmar’s Naga areas identify 'mystery [96] “Das Masern-Virus 100.000 € Belohnung! WANTeD disease' – Eastern Mirror”. www.easternmirrornagaland. Der Durchmesser” (PDF) (in German). 2011-11-24. Re- com. Retrieved 8 August 2016. trieved 2015-03-31. [80] “Myanmar (02): (SA) fatal, measles conf”. www. [97] “Germany court orders measles sceptic to pay 100,000 eu- promedmail.org (Archive Number: 20160806.4398118). ros”. BBC News Online. 2015-03-12. Retrieved 2015- International Society for Infectious Diseases. Retrieved 8 03-31. August 2016. [98] Steven Novella (2015-03-13). “Yes, Dr. Lanka, Measles [81] Furuse, Yuki; Akira Suzuki; Hitoshi Oshitani (2010-03- is Real”. NeuroLogica Blog. Retrieved 2015-03-31. 04). “Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries”. Virol- [99] Bakalar, Nicholas. “Measles May Increase Susceptibility ogy Journal. 7: 52. doi:10.1186/1743-422X-7-52. ISSN to Other Infections”. The New York Times. The New York 1743-422X. PMC 2838858 . PMID 20202190. Times Company. Retrieved 7 June 2015. 5.12. EXTERNAL LINKS 45

[100] Mina; et al. (8 May 2015). “Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality”. Science. 348 (6235): 694–699. doi:10.1126/science.aaa3662. Retrieved 7 June 2015.

[101] White LK, Yoon JJ, Lee JK, Sun A, Du Y, Fu H, Sny- der JP, Plemper RK (2007). “Nonnucleoside Inhibitor of Measles Virus RNA-Dependent RNA Polymerase Com- plex Activity”. Antimicrobial Agents and Chemotherapy. 51 (7): 2293–303. doi:10.1128/AAC.00289-07. PMC 1913224 . PMID 17470652.

[102] Krumm SA, Yan D, Hovingh ES, Evers TJ, Enkirch T, Reddy GP, Sun A, Saindane MT, Arrendale RF, Painter G, Liotta DC, Natchus MG, von Messling V, Plemper RK (2014). “An Orally Available, Small- Molecule Polymerase Inhibitor Shows Eﬃcacy Against a Lethal Morbillivirus Infection in a Large Animal Model”. Science Translational Medicine. 6 (232): 232ra52. doi:10.1126/scitranslmed.3008517. PMID 24739760.

[103] “The measles virus is highly infectious, but rarely deadly”. NewScientist.com. Retrieved 5 February 2017.

5.12 External links

• Initiative for Vaccine Research (IVR): Measles, World Health Organization (WHO) • Measles FAQ from Centers for Disease Control and Prevention in the United States • Case of an adult male with measles (facial photo)

• Pictures of measles

• Virus Pathogen Database and Analysis Resource (ViPR): Paramyxoviridae Chapter 6

Parotitis

Parotitis is an inflammation of one or both parotid pears in people aged 40–60 years, but it may affect small glands, the major salivary glands located on either side children. In Sjögren syndrome, the prevalence of paroti- of the face, in humans. The parotid gland is the salivary tis in women versus men is approximately 9:1. The in- gland most commonly affected by inflammation. volved parotid gland is enlarged and tender at times. The cause is unknown. The syndrome is often characterized by excessive dryness in the eyes, mouth, nose, vagina, and 6.1 Causes skin.[2] Lymphoepithelial lesion of Godwin: Most frequently as- 6.1.1 Dehydration sociated with a circumscribed tumor with the histologic features of Sjögren syndrome. This designation has also fallen out of favour. Dehydration: This is a common, non-infectious cause of parotitis. It may occur in elderly or after surgery. [1] 6.1.4 Blockage

6.1.2 Infectious parotitis Blockage of the main parotid duct, or one of its branches, is often a primary cause of acute parotitis, with further Acute bacterial parotitis: is most often caused by a bacte- inflammation secondary to bacterial superinfection. The rial infection of Staphylococcus aureus but may be caused [2] blockage may be from a salivary stone, a mucous plug, or, by any commensal bacteria. more rarely, by a tumor, usually benign. Salivary stones Parotitis as Extrapulmonary Tuberculosis: The mycobac- (also called sialolithiasis, or salivary duct calculus) are terium that cause tuberculosis can also cause parotid in- mainly made of calcium, but do not indicate any kind of fection. Those infected tend to have enlarged, nontender, calcium disorder.[3] Stones may be diagnosed via X-ray but moderately painful glands. The diagnosis is made by (with a success rate of about 80%[3]), a computed tomog- typical chest radiograph findings, cultures, or histologic raphy (CT) scan or Medical ultrasonography. Stones may diagnosis after the gland has been removed. When di- be removed by manipulation in the doctor’s office, or, in agnosed and treated with antitubercular medications, the the worst cases, by surgery. Lithotripsy, also known as gland may return to normal in 1–3 months.[2] “shock wave” treatment, is best known for its use break- ing up kidney stones. Lithotripsy can now be used on Acute viral parotitis (mumps): The most common viral salivary stones as well. Ultrasound waves break up the cause of parotitis is mumps. Routine vaccinations have stones, and the fragments flush out of the salivary duct.[3] dropped the incidence of mumps to a very low level. Mumps resolves on its own in about ten days. HIV parotitis: Generalized lymphadenopathy has long 6.1.5 Diseases of uncertain cause been associated with HIV, but the localized enlargement of the parotid gland is less well known. Chronic nonspecific parotitis: This term is generally used for patients in whom no definite etiology is found. Episodes may last for several days, paralleling the time 6.1.3 Autoimmune causes course of a bacterial or viral illness. Others may experience episodes that last only a few hours from onset to These are also collectively known as chronic punctate resolution. Some episodes may last for several weeks. parotitis or chronic autoimmune parotitis. Quiescent periods between episodes last for hours, days, [2] Sjögren’s syndrome: Chronic inflammation of the sali- or even years. vary glands may also be an autoimmune disease known Recurrent parotitis of childhood: An uncommon syn- as Sjögren’s syndrome. The disease most commonly ap- drome in which recurring episodes clinically resembling

46 6.2. NOTES 47 mumps. Generally, episodes begin by age 5 years, and 6.2 Notes virtually all patients become asymptomatic by age 10– 15 years. The duration of attacks averages 3–7 days but [1] “UpToDate on parotitis”. UpToDate. UpToDate. Re- may last 2–3 weeks in some individuals. The spectrum trieved 19 February 2017. varies from mild and infrequent attacks to episodes so frequent that they prevent regular school attendance. Lo- [2] Templer JW , MD, Professor of Otolaryngology, Univer- sity of Missouri Medical Center at Columbia. Parotitis: cal heat applied to the gland, massaging the gland from Overview, Accessed 03/04/2009 back to front, and taking penicillin usually cure individual episodes. Treatment of individual infections may prevent [3] Salivary Gland Stones (Salivary Calculi) Accessed March injury to the gland parenchyma. Severe disease may be 20, 2008. treated by parotidectomy.[2] [4] John H. Stone; Arezou Khosroshahi; Vikram Deshpande; Sialadenosis (sialosis): In this disorder, both parotid John K. C. Chan; J. Godfrey Heathcote; Rob Aalberse; glands may be diffusely enlarged with only modest symp- Atsushi Azumi; Donald B. Bloch; William R. Brugge; toms. Patients are aged 20–60 years at onset, and the Mollie N. Carruthers; Wah Cheuk; Lynn Cornell; Car- sexes are equally involved. The glands are soft and non- los Fernandez-Del Castillo; Judith A. Ferry; David For- tender. Approximately half of the patients have en- cione; Günter Klöppe; Daniel L. Hamilos; Terumi Kami- docrine disorders such as diabetes, nutritional disorders sawa; Satomi Kasashima; Shigeyuki Kawa; Mitsuhiro Kawano; Yasufumi Masaki; Kenji Notohara; Kazuichi such as pellagra or kwashiorkor, or have taken drugs such Okazaki; Ji Kon Ryu; Takako Saeki; Dushyant Sa- as guanethidine, thioridazine, or isoprenaline. hani; Yasuharu Sato; Thomas Smyrk; James R. Stone; Sarcoidosis: The lungs, skin, and lymph nodes are most Masayuki Takahira; Hisanori Umehara; George Web- often affected, but the salivary glands are involved in ap- ster; Motohisa Yamamoto; Eunhee Yi; Tadashi Yoshino; proximately 10% of cases. Bilateral firm, smooth, and Giuseppe Zamboni; Yoh Zen; Suresh Chari (October non-tender parotid enlargement is classic. Xerostomia 2012). “Recommendations for the nomenclature of IgG4- related disease and its individual organ system manifes- occasionally occurs. The Heerfordt-Waldenstrom syn- tations”. Arthritis & Rheumatism. 64 (10): 3061–3067. drome consists of sarcoidosis with parotid enlargement, doi:10.1002/art.34593. PMID 22736240. fever, anterior uveitis, and facial nerve palsy.[2] IgG4-related sialadenitis: This term refers to IgG4- related disease (IgG4-RD) involving any of the major 6.3 References salivary glands, i.e. parotid or submandibular glands. This is often symmetrical and is usually associated with • Brook I. Acute bacterial suppurative parotitis: mi- manifestations of IgG4-RD elsewhere in the body. IgG4- crobiology and management. [Journal Article] Jour- related sialadenitis is particularly associated with involve- nal of Craniofacial Surgery. 14(1):37-40, 2003. ment of one or both of the lacrimal glands (referred to as IgG4-related dacryo-sialadenitis). Mikulicz's dis- • Mandel L. Surattanont F. Bilateral parotid swelling: ease, now considered to be a subtype of IgG4-related a review. [Review] [160 refs] [Journal Article. disease,[4] was a term used when (i) any two of the Review] Oral Surgery Oral Medicine Oral Pathol- parotid, submandibular and lacrimal glands were persis- ogy Oral Radiology & Endodontics. 93(3):221-37, tently and symmetrically enlarged and (ii) other diseases 2002. that may mimic this presentation were excluded. Pneumoparotitis: Air within the ducts of the parotid gland with or without inflammation. The duct orifice normally 6.4 External links functions as a valve to prevent air from entering the gland from a pressurized oral cavity. Rarely, an incompetent • eMedicine valve allows insufflation of air into the duct system. Pneu- moparotitis most commonly occurs in wind instrument players, glass blowers, and scuba divers.[2] Several lymph nodes reside within the parotid gland as a superficial and deep group of nodes. These nodes may be involved with any process that affects lymph nodes, including bacterial, fungal, viral, and neoplastic processes. Rarely, drugs such as iodides, phenylbutazone, thiouracil, isoproterenol, heavy metals, sulfisoxazole, and phenoth- iazines cause parotid swelling. Chapter 7

Inﬂuenza

Not to be confused with Haemophilus influenzae. hibitor oseltamivir, among others, have been used to treat influenza.[1] Their benefits in those who are otherwise healthy do not appear to be greater than their risks.[7] “Flu” and “Grippe” redirect here. For other uses, see Flu (disambiguation) and Grippe (disambiguation). No benefit has been found in those with other health problems.[7][8]

Influenza, commonly known as “the flu", is an infectious Influenza spreads around the world in a yearly outbreak, [1] resulting in about three to five million cases of severe disease caused by an influenza virus. Symptoms can [1] be mild to severe.[2] The most common symptoms in- illness and about 250,000 to 500,000 deaths. In the clude: a high fever, runny nose, sore throat, muscle pains, Northern and Southern parts of the world outbreaks occur mainly in winter while in areas around the equator headache, coughing, and feeling tired. These symptoms [1] typically begin two days after exposure to the virus and outbreaks may occur at any time of the year. Death occurs mostly in the young, the old and those with other most last less than a week. The cough, however, may [1] [1] health problems. Larger outbreaks known as pandemics last for more than two weeks. In children, there may be [4] nausea and vomiting, but these are not common in adults. are less frequent. In the 20th century three influenza Nausea and vomiting occur more commonly in the unre- pandemics occurred: Spanish influenza in 1918, Asian influenza in 1958, and Hong Kong influenza in 1968, lated infection gastroenteritis, which is sometimes inac- [9] curately referred to as “stomach flu” or “24-hour flu”.[3] each resulting in more than a million deaths. The World Health Organization declared an outbreak of a new type Complications of influenza may include viral pneumo- [10] nia, secondary bacterial pneumonia, sinus infections, and of influenza A/H1N1 to be a pandemic in June 2009. Influenza may also affect other animals, including pigs, worsening of previous health problems such as asthma or [11] heart failure.[2][4] horses and birds. Three types of influenza viruses affect people, called Type A, Type B, and Type C.[4] Usually, the virus is spread through the air from coughs or sneezes.[1] This is 7.1 Signs and symptoms believed to occur mostly over relatively short distances.[5] It can also be spread by touching surfaces contaminated by the virus and then touching the mouth or eyes.[2][5] A Symptoms of person may be infectious to others both before and dur- Influenza ing the time they are showing symptoms.[2] The infection may be confirmed by testing the throat, sputum, or nose Central Nasopharynx for the virus. A number of rapid tests are available; how- - Headache - Runny or stuffy ever, people may still have the infection if the results are Systemic nose negative. A type of polymerase chain reaction that de- - Fever - Sore throat tects the virus’s RNA is more accurate.[4] (usually high) - Aches Frequent hand washing reduces the risk of infection because the virus is inactivated by soap.[6] Wearing a Muscular Respiratory [6] - (Extreme) - Coughing surgical mask is also useful. Yearly vaccinations against tiredness influenza are recommended by the World Health Organi- zation for those at high risk. The vaccine is usually effec- Gastric [1] Joints tive against three or four types of influenza. It is usu- - Vomiting ally well tolerated. A vaccine made for one year may not - Aches be useful in the following year, since the virus evolves rapidly. Antiviral drugs such as the neuraminidase in- Symptoms of influenza,[13] with fever and cough the most common symptoms.[12]

48 7.2. VIROLOGY 49

Approximately 33% of people with influenza are absence of a local outbreak, treatment may be justified asymptomatic.[14] in the elderly during the influenza season as long as the [25] Symptoms of influenza can start quite suddenly one to prevalence is over 15%. two days after infection. Usually the first symptoms are The available laboratory tests for influenza continue to chills or a chilly sensation, but fever is also common early improve. The United States Centers for Disease Con- in the infection, with body temperatures ranging from 38 trol and Prevention (CDC) maintains an up-to-date sum- to 39 °C (approximately 100 to 103 °F).[15] Many people mary of available laboratory tests.[26] According to the are so ill that they are confined to bed for several days, CDC, rapid diagnostic tests have a sensitivity of 50– with aches and pains throughout their bodies, which are 75% and specificity of 90–95% when compared with worse in their backs and legs.[16] Symptoms of influenza viral culture.[27] These tests may be especially useful dur- may include: ing the influenza season (prevalence=25%) but in the absence of a local outbreak, or peri-influenza season [25] • Fever and extreme coldness (chills shivering, shak- (prevalence=10% ). ing (rigor)) Occasionally, influenza can cause severe illness including primary viral pneumonia or secondary bacte- • Cough rial pneumonia.[28][29] The obvious symptom is trouble • Nasal congestion breathing. In addition, if a child (or presumably an adult) seems to be getting better and then relapses with a high • Vomiting fever, that is a danger sign since this relapse can be bacterial pneumonia.[30] • Runny nose

• Sneezing 7.2 Virology • Body aches, especially joints and throat • Fatigue 7.2.1 Types of virus • Headache

• Irritated, watering eyes

• Reddened eyes, skin (especially face), mouth, throat and nose

• Petechial rash[17]

• In children, gastrointestinal symptoms such as diarrhea and abdominal pain,[18][19] (may be severe in children with inﬂuenza B)[20]

It can be difficult to distinguish between the common cold and influenza in the early stages of these infections.[21] Influenza is a mixture of symptoms of common cold and pneumonia, body ache, headache, and fatigue. Diarrhea Structure of the influenza virion. The hemagglutinin (HA) and is not normally a symptom of influenza in adults,[12] al- neuraminidase (NA) proteins are shown on the surface of the though it has been seen in some human cases of the H5N1 particle. The viral RNAs that make up the genome are shown as red coils inside the particle and bound to ribonuclearproteins “bird flu”[22] and can be a symptom in children.[18] The (RNP). symptoms most reliably seen in influenza are shown in the [12] adjacent table. In virus classification influenza viruses are RNA viruses Since antiviral drugs are effective in treating influenza that make up three of the five genera of the family if given early (see treatment section, below), it can be Orthomyxoviridae:[31] important to identify cases early. Of the symptoms listed above, the combinations of fever with cough, sore • Influenzavirus A throat and/or nasal congestion can improve diagnostic • Influenzavirus B accuracy.[23] Two decision analysis studies[24][25] suggest that during local outbreaks of influenza, the prevalence • Influenzavirus C will be over 70%,[25] and thus patients with any of these combinations of symptoms may be treated with These viruses are only distantly related to the human neuraminidase inhibitors without testing. Even in the parainfluenza viruses, which are RNA viruses belonging 50 CHAPTER 7. INFLUENZA to the paramyxovirus family that are a common cause of respiratory infections in children such as croup,[32] but can also cause a disease similar to influenza in adults.[33] A fourth family of influenza viruses has been proposed Type of [34][35][36][37][38][39][40] nuclear - influenza D. The type species for material this family is Bovine Influenza D virus which was first isolated in 2012. Hemagglutinin Neuraminidase A/Fujian/411/2002 (H3N2) Influenzavirus A Virus Geographic Strain Year of Virus type origin number isolation subtype This genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety Influenza virus nomenclature (for a Fujian flu virus) of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza Influenzavirus C pandemics.[41] The type A viruses are the most virulent human pathogens among the three influenza types and This genus has one species, influenza C virus, which in- cause the severest disease. The influenza A virus can be fects humans, dogs and pigs, sometimes causing both subdivided into different serotypes based on the antibody severe illness and local epidemics.[49][50] However, in- response to these viruses.[42] The serotypes that have been fluenza C is less common than the other types and usually confirmed in humans, ordered by the number of known only causes mild disease in children.[51][52] human pandemic deaths, are:

• H1N1, which caused Spanish Flu in 1918, and 7.2.2 Structure, properties, and subtype Swine Flu in 2009 nomenclature • H2N2, which caused Asian Flu in 1957 Influenzaviruses A, B and C are very similar in overall • H3N2, which caused Hong Kong Flu in 1968 structure.[53] The virus particle is 80–120 nanometers in • H5N1, which caused Bird Flu in 2004 diameter and usually roughly spherical, although filamentous forms can occur.[54][55] These filamentous forms are [43] • H7N7, which has unusual zoonotic potential more common in influenza C, which can form cordlike • H1N2, endemic in humans, pigs and birds structures up to 500 micrometers long on the surfaces of infected cells.[56] However, despite these varied shapes, • H9N2 the viral particles of all influenza viruses are similar in [56] • H7N2 composition. These are made of a viral envelope containing two main types of glycoproteins, wrapped around • H7N3 a central core. The central core contains the viral RNA • H10N7 genome and other viral proteins that package and protect this RNA. RNA tends to be single stranded but in special • H7N9 cases it is double.[55] Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA, Influenzavirus B each piece of RNA containing either one or two genes, [56] This genus has one species, influenza B virus. Influenza which code for a gene product (protein). For exam- B almost exclusively infects humans[42] and is less comple, the influenza A genome contains 11 genes on eight mon than influenza A. The only other animals known to pieces of RNA, encoding for 11 proteins: hemagglutinin be susceptible to influenza B infection are the seal[44] and (HA), neuraminidase (NA), nucleoprotein (NP), M1, [45] M2, NS1, NS2 (NEP: nuclear export protein), PA, PB1 the ferret. This type of influenza mutates at a rate 2–3 [57] times slower than type A[46] and consequently is less ge- (polymerase basic 1), PB1-F2 and PB2. netically diverse, with only one influenza B serotype.[42] Hemagglutinin (HA) and neuraminidase (NA) are the As a result of this lack of antigenic diversity, a degree of two large glycoproteins on the outside of the viral par- immunity to influenza B is usually acquired at an early ticles. HA is a lectin that mediates binding of the virus age. However, influenza B mutates enough that lasting to target cells and entry of the viral genome into the tar- immunity is not possible.[47] This reduced rate of anti- get cell, while NA is involved in the release of progeny genic change, combined with its limited host range (in- virus from infected cells, by cleaving sugars that bind the hibiting cross species antigenic shift), ensures that pan- mature viral particles.[58] Thus, these proteins are targets demics of influenza B do not occur.[48] for antiviral drugs.[59] Furthermore, they are antigens to 7.3. MECHANISM 51

which antibodies can be raised. Influenza A viruses are by amantadine drugs, preventing infection.[67] classified into subtypes based on antibody responses to These core proteins and vRNA form a complex that HA and NA. These different types of HA and NA form is transported into the cell nucleus, where the RNA- the basis of the H and N distinctions in, for example, [60] dependent RNA polymerase begins transcribing comple- H5N1. There are 16 H and 9 N subtypes known, but mentary positive-sense vRNA (Steps 3a and b).[68] The only H 1, 2 and 3, and N 1 and 2 are commonly found in [61] vRNA either is exported into the cytoplasm and trans- humans. lated (step 4) or remains in the nucleus. Newly synthesized viral proteins are either secreted through the 7.2.3 Replication Golgi apparatus onto the cell surface (in the case of neuraminidase and hemagglutinin, step 5b) or transported back into the nucleus to bind vRNA and form new viral genome particles (step 5a). Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host- cell mRNAs.[69] Negative-sense vRNAs that form the genomes of future viruses, RNA-dependent RNA polymerase, and other viral proteins are assembled into a virion. Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion (step 6). The mature virus buds off from the cell in a sphere of host phospholipid membrane, acquiring hemagglutinin and neuraminidase with this membrane coat (step 7).[70] As before, the viruses adhere to the cell through hemagglutinin; the mature viruses detach once their neuraminidase has cleaved sialic acid residues from the host cell.[63] Af- Host cell invasion and replication by the influenza virus. The ter the release of new influenza viruses, the host cell dies. steps in this process are discussed in the text. Because of the absence of RNA proofreading enzymes, Viruses can replicate only in living cells.[62] Influenza in- the RNA-dependent RNA polymerase that copies the vi- fection and replication is a multi-step process: First, the ral genome makes an error roughly every 10 thousand virus has to bind to and enter the cell, then deliver its nucleotides, which is the approximate length of the in- genome to a site where it can produce new copies of viral fluenza vRNA. Hence, the majority of newly manufac- proteins and RNA, assemble these components into new tured influenza viruses are mutants; this causes antigenic viral particles, and, last, exit the host cell.[56] drift, which is a slow change in the antigens on the viral surface over time.[71] The separation of the genome Influenza viruses bind through hemagglutinin onto sialic into eight separate segments of vRNA allows mixing or acid sugars on the surfaces of epithelial cells, typically in reassortment of vRNAs if more than one type of in- the nose, throat, and lungs of mammals, and intestines of fluenza virus infects a single cell. The resulting rapid birds (Stage 1 in infection figure).[63] After the hemagglu- change in viral genetics produces antigenic shifts, which tinin is cleaved by a protease, the cell imports the virus are sudden changes from one antigen to another. These by endocytosis.[64] sudden large changes allow the virus to infect new host The intracellular details are still being elucidated. It is species and quickly overcome protective immunity.[60] known that virions converge to the microtubule organiz- This is important in the emergence of pandemics, as dis- ing center, interact with acidic endosomes and finally en- cussed below in the section on Epidemiology. ter the target endosomes for genome release.[65] Once inside the cell, the acidic conditions in the endosome cause two events to happen: First, part of 7.3 Mechanism the hemagglutinin protein fuses the viral envelope with the vacuole’s membrane, then the M2 ion channel allows protons to move through the viral envelope and acidify 7.3.1 Transmission the core of the virus, which causes the core to disassemble and release the viral RNA and core proteins.[56] The viral When an infected person sneezes or coughs more than RNA (vRNA) molecules, accessory proteins and RNA- half a million virus particles can be spread to those close dependent RNA polymerase are then released into the by.[72] In otherwise healthy adults, influenza virus shed- cytoplasm (Stage 2).[66] The M2 ion channel is blocked ding (the time during which a person might be infectious 52 CHAPTER 7. INFLUENZA

to another person) increases sharply one-half to one day after infection, peaks on day 2 and persists for an average total duration of 5 days—but can persist as long as 9 days.[73] In those who develop symptoms from experimental infection (only 67% of healthy experimentally infected individuals), symptoms and viral shedding show a similar pattern, but with viral shedding preceding illness by one day.[73] Children are much more infectious than adults and shed virus from just before they develop symptoms until two weeks after infection.[74] In immunocompromised people, viral shedding can continue for longer than two weeks.[75] Influenza can be spread in three main ways:[76][77] by direct transmission (when an infected person sneezes mucus The different sites of infection (shown in red) of seasonal H1N1 directly into the eyes, nose or mouth of another person); versus avian H5N1. This influences their lethality and ability to the airborne route (when someone inhales the aerosols spread. produced by an infected person coughing, sneezing or spitting) and through hand-to-eye, hand-to-nose, or hand- to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a handshake. For instance, part of the process that allows influenza The relative importance of these three modes of transmis- viruses to invade cells is the cleavage of the viral sion is unclear, and they may all contribute to the spread hemagglutinin protein by any one of several human [5] of the virus. In the airborne route, the droplets that are proteases.[64] In mild and avirulent viruses, the structure small enough for people to inhale are 0.5 to 5 µm in di- of the hemagglutinin means that it can only be cleaved by ameter and inhaling just one droplet might be enough to proteases found in the throat and lungs, so these viruses [76] cause an infection. Although a single sneeze releases cannot infect other tissues. However, in highly virulent [78] up to 40,000 droplets, most of these droplets are quite strains, such as H5N1, the hemagglutinin can be cleaved [76] large and will quickly settle out of the air. How long by a wide variety of proteases, allowing the virus to spread influenza survives in airborne droplets seems to be influ- throughout the body.[83] enced by the levels of humidity and UV radiation, with low humidity and a lack of sunlight in winter aiding its The viral hemagglutinin protein is responsible for deter- survival.[76] mining both which species a strain can infect and where in the human respiratory tract a strain of influenza will As the influenza virus can persist outside of the body, it bind.[84] Strains that are easily transmitted between peo- can also be transmitted by contaminated surfaces such as ple have hemagglutinin proteins that bind to receptors in [79] banknotes, doorknobs, light switches and other house- the upper part of the respiratory tract, such as in the nose, [16] hold items. The length of time the virus will persist throat and mouth. In contrast, the highly lethal H5N1 on a surface varies, with the virus surviving for one to strain binds to receptors that are mostly found deep in the two days on hard, non-porous surfaces such as plastic or lungs.[85] This difference in the site of infection may be metal, for about fifteen minutes from dry paper tissues, part of the reason why the H5N1 strain causes severe vi- [80] and only five minutes on skin. However, if the virus is ral pneumonia in the lungs, but is not easily transmitted present in mucus, this can protect it for longer periods (up by people coughing and sneezing.[86][87] to 17 days on banknotes).[76][79] Avian influenza viruses can survive indefinitely when frozen.[81] They are inacti- Common symptoms of the flu such as fever, headaches, vated by heating to 56 °C (133 °F) for a minimum of 60 and fatigue are the result of the huge amounts of proin- minutes, as well as by acids (at pH <2).[81] flammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza- infected cells.[21][88] In contrast to the rhinovirus that causes the common cold, influenza does cause tissue dam- 7.3.2 Pathophysiology age, so symptoms are not entirely due to the inflammatory response.[89] This massive immune response might pro- The mechanisms by which influenza infection causes duce a life-threatening cytokine storm. This effect has symptoms in humans have been studied intensively. One been proposed to be the cause of the unusual lethal- of the mechanisms is believed to be the inhibition of ity of both the H5N1 avian influenza,[90] and the 1918 adrenocorticotropic hormone (ACTH) resulting in low- pandemic strain.[91][92] However, another possibility is ered cortisol levels.[82] Knowing which genes are carried that these large amounts of cytokines are just a result of by a particular strain can help predict how well it will in- the massive levels of viral replication produced by these fect humans and how severe this infection will be (that is, strains, and the immune response does not itself con- predict the strain’s pathophysiology).[50][83] tribute to the disease.[93] 7.4. PREVENTION 53

7.4 Prevention vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective.[108] 7.4.1 Vaccination Vaccines can cause the immune system to react as if the body were actually being infected, and general infection Main article: Influenza vaccine symptoms (many cold and flu symptoms are just general The influenza vaccine is recommended by the World infection symptoms) can appear, though these symptoms are usually not as severe or long-lasting as influenza. The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.[109] The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings.[110] It has generally been found to be a cost-effective intervention, especially in children[111] and the elderly,[112] however the results of economic evaluations of influenza vaccination have often been found to be dependent on key assumptions.[113][114]

Giving an influenza vaccination 7.4.2 Infection control Health Organization and United States Centers for Dis- ease Control and Prevention for high-risk groups, such as Further information: Influenza prevention children, the elderly, health care workers, and people who have chronic illnesses such as asthma, diabetes, heart disease, or are immuno-compromised among others.[94][95] Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits In healthy adults it is modestly effective in decreasing the [115] amount of influenza-like symptoms in a population.[96] such as: not touching your eyes, nose or mouth; frequent hand washing (with soap and water, or with alcohol- Evidence is supportive of a decreased rate of influenza [116] in children over the age of two.[97] In those with based hand rubs); covering coughs and sneezes; chronic obstructive pulmonary disease vaccination re- avoiding close contact with sick people; and staying [98] home yourself if you are sick. Avoiding spitting is duces exacerbations, it is not clear if it reduces asthma [117] [99] also recommended. Although face masks might help exacerbations. Evidence supports a lower rate of [118][119] influenza-like illness in many groups who are immuno- prevent transmission when caring for the sick, there is mixed evidence on beneficial effects in the compromised such as those with: HIV/AIDS, cancer, [117][120] and post organ transplant.[100] In those at high risk im- community. Smoking raises the risk of contract- [101] ing influenza, as well as producing more severe disease munization may reduce the risk of heart disease. [121][122] Whether immunizing health care workers affects patient symptoms. outcomes is controversial with some reviews finding in- Since influenza spreads through both aerosols and contact sufficient evidence[102][103] and others finding tentative with contaminated surfaces, surface sanitizing may help evidence.[104][105] prevent some infections.[123] Alcohol is an effective san- Due to the high mutation rate of the virus, a particular itizer against influenza viruses, while quaternary ammonium compounds can be used with alcohol so that the san- influenza vaccine usually confers protection for no more [124] than a few years. Every year, the World Health Or- itizing effect lasts for longer. In hospitals, quaternary ganization predicts which strains of the virus are most ammonium compounds and bleach are used to sanitize likely to be circulating in the next year (see Historical rooms or equipment that have been occupied by patients with influenza symptoms.[124] At home, this can be done annual reformulations of the influenza vaccine), allowing [125] pharmaceutical companies to develop vaccines that will effectively with a diluted chlorine bleach. provide the best immunity against these strains.[106] The During past pandemics, closing schools, churches and vaccine is reformulated each season for a few specific flu theaters slowed the spread of the virus but did not have a strains but does not include all the strains active in the large effect on the overall death rate.[126][127] It is uncer- world during that season. It takes about six months for tain if reducing public gatherings, by for example closing the manufacturers to formulate and produce the millions schools and workplaces, will reduce transmission since of doses required to deal with the seasonal epidemics; oc- people with influenza may just be moved from one area casionally, a new or overlooked strain becomes prominent to another; such measures would also be difficult to en- during that time.[107] It is also possible to get infected just force and might be unpopular.[117] When small numbers before vaccination and get sick with the strain that the of people are infected, isolating the sick might reduce the 54 CHAPTER 7. INFLUENZA risk of transmission.[117] of resistance may be due to the easy availability of aman- tadines as part of over-the-counter cold remedies in countries such as China and Russia,[135] and their use to pre- 7.5 Treatment vent outbreaks of influenza in farmed poultry.[136][137] The CDC recommended against using M2 inhibitors during the 2005–06 influenza season due to high levels of Main article: Influenza treatment drug resistance.[138]

People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen 7.6 Prognosis (paracetamol) to relieve the fever and muscle aches as- [128] sociated with the flu. Children and teenagers with flu Influenza’s effects are much more severe and last longer symptoms (particularly fever) should avoid taking aspirin than those of the common cold. Most people will re- during an influenza infection (especially influenza type cover completely in about one to two weeks, but oth- B), because doing so can lead to Reye’s syndrome, a rare ers will develop life-threatening complications (such as [129] but potentially fatal disease of the liver. Since in- pneumonia). Thus, influenza can be deadly, especially for fluenza is caused by a virus, antibiotics have no effect on the weak, young and old, or chronically ill.[60] People with the infection; unless prescribed for secondary infections a weak immune system, such as people with advanced such as bacterial pneumonia. Antiviral medication may HIV infection or transplant patients (whose immune sys- be effective, if given early, but some strains of influenza tems are medically suppressed to prevent transplant organ can show resistance to the standard antiviral drugs and rejection), suffer from particularly severe disease.[139] [130] there is concern about the quality of the research. Pregnant women and young children are also at a high risk for complications.[140] 7.5.1 Antivirals The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experi- The two classes of antiviral drugs used against influenza ence shortness of breath while they have the flu, and in- are neuraminidase inhibitors (oseltamivir and zanamivir) fluenza may cause worsening of coronary heart disease or [141] and M2 protein inhibitors (adamantane derivatives). congestive heart failure. Smoking is another risk factor associated with more serious disease and increased mortality from influenza.[142] Neuraminidase inhibitors According to the World Health Organization: “Every winter, tens of millions of people get the flu. Most are Overall the benefits of neuraminidase inhibitors in those only ill and out of work for a week, yet the elderly are who are otherwise healthy do not appear to be greater at a higher risk of death from the illness. We know the [7] than the risks. There does not appear to be any benefit worldwide death toll exceeds a few hundred thousand [7] in those with other health problems. In those believed to people a year, but even in developed countries the num- have the flu, they decreased the length of time symptoms bers are uncertain, because medical authorities don't usu- were present by slightly less than a day but did not appear ally verify who actually died of influenza and who died to affect the risk of complications such as needing hospi- of a flu-like illness.”[143] Even healthy people can be af- [8] talization or pneumonia. Previous to 2013 the benefits fected, and serious problems from influenza can happen were unclear as the manufacturer (Roche) refused to re- at any age. People over 65 years old, pregnant women, [131] lease trial data for independent analysis. Increasingly very young children and people of any age with chronic prevalent resistance to neuraminidase inhibitors has led medical conditions are more likely to get complications to researchers to seek alternative antiviral drugs with dif- from influenza, such as pneumonia, bronchitis, sinus, and [132] ferent mechanisms of action. ear infections.[144] In some cases, an autoimmune response to an influenza M2 inhibitors infection may contribute to the development of Guillain– Barré syndrome.[145] However, as many other infections The antiviral drugs amantadine and rimantadine inhibit can increase the risk of this disease, influenza may only be a viral ion channel (M2 protein), thus inhibiting replica- an important cause during epidemics.[145][146] This syn- tion of the influenza A virus.[67] These drugs are some- drome has been believed to also be a rare side effect of in- times effective against influenza A if given early in the fluenza vaccines. One review gives an incidence of about infection but are ineffective against influenza B viruses, one case per million vaccinations.[147] Getting infected by which lack the M2 drug target.[133] Measured resistance influenza itself increases both the risk of death (up to 1 to amantadine and rimantadine in American isolates of in 10,000) and increases the risk of developing GBS to H3N2 has increased to 91% in 2005.[134] This high level a much higher level than the highest level of suspected 7.7. EPIDEMIOLOGY 55

vaccine involvement (approx. 10 times higher by recent An alternative hypothesis to explain seasonality in in- estimates).[148][149] fluenza infections is an effect of vitamin D levels on immunity to the virus.[157] This idea was first proposed by Robert Edgar Hope-Simpson in 1965.[158] He proposed 7.7 Epidemiology that the cause of influenza epidemics during winter may be connected to seasonal fluctuations of vitamin D, which is produced in the skin under the influence of solar (or ar- 7.7.1 Seasonal variations tificial) UV radiation. This could explain why influenza occurs mostly in winter and during the tropical rainy sea- Further information: Flu season son, when people stay indoors, away from the sun, and Influenza reaches peak prevalence in winter, and because their vitamin D levels fall.

7.7.2 Epidemic and pandemic spread

Further information: Flu pandemic As inﬂuenza is caused by a variety of species and strains

Seasonal risk areas for inﬂuenza: November–April (blue), April– November (red), and year-round (yellow).

the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year. This is why the World Health Organization (assisted by the National Influenza Centers) makes recommendations for two different vaccine formu- lations every year; one for the Northern, and one for the Antigenic drift creates influenza viruses with slightly modified [106] Southern Hemisphere. antigens, while antigenic shift generates viruses with entirely A long-standing puzzle has been why outbreaks of the novel antigens. flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people of viruses, in any given year some strains can die out are indoors more often during the winter, they are in while others create epidemics, while yet another strain close contact more often, and this promotes transmis- can cause a pandemic. Typically, in a year’s normal two flu seasons (one per hemisphere), there are between sion from person to person. Increased travel due to the three and five million cases of severe illness and around Northern Hemisphere winter holiday season may also [159] [150] 500,000 deaths worldwide, which by some defini- play a role. Another factor is that cold temperatures [160] lead to drier air, which may dehydrate mucus, prevent- tions is a yearly influenza epidemic. Although the incidence of influenza can vary widely between years, ap- ing the body from effectively expelling virus particles. The virus also survives longer on surfaces at colder tem- proximately 36,000 deaths and more than 200,000 hospitalizations are directly associated with influenza every peratures and aerosol transmission of the virus is highest [161][162] in cold environments (less than 5 °C) with low relative year in the United States. One method of calcu- humidity.[151] The lower air humidity in winter seems to lating influenza mortality produced an estimate of 41,400 average deaths per year in the United States between 1979 be the main cause of seasonal influenza transmission in [163] temperate regions.[152][153] and 2001. Different methods in 2010 by the Centers for Disease Control and Prevention (CDC) reported a However, seasonal changes in infection rates also occur in range from a low of about 3,300 deaths to a high of tropical regions, and in some countries these peaks of in- 49,000 per year.[164] fection are seen mainly during the rainy season.[154] Sea- sonal changes in contact rates from school terms, which Roughly three times per century, a pandemic occurs, are a major factor in other childhood diseases such as which infects a large proportion of the world’s popula- measles and pertussis, may also play a role in the flu. tion and can kill tens of millions of people (see pandemics A combination of these small seasonal effects may be section). One study estimated that if a strain with similar virulence to the 1918 influenza emerged today, it could amplified by dynamical resonance with the endogenous [165] disease cycles.[155] H5N1 exhibits seasonality in both hu- kill between 50 and 80 million people. mans and birds.[156] New influenza viruses are constantly evolving by mutation 56 CHAPTER 7. INFLUENZA

highly pathogenic human strain avian strain

The generation time for influenza (the time from one infection to the next) is very short (only 2 days). This explains why influenza epidemics start and finish in a short time scale of only a few months.[169]

new highly pathogenic human strain burn out after 3 months: the decision to intervene in an inﬂuenza epidemic therefore has to be taken early, and Antigenic shift, or reassortment, can result in novel and highly the decision is therefore often made on the back of in- pathogenic strains of human inﬂuenza complete data. Another problem is that individuals become infectious before they become symptomatic, which

[42] means that putting people in quarantine after they be- or by reassortment. Mutations can cause small changes come ill is not an effective public health intervention.[169] in the hemagglutinin and neuraminidase antigens on the For the average person, viral shedding tends to peak on surface of the virus. This is called antigenic drift, which day two whereas symptoms peak on day three.[14] slowly creates an increasing variety of strains until one evolves that can infect people who are immune to the pre- existing strains. This new variant then replaces the older strains as it rapidly sweeps through the human popula- 7.8 History tion, often causing an epidemic.[166] However, since the strains produced by drift will still be reasonably similar See also: Timeline of influenza to the older strains, some people will still be immune to them. In contrast, when influenza viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains and human strains; this is 7.8.1 Etymology called antigenic shift. If a human influenza virus is produced that has entirely new antigens, everybody will be The word Influenza comes from the Italian language susceptible, and the novel influenza will spread uncontrol- meaning “influence” and refers to the cause of the disease; [167] initially, this ascribed illness to unfavorable astrological lably, causing a pandemic. In contrast to this model [170] of pandemics based on antigenic drift and shift, an al- influences. Changes in medical thought led to its ternative approach has been proposed where the periodic modification to influenza del freddo, meaning “influence pandemics are produced by interactions of a fixed set of of the cold”. The word influenza was first used in En- viral strains with a human population with a constantly glish to refer to the disease we know today in 1703 by J. changing set of immunities to different viral strains.[168] Hugger of the University of Edinburgh in his thesis De Catarrho epidemio, vel Influenza, prout in India occiden- From a public health point of view, flu epidemics spread tali sese ostendit.[171] Archaic terms for influenza include rapidly and are very difficult to control. Most influenza epidemic catarrh, grippe (from the French, first used by virus strains are not very infectious and each infected in- Molyneaux in 1694 [172]), sweating sickness, and Spanish dividual will only go on to infect one or two other in- fever (particularly for the 1918 flu pandemic strain).[173] dividuals (the basic reproduction number for influenza is generally around 1.4). However, the generation time for influenza is extremely short: the time from a person 7.8.2 Pandemics becoming infected to when he infects the next person is only two days. The short generation time means that in- Further information: Influenza pandemic, Spanish flu, fluenza epidemics generally peak at around 2 months and and Hong Kong flu 7.8. HISTORY 57

The symptoms of human influenza were clearly de- ing particularly widespread; it infected approximately a quarter of the people exposed.[178] The most famous and lethal outbreak was the 1918 flu pandemic (Spanish flu pandemic) (type A influenza, H1N1 subtype), which lasted from 1918 to 1919. It is not known exactly how many it killed, but estimates range from 50 to 100 million people.[174][181][182] This pandemic has been described as “the greatest medical holocaust in history” and may have killed as many people as the Black Death.[178] This huge death toll was caused by an extremely high infection rate of up to 50% and the extreme severity of the symptoms, suspected to be caused by cytokine storms.[182] Symptoms in 1918 were so unusual that initially influenza was misdiagnosed as dengue, cholera, or typhoid. One observer wrote, “One of the The difference between the influenza mortality age distributions most striking of the complications was hemorrhage from of the 1918 epidemic and normal epidemics. Deaths per 100,000 mucous membranes, especially from the nose, stomach, persons in each age group, United States, for the interpandemic and intestine. Bleeding from the ears and petechial hem- years 1911–1917 (dashed line) and the pandemic year 1918 orrhages in the skin also occurred.”[181] The majority of [174] (solid line). deaths were from bacterial pneumonia, a secondary infection caused by influenza, but the virus also killed people directly, causing massive hemorrhages and edema in the lung.[183] The 1918 flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands. The unusually severe disease killed between 2 and 20% of those infected, as opposed to the more usual flu epidemic mortality rate of 0.1%.[174][181] Another unusual feature of this pandemic was that it mostly killed young adults, with 99% of pandemic influenza deaths occurring in people under 65, and more than half in young adults 20 to 40 years old.[184] This is unusual since influenza is normally most deadly to the very young (under age 2) and the very old (over age 70). The total mortality of the 1918–1919 pandemic is not known, but it is estimated that 2.5% to 5% of the world’s population was killed. As many as 25 million Thermal imaging camera and screen, photographed in an air- may have been killed in the first 25 weeks; in contrast, port terminal in Greece during the 2009 flu pandemic. Thermal [181] imaging can detect elevated body temperature, one of the signs HIV/AIDS has killed 25 million in its first 25 years. of swine flu. Later flu pandemics were not so devastating. They included the 1957 Asian Flu (type A, H2N2 strain) and scribed by Hippocrates roughly 2,400 years ago.[175][176] the 1968 Hong Kong Flu (type A, H3N2 strain), but Although the virus seems to have caused epidemics even these smaller outbreaks killed millions of people. In throughout human history, historical data on influenza are later pandemics antibiotics were available to control sec- difficult to interpret, because the symptoms can be sim- ondary infections and this may have helped reduce mor- ilar to those of other respiratory diseases.[177][178] The tality compared to the Spanish Flu of 1918.[174] disease may have spread from Europe to the Americas The first influenza virus to be isolated was from poul- as early as the European colonization of the Americas; try, when in 1901 the agent causing a disease called since almost the entire indigenous population of the An- “fowl plague” was passed through Chamberland filters, tilles was killed by an epidemic resembling influenza that which have pores that are too small for bacteria to pass broke out in 1493, after the arrival of Christopher Colum- through.[189] The etiological cause of influenza, the Or- bus.[179][180] thomyxoviridae family of viruses, was first discovered in The first convincing record of an influenza pandemic was pigs by Richard Shope in 1931.[190] This discovery was of an outbreak in 1580, which began in Russia and spread shortly followed by the isolation of the virus from humans to Europe via Africa. In Rome, over 8,000 people were by a group headed by Patrick Laidlaw at the Medical Re- killed, and several Spanish cities were almost wiped out. search Council of the United Kingdom in 1933.[191] How- Pandemics continued sporadically throughout the 17th ever, it was not until Wendell Stanley first crystallized and 18th centuries, with the pandemic of 1830–1833 be- 58 CHAPTER 7. INFLUENZA

tobacco mosaic virus in 1935 that the non-cellular nature Preventative costs are also high. Governments worldwide of viruses was appreciated. have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.[198] On 1 November 2005, United States President George W. Bush unveiled the National Strategy to Safeguard Against the Danger of Pandemic Influenza[195] backed by a request to Congress for $7.1 billion to begin implementing the plan.[199] Internation- ally, on 18 January 2006, donor nations pledged US$2 The main types of influenza viruses in humans. Solid squares billion to combat bird flu at the two-day International show the appearance of a new strain, causing recurring in- Pledging Conference on Avian and Human Influenza held fluenza pandemics. Broken lines indicate uncertain strain in China.[200] identifications.[192] In an assessment of the 2009 H1N1 pandemic on selected The first significant step towards preventing influenza was countries in the Southern Hemisphere, data suggest that the development in 1944 of a killed-virus vaccine for in- all countries experienced some time-limited and/or geo- fluenza by Thomas Francis, Jr.. This built on work by graphically isolated socio/economic effects and a tempo- Australian Frank Macfarlane Burnet, who showed that rary decrease in tourism most likely due to fear of 2009 the virus lost virulence when it was cultured in fertilized H1N1 disease. It is still too early to determine whether hen’s eggs.[193] Application of this observation by Fran- the H1N1 pandemic has caused any long-term economic [201] cis allowed his group of researchers at the University of impacts. Michigan to develop the first influenza vaccine, with support from the U.S. Army.[194] The Army was deeply involved in this research due to its experience of influenza 7.10 Research in World War I, when thousands of troops were killed by the virus in a matter of months.[181] In comparison Further information: Influenza research to vaccines, the development of anti-influenza drugs has Research on influenza includes studies on molecular vi- been slower, with amantadine being licensed in 1966 and, almost thirty years later, the next class of drugs (the neuraminidase inhibitors) being developed.[61]

7.9 Society and culture

Further information: Social impact of H5N1

Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs.[195] However, the economic impacts of past pandemics have not been intensively studied, and some authors have suggested that the Spanish influenza actually had a positive long-term effect on per-capita income growth, despite a large reduction in the working population and severe short-term depressive effects.[196] Other studies have attempted to predict the costs of a pandemic as serious as the 1918 Spanish flu on the U.S. economy, where 30% of all workers became ill, and 2.5% were killed. A 30% sickness rate and a three-week length of illness would decrease the gross domestic product by 5%. Additional costs would come from medical treatment of Dr. Terrence Tumpey examining a laboratory-grown reconstruc- 18 million to 45 million people, and total economic costs tion of the 1918 Spanish flu virus in a biosafety level 3 environ- would be approximately $700 billion.[197] ment. 7.11. OTHER ANIMALS 59

rology, how the virus produces disease (pathogenesis), forms of neuraminidase have been identified. All known host immune responses, viral genomics, and how the subtypes (HxNy) are found in birds, but many subtypes virus spreads (epidemiology). These studies help in de- are endemic in humans, dogs, horses, and pigs; popu- veloping influenza countermeasures; for example, a bet- lations of camels, ferrets, cats, seals, mink, and whales ter understanding of the body’s immune system response also show evidence of prior infection or exposure to helps vaccine development, and a detailed picture of how influenza.[47] Variants of flu virus are sometimes named influenza invades cells aids the development of antivi- according to the species the strain is endemic in or ral drugs. One important basic research program is the adapted to. The main variants named using this con- Influenza Genome Sequencing Project, which is creating vention are: bird flu, human flu, swine flu, horse flu and a library of influenza sequences; this library should help dog flu.(Cat flu generally refers to feline viral rhinotra- clarify which factors make one strain more lethal than an- cheitis or feline calicivirus and not infection from an in- other, which genes most affect immunogenicity, and how fluenza virus.) In pigs, horses and dogs, influenza symp- the virus evolves over time.[202] toms are similar to humans, with cough, fever and loss [47] Research into new vaccines is particularly important, as of appetite. The frequency of animal diseases are not current vaccines are very slow and expensive to produce as well-studied as human infection, but an outbreak of influenza in harbor seals caused approximately 500 seal and must be reformulated every year. The sequencing [213] of the influenza genome and recombinant DNA technol- deaths off the New England coast in 1979–1980. However, outbreaks in pigs are common and do not cause ogy may accelerate the generation of new vaccine strains [47] by allowing scientists to substitute new antigens into a severe mortality. Vaccines have also been developed to previously developed vaccine strain.[203] New technolo- protect poultry from avian influenza. These vaccines can gies are also being developed to grow viruses in cell cul- be effective against multiple strains and are used either as part of a preventative strategy, or combined with culling ture, which promises higher yields, less cost, better qual- [214] ity and surge capacity.[204] Research on a universal in- in attempts to eradicate outbreaks. fluenza A vaccine, targeted against the external domain of the transmembrane viral M2 protein (M2e), is being done at the University of Ghent by Walter Fiers, Xavier 7.11.1 Bird flu Saelens and their team[205][206][207] and has now successfully concluded Phase I clinical trials. There has been Flu symptoms in birds are variable and can be [215] some research success towards a “universal flu vaccine” unspecific. The symptoms following infection with that produces antibodies against proteins on the viral coat low-pathogenicity avian influenza may be as mild as ruf- which mutate less rapidly, and thus a single shot could fled feathers, a small reduction in egg production, or [216] potentially provide longer-lasting protection.[208][209][210] weight loss combined with minor respiratory disease. Since these mild symptoms can make diagnosis in the A number of biologics, therapeutic vaccines and im- field difficult, tracking the spread of avian influenza re- munobiologics are also being investigated for treatment quires laboratory testing of samples from infected birds. of infection caused by viruses. Therapeutic biologics are Some strains such as Asian H9N2 are highly virulent to designed to activate the immune response to virus or anti- poultry and may cause more extreme symptoms and sig- gens. Typically, biologics do not target metabolic path- nificant mortality.[217] In its most highly pathogenic form, ways like anti-viral drugs, but stimulate immune cells influenza in chickens and turkeys produces a sudden ap- such as lymphocytes, macrophages, and/or antigen pre- pearance of severe symptoms and almost 100% mortal- senting cells, in an effort to drive an immune response to- ity within two days.[218] As the virus spreads rapidly in wards a cytotoxic effect against the virus. Influenza mod- the crowded conditions seen in the intensive farming of els, such as murine influenza, are convenient models to chickens and turkeys, these outbreaks can cause large test the effects of prophylactic and therapeutic biologics. economic losses to poultry farmers. For example, Lymphocyte T-Cell Immune Modulator in- hibits viral growth in the murine model of influenza.[211] An avian-adapted, highly pathogenic strain of H5N1 (called HPAI A(H5N1), for “highly pathogenic avian influenza virus of type A of subtype H5N1”) causes H5N1 flu, commonly known as “avian influenza” or simply “bird 7.11 Other animals flu”, and is endemic in many bird populations, especially in Southeast Asia. This Asian lineage strain of HPAI A(H5N1) is spreading globally. It is epizootic (an epi- Further information: Influenzavirus A, H5N1, and demic in non-humans) and panzootic (a disease affect- Transmission and infection of H5N1 ing animals of many species, especially over a wide area), killing tens of millions of birds and spurring the culling Influenza infects many animal species, and transfer of of hundreds of millions of other birds in an attempt to viral strains between species can occur. Birds are control its spread. Most references in the media to “bird thought to be the main animal reservoirs of influenza flu” and most references to H5N1 are about this specific viruses.[212] Sixteen forms of hemagglutinin and nine strain.[219][220] 60 CHAPTER 7. INFLUENZA

At present, HPAI A(H5N1) is an avian disease, and tion. Although mortality is usually low, the virus can pro- there is no evidence suggesting efficient human-to-human duce weight loss and poor growth, causing economic loss transmission of HPAI A(H5N1). In almost all cases, to farmers.[227] Infected pigs can lose up to 12 pounds of those infected have had extensive physical contact with body weight over a 3- to 4-week period.[227] Direct trans- infected birds.[221] In the future, H5N1 may mutate or re- mission of an influenza virus from pigs to humans is oc- assort into a strain capable of efficient human-to-human casionally possible (this is called zoonotic swine flu). In transmission. The exact changes that are required for all, 50 human cases are known to have occurred since the this to happen are not well understood.[222] However, virus was identified in the mid-20th century, which have due to the high lethality and virulence of H5N1, its resulted in six deaths.[228] endemic presence, and its large and increasing biological In 2009, a swine-origin H1N1 virus strain commonly re- host reservoir, the H5N1 virus was the world’s pandemic ferred to as “swine flu” caused the 2009 flu pandemic, but threat in the 2006–07 flu season, and billions of dollars there is no evidence that it is endemic to pigs (i.e. actually are being raised and spent researching H5N1 and prepar- [198] a swine flu) or of transmission from pigs to people, instead ing for a potential influenza pandemic. the virus is spreading from person to person.[229][230] This strain is a reassortment of several strains of H1N1 that are usually found separately, in humans, birds, and pigs.[231]

7.12 References

[1] “Influenza (Seasonal) Fact sheet N°211”. who.int. March 2014. Retrieved 25 November 2014. [2] “Key Facts about Influenza (Flu) & Flu Vaccine”. cdc.gov. 9 September 2014. Retrieved 26 November 2014. [3] Duben-Engelkirk, Paul G. Engelkirk, Janet (2011). Burton’s microbiology for the health sciences (9th ed.). Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 314. ISBN 9781605476735. [4] Longo, Dan L. (2012). “187: Influenza”. Harrison’s principles of internal medicine. (18th ed.). New York: McGraw-Hill. ISBN 9780071748896. [5] Brankston G, Gitterman L, Hirji Z, Lemieux C, Gar- Chinese inspectors on an airplane, checking passengers for dam M (April 2007). “Transmission of influenza A in fevers, a common symptom of swine flu human beings”. Lancet Infect Dis. 7 (4): 257–65. doi:10.1016/S1473-3099(07)70029-4. PMID 17376383. In March 2013, the Chinese government reported three cases of H7N9 influenza infections in humans. Two of [6] Jefferson T, Del Mar CB, Dooley L, et al. (2011). “Phys- whom had died and the third was critically ill. Although ical interventions to interrupt or reduce the spread of respiratory viruses”. Cochrane Database Syst Rev (7): the strain of the virus is not thought to spread efficiently [223][224] CD006207. doi:10.1002/14651858.CD006207.pub4. between humans, by mid-April, at least 82 per- PMID 21735402. sons had become ill from H7N9, of which 17 had died. These cases include three small family clusters in Shang- [7] Michiels, B; Van Puyenbroeck, K; Verhoeven, V; Ver- hai and one cluster between a neighboring girl and boy meire, E; Coenen, S (2013). “The value of neu- in Beijing, raising at least the possibility of human-to- raminidase inhibitors for the prevention and treat- human transmission. WHO points out that one cluster did ment of seasonal influenza: a systematic review of systematic reviews.”. PLoS ONE. 8 (4): e60348. not have two of the cases lab confirmed and further points out, as a matter of baseline information, that some viruses doi:10.1371/journal.pone.0060348. PMC 3614893 . are able to cause limited human-to-human transmission PMID 23565231. under conditions of close contact but are not transmissi- [8] Ebell, MH; Call, M; Shinholser, J (April 2013). “Effec- ble enough to cause large community outbreaks.[225][226] tiveness of oseltamivir in adults: a meta-analysis of published and unpublished clinical trials.”. Family practice. 30 (2): 125–33. doi:10.1093/fampra/cms059. PMID 7.11.2 Swine flu 22997224. [9] “Ten things you need to know about pandemic influenza”. In pigs swine influenza produces fever, lethargy, World Health Organization. 14 October 2005. Archived sneezing, coughing, difficulty breathing and decreased from the original on 8 October 2009. Retrieved 26 appetite.[227] In some cases the infection can cause abor- September 2009. 7.12. REFERENCES 61

[10] World Health Organization. World now at [24] Smith K, Roberts M (2002). “Cost-effectiveness of newer the start of 2009 influenza pandemic. http: treatment strategies for influenza”. Am J Med. 113 (4): //www.who.int/mediacentre/news/statements/2009/ 300–7. doi:10.1016/S0002-9343(02)01222-6. PMID h1n1_pandemic_phase6_20090611/en/index.html 12361816.

[11] Palmer, S. R. (2011). Oxford textbook of zoonoses : biol- [25] Rothberg M, Bellantonio S, Rose D (2 September 2003). ogy, clinical practice, and public health control (2. ed.). “Management of influenza in adults older than 65 years Oxford u.a.: Oxford Univ. Press. p. 332. ISBN of age: cost-effectiveness of rapid testing and antiviral 9780198570028. therapy” (PDF). Annals of Internal Medicine. 139 (5 Pt 1): 321–9. doi:10.7326/0003-4819-139-5_part_1- [12] Call S, Vollenweider M, Hornung C, Simel D, McKinney 200309020-00007. PMID 12965940. W (2005). “Does this patient have influenza?". JAMA. 293 (8): 987–97. doi:10.1001/jama.293.8.987. PMID [26] Centers for Disease Control and Prevention. Lab Diagno- 15728170. sis of Influenza. Retrieved 1 May 2009 [13] Centers for Disease Control and Prevention > Influenza [27] “Rapid Diagnostic Testing for Influenza: Information for Symptoms Page last updated 16 November 2007. Re- Clinical Laboratory Directors”. Centers for Disease Con- trieved 28 April 2009. trol and Prevention. 13 October 2015. Retrieved 2 Febru- [14] Time Lines of Infection and Disease in Human Influenza: ary 2016. A Review of Volunteer Challenge Studies, American [28] Hospitalized Patients with 2009 H1N1 Influenza in the Journal of Epidemiology, Carrat, Vergu, Ferguson, et al., United States, April–June 2009, New England Journal of 167 (7): 775–785, 2008. "... In almost all studies, par- Medicine, Jain, Kamimoto, et al., 12 November 2009. ticipants were individually confined for 1 week ...” See especially Figure 5 which shows that virus shedding tends [29] Transcript of virtual press conference with Gregory Hartl, to peak on day 2 whereas symptoms tend to peak on day Spokesperson for H1N1, and Dr Nikki Shindo, Medical 3. Officer, Global Influenza Programme, World Health Or- [15] Suzuki E, Ichihara K, Johnson AM (January 2007). ganization, 12 November 2009. “Natural course of fever during influenza virus infec- [30] Report Finds Swine Flu Has Killed 36 Children, New tion in children”. Clin Pediatr (Phila). 46 (1): 76–9. York Times, DENISE GRADY, 3 September 2009. doi:10.1177/0009922806289588. PMID 17164515. [31] Kawaoka Y (editor) (2006). Influenza Virology: Current [16] “Influenza: Viral Infections: Merck Manual Home Edi- Topics. Caister Academic Press. ISBN 978-1-904455- tion”. Merck. Retrieved 15 March 2008. 06-6. [17] Silva ME, Cherry JD, Wilton RJ, Ghafouri NM, Bruckner DA, Miller MJ (August 1999). “Acute fever and petechial [32] Vainionpää R, Hyypiä T (April 1994). “Biology of parain- rash associated with influenza A virus infection”. Clinical fluenza viruses”. Clin. Microbiol. Rev. 7 (2): 265– Infectious Diseases. 29 (2): 453–4. doi:10.1086/520240. 75. doi:10.1128/CMR.7.2.265. PMC 358320 . PMID PMID 10476766. 8055470.

[18] Richards S (2005). “Flu blues”. Nurs Stand. 20 (8): 26–7. [33] Hall CB (June 2001). “Respiratory syncytial virus and PMID 16295596. parainfluenza virus”. N. Engl. J. Med. 344 (25): 1917–28. doi:10.1056/NEJM200106213442507. PMID [19] Heikkinen T (July 2006). “Influenza in chil- 11419430. dren”. Acta Paediatr. 95 (7): 778–84. doi:10.1080/08035250600612272. PMID 16801171. [34] Hause BM, Collin EA, Liu R, Huang B, Sheng Z, Lu W, Wang D, Nelson EA, Li F (2014). “Characterization of [20] Kerr AA, McQuillin J, Downham MA, Gardner PS a novel influenza virus in cattle and swine: proposal for a (1975). “Gastric 'flu influenza B causing abdominal new genus in the Orthomyxoviridae family”. MBio. 5 (2): symptoms in children”. Lancet. 1 (7902): 291–5. e00031–14. doi:10.1128/mBio.00031-14. doi:10.1016/S0140-6736(75)91205-2. PMID 46444. [21] Eccles, R (2005). “Understanding the symptoms of the [35] Collin EA, Sheng Z, Lang Y, Ma W, Hause BM, Li F common cold and influenza”. Lancet Infect Dis. 5 (11): (2015). “Cocirculation of two distinct genetic and anti- 718–25. doi:10.1016/S1473-3099(05)70270-X. PMID genic lineages of proposed influenza D virus in cattle”. J 16253889. Virol. 89 (2): 1036–1042. doi:10.1128/JVI.02718-14. [22] Hui DS (March 2008). “Review of clinical symptoms and [36] Ducatez MF, Pelletier C, Meyer G (2015). “Influenza D spectrum in humans with influenza A/H5N1 infection”. virus in cattle, France, 2011-2014”. Emerg Infect Dis. 21 Respirology. 13 Suppl 1: S10–3. doi:10.1111/j.1440- (2): 368–371. doi:10.3201/eid2102.141449. 1843.2008.01247.x. PMID 18366521. [37] Song H, Qi J, Khedri Z, Diaz S, Yu H, Chen X, [23] Monto A, Gravenstein S, Elliott M, Colopy M, Schweinle Varki A, Shi Y, Gao GF (2016). “An open receptor- J (2000). “Clinical signs and symptoms predicting in- binding cavity of hemagglutinin-esterase-fusion glycopro- fluenza infection” (PDF). Arch Intern Med. 160 (21): tein from newly-identified Influenza D Virus: Basis for 3243–7. doi:10.1001/archinte.160.21.3243. PMID its broad cell tropism”. PLoS Pathog. 12 (1): e1005411. 11088084. doi:10.1371/journal.ppat.1005411. 62 CHAPTER 7. INFLUENZA

[38] Sheng Z, Ran Z, Wang D, Hoppe AD, Simonson R, [49] Matsuzaki, Y; Sugawara K; Mizuta K; Tsuchiya E; Chakravarty S, Hause BM, Li F (2014). “Genomic and Muraki Y; Hongo S; Suzuki H; Nakamura K (2002). evolutionary characterization of a novel influenza-C-like “Antigenic and genetic characterization of influenza C virus from swine”. Arch Virol. 159 (2): 249–255. viruses which caused two outbreaks in Yamagata City, doi:10.1007/s00705-013-1815-3. Japan, in 1996 and 1998”. J Clin Microbiol. 40 (2): 422–9. doi:10.1128/JCM.40.2.422-429.2002. PMC [39] Quast M, Sreenivasan C, Sexton G, Nedland H, Singrey 153379 . PMID 11825952. A, Fawcett L, Miller G, Lauer D, Voss S, Pollock S, Cunha CW, Christopher-Hennings J, Nelson E, Li F (2015). [50] Taubenberger, JK; Morens, DM (2008). “Serological evidence for the presence of influenza D virus “The pathology of influenza virus infec- in small ruminants”. Vet Microbiol. 180 (3–4): 281–285. tions”. Annu Rev Pathol. 3: 499–522. doi:10.1016/j.vetmic.2015.09.005. doi:10.1146/annurev.pathmechdis.3.121806.154316. [40] Smith DB, Gaunt ER, Digard P, Templeton K, Simmonds PMC 2504709 . PMID 18039138. P (2016). “Detection of influenza C virus but not influenza [51] Matsuzaki, Y; Katsushima N; Nagai Y; Shoji M; Itagaki D virus in Scottish respiratory samples”. J Clin Virol. 74: T; Sakamoto M; Kitaoka S; Mizuta K; Nishimura H (1 50–53. doi:10.1016/j.jcv.2015.11.036. May 2006). “Clinical features of influenza C virus in- [41] Klenk, Hans-Dieter; Matrosovich, Mikhail; Stech, Jür- fection in children”. J Infect Dis. 193 (9): 1229–35. gen (2008). “Avian Influenza: Molecular Mechanisms of doi:10.1086/502973. PMID 16586359. Pathogenesis and Host Range”. Animal Viruses: Molec- [52] Katagiri, S; Ohizumi A; Homma M (July 1983). “An out- ular Biology. Caister Academic Press. ISBN 978-1- break of type C influenza in a children’s home”. J Infect 904455-22-6. Dis. 148 (1): 51–6. doi:10.1093/infdis/148.1.51. PMID [42] Hay, A; Gregory V; Douglas A; Lin Y (29 Decem- 6309999. ber 2001). “The evolution of human influenza viruses”. [53] International Committee on Taxonomy of Viruses Philosophical Transactions of the Royal Society B. 356 descriptions of:Orthomyxoviridae,Influenzavirus B and (1416): 1861–70. doi:10.1098/rstb.2001.0999. PMC Influenzavirus C 1088562 . PMID 11779385. [54] International Committee on Taxonomy of Viruses. “The [43] Fouchier, RAM; Schneeberger, PM; Rozendaal, FW; Universal Virus Database, version 4: Influenza A”. Broekman, JM; Kemink, SA; Munster, V; Kuiken, T; Archived from the original on 14 October 2006. Rimmelzwaan, GF; et al. (2004). “Avian influenza A virus (H7N7) associated with human conjunctivitis [55] Lamb RA, Choppin PW (1983). “The gene structure and and a fatal case of acute respiratory distress syndrome” replication of influenza virus”. Annu. Rev. Biochem. 52: (PDF). Proceedings of the National Academy of Sciences. 467–506. doi:10.1146/annurev.bi.52.070183.002343. 101 (5): 1356–61. Bibcode:2004PNAS..101.1356F. PMID 6351727. doi:10.1073/pnas.0308352100. PMC 337057 . PMID 14745020. [56] Bouvier NM, Palese P (September 2008). “The biology of influenza viruses”. Vaccine. 26 Suppl 4: D49–53. [44] Osterhaus, A; Rimmelzwaan G; Martina B; Bestebroer T; doi:10.1016/j.vaccine.2008.07.039. PMC 3074182 . Fouchier R (2000). “Influenza B virus in seals”. Science. PMID 19230160. 288 (5468): 1051–3. Bibcode:2000Sci...288.1051O. doi:10.1126/science.288.5468.1051. PMID 10807575. [57] Ghedin, E; Sengamalay, NA; Shumway, M; Zaborsky, J; Feldblyum, T; Subbu, V; Spiro, DJ; Sitz, J; [45] Jakeman KJ, Tisdale M, Russell S, Leone A, Sweet C et al. (October 2005). “Large-scale sequenc- (August 1994). “Efficacy of 2'-deoxy-2'-fluororibosides ing of human influenza reveals the dynamic na- against influenza A and B viruses in ferrets”. An- ture of viral genome evolution”. Nature. 437 timicrob. Agents Chemother. 38 (8): 1864–7. (7062): 1162–6. Bibcode:2005Natur.437.1162G. doi:10.1128/aac.38.8.1864. PMC 284652 . PMID doi:10.1038/nature04239. PMID 16208317. 7986023. [58] Suzuki, Y (2005). “Sialobiology of influenza: molec- [46] Nobusawa, E; Sato K (April 2006). “Comparison of ular mechanism of host range variation of influenza the mutation rates of human influenza A and B viruses”. viruses”. Biol Pharm Bull. 28 (3): 399–408. J Virol. 80 (7): 3675–8. doi:10.1128/JVI.80.7.3675- doi:10.1248/bpb.28.399. PMID 15744059. 3678.2006. PMC 1440390 . PMID 16537638. [59] Wilson, J; von Itzstein M (July 2003). “Recent [47] R, Webster; Bean W; Gorman O; Chambers T; Kawaoka strategies in the search for new anti-influenza ther- Y (1992). “Evolution and ecology of influenza A viruses”. apies”. Curr Drug Targets. 4 (5): 389–408. Microbiol Rev. 56 (1): 152–79. PMC 372859 . PMID doi:10.2174/1389450033491019. PMID 12816348. 1579108. [60] Hilleman, M (19 August 2002). “Realities and enig- [48] Zambon, M (November 1999). “Epidemiology mas of human viral influenza: pathogenesis, epidemi- and pathogenesis of influenza” (PDF). J An- ology and control”. Vaccine. 20 (25–26): 3068– timicrob Chemother. 44 Suppl B (90002): 3–9. 87. doi:10.1016/S0264-410X(02)00254-2. PMID doi:10.1093/jac/44.suppl_2.3. PMID 10877456. 12163258. 7.12. REFERENCES 63

[61] Lynch JP, Walsh EE (April 2007). “Influenza: evolving [73] Carrat, F.; Vergu, E.; Ferguson, N. M.; Lemaitre, M.; strategies in treatment and prevention”. Semin Respir Crit Cauchemez, S.; Leach, S.; Valleron, A.-J. (14 March Care Med. 28 (2): 144–58. doi:10.1055/s-2007-976487. 2008). “Time Lines of Infection and Disease in Human PMID 17458769. Influenza: A Review of Volunteer Challenge Studies”. American Journal of Epidemiology. 167 (7): 775–785. [62] Smith AE, Helenius A (April 2004). “How doi:10.1093/aje/kwm375. viruses enter animal cells”. Science. 304 (5668): 237–42. Bibcode:2004Sci...304..237S. [74] Mitamura K, Sugaya N (2006). "[Diagnosis and Treat- doi:10.1126/science.1094823. PMID 15073366. ment of influenza—clinical investigation on viral shedding in children with influenza]". Uirusu. 56 (1): 109–16. [63] Wagner, R; Matrosovich M; Klenk H (May–June 2002). doi:10.2222/jsv.56.109. PMID 17038819. “Functional balance between haemagglutinin and neuraminidase in influenza virus infections”. Rev Med Virol. [75] Gooskens, Jairo; Jonges, Marcel; Claas, Eric C. J.; Mei- 12 (3): 159–66. doi:10.1002/rmv.352. PMID 11987141. jer, Adam; Kroes, Aloys C. M. (15 May 2009). “Pro- longed Influenza Virus Infection during Lymphocytope- [64] Steinhauer DA (May 1999). “Role of hemagglutinin nia and Frequent Detection of Drug‐Resistant Viruses”. cleavage for the pathogenicity of influenza virus”. Virol- The Journal of Infectious Diseases. 199 (10): 1435–1441. ogy. 258 (1): 1–20. doi:10.1006/viro.1999.9716. PMID doi:10.1086/598684. PMID 19392620. 10329563. [76] Weber TP, Stilianakis NI (November 2008). “Inactivation [65] Liu SL, Zhang ZL, Tian ZQ, Zhao HS, Liu H, Sun EZ, of influenza A viruses in the environment and modes of Xiao GF, Zhang W, Wang HZ, Pang DW (2011) Effec- transmission: a critical review”. J. Infect. 57 (5): 361–73. tively and efficiently dissecting the infection of influenza doi:10.1016/j.jinf.2008.08.013. PMID 18848358. virus by quantum dot-based single-particle tracking. ACS Nano [77] Hall CB (August 2007). “The spread of influenza and other respiratory viruses: complexities and con- [66] Lakadamyali, M; Rust M; Babcock H; Zhuang X jectures” (PDF). Clin. Infect. Dis. 45 (3): 353–9. (5 August 2003). “Visualizing infection of individ- doi:10.1086/519433. PMID 17599315. ual influenza viruses”. Proc Natl Acad Sci USA. 100 (16): 9280–5. Bibcode:2003PNAS..100.9280L. [78] Cole E, Cook C (1998). “Characterization of infec- doi:10.1073/pnas.0832269100. PMC 170909 . PMID tious aerosols in health care facilities: an aid to effec- 12883000. tive engineering controls and preventive strategies”. Am J Infect Control. 26 (4): 453–64. doi:10.1016/S0196- [67] Pinto LH, Lamb RA (April 2006). “The M2 proton chan- 6553(98)70046-X. PMID 9721404. nels of influenza A and B viruses”. J. Biol. Chem. 281 (14): 8997–9000. doi:10.1074/jbc.R500020200. PMID [79] Thomas Y, Vogel G, Wunderli W, et al. (May 16407184. 2008). “Survival of influenza virus on banknotes”. Appl. Environ. Microbiol. 74 (10): 3002–7. [68] Cros, J; Palese P (September 2003). “Trafficking of vi- doi:10.1128/AEM.00076-08. PMC 2394922 . PMID ral genomic RNA into and out of the nucleus: influenza, 18359825. Thogoto and Borna disease viruses”. Virus Res. 95 (1– 2): 3–12. doi:10.1016/S0168-1702(03)00159-X. PMID [80] Bean B, Moore BM, Sterner B, Peterson LR, Gerding DN, 12921991. Balfour HH (July 1982). “Survival of influenza viruses on environmental surfaces”. J. Infect. Dis. 146 (1): 47–51. [69] Kash, J; Goodman A; Korth M; Katze M (July 2006). “Hi- doi:10.1093/infdis/146.1.47. PMID 6282993. jacking of the host-cell response and translational control during influenza virus infection”. Virus Res. 119 [81] “Influenza Factsheet” (PDF). Center for Food Security (1): 111–20. doi:10.1016/j.virusres.2005.10.013. PMID and Public Health, Iowa State University. p. 7 16630668. [82] Jefferies WM, Turner JC, Lobo M, Gwaltney JM (1998). [70] Nayak, D; Hui E; Barman S (December 2004). “As- “Low plasma levels of adrenocorticotropic hormone in pa- sembly and budding of influenza virus”. Virus Res. 106 tients with acute influenza” (PDF). Clin Infect Dis. 26 (3): (2): 147–65. doi:10.1016/j.virusres.2004.08.012. PMID 708–10. doi:10.1086/514594. PMID 9524849. 15567494. [83] Korteweg C, Gu J (May 2008). “Pathology, molecular [71] Drake, J (1 May 1993). “Rates of spontaneous mu- biology, and pathogenesis of avian influenza A (H5N1) tation among RNA viruses”. Proc Natl Acad Sci infection in humans”. Am. J. Pathol. 172 (5): 1155– USA. 90 (9): 4171–5. Bibcode:1993PNAS...90.4171D. 70. doi:10.2353/ajpath.2008.070791. PMC 2329826 . doi:10.1073/pnas.90.9.4171. PMC 46468 . PMID PMID 18403604. 8387212. [84] Nicholls JM, Chan RW, Russell RJ, Air GM, Peiris JS [72] Sherman, Irwin W. (2007). Twelve diseases that changed (April 2008). “Evolving complexities of influenza virus our world. Washington, DC: ASM Press. p. 161. ISBN and its receptors”. Trends Microbiol. 16 (4): 149–57. 978-1-55581-466-3. doi:10.1016/j.tim.2008.01.008. PMID 18375125. 64 CHAPTER 7. INFLUENZA

[85] van Riel D, Munster VJ, de Wit E, et al. (April 2006). “Vaccines for preventing inﬂuenza in healthy adults.”. “H5N1 Virus Attachment to Lower Respiratory Tract”. The Cochrane database of systematic reviews. 3: Science. 312 (5772): 399. doi:10.1126/science.1125548. CD001269. doi:10.1002/14651858.CD001269.pub5. PMID 16556800. PMID 24623315.

[86] Shinya K, Ebina M, Yamada S, Ono M, Kasai N, Kawaoka [97] Jefferson T, Rivetti A, Di Pietrantonj C, Demicheli V, Y (March 2006). “Avian flu: influenza virus recep- Ferroni E (2012). “Vaccines for preventing influenza tors in the human airway”. Nature. 440 (7083): 435– in healthy children”. Cochrane Database Syst Rev. 6. Bibcode:2006Natur.440..435S. doi:10.1038/440435a. 8: CD004879. doi:10.1002/14651858.CD004879.pub4. PMID 16554799. PMID 22895945.

[87] van Riel D, Munster VJ, de Wit E, et al. (October [98] Poole PJ, Chacko E, Wood-Baker RW, Cates CJ (2006). 2007). “Human and avian influenza viruses target dif- “Influenza vaccine for patients with chronic obstructive ferent cells in the lower respiratory tract of humans and pulmonary disease”. Cochrane Database Syst Rev (1): other mammals”. Am. J. Pathol. 171 (4): 1215– CD002733. doi:10.1002/14651858.CD002733.pub2. PMID 16437444. 23. doi:10.2353/ajpath.2007.070248. PMC 1988871 . PMID 17717141. [99] Cates, CJ; Rowe, BH (28 February 2013). “Vac- cines for preventing influenza in people with asthma.”. [88] Schmitz N, Kurrer M, Bachmann M, Kopf M (2005). The Cochrane database of systematic reviews. 2: “Interleukin-1 is responsible for acute lung im- CD000364. doi:10.1002/14651858.CD000364.pub4. munopathology but increases survival of respiratory PMID 23450529. influenza virus infection”. J Virol. 79 (10): 6441– 8. doi:10.1128/JVI.79.10.6441-6448.2005. PMC [100] Beck, CR; McKenzie, BC; Hashim, AB; Harris, RC; Uni- 1091664 . PMID 15858027. versity of Nottingham Influenza and the ImmunoCompro- mised (UNIIC) Study Group; Nguyen-Van-Tam, JS (Oc- [89] Winther B, Gwaltney J, Mygind N, Hendley J (1998). tober 2012). “Influenza vaccination for immunocompro- “Viral-induced rhinitis”. Am J Rhinol. 12 (1): 17–20. mised patients: systematic review and meta-analysis by doi:10.2500/105065898782102954. PMID 9513654. etiology.”. The Journal of Infectious Diseases. 206 (8): 1250–9. doi:10.1093/infdis/jis487. PMID 22904335. [90] Cheung CY, Poon LL, Lau AS, et al. (December 2002). “Induction of proinflammatory cytokines in hu- [101] Udell, JA.; Zawi, R.; Bhatt, DL.; Keshtkar-Jahromi, M.; man macrophages by influenza A (H5N1) viruses: a Gaughran, F.; Phrommintikul, A.; Ciszewski, A.; Vak- mechanism for the unusual severity of human disease?". ili, H.; et al. (Oct 2013). “Association between influenza Lancet. 360 (9348): 1831–7. doi:10.1016/S0140- vaccination and cardiovascular outcomes in high-risk pa- 6736(02)11772-7. PMID 12480361. tients: a meta-analysis.”. JAMA. 310 (16): 1711–20. doi:10.1001/jama.2013.279206. PMID 24150467. [91] Kobasa D, Jones SM, Shinya K, et al. (January 2007). “Aberrant innate immune response in lethal infection [102] Abramson ZH (2012). “What, in Fact, Is the Evidence of macaques with the 1918 influenza virus”. Nature. That Vaccinating Healthcare Workers against Seasonal In- 445 (7125): 319–23. Bibcode:2007Natur.445..319K. fluenza Protects Their Patients? A Critical Review”. Int J doi:10.1038/nature05495. PMID 17230189. Family Med. 2012: 205464. doi:10.1155/2012/205464. PMC 3502850 . PMID 23209901. [92] Kash JC, Tumpey TM, Proll SC, et al. (October 2006). “Genomic analysis of increased host immune and cell [103] Thomas, RE; Jefferson, T; Lasserson, TJ (22 July 2013). death responses induced by 1918 influenza virus”. Nature. “Influenza vaccination for healthcare workers who care 443 (7111): 578–81. Bibcode:2006Natur.443..578K. for people aged 60 or older living in long-term care in- doi:10.1038/nature05181. PMC 2615558 . PMID stitutions.”. The Cochrane database of systematic reviews. 17006449. 7: CD005187. doi:10.1002/14651858.CD005187.pub4. PMID 23881655. [93] Beigel J, Bray M (April 2008). “Current and future antiviral therapy of severe seasonal and [104] Ahmed, F; Lindley, MC; Allred, N; Weinbaum, CM; avian influenza”. Antiviral Res. 78 (1): 91–102. Grohskopf, L (13 November 2013). “Effect of Influenza doi:10.1016/j.antiviral.2008.01.003. PMC 2346583 . Vaccination of Healthcare Personnel on Morbidity and PMID 18328578. Mortality Among Patients: Systematic Review and Grad- ing of Evidence.”. Clinical Infectious Diseases. 58 (1): [94] “Vaccine use”. World Health Organization. Retrieved 6 50–7. doi:10.1093/cid/cit580. PMID 24046301. December 2012. [105] Dolan, GP; Harris, RC; Clarkson, M; Sokal, R; Morgan, [95] Smith NM, Bresee JS, Shay DK, Uyeki TM, Cox NJ, G; Mukaigawara, M; Horiuchi, H; Hale, R; Stormont, Strikas RA (July 2006). “Prevention and Control of In- L; Béchard-Evans, L; Chao, YS; Eremin, S; Martins, S; fluenza: recommendations of the Advisory Committee on Tam, J; Peñalver, J; Zanuzadana, A; Nguyen-Van-Tam, Immunization Practices (ACIP)" (PDF). MMWR Recomm JS (September 2013). “Vaccination of healthcare work- Rep. 55 (RR–10): 1–42. PMID 16874296. ers to protect patients at increased risk of acute respiratory disease: summary of a systematic review.”. In- [96] Jefferson, T; Di Pietrantonj, C; Rivetti, A; Bawazeer, fluenza and other respiratory viruses. 7 Suppl 2: 93–6. GA; Al-Ansary, LA; Ferroni, E (13 March 2014). doi:10.1111/irv.12087. PMID 24034492. 7.12. REFERENCES 65

[106] “Recommended composition of influenza virus vaccines [118] MacIntyre CR, Cauchemez S, Dwyer DE, et al. (Febru- for use in the 2006–2007 influenza season” (PDF). WHO ary 2009). “Face mask use and control of respiratory Report. 14 February 2006. Retrieved 28 December 2016. virus transmission in households” (PDF). Emerging In- fect. Dis. 15 (2): 233–41. doi:10.3201/eid1502.081167. [107] Holmes E, Ghedin E, Miller N, Taylor J, Bao Y, PMC 2662657 . PMID 19193267. St George K, Grenfell B, Salzberg S, Fraser C, Lip- man D, Taubenberger J (September 2005). “Whole- [119] Bridges CB, Kuehnert MJ, Hall CB (October 2003). genome analysis of human influenza A virus reveals “Transmission of influenza: implications for control in multiple persistent lineages and reassortment among health care settings”. Clin. Infect. Dis. 37 (8): 1094– recent H3N2 viruses”. PLoS Biol. 3 (9): e300. 101. doi:10.1086/378292. PMID 14523774. doi:10.1371/journal.pbio.0030300. PMC 1180517 . PMID 16026181. [120] Interim Guidance for the Use of Masks to Control In- [108] Key Facts about Influenza (Flu) Vaccine CDC publication. fluenza Transmission Coordinating Center for Infectious Published 17 October 2006. Retrieved 18 October 2006. Diseases (CCID) 8 August 2005

[109] Questions & Answers: Flu Shot CDC publication updated [121] Murin, Susan; Kathryn Smith Bilello (2005). “Respi- 24 July 2006. Retrieved 19 October 2006. ratory tract infections: another reason not to smoke”. Cleveland Clinic Journal of Medicine. 72 (10): 916–920. [110] Jit, Mark; Newall, Anthony T.; Beutels, Philippe (1 April doi:10.3949/ccjm.72.10.916. PMID 16231688. 2013). “Key issues for estimating the impact and cost- effectiveness of seasonal influenza vaccination strategies”. [122] Kark, J D; M Lebiush; L Rannon (1982). “Cigarette Human vaccines & immunotherapeutics. 9 (4): 834– smoking as a risk factor for epidemic a(h1n1) 840. doi:10.4161/hv.23637. PMC 3903903 . PMID influenza in young men”. The New England 23357859. Journal of Medicine. 307 (17): 1042–1046. doi:10.1056/NEJM198210213071702. ISSN 0028- [111] Newall, Anthony T.; Jit, Mark; Beutels, Philippe (1 Au- 4793. PMID 7121513. gust 2012). “Economic Evaluations of Childhood In- fluenza Vaccination”. PharmacoEconomics. 30 (8): 647– [123] Hota B; Hota, B. (2004). “Contamination, disinfection, 660. doi:10.2165/11599130-000000000-00000. and cross-colonization: are hospital surfaces reservoirs for [112] Postma, Maarten J; Baltussen, Rob PM; Palache, Abra- nosocomial infection?". Clin Infect Dis. 39 (8): 1182–9. ham M; Wilschut, Jan C (1 April 2006). “Fur- doi:10.1086/424667. PMID 15486843. ther evidence for favorable cost-effectiveness of elderly influenza vaccination”. Expert Review of Pharma- [124] McDonnell G, Russell A (1 January 1999). “Antiseptics coeconomics & Outcomes Research. 6 (2): 215–227. and disinfectants: activity, action, and resistance” (PDF). doi:10.1586/14737167.6.2.215. PMID 20528557. Clin Microbiol Rev. 12 (1): 147–79. PMC 88911 . PMID 9880479. [113] Newall, Anthony T.; Dehollain, Juan Pablo; Creighton, Prudence; Beutels, Philippe; Wood, James G. (4 May [125] “Chlorine Bleach: Helping to Manage the Flu Risk”. Wa- 2013). “Understanding the Cost-Effectiveness of In- ter Quality & Health Council. April 2009. Retrieved 12 fluenza Vaccination in Children: Methodological Choices May 2009. and Seasonal Variability”. PharmacoEconomics. 31 (8): 693–702. doi:10.1007/s40273-013-0060-7. PMID [126] Hatchett RJ, Mecher CE, Lipsitch M (2007). 23645539. “Public health interventions and epidemic in- [114] Newall, Anthony T.; Kelly, Heath; Harsley, Stuart; tensity during the 1918 influenza pandemic” Scuffham, Paul A. (1 June 2009). “Cost Effectiveness (PDF). Proc Natl Acad Sci U S A. 104 (18): of Influenza Vaccination in Older Adults”. Pharma- 7582–7587. Bibcode:2007PNAS..104.7582H. coEconomics. 27 (6): 439–450. doi:10.2165/00019053- doi:10.1073/pnas.0610941104. PMC 1849867 . 200927060-00001. PMID 19640008. PMID 17416679.

[115] Centers for Disease Control and Prevention: “QUES- [127] Bootsma MC, Ferguson NM (2007). “The effect of TIONS & ANSWERS: Novel H1N1 Flu (Swine Flu) and public health measures on the 1918 influenza pandemic You”. Retrieved 15 December 2009. in U.S. cities” (PDF). Proc Natl Acad Sci U S A. 104 (18): 7588–7593. Bibcode:2007PNAS..104.7588B. [116] Grayson ML, Melvani S, Druce J, et al. (February 2009). doi:10.1073/pnas.0611071104. PMC 1849868 . PMID “Efficacy of soap and water and alcohol-based hand-rub 17416677. preparations against live H1N1 influenza virus on the hands of human volunteers”. Clin. Infect. Dis. 48 (3): [128] “Flu: MedlinePlus Medical Encyclopedia”. U.S. National 285–91. doi:10.1086/595845. PMID 19115974. Library of Medicine. Retrieved 7 February 2010. [117] Aledort JE, Lurie N, Wasserman J, Bozzette SA (2007). “Non-pharmaceutical public health interventions for pan- [129] Glasgow, J; Middleton B (2001). “Reye syndrome — demic influenza: an evaluation of the evidence base”. insights on causation and prognosis” (PDF). Arch Dis BMC Public Health. 7: 208. doi:10.1186/1471-2458-7- Child. 85 (5): 351–3. doi:10.1136/adc.85.5.351. PMC 208. PMC 2040158 . PMID 17697389. 1718987 . PMID 11668090. 66 CHAPTER 7. INFLUENZA

[130] Hurt AC, Ho HT, Barr I (October 2006). “Resistance to [141] Angelo SJ, Marshall PS, Chrissoheris MP, Chaves AM anti-inﬂuenza drugs: adamantanes and neuraminidase in- (April 2004). “Clinical characteristics associated with hibitors”. Expert Rev Anti Infect Ther. 4 (5): 795–805. poor outcome in patients acutely infected with Inﬂuenza doi:10.1586/14787210.4.5.795. PMID 17140356. A”. Conn Med. 68 (4): 199–205. PMID 15095826.

[131] Jeﬀerson T, Jones MA, Doshi P, et al. (2012). [142] Murin S, Bilello K (2005). “Respiratory tract infections: “Neuraminidase inhibitors for preventing and another reason not to smoke”. Cleve Clin J Med. 72 (10): treating inﬂuenza in healthy adults and children”. 916–20. doi:10.3949/ccjm.72.10.916. PMID 16231688. Cochrane Database Syst Rev. 1: CD008965. [143] Sandman, Peter M; Lanard, Jody (2005). “Bird Flu: doi:10.1002/14651858.CD008965.pub3. PMID Communicating the Risk” (PDF). Perspectives in Health 22258996. Magazine. 10 (2): 1–6.

[132] Moscona, Anne (5 March 2009). “Global Transmis- [144] People at High Risk of Developing Flu–Related Compli- sion of Oseltamivir-Resistant Influenza”. New Eng- cations CDC publication. Published 26 August 2016. Re- land Journal of Medicine. 360 (10): 953–956. trieved 20 March 2017. doi:10.1056/NEJMp0900648. ISSN 0028-4793. PMID 19258250. [145] Sivadon-Tardy V, Orlikowski D, Porcher R, et al. (Jan- uary 2009). “Guillain–Barré syndrome and influenza [133] Stephenson, I; Nicholson K (1999). “Chemotherapeutic virus infection”. Clin. Infect. Dis. 48 (1): 48–56. control of influenza” (PDF). J Antimicrob Chemother. 44 doi:10.1086/594124. PMID 19025491. (1): 6–10. doi:10.1093/jac/44.1.6. PMID 10459804. [146] Jacobs BC, Rothbarth PH, van der Meché FG, et al. (Oc- [134] Centers for Disease Control and Prevention (CDC) tober 1998). “The spectrum of antecedent infections in (2006). “High levels of adamantane resistance among in- Guillain–Barré syndrome: a case-control study”. Neurol- fluenza A (H3N2) viruses and interim guidelines for use ogy. 51 (4): 1110–5. doi:10.1212/wnl.51.4.1110. PMID of antiviral agents — United States, 2005–06 influenza 9781538. season” (PDF). MMWR Morb Mortal Wkly Rep. 55 (2): 44–6. PMID 16424859. [147] Vellozzi C, Burwen DR, Dobardzic A, Ball R, Walton K, Haber P (March 2009). “Safety of trivalent inactivated [135] Bright, Rick A; Medina, Marie-jo; Xu, Xiyan; Perez- influenza vaccines in adults: Background for pandemic Oronoz, Gilda; Wallis, Teresa R; Davis, Xiaohong M; influenza vaccine safety monitoring”. Vaccine. 27 (15): Povinelli, Laura; Cox, Nancy J; Klimov, Alexander I 2114–2120. doi:10.1016/j.vaccine.2009.01.125. PMID (2005). “Incidence of adamantane resistance among in- 19356614. fluenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern”. The Lancet. 366 (9492): [148] Stowe J, Andrews N, Wise L, Miller E (February 2009). 1175–81. doi:10.1016/S0140-6736(05)67338-2. PMID “Investigation of the temporal association of Guillain– 16198766. Barré syndrome with influenza vaccine and influenzalike illness using the United Kingdom General Practice Re- [136] Ilyushina NA, Govorkova EA, Webster RG (Octo- search Database” (PDF). Am. J. Epidemiol. 169 (3): 382– ber 2005). “Detection of amantadine-resistant vari- 8. doi:10.1093/aje/kwn310. PMID 19033158. ants among avian influenza viruses isolated in North [149] Sivadon-Tardy V, Orlikowski D, Porcher R, et al. (Jan- America and Asia” (PDF). Virology. 341 (1): 102–6. uary 2009). “Guillain–Barré syndrome and influenza doi:10.1016/j.virol.2005.07.003. PMID 16081121. virus infection” (PDF). Clin. Infect. Dis. 48 (1): 48–56. doi:10.1086/594124. PMID 19025491. [137] Parry J (July 2005). “Use of antiviral drug in poultry is blamed for drug resistant strains of avian flu”. BMJ. [150] Weather and the Flu Season NPR Day to Day, 17 Decem- 331 (7507): 10. doi:10.1136/bmj.331.7507.10. PMC ber 2003. Retrieved, 19 October 2006 558527 . PMID 15994677. [151] Lowen, AC; Mubareka, S; Steel, J; Palese, P (October [138] “CDC Recommends against the Use of Amantadine and 2007). “Influenza virus transmission is dependent on rel- Rimantadine for the Treatment or Prophylaxis of In- ative humidity and temperature”. PLoS Pathogens. 3 fluenza in the United States during the 2005–06 Influenza (10): e151. doi:10.1371/journal.ppat.0030151. PMC Season”. Centers for Disease Control and Prevention. 14 2034399 . PMID 17953482. January 2006. Retrieved 28 December 2016. [152] Shaman J, Kohn M (March 2009). “Absolute hu- [139] Hayden FG (March 1997). “Prevention and treatment of midity modulates influenza survival, transmission, and influenza in immunocompromised patients”. Am. J. Med. seasonality”. Proc. Natl. Acad. Sci. U.S.A. 102 (3A): 55–60; discussion 75–6. doi:10.1016/S0002- 106 (9): 3243–8. Bibcode:2009PNAS..106.3243S. 9343(97)80013-7. PMID 10868144. doi:10.1073/pnas.0806852106. PMC 2651255 . PMID 19204283. [140] Whitley RJ, Monto AS (2006). “Prevention and treatment of influenza in high-risk groups: children, preg- [153] Shaman J, Pitzer VE, Viboud C, Grenfell BT, Lipsitch nant women, immunocompromised hosts, and nursing M (February 2010). Ferguson NM, ed. “Absolute hu- home residents” (PDF). J Infect Dis. 194 S2: S133–8. midity and the seasonal onset of influenza in the con- doi:10.1086/507548. PMID 17163386. tinental United States”. PLoS Biol. 8 (2): e1000316. 7.12. REFERENCES 67

doi:10.1371/journal.pbio.1000316. PMC 2826374 . 13 September 2010. Instead of the estimated 36,000 an- PMID 20186267. nual flu deaths in the United States ... the actual number in the past 30 years has ranged from a low of about 3,300 [154] Shek, LP; Lee, BW (2003). “Epidemiology and sea- deaths to a high of nearly 49,000, the CDC said on Thurs- sonality of respiratory tract virus infections in the trop- day ics”. Paediatric respiratory reviews. 4 (2): 105–11. doi:10.1016/S1526-0542(03)00024-1. PMID 12758047. [165] Murray CJ, Lopez AD, Chin B, Feehan D, Hill KH (December 2006). “Estimation of potential global pan- [155] Dushoff, J; Plotkin, JB; Levin, SA; Earn, DJ (2004). demic influenza mortality on the basis of vital registry “Dynamical resonance can account for seasonality of data from the 1918–20 pandemic: a quantitative analy- influenza epidemics”. Proceedings of the National sis”. Lancet. 368 (9554): 2211–8. doi:10.1016/S0140- Academy of Sciences of the United States of America. 6736(06)69895-4. PMID 17189032. 101 (48): 16915–6. Bibcode:2004PNAS..10116915D. doi:10.1073/pnas.0407293101. PMC 534740 . PMID [166] Wolf, Yuri I; Viboud, C; Holmes, EC; Koonin, EV; 15557003. Lipman, DJ (2006). “Long intervals of stasis punctuated by bursts of positive selection in the seasonal evo- [156] “WHO Confirmed Human Cases of H5N1”. WHO Epi- lution of influenza A virus”. Biol Direct. 1 (1): 34. demic and Pandemic Alert and Response (EPR). Re- doi:10.1186/1745-6150-1-34. PMC 1647279 . PMID trieved 28 December 2016. 17067369.

[157] Cannell, J; Vieth R; Umhau J; Holick M; Grant [167] Parrish, C; Kawaoka Y (2005). “The origins of W; Madronich S; Garland C; Giovannucci E (2006). new pandemic viruses: the acquisition of new “Epidemic influenza and vitamin D”. Epidemiol Infect. host ranges by canine parvovirus and influenza 134 (6): 1129–40. doi:10.1017/S0950268806007175. A viruses”. Annu Rev Microbiol. 59: 553–86. PMC 2870528 . PMID 16959053. doi:10.1146/annurev.micro.59.030804.121059. PMID 16153179. [158] HOPE-SIMPSON, R (1965). “The nature of herpes zoster: a long-term study and a new hypothesis”. Proceed- [168] Recker M, Pybus OG, Nee S, Gupta S (2007). “The ings of the Royal Society of Medicine. 58: 9–20. PMC generation of influenza outbreaks by a network of host immune responses against a limited set of anti- 1898279 . PMID 14267505. genic types” (PDF). Proc Natl Acad Sci U S A. [159] Lozano, R (15 December 2012). “Global and re- 104 (18): 7711–16. Bibcode:2007PNAS..104.7711R. gional mortality from 235 causes of death for 20 age doi:10.1073/pnas.0702154104. PMC 1855915 . PMID groups in 1990 and 2010: a systematic analysis for the 17460037. Global Burden of Disease Study 2010.”. Lancet. 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728- [169] Ferguson, NM; Cummings DA; Cauchemez S; Fraser 0. PMID 23245604. C; Riley S; Meeyai A; Iamsirithaworn S; Burke DS (2005). “Strategies for containing an emerging in- [160] Influenza WHO Fact sheet No. 211 revised March 2003. fluenza pandemic in Southeast Asia”. Nature. 437 Retrieved 22 October 2006. (7056): 209–14. Bibcode:2005Natur.437..209F. doi:10.1038/nature04017. PMID 16079797. [161] Thompson, W; Shay D; Weintraub E; Brammer L; Cox N; Anderson L; Fukuda K (2003). “Mortality asso- [170] Influenza, The Oxford English Dictionary, second edition. ciated with influenza and respiratory syncytial virus in the United States” (PDF). JAMA. 289 (2): 179–86. [171] Creighton, Charles (1965): A History Of Epidemics In doi:10.1001/jama.289.2.179. PMID 12517228. Britain, With Additional Material By D.E.C. Eversley

[162] Thompson, W; Shay D; Weintraub E; Brammer L; [172] Potter, CW (2001). “A history of influenza”. Jour- Bridges C; Cox N; Fukuda K (2004). “Influenza- nal of applied microbiology. 91 (4): 572–579. associated hospitalizations in the United States”. JAMA. doi:10.1046/j.1365-2672.2001.01492.x. PMID 292 (11): 1333–40. doi:10.1001/jama.292.11.1333. 11576290. PMID 15367555. [173] Smith, P (2009). “Swine Flu”. Croatian Medical Jour- nal. 50 (4): 412–5. doi:10.3325/cmj.2009.50.412. PMC [163] Jonathan Dushoff; Plotkin, JB; Viboud, C; Earn, DJ; Simonsen, L (2006). “Mortality due to In- 2728380 . PMID 19673043. fluenza in the United States — An Annualized Regres- sion Approach Using Multiple-Cause Mortality Data”. [174] Taubenberger, J; Morens D (2006). “1918 Influenza: the American Journal of Epidemiology. 163 (2): 181–7. mother of all pandemics”. Emerg Infect Dis. 12 (1): doi:10.1093/aje/kwj024. PMID 16319291. Retrieved 29 15–22. doi:10.3201/eid1201.050979. PMC 3291398 . October 2009. The regression model attributes an an- PMID 16494711. nual average of 41,400 (95% confidence interval: 27,100, 55,700) deaths to influenza over the period 1979–2001 [175] Martin, P; Martin-Granel E (June 2006). “2,500-year evolution of the term epidemic”. Emerg Infect Dis. 12 (6): [164] Julie Steenhuysen (26 August 2010). “CDC backs away 976–80. doi:10.3201/eid1206.051263. PMC 3373038 . from decades-old flu death estimate”. Reuters. Retrieved PMID 16707055. 68 CHAPTER 7. INFLUENZA

[176] Hippocrates. “Of the Epidemics, c. 400 BCE”. Adams, [188] Fatimah S Dawood, A Danielle Iuliano, Carrie Reed, Francis (transl.). Retrieved 18 October 2006. Martin I Meltzer, David K Shay, Po-Yung Cheng, Don Bandaranayake, Robert F Breiman, W Abdullah Brooks, [177] Beveridge, W I (1991). “The chronicle of influenza epi- Philippe Buchy, Daniel R Feikin, Karen B Fowler, Aubree demics”. History and Philosophy of the Life Sciences. 13 Gordon, Nguyen Tran Hien, Peter Horby, Q Sue Huang, (2): 223–234. PMID 1724803. Mark A Katz, Anand Krishnan, Renu Lal, Joel M Mont- gomery, Kåre Mølbak, Richard Pebody, Anne M Presa- [178] Potter CW (October 2001). “A History of Influenza”. nis, Hugo Razuri, Anneke Steens, Yeny O Tinoco, Jacco Journal of Applied Microbiology. 91 (4): 572– Wallinga, Hongjie, Sirenda Vong, Joseph Bresee, Marc- 579. doi:10.1046/j.1365-2672.2001.01492.x. PMID Alain Widdowson (26 June 2012). “Estimated global 11576290. mortality associated with the first 12 months of 2009 pan- [179] Guerra, Francisco (1988). “The Earliest American Epi- demic influenza A H1N1 virus circulation: a modelling demic: The Influenza of 1493”. Social Science History. 12 study”. The Lancet Infectious Diseases. 12 (9): 687–95. (3): 305–325. doi:10.2307/1171451. JSTOR 1171451. doi:10.1016/S1473-3099(12)70121-4. PMID 22738893. PMID 11618144. (only the first page can be read for free, Retrieved 19 March 2014. but that has enough information about influenza being the [189] Heinen PP (15 September 2003). “Swine influenza: a main disease brought by Columbus killing 90 % of the zoonosis”. Veterinary Sciences Tomorrow. ISSN 1569- indigenous population) 0830. Retrieved 28 December 2016. [180] Guerra, F (1993). “The European-American exchange”. [190] Shimizu, K (October 1997). “History of influenza epi- History and Philosophy of the Life Sciences. 15 (3): 313– demics and discovery of influenza virus”. Nippon Rinsho. 327. PMID 7529930. 55 (10): 2505–201. PMID 9360364.

[181] Knobler S, Mack A, Mahmoud A, Lemon S (eds.). “1: [191] Smith, W; Andrewes CH; Laidlaw PP (1933). “A virus The Story of Influenza”. The Threat of Pandemic In- obtained from influenza patients”. Lancet. 2 (5732): 66– fluenza: Are We Ready? Workshop Summary (2005). 68. doi:10.1016/S0140-6736(00)78541-2. Washington, D.C.: The National Academies Press. pp. 60–61. [192] Palese P (December 2004). “Influenza: old and new threats”. Nat. Med. 10 (12 Suppl): S82–7. [182] Patterson, KD; Pyle GF (Spring 1991). “The geography doi:10.1038/nm1141. PMID 15577936. and mortality of the 1918 influenza pandemic”. Bull Hist Med. 65 (1): 4–21. PMID 2021692. [193] Sir Frank Macfarlane Burnet: Biography The Nobel Foundation. Retrieved 22 October 2006 [183] Taubenberger JK, Reid AH, Janczewski TA, Fanning TG (December 2001). “Integrating historical, clinical [194] Kendall, H (2006). “Vaccine Innovation: Lessons from and molecular genetic data in order to explain the ori- World War II”. Journal of Public Health Policy. 27 gin and virulence of the 1918 Spanish influenza virus”. (1): 38–57. doi:10.1057/palgrave.jphp.3200064. PMID Philosophical Transactions of the Royal Society B. 356 16681187. (1416): 1829–39. doi:10.1098/rstb.2001.1020. PMC [195] “Statement from President George W. Bush on Influenza”. 1088558 . PMID 11779381. Archived from the original on 9 January 2009. Retrieved [184] Simonsen, L; Clarke M; Schonberger L; Arden N; Cox 26 October 2006. N; Fukuda K (July 1998). “Pandemic versus epidemic in- [196] Brainerd, E. and M. Siegler (2003), “The Economic Ef- fluenza mortality: a pattern of changing age distribution”. fects of the 1918 Influenza Epidemic”, CEPR Discussion J Infect Dis. 178 (1): 53–60. doi:10.1086/515616. PMID Paper, no. 3791. 9652423. [197] Poland G (2006). “Vaccines against avian influenza—a [185] Valleron AJ, Cori A, Valtat S, Meurisse S, Car- race against time” (PDF). N Engl J Med. 354 (13): 1411– rat F, Boëlle PY (May 2010). “Transmissibility 3. doi:10.1056/NEJMe068047. PMID 16571885. and geographic spread of the 1889 influenza pandemic”. Proc. Natl. Acad. Sci. U.S.A. [198] Rosenthal, E; Bradsher, K (16 March 2006). “Is Business 107 (19): 8778–81. Bibcode:2010PNAS..107.8778V. Ready for a Flu Pandemic?". The New York Times. Re- doi:10.1073/pnas.1000886107. PMC 2889325 . PMID trieved 17 April 2006. 20421481. [199] Bush Outlines $7 Billion Pandemic Flu Preparedness Plan [186] Mills CE, Robins JM, Lipsitch M (December 2004). US Mission to the EU. Retrieved 12 December 2009. “Transmissibility of 1918 pandemic influenza”. Nature. [200] Donor Nations Pledge $1.85 Billion to Combat Bird Flu 432 (7019): 904–6. Bibcode:2004Natur.432..904M. Newswire Retrieved 26 October 2006. doi:10.1038/nature03063. PMID 15602562. [201] Assessment of the 2009 Influenza A (H1N1) Outbreak on [187] Donaldson LJ, Rutter PD, Ellis BM, et al. (2009). Selected Countries in the Southern Hemisphere. 2009. “Mortality from pandemic A/H1N1 2009 influenza in http://flu.gov/professional/global/southhemisphere.html England: public health surveillance study”. BMJ. 339: b5213. doi:10.1136/bmj.b5213. PMC 2791802 . [202] Influenza A Virus Genome Project at The Institute of Ge- PMID 20007665. nomic Research. Retrieved 19 October 2006 7.12. REFERENCES 69

[203] Subbarao K, Katz J (2004). “Influenza vaccines gen- [215] Elbers A, Koch G, Bouma A (2005). “Performance of erated by reverse genetics”. Curr Top Microbiol Im- clinical signs in poultry for the detection of outbreaks munol. 283: 313–42. doi:10.1007/978-3-662-06099- during the avian influenza A (H7N7) epidemic in The 5_9. PMID 15298174. Netherlands in 2003”. Avian Pathol. 34 (3): 181–7. doi:10.1080/03079450500096497. PMID 16191700. [204] Bardiya N, Bae J (2005). “Influenza vaccines: recent advances in production technologies”. Appl Microbiol [216] Capua, I; Mutinelli, F (2001). “Low pathogenicity (LPAI) Biotechnol. 67 (3): 299–305. doi:10.1007/s00253-004- and highly pathogenic (HPAI) avian influenza in turkeys 1874-1. PMID 15660212. and chicken”. A Colour Atlas and Text on Avian Influenza. Bologna: Papi Editore. pp. 13–20. ISBN 88-88369-00- [205] Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou 7. WM, Fiers W (October 1999). “A universal influenza A vaccine based on the extracellular domain of the M2 pro- [217] Bano S, Naeem K, Malik S (2003). “Evaluation of tein”. Nat. Med. 5 (10): 1157–63. doi:10.1038/13484. pathogenic potential of avian influenza virus serotype PMID 10502819. H9N2 in chickens”. Avian Dis. 47 (3 Suppl): 817–22. doi:10.1637/0005-2086-47.s3.817. PMID 14575070. [206] Fiers W, Neirynck S, Deroo T, Saelens X, Jou WM (De- cember 2001). “Soluble recombinant influenza vaccines”. [218] Swayne D, Suarez D (2000). “Highly pathogenic avian in- Philosophical Transactions of the Royal Society B. 356 fluenza”. Rev Sci Tech. 19 (2): 463–82. PMID 10935274. (1416): 1961–3. doi:10.1098/rstb.2001.0980. PMC 1088575 . PMID 11779398. [219] Li K, Guan Y, Wang J, Smith G, Xu K, Duan L, Ra- hardjo A, Puthavathana P, Buranathai C, Nguyen T, [207] Fiers W, De Filette M, Birkett A, Neirynck S, Min Estoepangestie A, Chaisingh A, Auewarakul P, Long Jou W (July 2004). “A “universal” human in- H, Hanh N, Webby R, Poon L, Chen H, Shortridge fluenza A vaccine”. Virus Res. 103 (1–2): 173–6. K, Yuen K, Webster R, Peiris J (2004). “Gene- doi:10.1016/j.virusres.2004.02.030. PMID 15163506. sis of a highly pathogenic and potentially pandemic H5N1 influenza virus in eastern Asia”. Nature. [208] Petsch B, Schnee M, Vogel AB, et al. (November 430 (6996): 209–13. Bibcode:2004Natur.430..209L. 2012). “Protective efficacy of in vitro synthesized, spe- doi:10.1038/nature02746. PMID 15241415. cific mRNA vaccines against influenza A virus infection”. Nat. Biotechnol. 30 (12): 1210–6. doi:10.1038/nbt.2436. [220] Li KS, Guan Y, Wang J, Smith GJ, Xu KM, Duan L, Ra- PMID 23159882. hardjo AP, Puthavathana P, Buranathai C, Nguyen TD, Estoepangestie AT, Chaisingh A, Auewarakul P, Long [209] Stephen Adams (8 July 2011). “Universal flu vaccine a HT, Hanh NT, Webby RJ, Poon LL, Chen H, Shortridge step closer”. The Telegraph. KF, Yuen KY, Webster RG, Peiris JS. “The Threat of Pandemic Influenza: Are We Ready?" Workshop Sum- [210] Ekiert, DC; Friesen, RHE; Bhabha, G; Kwaks, T; mary The National Academies Press (2005) “Today’s Pan- Jongeneelen, M; Yu, W; Ophorst, C; Cox, F; et demic Threat: Genesis of a Highly Pathogenic and Poten- al. (2011). “A Highly Conserved Neutralizing Epi- tially Pandemic H5N1 Influenza Virus in Eastern Asia”, tope on Group 2 Influenza a Viruses”. Science. pages 116–130 333 (6044): 843–50. Bibcode:2011Sci...333..843E. doi:10.1126/science.1204839. PMC 3210727 . PMID [221] Liu J (2006). “Avian influenza—a pandemic waiting to 21737702. happen?" (PDF). J Microbiol Immunol Infect. 39 (1): 4– 10. PMID 16440117. [211] Gingerich, DA (2008). “Lymphocyte T-Cell Im- munomodulator: Review of the ImmunoPharmacology of [222] Salomon R, Webster RG (February 2009). “The a new Veterinary Biologic” (PDF). Journal of Applied Re- influenza virus enigma”. Cell. 136 (3): 402– search in Veterinary Medicine. 6 (2): 61–68. Retrieved 5 10. doi:10.1016/j.cell.2009.01.029. PMC 2971533 . December 2010. PMID 19203576.

[212] Gorman O, Bean W, Kawaoka Y, Webster R (1990). [223] 2 Men in China Die of Lesser-Known Strain of Bird Flu, “Evolution of the nucleoprotein gene of influenza A New York Times, DAVID BARBOZA, 31 March 2013. virus”. J Virol. 64 (4): 1487–97. PMC 249282 . PMID 2319644. [224] H7N9 avian influenza human infections in China, World Health Organization, 1 April 2013. "... So far no further [213] Hinshaw V, Bean W, Webster R, Rehg J, Fiorelli P, Early cases have been identified among the 88 identified con- G, Geraci J, St Aubin D (1984). “Are seals frequently tacts under follow up.” infected with avian influenza viruses?". J Virol. 51 (3): 863–5. PMC 255856 . PMID 6471169. [225] Deadly Bird Flu Spreading in China, Unclear How, ABC News, Katie Moisse, 18 April 2013. [214] Capua, I; Alexander D (2006). “The challenge of avian influenza to the veterinary commu- [226] Background and summary of human infection with in- nity” (PDF). Avian Pathol. 35 (3): 189–205. fluenza A(H7N9) virus– as of 5 April 2013, World Health doi:10.1080/03079450600717174. PMID 16753610. Organization. 70 CHAPTER 7. INFLUENZA

[227] Kothalawala H, Toussaint MJ, Gruys E (June 2006). “An overview of swine inﬂuenza”. Vet Q. 28 (2): 46–53. doi:10.1080/01652176.2006.9695207. PMID 16841566.

[228] Myers KP, Olsen CW, Gray GC (April 2007). “Cases of swine inﬂuenza in humans: a review of the literature”. Clin. Infect. Dis. 44 (8): 1084–8. doi:10.1086/512813. PMC 1973337 . PMID 17366454.

[229] Maria Zampaglione (29 April 2009). “Press Release: A/H1N1 inﬂuenza like human illness in Mexico and the USA: OIE statement”. World Organisation for Animal Health. Archived from the original on 30 April 2009. Re- trieved 29 April 2009.

[230] Grady, Denise (1 May 2009). “W.H.O. Gives Swine Flu a Less Loaded, More Scientiﬁc Name”. The New York Times. Retrieved 31 March 2010.

[231] McNeil Jr, Donald G (1 May 2009). “Virus’s Tangled Genes Straddle Continents, Raising a Mystery About Its Origins”. The New York Times. Retrieved 31 March 2010.

7.13 Further reading

7.14 External links

• Inﬂuenza at DMOZ • Info on inﬂuenza at CDC

• Fact Sheet Overview of inﬂuenza at World Health Organization Chapter 8

Chickenpox

For other uses, see Chickenpox (disambiguation). creased risk of complications antiviral medication such “Varicella” redirects here. For other uses, see Varicella as aciclovir are recommended.[2] (disambiguation). Chickenpox occurs in all parts of the world.[7] As of Not to be confused with Fowlpox or Smallpox. 2013 140 million cases of chickenpox and herpes zoster occurred.[12] Before routine immunization the number of Chickenpox, also known as varicella, is a highly cases occurring each year was similar to the number of contagious disease caused by the initial infection with people born.[7] Since immunization the number of infec- varicella zoster virus (VZV).[3] The disease results in tions in the United States has decreased nearly 90%.[7] a characteristic skin rash that forms small, itchy blis- In 2015 chickenpox resulted in 6,400 deaths globally – ters, which eventually scab over.[1] It usually starts on down from 8,900 in 1990.[5][13] Death occurs in about 1 the chest, back, and face then spreads to the rest of per 60,000 cases.[7] Chickenpox was not separated from the body.[1] Other symptoms may include fever, feeling smallpox until the late 19th century.[7] In 1888 its con- tired, and headaches.[1] Symptoms usually last five to nection to shingles was determined.[7] The first docu- ten days.[1] Complications may occasionally include mented use of the term chicken pox was in 1658.[14] pneumonia, inflammation of the brain, or bacterial in- Various explanations have been suggested for the use of fections of the skin among others.[6] The disease is often “chicken” in the name, one being the relative mildness of more severe in adults than children.[7] Symptoms begin the disease.[14] ten to twenty-one days after exposure to the virus.[2] Chickenpox is an airborne disease which spreads easily through the coughs and sneezes of an infected person.[2] It may be spread from one to two days before the rash 8.1 Signs and symptoms appears until all lesions have crusted over.[2] It may also spread through contact with the blisters.[2] Those with The early (prodromal) symptoms in adolescents and shingles may spread chickenpox to those who are not adults are nausea, loss of appetite, aching muscles, and immune through contact with the blisters.[2] The dis- headache. This is followed by the characteristic rash or ease can usually be diagnosed based on the presenting oral sores, malaise, and a low-grade fever that signal the symptom;[8] however, in unusual cases may be confirmed presence of the disease. Oral manifestations of the dis- by polymerase chain reaction (PCR) testing of the blister ease (enanthem) not uncommonly may precede the exter- fluid or scabs.[7] Testing for antibodies may be done to de- nal rash (exanthem). In children the illness is not usually termine if a person is or is not immune.[7] People usually preceded by prodromal symptoms, and the first sign is only get the disease once.[2] Although reinfections by the the rash or the spots in the oral cavity. The rash begins as virus occur, these reinfections usually do not cause any small red dots on the face, scalp, torso, upper arms and symptoms.[9] legs; progressing over 10–12 hours to small bumps, blisters and pustules; followed by umbilication and the for- The varicella vaccine has resulted in a decrease in the [15][16] number of cases and complications from the disease.[4] mation of scabs. It protects about 70 to 90 percent of people from dis- At the blister stage, intense itching is usually present. ease with a greater benefit for severe disease.[7] Rou- Blisters may also occur on the palms, soles, and genital tine immunization of children is recommended in many area. Commonly, visible evidence of the disease develops countries.[10] Immunization within three days of expo- in the oral cavity and tonsil areas in the form of small ul- sure may improve outcomes in children.[11] Treatment cers which can be painful or itchy or both; this enanthem of those infected may include calamine lotion to help (internal rash) can precede the exanthem (external rash) with itching, keeping the fingernails short to decrease in- by 1 to 3 days or can be concurrent. These symptoms of jury from scratching, and the use of paracetamol (ac- chickenpox appear 10 to 21 days after exposure to a con- etaminophen) to help with fevers.[2] For those at in- tagious person. Adults may have a more widespread rash

71 72 CHAPTER 8. CHICKENPOX

• The back of a 30-year-old male after ﬁve days of the rash

• A 3-year-old girl with a chickenpox rash on her torso

A single blister, typical during the early stages of the rash

• A child with chickenpox at an orphanage.

and longer fever, and they are more likely to experience complications, such as varicella pneumonia.[15] • Lower leg of a child with chickenpox Because watery nasal discharge containing live virus usually precedes both exanthem (external rash) and enanthem (oral ulcers) by 1 to 2 days, the infected person actually becomes contagious one to two days before recogni- 8.1.1 Pregnancy and neonates tion of the disease. Contagiousness persists until all vesicular lesions have become dry crusts (scabs), which usually During pregnancy the dangers to the fetus associated entails four or five days, by which time nasal shedding of with a primary VZV infection are greater in the first live virus ceases. six months. In the third trimester, the mother is more The condition usually resolves by itself within a couple likely to have severe symptoms.[19] For pregnant women, of weeks.[17] The rash may, however, last for up to one antibodies produced as a result of immunization or pre- month, although the infectious stage does not last longer vious infection are transferred via the placenta to the than a week or two. fetus.[20] Women who are immune to chickenpox cannot become infected and do not need to be concerned about Chickenpox is rarely fatal, although it is generally more [21] severe in adult men than in women or children. Non- it for themselves or their infant during pregnancy. immune pregnant women and those with a suppressed im- Varicella infection in pregnant women could lead to mune system are at highest risk of serious complications. spread via the placenta and infection of the fetus. If in- Arterial ischemic stroke (AIS) associated with chicken- fection occurs during the first 28 weeks of gestation, this pox in the previous year accounts for nearly one third of can lead to fetal varicella syndrome (also known as con- childhood AIS.[18] The most common late complication genital varicella syndrome).[22] Effects on the fetus can of chickenpox is shingles (herpes zoster), caused by re- range in severity from underdeveloped toes and fingers to activation of the varicella zoster virus decades after the severe anal and bladder malformation. Possible problems initial, often childhood, chickenpox infection. include: 8.3. PATHOPHYSIOLOGY 73

• Damage to brain: encephalitis,[23] microcephaly, or by testing blood for evidence of an acute immunologic hydrocephaly,[24] aplasia of brain response.

• Damage to the eye: optic stalk, optic cup, and lens Vesicular fluid can be examined with a Tzanck smear, vesicles, microphthalmia, cataracts, chorioretinitis, or better by testing for direct fluorescent antibody. The optic atrophy fluid can also be “cultured”, whereby attempts are made to grow the virus from a fluid sample. Blood tests can • Other neurological disorder: damage to cervical and be used to identify a response to acute infection (IgM) or [27] lumbosacral spinal cord, motor/sensory deficits, ab- previous infection and subsequent immunity (IgG). sent deep tendon reflexes, anisocoria/Horner’s syn- Prenatal diagnosis of fetal varicella infection can be per- drome formed using ultrasound, though a delay of 5 weeks following primary maternal infection is advised. A PCR • Damage to body: hypoplasia of upper/lower extrem- (DNA) test of the mother’s amniotic fluid can also be per- ities, anal and bladder sphincter dysfunction formed, though the risk of spontaneous abortion due to the amniocentesis procedure is higher than the risk of the • Skin disorders: (cicatricial) skin lesions, baby’s developing fetal varicella syndrome.[26] hypopigmentation

Infection late in gestation or immediately following birth 8.3 Pathophysiology is referred to as "neonatal varicella".[25] Maternal infection is associated with premature delivery. The risk of the baby developing the disease is greatest following ex- Main article: Varicella zoster virus posure to infection in the period 7 days before delivery and up to 8 days following the birth. The baby may also Exposure to VZV in a healthy child initiates the produc- be exposed to the virus via infectious siblings or other tion of host immunoglobulin G (IgG), immunoglobulin contacts, but this is of less concern if the mother is im- M (IgM), and immunoglobulin A (IgA) antibodies; IgG mune. Newborns who develop symptoms are at a high antibodies persist for life and confer immunity. Cell- risk of pneumonia and other serious complications of the mediated immune responses are also important in lim- [26] disease. iting the scope and the duration of primary varicella infection. After primary infection, VZV is hypothesized to spread from mucosal and epidermal lesions to local 8.2 Diagnosis sensory nerves. VZV then remains latent in the dorsal ganglion cells of the sensory nerves. Reactivation of VZV results in the clinically distinct syndrome of herpes zoster (i.e., shingles), postherpetic neuralgia,[28] and sometimes Ramsay Hunt syndrome type II.[29] Varicella zoster can aﬀect the arteries in the neck and head, producing stroke, either during childhood, or after a latency period of many years.[30]

8.3.1 Shingles

Main article: Herpes zoster

After a chickenpox infection, the virus remains dormant in the body’s nerve tissues. The immune system keeps the virus at bay, but later in life, usually in an adult, it can be reactivated and cause a different form of the viral infection called shingles (also known as herpes zoster).[31] The United States Advisory Committee on Immunization Practices (ACIP) suggests that every adult over the age of 60 years get the herpes zoster vaccine.[32] Chickenpox. Shingles affects one in five adults infected with chick- The diagnosis of chickenpox is primarily based on the enpox as children, especially those who are immune- signs and symptom, with typical early symptoms followed suppressed, particularly from cancer, HIV, or other con- by a characteristic rash. Confirmation of the diagnosis is ditions. Stress can bring on shingles as well, although by examination of the fluid within the vesicles of the rash, scientists are still researching the connection.[33] Shingles 74 CHAPTER 8. CHICKENPOX

are most commonly found in adults over the age of 60 who lotion (a topical barrier preparation containing zinc oxide, were diagnosed with chickenpox when they were under and one of the most commonly used interventions), it has the age of 1.[34] an excellent safety profile.[42] It is important to maintain good hygiene and daily cleaning of skin with warm water to avoid secondary bacterial infection.[43] Scratching may 8.4 Prevention also increase the risk of secondary infection.[44] Paracetamol (acetaminophen) but not aspirin may be 8.4.1 Hygiene measures used to reduce fever. Aspirin use by someone with chickenpox may cause the serious, sometimes fatal disease of The spread of chickenpox can be prevented by isolating the liver and brain, Reye syndrome. People at risk of de- affected individuals. Contagion is by exposure to respira- veloping severe complications who have had significant tory droplets, or direct contact with lesions, within a pe- exposure to the virus may be given intra-muscular vari- riod lasting from three days before the onset of the rash, cella zoster immune globulin (VZIG), a preparation con- [35] taining high titres of antibodies to varicella zoster virus, to four days after the onset of the rash. The chicken- [45][46] pox virus is susceptible to disinfectants, notably chlorine to ward off the disease. bleach (i.e., sodium hypochlorite). Like all enveloped Antivirals are sometimes used.[47][48] viruses, it is sensitive to desiccation, heat and detergents.

8.5.1 Children 8.4.2 Vaccine If aciclovir by mouth is started within 24 hours of rash Main article: Varicella vaccine onset, it decreases symptoms by one day but has no effect on complication rates.[49][50] Use of acyclovir therefore is The varicella vaccine is recommended in many not currently recommended for individuals with normal countries.[10] Some countries require the varicella immune function. Children younger than 12 years old and vaccination or an exemption before entering elementary older than one month are not meant to receive antiviral school. A second dose is recommended five years after drugs unless they have another medical condition which [51] the initial immunization.[36] A vaccinated person is likely puts them at risk of developing complications. to have a milder case of chickenpox if they become Treatment of chickenpox in children is aimed at symp- infected.[37] Immunization within three days following toms while the immune system deals with the virus. With household contact reduces infection rates and severity in children younger than 12 years, cutting nails and keep- children.[11] ing them clean is an important part of treatment as they It is part of the routine immunization schedule in the are more likely to scratch their blisters more deeply than [52] US.[38] Some European countries include it as part of uni- adults. versal vaccinations in children,[39] but not all countries Aspirin is highly contraindicated in children younger than provide the vaccine due to its cost.[10] In the UK as of 16 years, as it has been related to Reye syndrome.[53] 2014, the vaccine is only recommended in people who are particularly vulnerable to chickenpox.[40] In populations that have not been immunized or if immunity is question- 8.5.2 Adults able, a clinician may order an Enzyme immunoassay. An immunoessay measures the levels of antibodies against Infection in otherwise healthy adults tends to be more the virus that give immunity to a person. If the levels of severe.[54] Treatment with antiviral drugs (e.g. acyclovir antibodies are low (low titer) or questionable, reimmu- or valacyclovir) is generally advised, as long as it is started nization may be done.[41] within 24–48 hours from rash onset.[51] Remedies to ease the symptoms of chickenpox in adults are basically the same as those used for children. Adults are more often 8.5 Treatment prescribed antiviral medication, as it is effective in reducing the severity of the condition and the likelihood of developing complications. Antiviral medicines do not Treatment mainly consists of easing the symptoms. As a kill the virus but stop it from multiplying. Adults are protective measure, people are usually required to stay at advised to increase water intake to reduce dehydration home while they are infectious to avoid spreading the dis- and to relieve headaches. Painkillers such as paracetamol ease to others. Cutting the nails short or wearing gloves (acetaminophen) are recommended, as they are effective may prevent scratching and minimize the risk of sec- in relieving itching and other symptoms such as fever or ondary infections. pains. Antihistamines relieve itching and may be used Although there have been no formal clinical studies eval- in cases where the itching prevents sleep, because they uating the effectiveness of topical application of calamine also act as a sedative. As with children, antiviral med- 8.7. EPIDEMIOLOGY 75

ication is considered more useful for those adults who cases of varicella pneumonia occur in the adult popula- are more prone to develop complications. These include tion. Rarer complications of disseminated chickenpox in- pregnant women or people who have a weakened immune clude myocarditis, hepatitis, and glomerulonephritis.[67] [55] system. Hemorrhagic complications are more common in the im- Sorivudine, a nucleoside analogue, has been reported munocompromised or immunosuppressed populations, to be eﬀective in the treatment of primary varicella in although healthy children and adults have been af- healthy adults (case reports only), but large-scale clinical fected. Five major clinical syndromes have been de- trials are still needed to demonstrate its eﬃcacy.[56] scribed: febrile purpura, malignant chickenpox with After recovering from chickenpox, it is recommended by purpura, postinfectious purpura, purpura fulminans, and doctors that adults take one injection of VZV immune anaphylactoid purpura. These syndromes have variable globulin and one injection of varicella vaccine or herpes courses, with febrile purpura being the most benign of zoster vaccine. the syndromes and having an uncomplicated outcome. In contrast, malignant chickenpox with purpura is a grave clinical condition that has a mortality rate of greater than 70%. The cause of these hemorrhagic chickenpox syn- 8.6 Prognosis dromes is not known.[67]

The duration of the visible blistering caused by varicella zoster virus varies in children usually from 4 to 7 days, 8.7 Epidemiology and the appearance of new blisters begins to subside after the ﬁfth day. Chickenpox infection is milder in young Primary varicella occurs in all countries worldwide. In children, and symptomatic treatment, with sodium bicar- 2013 the disease resulted in 7,000 deaths – down from bonate baths or antihistamine medication may ease itch- 8,900 in 1990.[13] ing. It is recommended to keep new infants from birth up to age 6 months away from an infected person for In temperate countries, chickenpox is primarily a disease 10 to 21 days because their immune systems are not de- of children, with most cases occurring during the win- veloped enough to handle the stress it can bring on.[57] ter and spring, most likely due to school contact. It is Paracetamol (acetaminophen) is widely used to reduce one of the classic diseases of childhood, with the highest fever. Aspirin, or products containing aspirin, should prevalence in the 4–10-year-old age group. Like rubella, not be given to children with chickenpox, as it can cause it is uncommon in preschool children. Varicella is highly Reye’s Syndrome.[58] communicable, with an infection rate of 90% in close contacts. In temperate countries, most people become In adults, the disease is more severe,[59] though the in- infected before adulthood, and 10% of young adults re- cidence is much less common. Infection in adults is main susceptible. associated with greater morbidity and mortality due to pneumonia (either direct viral pneumonia or secondary In the tropics, chickenpox often occurs in older people bacterial pneumonia),[60] bronchitis (either viral bron- and may cause more serious disease.[68] In adults, the chitis or secondary bacterial bronchitis),[60] hepatitis,[61] pock marks are darker and the scars more prominent than and encephalitis.[62] In particular, up to 10% of pregnant in children.[69] women with chickenpox develop pneumonia, the severity In the United States, the Centers for Disease Control and of which increases with onset later in gestation. In Eng- Prevention (CDC) does not require state health depart- land and Wales, 75% of deaths due to chickenpox are in [26] ments to report infections of chickenpox, and only 31 adults. Inﬂammation of the brain, or encephalitis, can states currently volunteer this information.[70] However, occur in immunocompromised individuals, although the in a 2013 study conducted by the social media disease risk is higher with herpes zoster.[63] Necrotizing fasciitis [64] surveillance tool called Sickweather, anecdotal reports is also a rare complication. of chickenpox infections on Facebook and Twitter were Varicella can be lethal to adults with impaired immu- used to measure and rank states with the most infections nity. The number of people in this high-risk group has per capita, with Maryland, Tennessee and Illinois in the increased, due to the HIV epidemic and the increased top three.[71] use of immunosuppressive therapies.[65] Varicella is a particular problem in hospitals, when there are patients with immune systems weakened by drugs (e.g., high-dose 8.8 Etymology steroids) or HIV.[66] Secondary bacterial infection of skin lesions, manifesting Why the term was used is not clear but it may be due to as impetigo, cellulitis, and erysipelas, is the most com- it being a relatively mild disease.[14] It has been said to mon complication in healthy children. Disseminated pri- be derived from chickpeas, based on resemblance of the mary varicella infection usually seen in the immunocom- vesicles to chickpeas,[14][72][73] or to come from the rash promised may have high morbidity. Ninety percent of resembling chicken pecks.[73] Other suggestions include 76 CHAPTER 8. CHICKENPOX the designation chicken for a child (i.e., literally 'child [9] Breuer J (2010). “VZV molecular epidemiology”. Cur- pox'), a corruption of itching-pox,[72][74] or the idea that rent Topics in Microbiology and Immunology. 342: 15–42. the disease may have originated in chickens.[75] Samuel doi:10.1007/82_2010_9. PMID 20229231. Johnson explained the designation as “from its being of [76] [10] Flatt, A; Breuer, J (September 2012). “Varicella vac- no very great danger.” cines.”. British medical bulletin. 103 (1): 115–27. doi:10.1093/bmb/lds019. PMID 22859715.

[11] Macartney, K; Heywood, A; McIntyre, P (23 June 8.9 Society and culture 2014). “Vaccines for post-exposure prophylaxis against varicella (chickenpox) in children and adults.”. The Because chickenpox is usually more severe in adults Cochrane database of systematic reviews. 6: CD001833. than it is in children, some parents deliberately expose doi:10.1002/14651858.CD001833.pub3. PMID their children to the virus, sometimes by taking them to 24954057. "chickenpox parties.” Doctors counter that children are [12] Global Burden of Disease Study 2013, Collaborators (22 safer getting the vaccine, which is a weakened form of August 2015). “Global, regional, and national incidence, the virus, rather than getting the disease, which can be prevalence, and years lived with disability for 301 acute [77] fatal. and chronic diseases and injuries in 188 countries, 1990- 2013: a systematic analysis for the Global Burden of Disease Study 2013.”. Lancet (London, England). 386 8.10 Other animals (9995): 743–800. doi:10.1016/s0140-6736(15)60692-4. PMC 4561509 . PMID 26063472.

Humans are the only known animal that the dis- [13] GBD 2013 Mortality and Causes of Death, Collaborators ease affects naturally.[7] However, chickenpox has been (17 December 2014). “Global, regional, and national age- caused in other primates, including chimpanzees[78] and sex specific all-cause and cause-specific mortality for 240 gorillas.[79] causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.”. Lancet. 385 (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. 8.11 References PMC 4340604 . PMID 25530442. [14] Oxford University Press (December 2014). “chickenpox, [1] “Chickenpox (Varicella) Signs & Symptoms”. Centers for n.”. oed.com. Retrieved February 4, 2015. Disease Control and Prevention (cdc.gov). November 16, [15] Anthony J Papadopoulos. Dirk M Elston, ed. 2011. Retrieved 4 February 2015. “Chickenpox Clinical Presentation”. Medscape Ref- [2] “Chickenpox (Varicella) Prevention & Treatment”. erence. Retrieved 4 August 2012. cdc.gov. November 16, 2011. Retrieved 4 February [16] “Symptoms of Chickenpox”. Chickenpox. NHS Choices. 2015. Retrieved 14 March 2013.

[3] “Chickenpox (Varicella) Overview”. cdc.gov. November [17] “Chickenpox (varicella)". Retrieved 6 November 2010. 16, 2011. Retrieved 4 February 2015. [18] Askalan R, Laughlin S, Mayank S, Chan A, MacGregor [4] “Routine vaccination against chickenpox?". Drug Ther D, Andrew M, Curtis R, Meaney B, deVeber G (June Bull. 50: 42–5. 2012. doi:10.1136/dtb.2012.04.0098. 2001). “Chickenpox and stroke in childhood: a study PMID 22495050. of frequency and causation”. Stroke. 32 (6): 1257–62. doi:10.1161/01.STR.32.6.1257. PMID 11387484. [5] GBD 2015 Mortality and Causes of Death, Collaborators. (8 October 2016). “Global, regional, and national life ex- [19] Heuchan AM, Isaacs D (19 March 2001). “The man- pectancy, all-cause mortality, and cause-speciﬁc mortality agement of varicella-zoster virus exposure and infection for 249 causes of death, 1980-2015: a systematic analysis in pregnancy and the newborn period. Australasian Sub- for the Global Burden of Disease Study 2015.”. Lancet group in Paediatric Infectious Diseases of the Australasian (London, England). 388 (10053): 1459–1544. PMID Society for Infectious Diseases.”. The Medical journal of 27733281. Australia. 174 (6): 288–92. PMID 11297117.

[6] “Chickenpox (Varicella) Complications”. cdc.gov. [20] Brannon, Heather (22 July 2007). “Chickenpox in Preg- November 16, 2011. Retrieved 4 February 2015. nanc”. Dermatology. About.com. Retrieved 20 June 2009. [7] Atkinson, William (2011). Epidemiology and Prevention of Vaccine-Preventable Diseases (12 ed.). Public Health [21] “Chickenpox During Pregnancy”. March of Dimes. Foundation. pp. 301–323. ISBN 9780983263135. Re- November 11, 2014. trieved 4 February 2015. [22] Boussault P, Boralevi F, Labbe L, Sarlangue J, Taïeb A, [8] “Chickenpox (Varicella) Interpreting Laboratory Tests”. Leaute-Labreze C (2007). “Chronic varicella-zoster skin cdc.gov. June 19, 2012. Retrieved 4 February 2015. infection complicating the congenital varicella syndrome”. 8.11. REFERENCES 77

Pediatr Dermatol. 24 (4): 429–32. doi:10.1111/j.1525- [36] Chaves SS, Gargiullo P, Zhang JX, Civen R, Guris D, 1470.2007.00471.x. PMID 17845179. Mascola L, Seward JF (2007). “Loss of vaccine-induced immunity to varicella over time”. N Engl J Med. 356 [23] Matsuo T, Koyama M, Matsuo N (July 1990). “Acute (11): 1121–9. doi:10.1056/NEJMoa064040. PMID retinal necrosis as a novel complication of chicken- 17360990. pox in adults”. Br J Ophthalmol. 74 (7): 443–4. doi:10.1136/bjo.74.7.443. PMC 1042160 . PMID [37] “Chickenpox (varicella) vaccination”. NHS Choices. UK 2378860. Department of Health. 19 April 2012.

[24] Mazzella M, Arioni C, Bellini C, Allegri AE, Savioli C, [38] “Child, Adolescent & “Catch-up” Immunization Sched- Serra G (2003). “Severe hydrocephalus associated with ules”. Immunization Schedules. Centers for Disease Con- congenital varicella syndrome”. Canadian Medical As- trol and Prevention. sociation Journal. 168 (5): 561–563. PMC 149248 . [39] Carrillo-Santisteve, P; Lopalco, PL (May 2014). “Vari- PMID 12615748. cella vaccination: a laboured take-oﬀ.”. Clinical Microbiology and Infection. 20 Suppl 5: 86–91. [25] Sauerbrei A, Wutzler P (December 2001). doi:10.1111/1469-0691.12580. PMID 24494784. “Neonatal varicella”. J Perinatol. 21 (8): 545–9. doi:10.1038/sj.jp.7210599. PMID 11774017. [40] “Why aren't children in the UK vaccinated against chickenpox?". NHS Choices. UK National Health Service. Re- [26] Royal College of Obstetricians and Gynaecologists trieved 10 June 2015. (September 2007). “Chickenpox in Pregnancy” (PDF). Retrieved 22 July 2009. [41] Leeuwen, Anne (2015). Davis’s comprehensive handbook of laboratory & diagnostic tests with nursing implications. [27] Pincus, Matthew R.; McPherson, Richard A.; Henry, Philadelphia: F.A. Davis Company. p. 1579. ISBN John Bernard (2007). “Ch. 54”. Henry’s clinical diag- 9780803644052. nosis and management by laboratory methods (21st ed.). Saunders Elsevier. ISBN 1-4160-0287-1. [42] Tebruegge M, Kuruvilla M, Margarson I (2006). “Does the use of calamine or antihistamine provide symptomatic [28] Kanbayashi Y, Onishi K, Fukazawa K, Okamoto K, Ueno relief from pruritus in children with varicella zoster infec- H, Takagi T, Hosokawa T (2012). “Predictive Factors tion?" (Abstract). Arch. Dis. Child. 91 (12): 1035–6. for Postherpetic Neuralgia Using Ordered Logistic Re- doi:10.1136/adc.2006.105114. PMC 2082986 . PMID gression Analysis”. The Clinical Journal of Pain. 28 (8): 17119083. 712–714. doi:10.1097/AJP.0b013e318243ee01. PMID 22209800. [43] Domino, Frank J. (2007). The 5-Minute Clinical Consult. Lippincott Williams & Wilkins. p. 248. ISBN 978-0- [29] Pino Rivero V, González Palomino A, Pantoja Hernández 7817-6334-9. CG, Mora Santos ME, Trinidad Ramos G, Blasco Huelva A (2006). “Ramsay-Hunt syndrome associated to unilat- [44] Brannon, Heather (21 May 2008). Chicken Pox Treat- eral recurrential paralysis”. Anales otorrinolaringologicos ments. About.com. ibero-americanos. 33 (5): 489–494. PMID 17091862. [45] Parmet S, Lynm C, Glass RM (February 2004). “JAMA [30] Nagel MA, Cohrs RJ, Mahalingam R, Wellish MC, patient page. Chickenpox”. JAMA. 291 (7): 906. Forghani B, Schiller A, Safdieh JE, Kamenkovich E, doi:10.1001/jama.291.7.906. PMID 14970070. Ostrow LW, Levy M, Greenberg B, Russman AN, Katzan I, Gardner CJ, Häusler M, Nau R, Saraya T, [46] Naus M; et al. (15 October 2006). “Varizig™ as the Vari- Wada H, Goto H, de Martino M, Ueno M, Brown cella Zoster Immune Globulin for the Prevention of Vari- WD, Terborg C, Gilden DH (March 2008). “The varicella In At-Risk Patients”. Canada Communicable Dis- cella zoster virus vasculopathies: clinical, CSF, imag- ease Report. 32 (ACS-8). ing, and virologic features.”. Neurology. 70: 853– 60. doi:10.1212/01.wnl.0000304747.38502.e8. PMC [47] Huﬀ JC (January 1988). “Antiviral treatment in chick- 2938740 . PMID 18332343. enpox and herpes zoster.”. Journal of the Ameri- can Academy of Dermatology. 18 (1 Pt 2): 204–6. [31] “Chickenpox”. NHS Choices. UK Department of Health. doi:10.1016/S0190-9622(88)70029-8. PMID 3339143. 19 April 2012. [48] Gnann Jr, John W. (2007). “Chapter 65Antiviral therapy [32] “Shingles Vaccine”. WebMD. of varicella-zoster virus infections”. In Arvin, Ann; et al. Human herpesviruses : biology, therapy, and immunopro- [33] “An Overview of Shingles”. WebMD. phylaxis. Cambridge: Cambridge University Press. ISBN 978-0-521-82714-0. Retrieved 20 January 2014. [34] “Shingles”. PubMed Health. [49] Kay, A. B. (2001). “Allergy and allergic diseases. First [35] Murray, Patrick R.; Rosenthal, Ken S.; Pfaller, Michael A. of two parts”. The New England Journal of Medicine. (2005). Medical Microbiology (5th ed.). Elsevier Mosby. 344 (1): 30–7. doi:10.1056/NEJM200101043440106. p. 551. ISBN 0-323-03303-2., edition (Elsevier), p. PMID 11136958. 78 CHAPTER 8. CHICKENPOX

[50] Kay, A. B. (2001). “Allergy and allergic diseases. Sec- [66] Weller TH (1997). “Varicella-herpes zoster virus”. In ond of two parts”. The New England Journal of Medicine. Evans AS, Kaslow RA. Viral Infections of Humans: Epi- 344 (2): 109–13. doi:10.1056/NEJM200101113440206. demiology and Control. Plenum Press. pp. 865–92. ISBN PMID 11150362. 978-0-306-44855-3.

[51] “Antiviral medications for chickenpox”. Retrieved 27 [67] Chicken Pox Complications March 2011. [68] Wharton M (1996). “The epidemiology of varicella- [52] “Chickenpox in Children Under 12”. Retrieved 6 Novem- zoster virus infections”. Infect Dis Clin North Am. 10 (3): ber 2010. 571–81. doi:10.1016/S0891-5520(05)70313-5. PMID 8856352. [53] “Reye’s Syndrome-Topic Overview”. Retrieved 27 March 2011. [69] “Epidemiology of Varicella Zoster Virus Infection, Epi- demiology of VZV Infection, Epidemiology of Chicken [54] Tunbridge AJ, Breuer J, Jeﬀery KJ (August Pox, Epidemiology of Shingles”. Retrieved 22 April 2008). “Chickenpox in adults - clinical manage- 2008. ment”. The Journal of Infection. 57 (2): 95–102. doi:10.1016/j.jinf.2008.03.004. PMID 18555533. [70] “Georgia ranks 10th for social media admissions of chickenpox”. Retrieved 13 June 2013. [55] “What is chickenpox?". Retrieved 6 November 2010. [71] “Chickenpox in the USA”. Retrieved 12 June 2013. [56] Chickenpox~treatment at eMedicine [72] Belshe, Robert B. (1984). Textbook of human virology [57] Somekh E, Dalal I, Shohat T, Ginsberg GM, Romano (2nd ed.). Littleton MA: PSG. p. 829. ISBN 0-88416- O (2002). “The burden of uncomplicated cases of 458-6. chickenpox in Israel”. J. Infect. 45 (1): 54–7. doi:10.1053/jinf.2002.0977. PMID 12217733. [73] Teri Shors (2011). “Herpesviruses: Varicella Zoster Virus (VZV)". Understanding Viruses (2nd ed.). Jones [58] US Centers for Disease Control and Prevention. & Bartlett. p. 459. ISBN 978-0-7637-8553-6. “Varicella Treatment Questions & Answers”. CDC Guidelines. CDC. Retrieved 23 August 2007. [74] Pattison, John; Zuckerman, Arie J.; Banatvala, J.E. (1994). Principles and practice of clinical virology (3rd [59] Baren JM, Henneman PL, Lewis RJ (August 1996). ed.). Wiley. p. 37. ISBN 0-471-93106-3. “Primary Varicella in Adults: Pneumonia, Pregnancy, and Hospital Admissions”. Annals of Emergency Medicine. [75] Chicken-pox is recorded in Oxford English Dictionary 28 (2): 165–169. doi:10.1016/S0196-0644(96)70057-4. 2nd ed. since 1684; the OED records several suggested PMID 8759580. etymologies

[60] Mohsen AH, McKendrick M (May 2003). “Varicella [76] Johnson, Samuel (1839). Dictionary of the English lan- pneumonia in adults”. Eur. Respir. J. 21 (5): 886–91. guage. London: Williamson. p. 195. doi:10.1183/09031936.03.00103202. PMID 12765439. [77] “Chicken Pox parties do more harm than good, says [61] Anderson, D.R.; Schwartz, J.; Hunter, N.J.; Cot- doctor”. KSLA News 12 Shreveport, Louisiana News trill, C.; Bissaccia, E.; Klainer, A.S. (1994). Weather & Sports. “Varicella Hepatitis: A Fatal Case in a Previously [78] Cohen JI, Moskal T, Shapiro M, Purcell RH (December Healthy, Immunocompetent Adult”. Archives of 1996). “Varicella in Chimpanzees”. Journal of Medical Internal Medicine. JAMA. 154 (18): 2101–2106. Virology. 50 (4): 289–92. doi:10.1002/(SICI)1096- doi:10.1001/archinte.1994.00420180111013. PMID 9071(199612)50:4<289::AID-JMV2>3.0.CO;2-4. 8092915. PMID 8950684. [62] Abro AH, Ustadi AM, Das K, Abdou AM, Hussaini [79] Myers MG, Kramer LW, Stanberry LR (December 1987). HS, Chandra FS (December 2009). “Chickenpox: pre- “Varicella in a gorilla”. Journal of Medical Virology. sentation and complications in adults”. Journal of Pak- 23 (4): 317–22. doi:10.1002/jmv.1890230403. PMID istan Medical Association. 59 (12): 828–831. PMID 2826674. 20201174. Retrieved 17 April 2013.

[63] “Deﬁnition of Chickenpox”. MedicineNet.com. Re- trieved 18 August 2006. 8.12 External links [64] “Is Necrotizing Fasciitis a complication of Chickenpox of Cutaneous Vasculitis?". atmedstu.com. Retrieved 18 Jan- uary 2008.

[65] Strangfeld A, Listing J, Herzer P, Liebhaber A, Rock- Wikipedia’s health care articles can be viewed witz K, Richter C, Zink A (February 2009). “Risk of oﬄine with the Medical Wikipedia app. herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents”. JAMA. 301 (7): 737–44. doi:10.1001/jama.2009.146. PMID 19224750. • Chickenpox at DMOZ 8.12. EXTERNAL LINKS 79

• “Prevention of Varicella: Recommendations of the Advisory Committee on Immunization Practices (ACIP)". Centers for Disease Control and Preven- tion (CDC). 12 July 1996. Retrieved 18 May 2013. • “Management of Varicella Zoster Virus (VZV) In- fections” (PDF). Federal Bureau of Prisons: Clini- cal Practice Guideline. December 2011. Retrieved 18 May 2013. • John W. Gnann Jr. (2007). “Chapter 65 Antiviral therapy of varicella-zoster virus infections”. PMID 21348091.

• Sarah McSweeney-Ryan; Megan Sandel. “The Health Care of Homeless Persons - Part I - Vari- cella (Chickenpox” (PDF). Boston Health Care for the Homeless Program. Retrieved 18 May 2013. Chapter 9

Meningitis

Warning: Page using Template:Infobox medical condi- In 2015 meningitis occurred in about 8.7 million peo- tion with unknown parameter “Image” (this message is ple worldwide.[6] This resulted in 379,000 deaths – down shown only in preview). from 464,000 deaths in 1990.[7][9] With appropriate treat- Warning: Page using Template:Infobox medical condi- ment the risk of death in bacterial meningitis is less than tion with unknown parameter “Name” (this message is 15%.[1] Outbreaks of bacterial meningitis occur between shown only in preview). December and June each year in an area of sub-Saharan Warning: Page using Template:Infobox medical condi- Africa known as the meningitis belt.[10] Smaller out- tion with unknown parameter “Caption” (this message is breaks may also occur in other areas of the world.[10] The shown only in preview). word meningitis is from Greek μῆνιγξ méninx, “membrane” and the medical suffix -itis, “inflammation”.[11][12] Meningitis is an acute inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges.[3] The most common symp- 9.1 Signs and symptoms toms are fever, headache and neck stiffness. Other symptoms include confusion or altered consciousness, vomit- 9.1.1 Clinical features ing, and an inability to tolerate light or loud noises. Young children often exhibit only nonspecific symptoms, such as irritability, drowsiness, or poor feeding.[1] If a rash is present, it may indicate a particular cause of meningitis; for instance, meningitis caused by meningococcal bacteria may be accompanied by a characteristic rash.[3][8] The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs.[2] Meningitis can be life- threatening because of the inflammation’s proximity to the brain and spinal cord; therefore, the condition is classified as a medical emergency.[3][5] A lumbar puncture diagnoses or excludes meningitis.[1] A needle is inserted into the spinal canal to collect a sample of cerebrospinal fluid (CSF), that envelops the brain and spinal cord. The Neck stiffness, Texas meningitis epidemic of 1911–12 CSF is examined in a medical laboratory.[5] Some forms of meningitis are preventable by In adults, the most common symptom of meningitis is immunization with the meningococcal, mumps, a severe headache, occurring in almost 90% of cases of pneumococcal, and Hib vaccines.[3] Giving antibiotics bacterial meningitis, followed by nuchal rigidity (the in- to people with significant exposure to certain types of ability to flex the neck forward passively due to increased meningitis may also be useful.[1] The first treatment in neck muscle tone and stiffness).[13] The classic triad of acute meningitis consists of promptly giving antibiotics diagnostic signs consists of nuchal rigidity, sudden high and sometimes antiviral drugs.[1][4] Corticosteroids fever, and altered mental status; however, all three fea- can also be used to prevent complications from exces- tures are present in only 44–46% of bacterial meningitis sive inflammation.[8][5] Meningitis can lead to serious cases.[13][14] If none of the three signs are present, acute long-term consequences such as deafness, epilepsy, meningitis is extremely unlikely.[14] Other signs com- hydrocephalus, or cognitive deficits, especially if not monly associated with meningitis include photophobia treated quickly.[3][8] (intolerance to bright light) and phonophobia (intolerance to loud noises). Small children often do not exhibit the

80 9.1. SIGNS AND SYMPTOMS 81

aforementioned symptoms, and may only be irritable and look unwell.[3] The fontanelle (the soft spot on the top of a baby’s head) can bulge in infants aged up to 6 months. Other features that distinguish meningitis from less severe illnesses in young children are leg pain, cold extremities, and an abnormal skin color.[15][16] Nuchal rigidity occurs in 70% of bacterial meningitis in adults.[14] Other signs include the presence of positive Kernig’s sign or Brudziński sign. Kernig’s sign is assessed with the person lying supine, with the hip and knee flexed to 90 degrees. In a person with a positive Kernig’s sign, pain limits passive extension of the knee. A positive Brudzinski’s sign occurs when flexion of the neck causes involuntary flexion of the knee and hip. Al- Charlotte Cleverley-Bisman developed severe meningococcal though Kernig’s sign and Brudzinski’s sign are both com- meningitis as a young child; in her case, the petechial rash pro- monly used to screen for meningitis, the sensitivity of gressed to gangrene and required amputation of all limbs. She survived the disease and became a poster child for a meningitis these tests is limited.[14][17] They do, however, have very vaccination campaign in New Zealand. good specificity for meningitis: the signs rarely occur in other diseases.[14] Another test, known as the “jolt accen- tuation maneuver” helps determine whether meningitis is present in those reporting fever and headache. A person is asked to rapidly rotate the head horizontally; if this does not make the headache worse, meningitis is unlikely.[14] Other problems can produce symptoms similar to those cessive activation of blood clotting, may obstruct blood above, but from non-meningitic causes. This is called flow to organs and paradoxically increase the bleeding meningism or pseudomeningitis. risk. Gangrene of limbs can occur in meningococcal disease.[3] Severe meningococcal and pneumococcal in- Meningitis caused by the bacterium Neisseria menin- fections may result in hemorrhaging of the adrenal glands, gitidis (known as “meningococcal meningitis”) can be leading to Waterhouse-Friderichsen syndrome, which is differentiated from meningitis with other causes by a often fatal.[19] rapidly spreading petechial rash, which may precede other symptoms.[15] The rash consists of numerous small, The brain tissue may swell, pressure inside the skull may irregular purple or red spots (“petechiae”) on the trunk, increase and the swollen brain may herniate through the lower extremities, mucous membranes, conjuctiva, and skull base. This may be noticed by a decreasing level (occasionally) the palms of the hands or soles of the feet. of consciousness, loss of the pupillary light reflex, and The rash is typically non-blanching; the redness does not abnormal posturing.[8] The inflammation of the brain tis- disappear when pressed with a finger or a glass tumbler. sue may also obstruct the normal flow of CSF around the Although this rash is not necessarily present in meningo- brain (hydrocephalus).[8] Seizures may occur for various coccal meningitis, it is relatively specific for the disease; reasons; in children, seizures are common in the early it does, however, occasionally occur in meningitis due to stages of meningitis (in 30% of cases) and do not neces- other bacteria.[3] Other clues on the cause of meningitis sarily indicate an underlying cause.[5] Seizures may result may be the skin signs of hand, foot and mouth disease and from increased pressure and from areas of inflammation genital herpes, both of which are associated with various in the brain tissue.[8] Focal seizures (seizures that involve forms of viral meningitis.[18] one limb or part of the body), persistent seizures, late- onset seizures and those that are difficult to control with medication indicate a poorer long-term outcome.[3] 9.1.2 Early complications Inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising from Additional problems may occur in the early stage of the the brain stem that supply the head and neck area and illness. These may require specific treatment, and some- which control, among other functions, eye movement, times indicate severe illness or worse prognosis. The in- facial muscles, and hearing.[3][14] Visual symptoms and fection may trigger sepsis, a systemic inflammatory re- hearing loss may persist after an episode of meningitis.[3] sponse syndrome of falling blood pressure, fast heart rate, Inflammation of the brain (encephalitis) or its blood ves- high or abnormally low temperature, and rapid breath- sels (cerebral vasculitis), as well as the formation of blood ing. Very low blood pressure may occur at an early stage, clots in the veins (cerebral venous thrombosis), may all especially but not exclusively in meningococcal menin- lead to weakness, loss of sensation, or abnormal move- gitis; this may lead to insufficient blood supply to other ment or function of the part of the body supplied by the organs.[3] Disseminated intravascular coagulation, the ex- affected area of the brain.[3][8] 82 CHAPTER 9. MENINGITIS

9.2 Causes in the brain and meninges, such as cerebral shunts, extraventricular drains or Ommaya reservoirs, carry an Meningitis is typically caused by an infection with increased risk of meningitis. In these cases, the per- microorganisms. Most infections are due to viruses,[14] sons are more likely to be infected with Staphylococci, [5] with bacteria, fungi, and protozoa being the next most Pseudomonas, and other Gram-negative bacteria. common causes.[2] It may also result from various non- These pathogens are also associated with meningitis in [3] infectious causes.[2] The term aseptic meningitis refers to people with an impaired immune system. An infec- cases of meningitis in which no bacterial infection can be tion in the head and neck area, such as otitis media or demonstrated. This type of meningitis is usually caused mastoiditis, can lead to meningitis in a small proportion [5] by viruses but it may be due to bacterial infection that of people. Recipients of cochlear implants for hearing [22] has already been partially treated, when bacteria disap- loss are more at risk for pneumococcal meningitis. pear from the meninges, or pathogens infect a space ad- Tuberculous meningitis, which is meningitis caused by jacent to the meninges (e.g. sinusitis). Endocarditis (an Mycobacterium tuberculosis, is more common in people infection of the heart valves which spreads small clusters from countries in which tuberculosis is endemic, but is of bacteria through the bloodstream) may cause aseptic also encountered in persons with immune problems, such meningitis. Aseptic meningitis may also result from in- as AIDS.[23] fection with spirochetes, a type of bacteria that includes Recurrent bacterial meningitis may be caused by persist- Treponema pallidum (the cause of syphilis) and Borrelia ing anatomical defects, either congenital or acquired, or burgdorferi (known for causing Lyme disease). Menin- by disorders of the immune system.[24] Anatomical de- gitis may be encountered in cerebral malaria (malaria infects allow continuity between the external environment fecting the brain) or amoebic meningitis, meningitis due and the nervous system. The most common cause of re- to infection with amoebae such as Naegleria fowleri, concurrent meningitis is a skull fracture,[24] particularly frac- tracted from freshwater sources.[2] tures that affect the base of the skull or extend towards the sinuses and petrous pyramids.[24] Approximately 59% of 9.2.1 Bacterial recurrent meningitis cases are due to such anatomical abnormalities, 36% are due to immune deficiencies (such as See also: Neonatal infection complement deficiency, which predisposes especially to recurrent meningococcal meningitis), and 5% are due to ongoing infections in areas adjacent to the meninges.[24] The types of bacteria that cause bacterial meningitis vary according to the infected individual’s age group. 9.2.2 Viral • In premature babies and newborns up to three months old, common causes are group B strepto- Viruses that cause meningitis include enteroviruses, cocci (subtypes III which normally inhabit the vagina herpes simplex virus (generally type 2, which produces and are mainly a cause during the first week of life) most genital sores; less commonly type 1), varicella and bacteria that normally inhabit the digestive tract zoster virus (known for causing chickenpox and shingles), such as Escherichia coli (carrying the K1 antigen). mumps virus, HIV, and LCMV.[18] Mollaret’s meningi- Listeria monocytogenes (serotype IVb) is transmitted tis is a chronic recurrent form of herpes meningitis; it is by the mother before birth and may cause meningitis thought to be caused by herpes simplex virus type 2.[25] in the newborn.[20] • Older children are more commonly affected by Neisseria meningitidis (meningococcus) and 9.2.3 Fungal Streptococcus pneumoniae (serotypes 6, 9, 14, There are a number of risk factors for fungal meningitis, 18 and 23) and those under five by Haemophilus including the use of immunosuppressants (such as after influenzae type B (in countries that do not offer organ transplantation), HIV/AIDS,[26] and the loss of im- vaccination).[3][5] munity associated with aging.[27] It is uncommon in those • In adults, Neisseria meningitidis and Streptococcus with a normal immune system[28] but has occurred with pneumoniae together cause 80% of bacterial menin- medication contamination.[29] Symptom onset is typically gitis cases. Risk of infection with Listeria monocyto- more gradual, with headaches and fever being present genes is increased in persons over 50 years old.[8][5] for at least a couple of weeks before diagnosis.[27] The The introduction of pneumococcal vaccine has low- most common fungal meningitis is cryptococcal menin- ered rates of pneumococcal meningitis in both chil- gitis due to Cryptococcus neoformans.[30] In Africa, cryp- dren and adults.[21] tococcal meningitis is now the most common cause of meningitis in multiple studies,[31][32] and it accounts for Recent skull trauma potentially allows nasal cavity bac- 20–25% of AIDS-related deaths in Africa.[33] Other less teria to enter the meningeal space. Similarly, devices common fungal pathogens which can cause meningitis 9.4. DIAGNOSIS 83

include: Coccidioides immitis, Histoplasma capsulatum, enter the subarachnoid space in places where the blood– Blastomyces dermatitidis, and Candida species.[27] brain barrier is vulnerable—such as the choroid plexus. Meningitis occurs in 25% of newborns with bloodstream infections due to group B streptococci; this phenomenon 9.2.4 Parasitic is less common in adults.[3] Direct contamination of the cerebrospinal fluid may arise from indwelling devices, A parasitic cause is often assumed when there is a pre- skull fractures, or infections of the nasopharynx or the dominance of eosinophils (a type of white blood cell) nasal sinuses that have formed a tract with the subarach- in the CSF. The most common parasites implicated are noid space (see above); occasionally, congenital defects Angiostrongylus cantonensis, Gnathostoma spinigerum, of the dura mater can be identified.[3] Schistosoma, as well as the conditions cysticercosis, The large-scale inflammation that occurs in the subarach- toxocariasis, baylisascariasis, paragonimiasis, and a num- noid space during meningitis is not a direct result of bac- [34] ber of rarer infections and noninfective conditions. terial infection but can rather largely be attributed to the response of the immune system to the entry of bacteria into the central nervous system. When components of 9.2.5 Non-infectious the bacterial cell membrane are identified by the immune cells of the brain (astrocytes and microglia), they respond Meningitis may occur as the result of several non- by releasing large amounts of cytokines, hormone-like infectious causes: spread of cancer to the meninges mediators that recruit other immune cells and stimulate (malignant or neoplastic meningitis)[35] and certain other tissues to participate in an immune response. The drugs (mainly non-steroidal anti-inflammatory drugs, blood–brain barrier becomes more permeable, leading to antibiotics and intravenous immunoglobulins).[36] It may “vasogenic” cerebral edema (swelling of the brain due also be caused by several inflammatory conditions, such to fluid leakage from blood vessels). Large numbers of as sarcoidosis (which is then called neurosarcoidosis), white blood cells enter the CSF, causing inflammation of connective tissue disorders such as systemic lupus ery- the meninges and leading to “interstitial” edema (swelling thematosus, and certain forms of vasculitis (inflammatory due to fluid between the cells). In addition, the walls conditions of the blood vessel wall), such as Behçet’s dis- of the blood vessels themselves become inflamed (cere- ease.[2] Epidermoid cysts and dermoid cysts may cause bral vasculitis), which leads to decreased blood flow and a meningitis by releasing irritant matter into the subarach- third type of edema, “cytotoxic” edema. The three forms noid space.[2][24] Rarely, migraine may cause meningitis, of cerebral edema all lead to increased intracranial pres- but this diagnosis is usually only made when other causes sure; together with the lowered blood pressure often en- have been eliminated.[2] countered in acute infection, this means that it is harder for blood to enter the brain, consequently brain cells are deprived of oxygen and undergo apoptosis (programmed 9.3 Mechanism cell death).[3] It is recognized that administration of antibiotics may The meninges comprise three membranes that, together initially worsen the process outlined above, by increas- with the cerebrospinal fluid, enclose and protect the brain ing the amount of bacterial cell membrane products and spinal cord (the central nervous system). The pia released through the destruction of bacteria. Particu- mater is a very delicate impermeable membrane that lar treatments, such as the use of corticosteroids, are firmly adheres to the surface of the brain, following all the aimed at dampening the immune system’s response to this [3][8] minor contours. The arachnoid mater (so named because phenomenon. of its spider-web-like appearance) is a loosely fitting sac on top of the pia mater. The subarachnoid space separates the arachnoid and pia mater membranes and is filled with 9.4 Diagnosis cerebrospinal fluid. The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the arachnoid membrane and the skull. 9.4.1 Blood tests and imaging In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or In someone suspected of having meningitis, blood tests through direct contact between the meninges and either are performed for markers of inflammation (e.g. C- reactive protein, complete blood count), as well as blood the nasal cavity or the skin. In most cases, meningitis fol- [5][38] lows invasion of the bloodstream by organisms that live cultures. upon mucous surfaces such as the nasal cavity. This is The most important test in identifying or ruling out often in turn preceded by viral infections, which break meningitis is analysis of the cerebrospinal fluid through down the normal barrier provided by the mucous sur- lumbar puncture (LP, spinal tap).[39] However, lumbar faces. Once bacteria have entered the bloodstream, they puncture is contraindicated if there is a mass in the brain 84 CHAPTER 9. MENINGITIS

(tumor or abscess) or the intracranial pressure (ICP) is only seen in 60% of cases; this figure is reduced by a elevated, as it may lead to brain herniation. If someone further 20% if antibiotics were administered before the is at risk for either a mass or raised ICP (recent head in- sample was taken. Gram staining is also less reliable in jury, a known immune system problem, localizing neu- particular infections such as listeriosis. Microbiological rological signs, or evidence on examination of a raised culture of the sample is more sensitive (it identifies the ICP), a CT or MRI scan is recommended prior to the organism in 70–85% of cases) but results can take up to lumbar puncture.[5][38][40] This applies in 45% of all adult 48 hours to become available.[5] The type of white blood cases.[8] If a CT or MRI is required before LP, or if cell predominantly present (see table) indicates whether LP proves difficult, professional guidelines suggest that meningitis is bacterial (usually neutrophil-predominant) antibiotics should be administered first to prevent delay or viral (usually lymphocyte-predominant),[5] although at in treatment,[5] especially if this may be longer than 30 the beginning of the disease this is not always a reliable minutes.[38][40] Often, CT or MRI scans are performed at indicator. Less commonly, eosinophils predominate, sug- a later stage to assess for complications of meningitis.[3] gesting parasitic or fungal etiology, among others.[34] In severe forms of meningitis, monitoring of blood elec- The concentration of glucose in CSF is normally above trolytes may be important; for example, hyponatremia is 40% of that in blood. In bacterial meningitis it is typi- common in bacterial meningitis, due to a combination of cally lower; the CSF glucose level is therefore divided by factors, including dehydration, the inappropriate secre- the blood glucose (CSF glucose to serum glucose ratio). tion of the antidiuretic hormone (SIADH), or overly ag- A ratio ≤0.4 is indicative of bacterial meningitis;[39] in gressive intravenous fluid administration.[8][41] the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal.[5] High levels of lactate in CSF indicate a 9.4.2 Lumbar puncture higher likelihood of bacterial meningitis, as does a higher white blood cell count.[39] If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis.[43] Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli and group B streptococci; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful.[5] Polymerase chain reaction (PCR) is a Gram stain of meningococci from a culture showing Gram negative (pink) bacteria, often in pairs technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA A lumbar puncture is done by positioning the perin cerebrospinal fluid; it is a highly sensitive and spe- son, usually lying on the side, applying local anes- cific test since only trace amounts of the infecting agent’s thetic, and inserting a needle into the dural sac (a sac DNA is required. It may identify bacteria in bacterial around the spinal cord) to collect cerebrospinal fluid meningitis and may assist in distinguishing the various (CSF). When this has been achieved, the “opening causes of viral meningitis (enterovirus, herpes simplex [18] pressure” of the CSF is measured using a manometer. virus 2 and mumps in those not vaccinated for this). The pressure is normally between 6 and 18 cm water Serology (identification of antibodies to viruses) may be [18] [39] useful in viral meningitis. If tuberculous meningitis (cmH2O); in bacterial meningitis the pressure is usually elevated.[5][38] In cryptococcal meningitis, intracra- is suspected, the sample is processed for Ziehl-Neelsen nial pressure is markedly elevated.[42] The initial appear- stain, which has a low sensitivity, and tuberculosis cul- ance of the fluid may prove an indication of the nature ture, which takes a long time to process; PCR is being [23] of the infection: cloudy CSF indicates higher levels of used increasingly. Diagnosis of cryptococcal menin- protein, white and red blood cells and/or bacteria, and gitis can be made at low cost using an India ink stain therefore may suggest bacterial meningitis.[5] of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive, particularly in people The CSF sample is examined for presence and types of with AIDS.[44][45] white blood cells, red blood cells, protein content and glucose level.[5] Gram staining of the sample may demon- A diagnostic and therapeutic difficulty is “partially treated strate bacteria in bacterial meningitis, but absence of bac- meningitis”, where there are meningitis symptoms after teria does not exclude bacterial meningitis as they are receiving antibiotics (such as for presumptive sinusitis). 9.5. PREVENTION 85

When this happens, CSF ﬁndings may resemble those of 9.5.2 Vaccination viral meningitis, but antibiotic treatment may need to be continued until there is deﬁnitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).[18]

Since the 1980s, many countries have included 9.4.3 Postmortem immunization against Haemophilus influenzae type B in their routine childhood vaccination schemes. This has practically eliminated this pathogen as a cause of meningitis in young children in those countries. In the countries in which the disease burden is highest, however, the vaccine is still too expensive.[48][49] Similarly, immunization against mumps has led to a sharp fall in the number of cases of mumps meningitis, which prior to vaccination occurred in 15% of all cases of mumps.[18] Meningococcus vaccines exist against groups A, B, C, W135 and Y.[50][51][52] In countries where the vaccine for meningococcus group C was introduced, cases caused by this pathogen have decreased substantially.[48] A quadri- valent vaccine now exists, which combines four vaccines with the exception of B; immunization with this ACW135Y vaccine is now a visa requirement for taking Histopathology of bacterial meningitis: autopsy case of a per- part in Hajj.[53] Development of a vaccine against group son with pneumococcal meningitis showing inflammatory infil- B meningococci has proved much more difficult, as its trates of the pia mater consisting of neutrophil granulocytes (in- surface proteins (which would normally be used to make set, higher magnification). a vaccine) only elicit a weak response from the immune system, or cross-react with normal human proteins.[48][50] Meningitis can be diagnosed after death has occurred. Still, some countries (New Zealand, Cuba, Norway and The findings from a post mortem are usually a widespread Chile) have developed vaccines against local strains of inflammation of the pia mater and arachnoid layers of group B meningococci; some have shown good re- the meninges. Neutrophil granulocytes tend to have mi- sults and are used in local immunization schedules.[50] grated to the cerebrospinal fluid and the base of the brain, Two new vaccines, both approved in 2014, are effec- along with cranial nerves and the spinal cord, may be sur- tive against a wider range of group B meningococci rounded with pus – as may the meningeal vessels.[46] strains.[51][52] In Africa, until recently, the approach for prevention and control of meningococcal epidemics was based on early detection of the disease and emergency reactive mass vaccination of the at-risk population 9.5 Prevention with bivalent A/C or trivalent A/C/W135 polysaccharide vaccines,[54] though the introduction of MenAfriVac For some causes of meningitis, protection can be pro- (meningococcus group A vaccine) has demonstrated ef- vided in the long term through vaccination, or in the short fectiveness in young people and has been described as a term with antibiotics. Some behavioral measures may model for product development partnerships in resource- also be effective. limited settings.[55][56] Routine vaccination against Streptococcus pneumoniae with the pneumococcal conjugate vaccine (PCV), which 9.5.1 Behavioral is active against seven common serotypes of this pathogen, significantly reduces the incidence of pneu- Bacterial and viral meningitis are contagious, but neither mococcal meningitis.[48][57] The pneumococcal polysac- is as contagious as the common cold or flu.[47] Both can charide vaccine, which covers 23 strains, is only admin- be transmitted through droplets of respiratory secretions istered to certain groups (e.g. those who have had a during close contact such as kissing, sneezing or cough- splenectomy, the surgical removal of the spleen); it does ing on someone, but cannot be spread by only breathing not elicit a significant immune response in all recipi- the air where a person with meningitis has been.[47] Vi- ents, e.g. small children.[57] Childhood vaccination with ral meningitis is typically caused by enteroviruses, and is Bacillus Calmette-Guérin has been reported to signifi- most commonly spread through fecal contamination.[47] cantly reduce the rate of tuberculous meningitis, but its The risk of infection can be decreased by changing the waning effectiveness in adulthood has prompted a search behavior that led to transmission. for a better vaccine.[48] 86 CHAPTER 9. MENINGITIS

9.5.3 Antibiotics

Short-term antibiotic prophylaxis is another method of prevention, particularly of meningococcal meningitis. In cases of meningococcal meningitis, preventative treatment in close contacts with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) can reduce their risk of con- tracting the condition, but does not protect against future infections.[38][58] Resistance to rifampicin has been noted to increase after use, which has caused some to recommend considering other agents.[58] While antibi- Structural formula of ceftriaxone, one of the third-generation ce- otics are frequently used in an attempt to prevent menin- falosporin antibiotics recommended for the initial treatment of gitis in those with a basilar skull fracture there is not bacterial meningitis. enough evidence to determine whether this is beneficial or harmful.[59] This applies to those with or without a CSF [59] place and population. For instance, in the United King- leak. dom empirical treatment consists of a third-generation cefalosporin such as cefotaxime or ceftriaxone.[38][40] In the USA, where resistance to cefalosporins is increasingly 9.6 Management found in streptococci, addition of vancomycin to the initial treatment is recommended.[8][5][38] Chloramphenicol, Meningitis is potentially life-threatening and has a high either alone or in combination with ampicillin, however, mortality rate if untreated;[5] delay in treatment has been appears to work equally well.[61] [8] associated with a poorer outcome. Thus, treatment with Empirical therapy may be chosen on the basis of the wide-spectrum antibiotics should not be delayed while [40] person’s age, whether the infection was preceded by confirmatory tests are being conducted. If meningo- a head injury, whether the person has undergone re- coccal disease is suspected in primary care, guidelines cent neurosurgery and whether or not a cerebral shunt is recommend that benzylpenicillin be administered before [5] [15] present. In young children and those over 50 years of transfer to hospital. Intravenous fluids should be ad- age, as well as those who are immunocompromised, the ministered if hypotension (low blood pressure) or shock [40] addition of ampicillin is recommended to cover Listeria are present. In children routine intravenous fluids for monocytogenes.[5][38] Once the Gram stain results become two days may improve outcomes in those who arrive at [60] available, and the broad type of bacterial cause is known, hospital after being sick for some time. Given that it may be possible to change the antibiotics to those likely meningitis can cause a number of early severe complica- to deal with the presumed group of pathogens.[5] The re- tions, regular medical review is recommended to identify sults of the CSF culture generally take longer to become these complications early[40] and to admit the person to [8] available (24–48 hours). Once they do, empiric therapy an intensive care unit if deemed necessary. may be switched to specific antibiotic therapy targeted Mechanical ventilation may be needed if the level of to the specific causative organism and its sensitivities to consciousness is very low, or if there is evidence of antibiotics.[5] For an antibiotic to be effective in menin- respiratory failure. If there are signs of raised in- gitis it must not only be active against the pathogenic tracranial pressure, measures to monitor the pressure bacterium but also reach the meninges in adequate quan- may be taken; this would allow the optimization of the tities; some antibiotics have inadequate penetrance and cerebral perfusion pressure and various treatments to de- therefore have little use in meningitis. Most of the an- crease the intracranial pressure with medication (e.g. tibiotics used in meningitis have not been tested directly mannitol).[8] Seizures are treated with anticonvulsants.[8] on people with meningitis in clinical trials. Rather, the Hydrocephalus (obstructed flow of CSF) may require in- relevant knowledge has mostly derived from laboratory sertion of a temporary or long-term drainage device, such studies in rabbits.[5] Tuberculous meningitis requires pro- as a cerebral shunt.[8] longed treatment with antibiotics. While tuberculosis of the lungs is typically treated for six months, those with tuberculous meningitis are typically treated for a year or 9.6.1 Bacterial meningitis longer.[23]

Antibiotics Steroids Empiric antibiotics (treatment without exact diagnosis) should be started immediately, even before the results Additional treatment with corticosteroids (usually of the lumbar puncture and CSF analysis are known. dexamethasone) has shown some beneﬁts, such as a The choice of initial treatment depends largely on the reduction of hearing loss, and better short term neu- kind of bacteria that cause meningitis in a particular rological outcomes[62] in adolescents and adults from 9.7. PROGNOSIS 87

high-income countries with low rates of HIV.[63] Some research has found reduced rates of death[63] while other research has not.[62] They also appear to be beneficial in those with tuberculosis meningitis, at least in those who are HIV negative.[64] Professional guidelines therefore recommend the com- mencement of dexamethasone or a similar corticosteroid just before the first dose of antibiotics is given, and con- [38][40] tinued for four days. Given that most of the benefit Disability-adjusted life year for meningitis per 100,000 inhabi- of the treatment is confined to those with pneumococ- tants in 2004.[69] cal meningitis, some guidelines suggest that dexamethasone be discontinued if another cause for meningitis is identified.[5][38] The likely mechanism is suppression of overactive inflammation.[65] 9.7 Prognosis

Additional treatment with corticosteroids have a differ- Untreated, bacterial meningitis is almost always fatal. Vi- ent role in children than in adults. Though the bene- ral meningitis, in contrast, tends to resolve spontaneously fit of corticosteroids has been demonstrated in adults as and is rarely fatal. With treatment, mortality (risk of well as in children from high-income countries, their use death) from bacterial meningitis depends on the age of in children from low-income countries is not supported the person and the underlying cause. Of newborns, 20– by the evidence; the reason for this discrepancy is not [62] 30% may die from an episode of bacterial meningitis. clear. Even in high-income countries, the benefit of This risk is much lower in older children, whose mor- corticosteroids is only seen when they are given prior to tality is about 2%, but rises again to about 19–37% in the first dose of antibiotics, and is greatest in cases of [3][8] [5][66] adults. Risk of death is predicted by various factors H. influenzae meningitis, the incidence of which has apart from age, such as the pathogen and the time it takes decreased dramatically since the introduction of the Hib for the pathogen to be cleared from the cerebrospinal vaccine. Thus, corticosteroids are recommended in the fluid,[3] the severity of the generalized illness, a decreased treatment of pediatric meningitis if the cause is H. in- level of consciousness or an abnormally low count of fluenzae, and only if given prior to the first dose of an- [8] [5] white blood cells in the CSF. Meningitis caused by tibiotics; other uses are controversial. H. influenzae and meningococci has a better prognosis than cases caused by group B streptococci, coliforms and S. pneumonia.[3] In adults, too, meningococcal meningitis has a lower mortality (3–7%) than pneumococcal 9.6.2 Viral meningitis disease.[8] In children there are several potential disabilities which Viral meningitis typically only requires supportive ther- may result from damage to the nervous system, includ- apy; most viruses responsible for causing meningitis are ing sensorineural hearing loss, epilepsy, learning and be- not amenable to specific treatment. Viral meningitis havioral difficulties, as well as decreased intelligence.[3] tends to run a more benign course than bacterial menin- These occur in about 15% of survivors.[3] Some of the gitis. Herpes simplex virus and varicella zoster virus hearing loss may be reversible.[70] In adults, 66% of all may respond to treatment with antiviral drugs such as cases emerge without disability. The main problems are aciclovir, but there are no clinical trials that have specif- deafness (in 14%) and cognitive impairment (in 10%).[8] [18] ically addressed whether this treatment is effective. Tuberculous meningitis in children continues to be as- Mild cases of viral meningitis can be treated at home sociated with a significant risk of death even with treat- with conservative measures such as fluid, bedrest, and [67] ment (19%), and a significant proportion of the surviving analgesics. children have ongoing neurological problems. Just over a third of all cases survives with no problems.[71]

9.6.3 Fungal meningitis 9.8 Epidemiology

Fungal meningitis, such as cryptococcal meningitis, is Although meningitis is a notiﬁable disease in many coun- treated with long courses of high dose antifungals, such as tries, the exact incidence rate is unknown.[18] In 2013 amphotericin B and ﬂucytosine.[44][68] Raised intracranial meningitis resulted in 303,000 deaths – down from pressure is common in fungal meningitis, and frequent 464,000 deaths in 1990.[9] In 2010 it was estimated (ideally daily) lumbar punctures to relieve the pressure that meningitis resulted in 420,000 deaths,[72] excluding are recommended,[44] or alternatively a lumbar drain.[42] cryptococcal meningitis.[73] 88 CHAPTER 9. MENINGITIS

and the annual Hajj pilgrimage.[53] Although the pattern of epidemic cycles in Africa is not well understood, several factors have been associated with the development of epidemics in the meningitis belt. They include: medical conditions (immunological susceptibility of the population), demographic conditions (travel and large population displacements), socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent infections (acute respiratory infections).[76] Demography of meningococcal meningitis. meningitis belt There are signiﬁcant diﬀerences in the local distribution epidemic zones of causes for bacterial meningitis. For instance, while N. sporadic cases only meningitides groups B and C cause most disease episodes in Europe, group A is found in Asia and continues to predominate in Africa, where it causes most of the major epidemics in the meningitis belt, accounting for about 80% to 85% of documented meningococcal meningitis cases.[76]

9.9 History Deaths from meningitis per million persons in 2012 0-2 Some suggest that Hippocrates may have realized the ex- 3-3 [14] 4-6 istence of meningitis, and it seems that meningism 7-9 was known to pre-Renaissance physicians such as [78] 10-20 Avicenna. The description of tuberculous meningitis, 21-31 then called "dropsy in the brain”, is often attributed to 32-61 Edinburgh physician Sir Robert Whytt in a posthumous 62-153 report that appeared in 1768, although the link with tu- 154-308 berculosis and its pathogen was not made until the next 309-734 century.[78][79] It appears that epidemic meningitis is a relatively recent phenomenon.[80] The first recorded major outbreak oc- Bacterial meningitis occurs in about 3 people per 100,000 curred in Geneva in 1805.[80][81] Several other epidemics annually in Western countries. Population-wide studies in Europe and the United States were described shortly have shown that viral meningitis is more common, at 10.9 afterward, and the first report of an epidemic in Africa per 100,000, and occurs more often in the summer. In appeared in 1840. African epidemics became much more Brazil, the rate of bacterial meningitis is higher, at 45.8 common in the 20th century, starting with a major epi- per 100,000 annually.[14] Sub-Saharan Africa has been demic sweeping Nigeria and Ghana in 1905–1908.[80] plagued by large epidemics of meningococcal menin- [74] The first report of bacterial infection underlying meningitis for over a century, leading to it being labeled gitis was by the Austrian bacteriologist Anton Weich- the “meningitis belt”. Epidemics typically occur in the selbaum, who in 1887 described the meningococcus.[82] dry season (December to June), and an epidemic wave Mortality from meningitis was very high (over 90%) in can last two to three years, dying out during the inter- early reports. In 1906, antiserum was produced in horses; vening rainy seasons.[75] Attack rates of 100–800 cases [76] this was developed further by the American scientist per 100,000 are encountered in this area, which is Simon Flexner and markedly decreased mortality from poorly served by medical care. These cases are predomi- [83][84] [14] meningococcal disease. In 1944, penicillin was first nantly caused by meningococci. The largest epidemic reported to be effective in meningitis.[85] The introduc- ever recorded in history swept across the entire region tion in the late 20th century of Haemophilus vaccines led in 1996–1997, causing over 250,000 cases and 25,000 [77] to a marked fall in cases of meningitis associated with this deaths. pathogen,[49] and in 2002, evidence emerged that treat- Meningococcal disease occurs in epidemics in areas ment with steroids could improve the prognosis of bac- where many people live together for the first time, such as terial meningitis.[62][65][84] World Meningitis Day is cele- army barracks during mobilization, college campuses[3] brated on the 24th of April each year. 9.10. REFERENCES 89

9.10 References [14] Attia J, Hatala R, Cook DJ, Wong JG (July 1999). “The rational clinical examination. Does this adult [1] “Bacterial Meningitis”. CDC. April 1, 2014. Retrieved 5 patient have acute meningitis?". Journal of the March 2016. American Medical Association. 282 (2): 175–81. doi:10.1001/jama.282.2.175. PMID 10411200. [2] Ginsberg L (March 2004). “Diﬃcult and recurrent meningitis” (PDF). Journal of Neurology, Neuro- [15] Theilen U, Wilson L, Wilson G, Beattie JO, Qureshi surgery, and Psychiatry. 75 Suppl 1 (90001): i16– S, Simpson D (June 2008). “Management of invasive 21. doi:10.1136/jnnp.2003.034272. PMC 1765649 . meningococcal disease in children and young people: PMID 14978146. Summary of SIGN guidelines”. BMJ (Clinical research ed.). 336 (7657): 1367–70. doi:10.1136/bmj.a129. [3] Sáez-Llorens X, McCracken GH (June 2003). “Bacterial PMC 2427067 . PMID 18556318. meningitis in children”. Lancet. 361 (9375): 2139–48. doi:10.1016/S0140-6736(03)13693-8. PMID 12826449. [16] Management of invasive meningococcal disease in children [4] “Viral Meningitis”. CDC. November 26, 2014. Retrieved and young people (PDF). Edinburgh: Scottish Intercolle- 5 March 2016. giate Guidelines Network (SIGN). May 2008. ISBN 978- 1-905813-31-5. [5] Tunkel AR; Hartman BJ; Kaplan SL; et al. (November 2004). “Practice guidelines for the management of bac- [17] Thomas KE, Hasbun R, Jekel J, Quagliarello VJ (July terial meningitis” (PDF). Clinical Infectious Diseases. 39 2002). “The diagnostic accuracy of Kernig’s sign, (9): 1267–84. doi:10.1086/425368. PMID 15494903. Brudzinski neck sign, and nuchal rigidity in adults with suspected meningitis” (PDF). Clinical Infectious Diseases. [6] GBD 2015 Disease and Injury Incidence and Prevalence, 35 (1): 46–52. doi:10.1086/340979. PMID 12060874. Collaborators. (8 October 2016). “Global, regional, and national incidence, prevalence, and years lived with dis- [18] Logan SA, MacMahon E (January 2008). “Viral menin- ability for 310 diseases and injuries, 1990-2015: a sys- gitis”. BMJ (Clinical research ed.). 336 (7634): 36–40. tematic analysis for the Global Burden of Disease Study 2015.”. Lancet (London, England). 388 (10053): 1545– doi:10.1136/bmj.39409.673657.AE. PMC 2174764 . 1602. PMID 27733282. PMID 18174598. [7] GBD 2015 Mortality and Causes of Death, Collaborators. [19] Varon J, Chen K, Sternbach GL (1998). “Rupert Wa- (8 October 2016). “Global, regional, and national life ex- terhouse and Carl Friderichsen: adrenal apoplexy”. J pectancy, all-cause mortality, and cause-speciﬁc mortality Emerg Med. 16 (4): 643–7. doi:10.1016/S0736- for 249 causes of death, 1980-2015: a systematic analysis 4679(98)00061-4. PMID 9696186. for the Global Burden of Disease Study 2015.”. Lancet (London, England). 388 (10053): 1459–1544. PMID [20] “Listeria (Listeriosis)". Centers for Disease Control and 27733281. Prevention. 22 October 2015. Retrieved 2015-12-23.

[8] van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (Jan- [21] Hsu HE; Shutt KA; Moore MR; et al. (2009). “Ef- uary 2006). “Community-acquired bacterial meningitis in fect of pneumococcal conjugate vaccine on pneumococ- adults”. The New England Journal of Medicine. 354 (1): cal meningitis”. N Engl J Med. 360 (3): 244–256. 44–53. doi:10.1056/NEJMra052116. PMID 16394301. doi:10.1056/NEJMoa0800836. PMID 19144940. [9] GBD 2013 Mortality and Causes of Death, Collaborators [22] Wei BP, Robins-Browne RM, Shepherd RK, Clark GM, (17 December 2014). “Global, regional, and national age- O'Leary SJ (January 2008). “Can we prevent cochlear sex speciﬁc all-cause and cause-speciﬁc mortality for 240 implant recipients from developing pneumococcal menin- causes of death, 1990–2013: a systematic analysis for the gitis?" (PDF). Clin. Infect. Dis. 46 (1): e1–7. Global Burden of Disease Study 2013.”. Lancet. 385 doi:10.1086/524083. PMID 18171202. (9963): 117–71. doi:10.1016/S0140-6736(14)61682-2. PMC 4340604 . PMID 25530442. [23] Thwaites G, Chau TT, Mai NT, Drobniewski F, McAdam K, Farrar J (March 2000). “Tuberculous meningitis” [10] “Meningococcal meningitis Fact sheet N°141”. WHO. (PDF). Journal of Neurology, Neurosurgery, and Psychi- November 2015. Retrieved 5 March 2016. atry. 68 (3): 289–99. doi:10.1136/jnnp.68.3.289. PMC [11] Mosby’s pocket dictionary of medicine, nursing & health 1736815 . PMID 10675209. professions (6th ed.). St. Louis, Mo.: Mosby/Elsevier. 2010. p. traumatic meningitis. ISBN 9780323066044. [24] Tebruegge M, Curtis N (July 2008). “Epidemiology, etiology, pathogenesis, and diagnosis of recurrent bacte- [12] Liddell HG, Scott R (1940). "μήνιγξ". A Greek-English rial meningitis”. Clinical Microbiology Reviews. 21 (3): Lexicon. Oxford: Clarendon Press. 519–37. doi:10.1128/CMR.00009-08. PMC 2493086 . [13] van de Beek D, de Gans J, Spanjaard L, Weisfelt M, PMID 18625686. Reitsma JB, Vermeulen M (October 2004). “Clinical features and prognostic factors in adults with bacterial [25] Shalabi, M.; Whitley, R. J. (1 November 2006). meningitis”. The New England Journal of Medicine. 351 “Recurrent Benign Lymphocytic Meningitis”. (18): 1849–59. doi:10.1056/NEJMoa040845. PMID Clinical Infectious Diseases. 43 (9): 1194–1197. 15509818. doi:10.1086/508281. PMID 17029141. 90 CHAPTER 9. MENINGITIS

[26] Raman Sharma R (2010). “Fungal infections of EFNS Task Force on acute bacterial meningitis in older the nervous system: current perspective and con- children and adults”. European Journal of Neurolology. troversies in management”. International journal 15 (7): 649–59. doi:10.1111/j.1468-1331.2008.02193.x. of surgery (London, England). 8 (8): 591–601. PMID 18582342. doi:10.1016/j.ijsu.2010.07.293. PMID 20673817. [39] Straus SE, Thorpe KE, Holroyd-Leduc J (October 2006). [27] Sirven JI, Malamut BL (2008). Clinical neurology of “How do I perform a lumbar puncture and analyze the the older adult (2nd ed.). Philadelphia: Wolters Kluwer results to diagnose bacterial meningitis?". Journal of Health/Lippincott Williams & Wilkins. p. 439. ISBN the American Medical Association. 296 (16): 2012–22. 978-0-7817-6947-1. doi:10.1001/jama.296.16.2012. PMID 17062865. [28] Honda H, Warren DK (September 2009). “Central ner- [40] Heyderman RS, Lambert HP, O'Sullivan I, Stuart JM, vous system infections: meningitis and brain abscess”. In- Taylor BL, Wall RA (February 2003). “Early manage- fectious disease clinics of North America. 23 (3): 609–23. ment of suspected bacterial meningitis and meningococ- doi:10.1016/j.idc.2009.04.009. PMID 19665086. cal septicaemia in adults” (PDF). The Journal of infec- [29] Kauffman CA, Pappas PG, Patterson TF (19 October tion. 46 (2): 75–7. doi:10.1053/jinf.2002.1110. PMID 2012). “Fungal infections associated with contaminated 12634067. – formal guideline at British Infection Society; methyprednisolone injections—preliminary report”. New UK Meningitis Research Trust (December 2004). “Early England Journal of Medicine. Online first (26): 2495– management of suspected meningitis and meningococcal 500. doi:10.1056/NEJMra1212617. PMID 23083312. septicaemia in immunocompetent adults”. British Infec- tion Society Guidelines. Retrieved 19 October 2008. [30] Kauffman CA, Pappas PG, Sobel JD, Dismukes WE (1 January 2011). Essentials of clinical mycology (2nd ed.). [41] Maconochie IK, Bhaumik S (2014). Maconochie, Ian New York: Springer. p. 77. ISBN 978-1-4419-6639-1. K, ed. “Fluid therapy for acute bacterial meningitis”. Cochrane Database of Systematic Reviews. 5 (5): [31] Durski, Kara N.; Kuntz, Karen M.; Yasukawa, Kosuke; CD004786. doi:10.1002/14651858.CD004786.pub4. Virnig, Beth A.; Meya, David B.; Boulware, David R. PMID 24793545. CD004786. (Jul 1, 2013). “Cost-Effective Diagnostic Checklists for Meningitis in Resource-Limited Settings”. JAIDS [42] Perfect JR, Dismukes WE, Dromer F, et al. (2010). Journal of Acquired Immune Deficiency Syndromes. 63 “Clinical practice guidelines for the management of cryp- (3): e101–e108. doi:10.1097/QAI.0b013e31828e1e56. tococcal disease: 2010 update by the infectious diseases PMID 23466647. society of america”. Clinical Infectious Diseases. 50 (3): [32] Kauffman CA, Pappas PG, Sobel JD, Dismukes WE (1 291–322. doi:10.1086/649858. PMID 20047480. January 2011). Essentials of clinical mycology (2nd ed.). New York: Springer. p. 31. ISBN 978-1-4419-6639-1. [43] Sakushima, K; Hayashino, Y; Kawaguchi, T; Jack- son, JL; Fukuhara, S (April 2011). “Diagnostic ac- [33] Park, Benjamin J; Park BJ; Wannemuehler KA; Marston curacy of cerebrospinal fluid lactate for differentiating BJ; Govender N; Pappas PG; Chiller TM. (1 Febru- bacterial meningitis from aseptic meningitis: a meta- ary 2009). “Estimation of the current global bur- analysis”. The Journal of infection. 62 (4): 255–62. den of cryptococcal meningitis among persons liv- doi:10.1016/j.jinf.2011.02.010. PMID 21382412. ing with HIV/AIDS”. AIDS. 23 (4): 525–530. doi:10.1097/QAD.0b013e328322ffac. PMID 19182676. [44] Bicanic T, Harrison TS (2004). “Cryptococcal meningitis” (PDF). British Medical Bulletin. 72 (1): 99–118. [34] Graeff-Teixeira C, da Silva AC, Yoshimura K (Apr 2009). doi:10.1093/bmb/ldh043. PMID 15838017. “Update on eosinophilic meningoencephalitis and its clinical relevance” (PDF). Clinical Microbiology Reviews. [45] Sloan D, Dlamini S, Paul N, Dedicoat M (2008). Sloan 22 (2): 322–48. doi:10.1128/CMR.00044-08. PMC D, ed. “Treatment of acute cryptococcal meningitis in 2668237 . PMID 19366917. HIV infected adults, with an emphasis on resource-limited settings”. Cochrane Database of Systematic Reviews (4): [35] Gleissner B, Chamberlain MC (May 2006). “Neo- CD005647. doi:10.1002/14651858.CD005647.pub2. plastic meningitis”. Lancet Neurol. 5 (5): 443–52. PMID 18843697. CD005647. doi:10.1016/S1474-4422(06)70443-4. PMID 16632315. [46] Warrell DA, Farrar JJ, Crook DW (2003). “24.14.1 Bac- [36] Moris G, Garcia-Monco JC (June 1999). “The Chal- terial meningitis”. Oxford Textbook of Medicine Volume lenge of Drug-Induced Aseptic Meningitis” (PDF). 3 (Fourth ed.). Oxford University Press. pp. 1115–29. Archives of Internal Medicine. 159 (11): 1185–94. ISBN 0-19-852787-X. doi:10.1001/archinte.159.11.1185. PMID 10371226.

[37] Provan, Drew; Andrew Krentz (2005). Oxford Handbook [47] “CDC – Meningitis: Transmission”. Centers for Disease of Clinical and Laboratory Investigation. Oxford: Oxford Control and Prevention (CDC). 6 August 2009. Retrieved University Press. ISBN 0-19-856663-8. 18 June 2011.

[38] Chaudhuri A; Martinez–Martin P; Martin PM; et al. [48] Segal S, Pollard AJ (2004). “Vaccines against bacterial (July 2008). “EFNS guideline on the management of meningitis” (PDF). British Medical Bulletin. 72 (1): 65– community-acquired bacterial meningitis: report of an 81. doi:10.1093/bmb/ldh041. PMID 15802609. 9.10. REFERENCES 91

[49] Peltola H (April 2000). “Worldwide Haemophilus in- [60] Maconochie, IK; Bhaumik, S (May 5, 2014). “Fluid fluenzae type b disease at the beginning of the 21st cen- therapy for acute bacterial meningitis.”. The Cochrane tury: global analysis of the disease burden 25 years after database of systematic reviews. 5: CD004786. the use of the polysaccharide vaccine and a decade after doi:10.1002/14651858.CD004786.pub4. PMID the advent of conjugates” (PDF). Clinical Microbiology 24793545. Reviews. 13 (2): 302–17. doi:10.1128/CMR.13.2.302- 317.2000. PMC 100154 . PMID 10756001. [61] Prasad, K; Kumar, A; Gupta, PK; Singhal, T (17 October 2007). Prasad, Kameshwar, ed. “Third gen- [50] Harrison LH (January 2006). “Prospects for vac- eration cephalosporins versus conventional antibiotics cine prevention of meningococcal infection” (PDF). for treating acute bacterial meningitis”. Cochrane Clinical Microbiology Reviews. 19 (1): 142– database of systematic reviews (Online) (4): CD001832. 64. doi:10.1128/CMR.19.1.142-164.2006. PMC doi:10.1002/14651858.CD001832.pub3. PMID 1360272 . PMID 16418528. 17943757. [62] Brouwer, MC; McIntyre, P; Prasad, K; van [51] Man, Diana. “A new MenB (meningococcal B) vaccine”. de Beek, D (September 2015). “Corticos- Meningitis Research Foundation. Retrieved 23 November teroids for acute bacterial meningitis”. Cochrane 2014. Database of Systematic Reviews (9): CD004405. [52] FDA News Release (29 October 2014). “First vaccine doi:10.1002/14651858.CD004405.pub5. PMID approved by FDA to prevent serogroup B Meningococcal 26362566. disease”. FDA. [63] Assiri AM, Alasmari FA, Zimmerman VA, Baddour LM, Erwin PJ, Tleyjeh IM (May 2009). “Corticosteroid ad- [53] Wilder-Smith A (October 2007). “Meningococcal vac- ministration and outcome of adolescents and adults with cine in travelers”. Current Opinion in Infectious Diseases. acute bacterial meningitis: a meta-analysis”. Mayo Clin. 20 (5): 454–60. doi:10.1097/QCO.0b013e3282a64700. Proc. 84 (5): 403–9. doi:10.4065/84.5.403. PMC PMID 17762777. 2676122 . PMID 19411436. [54] WHO (September 2000). “Detecting meningococcal [64] Prasad, K; Singh, MB (23 January 2008). Prasad, meningitis epidemics in highly-endemic African coun- Kameshwar, ed. “Corticosteroids for manag- tries” (PDF). Weekly Epidemiological Record. 75 (38): ing tuberculous meningitis”. Cochrane database 306–9. PMID 11045076. of systematic reviews (Online) (1): CD002244. [55] Bishai, DM; Champion, C; Steele, ME; Thompson, L doi:10.1002/14651858.CD002244.pub3. PMID (June 2011). “Product development partnerships hit their 18254003. stride: lessons from developing a meningitis vaccine for [65] de Gans J, van de Beek D (November 2002). “Dex- Africa”. Health affairs (Project Hope). 30 (6): 1058–64. amethasone in adults with bacterial meningitis”. The doi:10.1377/hlthaff.2011.0295. PMID 21653957. New England Journal of Medicine. 347 (20): 1549–56. doi:10.1056/NEJMoa021334. PMID 12432041. [56] Marc LaForce, F; Ravenscroft, N; Djingarey, M; Viviani, S (24 June 2009). “Epidemic meningitis due to Group [66] McIntyre PB; Berkey CS; King SM; et al. (Septem- A Neisseria meningitidis in the African meningitis belt: a ber 1997). “Dexamethasone as adjunctive therapy persistent problem with an imminent solution”. Vaccine. in bacterial meningitis. A meta-analysis of ran- 27 Suppl 2: B13–9. doi:10.1016/j.vaccine.2009.04.062. domized clinical trials since 1988”. Journal of the PMID 19477559. American Medical Association. 278 (11): 925– 31. doi:10.1001/jama.1997.03550110063038. PMID [57] Weisfelt M, de Gans J, van der Poll T, van de Beek D 9302246. (April 2006). “Pneumococcal meningitis in adults: new approaches to management and prevention”. Lancet Neu- [67] “Meningitis and Encephalitis Fact Sheet”. National Insti- rol. 5 (4): 332–42. doi:10.1016/S1474-4422(06)70409- tute of Neurological Disorders and Stroke (NINDS). 11 4. PMID 16545750. December 2007. Retrieved 27 April 2009.

[58] Zalmanovici Trestioreanu, A; Fraser, A; Gafter-Gvili, [68] Gottfredsson M, Perfect JR (2000). “Fungal meningitis”. A; Paul, M; Leibovici, L (25 October 2013). “An- Seminars in Neurology. 20 (3): 307–22. doi:10.1055/s- tibiotics for preventing meningococcal infections.”. 2000-9394. PMID 11051295. The Cochrane database of systematic reviews. 10: CD004785. doi:10.1002/14651858.CD004785.pub5. [69] “Mortality and Burden of Disease Estimates for WHO PMID 24163051. Member States in 2002” (xls). World Health Organiza- tion (WHO). 2002. [59] Ratilal, BO; Costa, J; Pappamikail, L; Sampaio, C (28 April 2015). “Antibiotic prophylaxis for pre- [70] Richardson MP, Reid A, Tarlow MJ, Rudd PT (Febru- venting meningitis in patients with basilar skull frac- ary 1997). “Hearing loss during bacterial meningitis” tures.”. The Cochrane database of systematic reviews. (PDF). Archives of Disease in Childhood. 76 (2): 134– 4: CD004884. doi:10.1002/14651858.CD004884.pub4. 38. doi:10.1136/adc.76.2.134. PMC 1717058 . PMID PMID 25918919. 9068303. 92 CHAPTER 9. MENINGITIS

[71] Chiang, SS; Khan, FA; Milstein, MB; Tolman, AW; [83] Flexner S (1913). “The results of the serum treatment in Benedetti, A; Starke, JR; Becerra, MC. “Treatment out- thirteen hundred cases of epidemic meningitis” (PDF). J comes of childhood tuberculous meningitis: a system- Exp Med. 17 (5): 553–76. doi:10.1084/jem.17.5.553. atic review and meta-analysis”. The Lancet Infectious PMC 2125091 . PMID 19867668. Diseases. 14 (10): 947–957. doi:10.1016/S1473- 3099(14)70852-7. [84] Swartz MN (October 2004). “Bacterial meningitis— a view of the past 90 years”. The New Eng- [72] Lozano, R; Naghavi, M; Foreman, K; Lim, S; Shibuya, K; land Journal of Medicine. 351 (18): 1826–28. Aboyans, V; Abraham, J; Adair, T; et al. (15 December doi:10.1056/NEJMp048246. PMID 15509815. 2012). “Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic [85] Rosenberg DH, Arling PA (1944). “Penicillin in analysis for the Global Burden of Disease Study 2010”. the treatment of meningitis”. Journal of the Amer- Lancet. 380 (9859): 2095–128. doi:10.1016/S0140- ican Medical Association. 125 (15): 1011–17. 6736(12)61728-0. PMID 23245604. doi:10.1001/jama.1944.02850330009002. repro- duced in Rosenberg DH, Arling PA (April 1984). [73] Park, BJ; Wannemuehler, KA; Marston, BJ; Goven- “Penicillin in the treatment of meningitis”. Journal of der, N; Pappas, PG; Chiller, TM (Feb 20, 2009). the American Medical Association. 251 (14): 1870–6. “Estimation of the current global burden of cryp- doi:10.1001/jama.251.14.1870. PMID 6366279. tococcal meningitis among persons living with HIV/AIDS.”. AIDS (London, England). 23 (4): 525–30. doi:10.1097/QAD.0b013e328322ﬀac. PMID 9.11 External links 19182676. • [74] Lapeyssonnie L (1963). “Cerebrospinal meningitis in Meningitis at DMOZ Africa”. Bulletin of the World Health Organization. • Meningitis Centers for Disease Control and Preven- 28 (Suppl): SUPPL:1–114. PMC 2554630 . PMID tion (CDC) 14259333.

[75] Greenwood B (1999). “Manson Lecture. Meningococcal meningitis in Africa”. Trans. R. Soc. Trop. Med. Hyg. 93 (4): 341–53. doi:10.1016/S0035-9203(99)90106-2. PMID 10674069.

[76] World Health Organization (1998). Control of epidemic meningococcal disease, practical guidelines, 2nd edition, WHO/EMC/BA/98 (PDF). 3. pp. 1–83.

[77] WHO (2003). “Detecting meningococcal meningitis epidemics in highly-endemic African countries” (PDF). Weekly Epidemiological Record. 78 (33): 294–6. PMID 14509123.

[78] Arthur Earl Walker; Edward R. Laws; George B. Ud- varhelyi (1998). “Infections and inﬂammatory involvement of the CNS”. The Genesis of Neuroscience. Thieme. pp. 219–21. ISBN 1-879284-62-6.

[79] Whytt R (1768). Observations on the Dropsy in the Brain. Edinburgh: J. Balfour.

[80] Greenwood B (June 2006). “100 years of epidemic meningitis in West Africa – has anything changed?". Tropical Medicine & International health: TM & IH. 11 (6): 773–80. doi:10.1111/j.1365-3156.2006.01639.x. PMID 16771997.

[81] Vieusseux G (1806). “Mémoire sur le Maladie qui a regne à Génève au printemps de 1805”. Journal de Médecine, de Chirurgie et de Pharmacologie (Bruxelles) (in French). 11: 50–53.

[82] Weichselbaum A (1887). “Ueber die Aetiologie der akuten Meningitis cerebro-spinalis”. Fortschrift der Medi- zin (in German). 5: 573–583. Chapter 10

Pneumonia

For other uses, see Pneumonia (disambiguation).

Pneumonia is an inflammatory condition of the lung affecting primarily the microscopic air sacs known as alveoli.[2][3] Typical signs and symptoms include a varying severity and combination of productive or dry cough, chest pain, fever, and trouble breathing, depending on the underlying cause.[4] Pneumonia is usually caused by infection with viruses or bacteria and less commonly by other microorganisms, certain medications and conditions such as autoimmune A video explanation of pneumonia diseases.[2][5] Risk factors include other lung diseases such as cystic fibrosis, COPD, and asthma, diabetes, heart Main symptoms of infectious failure, a history of smoking, a poor ability to cough such Pneumonia as following a stroke, or a weak immune system.[6] Di- Systemic: - High fever Central: agnosis is often based on the symptoms and physical ex- - Chills - Headaches - Loss of appetite amination. Chest X-ray, blood tests, and culture of the Skin: - Mood swings [7] sputum may help confirm the diagnosis. The disease - Clamminess - Blueness may be classified by where it was acquired with commu- Vascular [8] nity, hospital, or health care associated pneumonia. Lungs: - Low blood pressure - Cough with Vaccines to prevent certain types of pneumonia are avail- sputum or Heart: phlegm - High heart rate able. Other methods of prevention include handwashing - Shortness [9] and not smoking. Treatment depends on the underly- of breath [10] - Pleuritic Gastric: ing cause. Pneumonia believed to be due to bacteria chest pain [11] - Nausea is treated with antibiotics. If the pneumonia is severe, - Hemoptysis - Vomiting the affected person is generally hospitalized.[10] Oxygen [11] Muscular: therapy may be used if oxygen levels are low. - Fatigue Joints: - Aches - Pain Pneumonia affects approximately 450 million people globally (7% of the population) and results in about 4 million deaths per year.[12][13] Pneumonia was regarded Main symptoms of infectious pneumonia by William Osler in the 19th century as “the captain of the men of death”.[14] With the introduction of antibiotics and vaccines in the 20th century, survival improved.[12] 10.1 Signs and symptoms Nevertheless, in developing countries, and among the very old, the very young, and the chronically ill, pneu- People with infectious pneumonia often have a productive monia remains a leading cause of death.[12][15] Pneumo- cough, fever accompanied by shaking chills, shortness of nia often shortens suffering among those already close to breath, sharp or stabbing chest pain during deep breaths, death and has thus been called “the old man’s friend”.[16] and an increased rate of breathing.[18] In the elderly, confusion may be the most prominent sign.[18] The typical signs and symptoms in children under five are fever, cough, and fast or difficult breathing.[19] Fever is not very specific, as it occurs in many other common illnesses, may be absent in those with severe disease,

93 94 CHAPTER 10. PNEUMONIA malnutrition or in the elderly. In addition, a cough is to any condition resulting in inflammation of the lungs frequently absent in children less than 2 months old.[19] (caused for example by autoimmune diseases, chemical More severe signs and symptoms in children may include burns or drug reactions); however, this inflammation is blue-tinged skin, unwillingness to drink, convulsions, on- more accurately referred to as pneumonitis.[25][26] going vomiting, extremes of temperature, or a decreased [19][20] Conditions and risk factors that predispose to pneu- level of consciousness. monia include smoking, immunodeficiency, alcoholism, Bacterial and viral cases of pneumonia usually present chronic obstructive pulmonary disease, asthma, chronic with similar symptoms.[21] Some causes are associated kidney disease, and liver disease.[20][27] The use of with classic, but non-specific, clinical characteristics. acid-suppressing medications—such as proton-pump in- Pneumonia caused by Legionella may occur with ab- hibitors or H2 blockers—is associated with an increased dominal pain, diarrhea, or confusion,[22] while pneumo- risk of pneumonia.[28] The risk is also increased in old nia caused by Streptococcus pneumoniae is associated age.[20] with rusty colored sputum,[23] and pneumonia caused by Klebsiella may have bloody sputum often described as “currant jelly”.[17] Bloody sputum (known as hemoptysis) 10.2.1 Bacteria may also occur with tuberculosis, Gram-negative pneumonia, and lung abscesses as well as more commonly with Main article: Bacterial pneumonia acute bronchitis.[20] Mycoplasma pneumonia may occur Bacteria are the most common cause of community- in association with swelling of the lymph nodes in the neck, joint pain, or a middle ear infection.[20] Viral pneumonia presents more commonly with wheezing than does bacterial pneumonia.[21] Pneumonia was historically divided into “typical” and “atypical” based on the belief that the presentation predicted the underlying cause.[24] How- ever, evidence has not supported this distinction, thus it is no longer emphasized.[24]

10.2 Cause

Cavitating pneumonia as seen on CT. Pneumonia due to MRSA

acquired pneumonia (CAP), with Streptococcus pneumoniae isolated in nearly 50% of cases.[29][30] Other commonly isolated bacteria include Haemophilus influenzae in 20%, Chlamydophila pneumoniae in 13%, and Mycoplasma pneumoniae in 3% of cases;[29] Staphylococcus aureus; Moraxella catarrhalis; Legionella pneumophila and Gram-negative bacilli.[16] A number of drug-resistant versions of the above infections are becom- The bacterium Streptococcus pneumoniae, a common cause of ing more common, including drug-resistant Streptococcus pneumonia, imaged by an electron microscope pneumoniae (DRSP) and methicillin-resistant Staphylo- coccus aureus (MRSA).[20] Pneumonia is due to infections caused primarily by The spreading of organisms is facilitated when risk fac- bacteria or viruses and less commonly by fungi and tors are present.[16] Alcoholism is associated with Strep- parasites. Although there are more than 100 strains of tococcus pneumoniae, anaerobic organisms, and My- infectious agents identified, only a few are responsible for cobacterium tuberculosis; smoking facilitates the effects the majority of the cases. Mixed infections with both of Streptococcus pneumoniae, Haemophilus influenzae, viruses and bacteria may occur in up to 45% of infec- [12] Moraxella catarrhalis, and Legionella pneumophila. Ex- tions in children and 15% of infections in adults. A posure to birds is associated with Chlamydia psittaci; causative agent may not be isolated in approximately half [16] farm animals with Coxiella burnetti; aspiration of stom- of cases despite careful testing. ach contents with anaerobic organisms; and cystic fibro- The term pneumonia is sometimes more broadly applied sis with Pseudomonas aeruginosa and Staphylococcus au- 10.3. MECHANISMS 95 reus.[16] Streptococcus pneumoniae is more common in the the skin, ingestion, or via an insect vector.[35] Except winter,[16] and should be suspected in persons aspirating for Paragonimus westermani, most parasites do not af- a large amount anaerobic organisms.[20] fect specifically the lungs but involve the lungs secondarily to other sites.[35] Some parasites, in particular those belonging to the Ascaris and Strongyloides 10.2.2 Viruses genera, stimulate a strong eosinophilic reaction, which may result in eosinophilic pneumonia.[35] In other infec- Main article: Viral pneumonia tions, such as malaria, lung involvement is due primarily to cytokine-induced systemic inflammation.[35] In the In adults, viruses account for approximately a third[12] developed world these infections are most common in and in children for about 15% of pneumonia cases.[31] people returning from travel or in immigrants.[35] Around Commonly implicated agents include rhinoviruses, the world, these infections are most common in the coronaviruses, influenza virus, respiratory syncytial immunodeficient.[36] virus (RSV), adenovirus, and parainfluenza.[12][32] Herpes simplex virus rarely causes pneumonia, except in groups such as: newborns, persons with cancer, 10.2.5 Noninfectious transplant recipients, and people with significant burns.[33] People following organ transplantation or Main article: Idiopathic interstitial pneumonia those otherwise-immunocompromised present high rates of cytomegalovirus pneumonia.[31][33] Those with viral Idiopathic interstitial pneumonia or noninfectious infections may be secondarily infected with the bacteria pneumonia[37] is a class of diffuse lung diseases. They Streptococcus pneumoniae, Staphylococcus aureus, or include diffuse alveolar damage, organizing pneumonia, Haemophilus influenzae, particularly when other health nonspecific interstitial pneumonia, lymphocytic inter- problems are present.[20][31] Different viruses predom- stitial pneumonia, desquamative interstitial pneumonia, inate at different periods of the year; during influenza respiratory bronchiolitis interstitial lung disease, and season, for example, influenza may account for over usual interstitial pneumonia.[38] half of all viral cases.[31] Outbreaks of other viruses also occasionally occur, including hantaviruses and coronavirus.[31] 10.3 Mechanisms

10.2.3 Fungi

Main article: Fungal pneumonia

Fungal pneumonia is uncommon, but occurs more commonly in individuals with weakened immune systems due to AIDS, immunosuppressive drugs, or other medical problems.[16][34] It is most often caused by Histoplasma capsulatum, blastomyces, Cryptococcus neoformans, Pneumocystis jiroveci (pneumocystis pneumonia), and Coccidioides immitis. Histoplasmosis is most common in the Mississippi River basin, and coccidioidomycosis is most common in the Southwestern United States.[16] The number of cases has been increasing in the later half of the 20th century due to increasing travel and rates of immunosuppression in the population.[34]

10.2.4 Parasites

Main article: Parasitic pneumonia Pneumonia fills the lung’s alveoli with fluid, hindering oxygena- A variety of parasites can affect the lungs, including tion. The alveolus on the left is normal, whereas the one on the Toxoplasma gondii, Strongyloides stercoralis, Ascaris lum- right is full of fluid from pneumonia. bricoides, and Plasmodium malariae.[35] These organisms typically enter the body through direct contact with Pneumonia frequently starts as an upper respiratory tract 96 CHAPTER 10. PNEUMONIA

infection that moves into the lower respiratory tract.[39] tion has defined pneumonia in children clinically based It is pneumonitis (lung inflammation) combined with on either a cough or difficulty breathing and a rapid res- consolidation (liquid in spaces normally inflated with piratory rate, chest indrawing, or a decreased level of air).[40] consciousness.[46] A rapid respiratory rate is defined as greater than 60 breaths per minute in children under 2 months old, 50 breaths per minute in children 2 months 10.3.1 Viral to 1 year old, or greater than 40 breaths per minute in children 1 to 5 years old.[46] In children, increased respi- Viruses may reach the lung by a number of different ratory rate and lower chest indrawing are more sensitive routes. Respiratory syncytial virus is typically contracted than hearing chest crackles with a stethoscope.[19] Grunt- when people touch contaminated objects and then they ing and nasal flaring may be other useful signs in children touch their eyes or nose.[31] Other viral infections oc- less than five.[47] cur when contaminated airborne droplets are inhaled In general, in adults, investigations are not needed in mild through the mouth or nose.[20] Once in the upper air- cases.[48] There is a very low risk of pneumonia if all way, the viruses may make their way in the lungs, where vital signs and auscultation are normal.[49] In persons re- they invade the cells lining the airways, alveoli, or lung quiring hospitalization, pulse oximetry, chest radiogra- parenchyma.[31] Some viruses such as measles and her- phy and blood tests—including a complete blood count, pes simplex may reach the lungs via the blood.[41] The serum electrolytes, C-reactive protein level, and possibly invasion of the lungs may lead to varying degrees of cell liver function tests—are recommended.[48] The diagnosis death.[31] When the immune system responds to the in- of influenza-like illness can be made based on the signs fection, even more lung damage may occur.[31] Primarily and symptoms; however, confirmation of an influenza in- white blood cells, mainly mononuclear cells, generate the fection requires testing.[50] Thus, treatment is frequently inflammation.[41] As well as damaging the lungs, many based on the presence of influenza in the community or a viruses simultaneously affect other organs and thus dis- rapid influenza test.[50] rupt other body functions. Viruses also make the body more susceptible to bacterial infections; in this way, bac- [32] terial pneumonia can arise as a co-morbid condition. 10.4.1 Physical exam

Physical examination may sometimes reveal low blood 10.3.2 Bacterial pressure, high heart rate, or low oxygen saturation.[20] The respiratory rate may be faster than normal, and this Most bacteria enter the lungs via small aspirations of or- may occur a day or two before other signs.[20][24] Ex- ganisms residing in the throat or nose.[20] Half of nor- [24] amination of the chest may be normal, but it may show mal people have these small aspirations during sleep. decreased chest expansion on the affected side. Harsh While the throat always contains bacteria, potentially in- breath sounds from the larger airways that are transmitted fectious ones reside there only at certain times and un- [24] through the inflamed lung are termed bronchial breath- der certain conditions. A minority of types of bac- ing and are heard on auscultation with a stethoscope.[20] teria such as Mycobacterium tuberculosis and Legionella Crackles (rales) may be heard over the affected area dur- pneumophila reach the lungs via contaminated airborne [20] [20] [21] ing inspiration. Percussion may be dulled over the af- droplets. Bacteria can spread also via the blood. fected lung, and increased, rather than decreased, vocal Once in the lungs, bacteria may invade the spaces be- resonance distinguishes pneumonia from a pleural effu- tween cells and between alveoli, where the macrophages sion.[18] and neutrophils (defensive white blood cells) attempt to inactivate the bacteria.[42] The neutrophils also release cytokines, causing a general activation of the immune 10.4.2 Imaging system.[43] This leads to the fever, chills, and fatigue com- [43] mon in bacterial pneumonia. The neutrophils, bacte- A chest radiograph is frequently used in diagnosis.[19] ria, and fluid from surrounding blood vessels fill the alve- In people with mild disease, imaging is needed only in [44] oli, resulting in the consolidation seen on chest X-ray. those with potential complications, those not having improved with treatment, or those in which the cause is uncertain.[19][48] If a person is sufficiently sick to require 10.4 Diagnosis hospitalization, a chest radiograph is recommended.[48] Findings do not always match the severity of disease and do not reliably separate between bacterial infection and Pneumonia is typically diagnosed based on a combination [19] of physical signs and a chest X-ray.[45] However, the un- viral infection. derlying cause can be difficult to confirm, as there is no X-ray presentations of pneumonia may be classified as definitive test able to distinguish between bacterial and lobar pneumonia, bronchopneumonia (also known as lob- non-bacterial origin.[12][45] The World Health Organiza- ular pneumonia), and interstitial pneumonia.[51] Bac- 10.4. DIAGNOSIS 97

10.4.3 Microbiology

In patients managed in the community, determining the causative agent is not cost-effective and typically does not alter management.[19] For people who do not respond to treatment, sputum culture should be considered, and culture for Mycobacterium tuberculosis should be carried out in persons with a chronic productive cough.[48] Testing for other specific organisms may be recommended during outbreaks, for public health reasons.[48] In those hospitalized for severe disease, both sputum and blood cultures are recommended,[48] as well as testing the urine for antigens to Legionella and Streptococcus.[53] Viral infections can be confirmed via detection of either the virus or its antigens with culture or polymerase chain reaction (PCR), among other techniques.[12] The causative agent is determined in only 15% of cases with routine microbiological tests.[18] Right middle lobe pneumonia in a child as seen on plain X ray

10.4.4 Classiﬁcation

Main article: Classiﬁcation of pneumonia

Pneumonitis refers to lung inflammation; pneumonia refers to pneumonitis, usually due to infection but sometimes non-infectious, that has the additional feature of pulmonary consolidation.[54] Pneumonia is most commonly classified by where or how it was acquired: community-acquired, aspiration, healthcare- associated, hospital-acquired, and ventilator-associated pneumonia.[29] It may also be classified by the area of lung affected: lobar pneumonia, bronchial pneumonia and acute interstitial pneumonia;[29] or by the causative organism.[55] Pneumonia in children may additionally be CT of the chest demonstrating right-side pneumonia (left side of classified based on signs and symptoms as non-severe, se- the image) vere, or very severe.[56] The setting in which pneumonia develops is important to treatment,[57][58] as it correlates to which pathogens are likely suspects,[57] which mechanisms are likely, which [57] terial, community-acquired pneumonia classically show antibiotics are likely to work or fail, and which com- lung consolidation of one lung segmental lobe, which is plications can be expected based on the person’s health known as lobar pneumonia.[29] However, findings may status. vary, and other patterns are common in other types of pneumonia.[29] Aspiration pneumonia may present with bilateral opacities primarily in the bases of the lungs Community and on the right side.[29] Radiographs of viral pneumonia may appear normal, appear hyper-inflated, have bilateral patchy areas, or present similar to bacterial pneumonia Main article: Community-acquired pneumonia with lobar consolidation.[29] Radiologic findings may not be present in the early stages of the disease, especially Community-acquired pneumonia (CAP) is acquired in in the presence of dehydration, or may be difficult to be the community,[57][58] outside of health care facilities. interpreted in the obese or those with a history of lung Compared with health care–associated pneumonia, it is disease.[20] A CT scan can give additional information in less likely to involve multidrug-resistant bacteria. Al- indeterminate cases.[29] Lung ultrasound may also be use- though the latter are no longer rare in CAP,[57] they are ful in helping to make the diagnosis.[52] still less likely. 98 CHAPTER 10. PNEUMONIA

Healthcare 10.5.1 Vaccination

Health care–associated pneumonia (HCAP) is an infec- Vaccination prevents against certain bacterial and viral tion associated with recent exposure to the health care pneumonias both in children and adults. Influenza vac- system,[57] including hospital, outpatient clinic, nursing cines are modestly effective at preventing symptoms of home, dialysis center, chemotherapy treatment, or home influenza.[12][59] The Center for Disease Control and Pre- care.[58] vention (CDC) recommends yearly vaccination for every [60] HCAP is sometimes called MCAP (medical care– person 6 months and older. Immunizing health care associated pneumonia). workers decreases the risk of viral pneumonia among their patients.[53] Vaccinations against Haemophilus influenzae and Hospital Hospital-acquired pneumonia is acquired in a Streptococcus pneumoniae have good evidence to support [57] hospital (specifically, pneumonia that occurs 48 hours their use.[39] Vaccinating children against Streptococcus or more after admission, which was not incubating at pneumoniae has led to a decreased incidence of these in- [58] the time of admission ), and as such is likely to infections in adults, because many adults acquire infections volve hospital-acquired infections, with higher risk of from children. A Streptococcus pneumoniae vaccine is multidrug-resistant pathogens. Also, because hospital pa- available for adults, and has been found to decrease the tients are often ill (which is why they are present in the risk of invasive pneumococcal disease.[61] Other vaccines hospital), comorbidities are an issue. for which there is support for a protective effect against pneumonia include pertussis, varicella, and measles.[62] Ventilator Ventilator-associated pneumonia occurs in people breathing with the help of mechanical ventilation[57] (specifically, it is pneumonia that arises more than 10.5.2 Medications 48 to 72 hours after endotracheal intubation[58]). Like any medical device, ventilators involve some risk of in- When influenza outbreaks occur, medications such as amantadine or rimantadine may help prevent the con- fection because of how difficult it is to prevent bacteria [63] from colonizing the internal parts and surfaces, even with dition; however are associated with side effects. diligent cleaning. People who need ventilators typically Zanamivir or oseltamivir decrease the chance that those are rather ill, to begin with, so a superimposed pneumonia exposed will develop symptoms; however, it is recommended that potential side effects are taken into is not always easily managed. Immunodeficiency may be [64] involved because of poor nutritional status and whichever account. disorders are comorbid. 10.5.3 Other 10.4.5 Differential diagnosis Smoking cessation[48] and reducing indoor air pollution, Several diseases can present with similar signs and symp- such as that from cooking indoors with wood or dung, toms to pneumonia, such as: chronic obstructive pul- are both recommended.[19][21] Smoking appears to be the monary disease (COPD), asthma, pulmonary edema, single biggest risk factor for pneumococcal pneumonia bronchiectasis, lung cancer, and pulmonary emboli.[18] in otherwise-healthy adults.[53] Hand hygiene and cough- Unlike pneumonia, asthma and COPD typically present ing into one’s sleeve may also be effective preventative with wheezing, pulmonary edema presents with an abnor- measures.[62] Wearing surgical masks by the sick may also mal electrocardiogram, cancer and bronchiectasis present prevent illness.[53] with a cough of longer duration, and pulmonary emboli Appropriately treating underlying illnesses (such as presents with acute onset sharp chest pain and shortness HIV/AIDS, diabetes mellitus, and malnutrition) can de- [18] of breath. crease the risk of pneumonia.[21][62][65] In children less than 6 months of age, exclusive breast feeding reduces both the risk and severity of disease.[21] In those with 10.5 Prevention HIV/AIDS and a CD4 count of less than 200 cells/uL the antibiotic trimethoprim/sulfamethoxazole decreases [66] Prevention includes vaccination, environmental measures the risk of Pneumocystis pneumonia and is also useful [19] for prevention in those that are immunocomprised but do and appropriate treatment of other health problems. It [67] is believed that, if appropriate preventive measures were not have HIV. instituted globally, mortality among children could be re- Testing pregnant women for Group B Streptococcus duced by 400,000; and, if proper treatment were univer- and Chlamydia trachomatis, and administering antibiotic sally available, childhood deaths could be decreased by treatment, if needed, reduces rates of pneumonia in another 600,000.[21] infants;[68][69] preventive measures for HIV transmission 10.7. PROGNOSIS 99 from mother to child may also be efficient.[70] Suctioning For those who require hospitalization and caught their the mouth and throat of infants with meconium-stained pneumonia in the community the use of a β-lactam such amniotic fluid has not been found to reduce the rate of as cephazolin plus macrolide such as azithromycin or aspiration pneumonia and may cause potential harm,[71] a fluoroquinolones is recommended.[81] The addition of thus this practice is not recommended in the majority of corticosteroids also appears to improve outcomes.[82][83] situations.[71] In the frail elderly good oral health care may [72] The duration of treatment has traditionally been seven lower the risk of aspiration pneumonia. Zinc supple- to ten days, but increasing evidence suggests that shorter mentation in children 2 months to five years old appears courses (three to five days) are similarly effective.[84] to reduce rates of pneumonia.[73] Recommended for hospital-acquired pneumonia include third- and fourth-generation cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and 10.6 Management vancomycin.[85] These antibiotics are often given intravenously and used in combination.[85] In those Oral antibiotics, rest, simple analgesics, and fluids usu- treated in hospital, more than 90% improve with the [24] ally suffice for complete resolution.[48] However, those initial antibiotics. with other medical conditions, the elderly, or those with significant trouble breathing may require more advanced care. If the symptoms worsen, the pneumonia 10.6.2 Viral does not improve with home treatment, or complica- Neuraminidase inhibitors may be used to treat viral tions occur, hospitalization may be required.[48] World- pneumonia caused by influenza viruses (influenza A and wide, approximately 7–13% of cases in children result influenza B).[12] No specific antiviral medications are rec- in hospitalization,[19] whereas in the developed world be- ommended for other types of community acquired vi- tween 22 and 42% of adults with community-acquired ral pneumonias including SARS coronavirus, adenovirus, pneumonia are admitted.[48] The CURB-65 score is use- hantavirus, and parainfluenza virus.[12] Influenza A may ful for determining the need for admission in adults.[48] be treated with rimantadine or amantadine, while in- If the score is 0 or 1, people can typically be managed at fluenza A or B may be treated with oseltamivir, zanamivir home; if it is 2, a short hospital stay or close follow-up is or peramivir.[12] These are of most benefit if they are needed; if it is 3–5, hospitalization is recommended.[48] started within 48 hours of the onset of symptoms.[12] In children those with respiratory distress or oxygen sat- Many strains of H5N1 influenza A, also known as avian urations of less than 90% should be hospitalized.[74] The influenza or “bird flu”, have shown resistance to riman- utility of chest physiotherapy in pneumonia has not yet tadine and amantadine.[12] The use of antibiotics in viral been determined.[75] Non-invasive ventilation may be pneumonia is recommended by some experts, as it is im- beneficial in those admitted to the intensive care unit.[76] possible to rule out a complicating bacterial infection.[12] Over-the-counter cough medicine has not been found to The British Thoracic Society recommends that antibi- be effective[77] nor has the use of zinc in children.[78] otics be withheld in those with mild disease.[12] The use There is insufficient evidence for mucolytics.[77] of corticosteroids is controversial.[12]

10.6.1 Bacterial 10.6.3 Aspiration Antibiotics improve outcomes in those with bacterial In general, aspiration pneumonitis is treated conserva- pneumonia.[13] Antibiotic choice depends initially on tively with antibiotics indicated only for aspiration pneu- the characteristics of the person affected, such as age, monia.[86] The choice of antibiotic will depend on sev- underlying health, and the location the infection was eral factors, including the suspected causative organism acquired. In the UK, treatment before culture re- and whether pneumonia was acquired in the commu- sults with amoxicillin is recommended as the first line nity or developed in a hospital setting. Common op- for community-acquired pneumonia, with doxycycline tions include clindamycin, a combination of a beta-lactam or clarithromycin as alternatives.[48] In North Amer- antibiotic and metronidazole, or an aminoglycoside.[87] ica, where the “atypical” forms of community-acquired Corticosteroids are sometimes used in aspiration pneu- pneumonia are more common, macrolides (such as monia, but there is limited evidence to support their azithromycin or erythromycin), and doxycycline have dis- effectiveness.[86] placed amoxicillin as first-line outpatient treatment in adults.[30][79] In children with mild or moderate symptoms, amoxicillin remains the first line.[74] The use of fluoroquinolones in uncomplicated cases is discour- 10.7 Prognosis aged due to concerns about side-effects and generat- ing resistance in light of there being no greater clinical With treatment, most types of bacterial pneumonia will benefit.[30][80] stabilize in 3–6 days.[88] It often takes a few weeks be- 100 CHAPTER 10. PNEUMONIA fore most symptoms resolve.[88] X-ray finding typically distinguish an empyema from the more common simple clear within four weeks and mortality is low (less than parapneumonic effusion, the fluid may be collected with 1%).[20][89] In the elderly or people with other lung prob- a needle (thoracentesis), and examined.[91] If this shows lems, recovery may take more than 12 weeks. In per- evidence of empyema, complete drainage of the fluid is sons requiring hospitalization, mortality may be as high necessary, often requiring a drainage catheter.[91] In se- as 10%, and in those requiring intensive care it may reach vere cases of empyema, surgery may be needed.[91] If the 30–50%.[20] Pneumonia is the most common hospital- infected fluid is not drained, the infection may persist, acquired infection that causes death.[24] Before the advent because antibiotics do not penetrate well into the pleural of antibiotics, mortality was typically 30% in those that cavity. If the fluid is sterile, it must be drained only if it were hospitalized.[16] is causing symptoms or remains unresolved.[91] Complications may occur in particular in the elderly In rare circumstances, bacteria in the lung will form and those with underlying health problems.[89] This a pocket of infected fluid called a lung abscess.[91] may include, among others: empyema, lung abscess, Lung abscesses can usually be seen with a chest X- bronchiolitis obliterans, acute respiratory distress syn- ray but frequently require a chest CT scan to confirm drome, sepsis, and worsening of underlying health the diagnosis.[91] Abscesses typically occur in aspiration problems.[89] pneumonia, and often contain several types of bacteria. Long-term antibiotics are usually adequate to treat a lung abscess, but sometimes the abscess must be drained by a 10.7.1 Clinical prediction rules surgeon or radiologist.[91]

Clinical prediction rules have been developed to more ob- jectively predict outcomes of pneumonia.[24] These rules are often used in deciding whether or not to hospitalize the person.[24] 10.7.3 Respiratory and circulatory failure

• Pneumonia severity index (or PSI Score)[24] Pneumonia can cause respiratory failure by triggering acute respiratory distress syndrome (ARDS), which re- • CURB-65 score, which takes into account the sever- sults from a combination of infection and inflammatory ity of symptoms, any underlying diseases, and response. The lungs quickly fill with fluid and become [90] age stiff. This stiffness, combined with severe difficulties ex- tracting oxygen due to the alveolar fluid, may require long periods of mechanical ventilation for survival.[31] 10.7.2 Pleural effusion, empyema, and abscess Sepsis is a potential complication of pneumonia but occurs usually in people with poor immunity or hyposplenism. The organisms most commonly involved are Streptococcus pneumoniae, Haemophilus influenzae, and Klebsiella pneumoniae. Other causes of the symptoms should be considered such as a myocardial infarction or a pulmonary embolism.[92]

10.8 Epidemiology

Main article: Epidemiology of pneumonia Pneumonia is a common illness affecting approximately 450 million people a year and occurring in all parts of the world.[12] It is a major cause of death among all age A pleural effusion: as seen on chest X-ray. The A arrow indicates groups resulting in 4 million deaths (7% of the world’s fluid layering in the right chest. The B arrow indicates the width total death) yearly.[12][13] Rates are greatest in children of the right lung. The volume of the lung is reduced because of less than five, and adults older than 75 years.[12] It oc- the collection of fluid around the lung. curs about five times more frequently in the developing world than in the developed world.[12] Viral pneumonia In pneumonia, a collection of fluid may form in the space accounts for about 200 million cases.[12] In the United that surrounds the lung.[91] Occasionally, microorgan- States, as of 2009, pneumonia is the 8th leading cause of isms will infect this fluid, causing an empyema.[91] To death.[20] 10.9. HISTORY 101

Health Organization estimates that one in three newborn infant deaths is due to pneumonia.[96] Approximately half of these deaths can be prevented, as they are caused by the bacteria for which an eﬀective vaccine is available.[97] In 2011, pneumonia was the most common reason for admission to the hospital after an emergency department visit in the U.S. for infants and children.[98]

Deaths from lower respiratory infections per million persons in 2012 10.9 History 24-120 121-151 152-200 201-241 242-345 346-436 437-673 674-864 865-1,209 1,210-2,085

Disability-adjusted life year for lower respiratory infections per 100,000 inhabitants in 2004.[93] no data less than 100 100–700 700–1,400 1,400–2,100 2,100–2,800 2,800–3,500 3,500–4,200 4,200–4,900 WPA poster, 1936/1937 4,900–5,600 5,600–6,300 Pneumonia has been a common disease throughout hu- 6,300–7,000 man history.[99] The word is from Greek πνεύμων more than 7,000 (pneúmōn) meaning “lung”.[100] The symptoms were described by Hippocrates (c. 460 BC – 370 BC):[99] “Perip- neumonia, and pleuritic affections, are to be thus ob- 10.8.1 Children served: If the fever be acute, and if there be pains on either side, or in both, and if expiration be if cough In 2008, pneumonia occurred in approximately 156 mil- be present, and the sputa expectorated be of a blond or lion children (151 million in the developing world and 5 livid color, or likewise thin, frothy, and florid, or having million in the developed world).[12] In 2010, it resulted any other character different from the common... When in 1.3 million deaths, or 18% of all deaths in those un- pneumonia is at its height, the case is beyond remedy if he der five years, of which 95% occurred in the developing is not purged, and it is bad if he has dyspnoea, and urine world.[12][19][94] Countries with the greatest burden of dis- that is thin and acrid, and if sweats come out about the ease include India (43 million), China (21 million) and neck and head, for such sweats are bad, as proceeding Pakistan (10 million).[95] It is the leading cause of death from the suffocation, rales, and the violence of the dis- among children in low income countries.[12][13] Many of ease which is obtaining the upper hand.”[101] However, these deaths occur in the newborn period. The World Hippocrates referred to pneumonia as a disease “named 102 CHAPTER 10. PNEUMONIA

by the ancients”. He also reported the results of surgical 10.10.2 Costs drainage of empyemas. Maimonides (1135–1204 AD) observed: “The basic symptoms that occur in pneumo- The global economic cost of community-acquired pneu- nia and that are never lacking are as follows: acute fever, monia has been estimated at $17 billion annually.[20] sticking pleuritic pain in the side, short rapid breaths, ser- Other estimates are considerably higher. In 2012 the rated pulse and cough.”[102] This clinical description is estimated aggregate costs of treating pneumonia in the quite similar to those found in modern textbooks, and United States were $20 billion;[113] the median cost it reflected the extent of medical knowledge through the of a single pneumonia-related hospitalization is over Middle Ages into the 19th century. $15,000.[114] According to data released by the Centers for Medicare and Medicaid Services, average 2012 hos- Edwin Klebs was the first to observe bacteria in the air- pital charges for inpatient treatment of uncomplicated ways of persons having died of pneumonia in 1875.[103] pneumonia in the U.S. were $24,549 and ranged as high Initial work identifying the two common bacterial causes, as $124,000. The average cost of an emergency room Streptococcus pneumoniae and Klebsiella pneumoniae, consult for pneumonia was $943 and the average cost for was performed by Carl Friedländer[104] and Albert medication was $66.[115] Aggregate annual costs of treat- Fraenkel[105] in 1882 and 1884, respectively. Friedlän- ing pneumonia in Europe have been estimated at €10 der’s initial work introduced the Gram stain, a fundamen- billion.[116] tal laboratory test still used today to identify and catego- rize bacteria. Christian Gram's paper describing the procedure in 1884 helped to differentiate the two bacteria, and showed that pneumonia could be caused by more than 10.11 Research one microorganism.[106] Sir William Osler, known as “the father of modern As of 2016 there has been one large trial studying the medicine”, appreciated the death and disability caused use of vitamin D to prevent pneumonia in children, which [117] by pneumonia, describing it as the “captain of the men found no effect. of death” in 1918, as it had overtaken tuberculosis as one of the leading causes of death in this time. This phrase was originally coined by John Bunyan in reference 10.12 References to “consumption” (tuberculosis).[107][108] Osler also described pneumonia as “the old man’s friend” as death was [1] “Other Names for Pneumonia”. NHLBI. March 1, 2011. often quick and painless when there were much slower Retrieved 2 March 2016. and more painful ways to die.[16] [2] McLuckie, A., ed. (2009). Respiratory disease and its Several developments in the 1900s improved the outcome management. New York: Springer. p. 51. ISBN 978-1- for those with pneumonia. With the advent of penicillin 84882-094-4. and other antibiotics, modern surgical techniques, and intensive care in the 20th century, mortality from pneumo- [3] Leach, Richard E. (2009). Acute and Critical Care nia, which had approached 30%, dropped precipitously Medicine at a Glance (2nd ed.). Wiley-Blackwell. ISBN in the developed world. Vaccination of infants against 1-4051-6139-6. Haemophilus influenzae type B began in 1988 and led to [4] Ashby, Bonnie; Turkington, Carol (2007). The encyclo- [109] a dramatic decline in cases shortly thereafter. Vacci- pedia of infectious diseases (3rd ed.). New York: Facts on nation against Streptococcus pneumoniae in adults began File. p. 242. ISBN 0-8160-6397-4. Retrieved 2011-04- in 1977, and in children in 2000, resulting in a similar 21. decline.[110] [5] Jeffrey C. Pommerville (2010). Alcamo’s Fundamentals of Microbiology (9th ed.). Sudbury MA: Jones & Bartlett. p. 323. ISBN 0-7637-6258-X. 10.10 Society and culture [6] “Who Is at Risk for Pneumonia?". NHLBI. March 1, 2011. Retrieved 3 March 2016. See also: List of notable pneumonia cases [7] “How Is Pneumonia Diagnosed?". NHLBI. March 1, 2011. Retrieved 3 March 2016.

[8] “Types of Pneumonia”. NHLBI. March 1, 2011. Re- 10.10.1 Awareness trieved 2 March 2016.

[9] “How Can Pneumonia Be Prevented?". NHLBI. March 1, Due to the relatively low awareness of the disease, 12 2011. Retrieved 3 March 2016. November was declared as the annual World Pneumonia Day, a day for concerned citizens and policy makers to [10] “What Is Pneumonia?". NHLBI. March 1, 2011. Re- take action against the disease, in 2009.[111][112] trieved 2 March 2016. 10.12. REFERENCES 103

[11] “How Is Pneumonia Treated?". NHLBI. March 1, 2011. [26] Snydman, editors, Raleigh A. Bowden, Per Ljung- Retrieved 3 March 2016. man, David R. (2010). Transplant infections (3rd ed.). Philadelphia: Wolters Kluwer Health/Lippincott [12] Ruuskanen, O; Lahti, E; Jennings, LC; Murdoch, DR Williams & Wilkins. p. 187. ISBN 978-1-58255-820- (2011-04-09). “Viral pneumonia”. Lancet. 377 (9773): 2. 1264–75. doi:10.1016/S0140-6736(10)61459-6. PMID 21435708. [27] Marrie, edited by Thomas J. (2002). Community-acquired pneumonia. New York: Kluwer Academic Publishers. p. [13] Lodha, R; Kabra, SK; Pandey, RM (4 June 2013). 20. ISBN 9780306468346. “Antibiotics for community-acquired pneumonia in children.”. The Cochrane database of systematic reviews. [28] Eom, CS; Jeon, CY; Lim, JW; Cho, EG; Park, SM; Lee, 6: CD004874. doi:10.1002/14651858.CD004874.pub4. KS (22 February 2011). “Use of acid-suppressive drugs PMID 23733365. and risk of pneumonia: a systematic review and meta- analysis”. CMAJ : Canadian Medical Association. 183 [14] Osler, William (1901). Principles and Practice of (3): 310–9. doi:10.1503/cmaj.092129. PMC 3042441 . Medicine, 4th Edition. New York: D. Appleton and Com- PMID 21173070. pany. p. 108. [29] Sharma, S; Maycher, B; Eschun, G (May 2007). “Radio- [15] George, Ronald B. (2005). Chest medicine : essentials of logical imaging in pneumonia: recent innovations”. Cur- pulmonary and critical care medicine (5th ed.). Philadel- rent Opinion in Pulmonary Medicine. 13 (3): 159–69. phia, PA: Lippincott Williams & Wilkins. p. 353. ISBN doi:10.1097/MCP.0b013e3280f3bﬀ4. PMID 17414122. 9780781752732. [30] Anevlavis S; Bouros D (February 2010). “Community ac- [16] Eddy, Orin (Dec 2005). “Community-Acquired Pneumo- quired bacterial pneumonia”. Expert Opin Pharmacother. nia: From Common Pathogens To Emerging Resistance”. 11 (3): 361–74. doi:10.1517/14656560903508770. Emergency Medicine Practice. 7 (12). PMID 20085502.

[17] Tintinalli, Judith E. (2010). Emergency Medicine: A Com- [31] Murray and Nadel (2010). Chapter 31. prehensive Study Guide (Emergency Medicine (Tintinalli)). New York: McGraw-Hill Companies. p. 480. ISBN 0- [32] Figueiredo LT (September 2009). “Viral pneumonia: 07-148480-9. epidemiological, clinical, pathophysiological, and therapeutic aspects”. J Bras Pneumol. 35 (9): 899– [18] Hoare Z; Lim WS (2006). “Pneumonia: update on diag- 906. doi:10.1590/S1806-37132009000900012. PMID nosis and management” (PDF). BMJ. 332 (7549): 1077– 19820817. 9. doi:10.1136/bmj.332.7549.1077. PMC 1458569 . [33] Behera, D. (2010). Textbook of pulmonary medicine (2nd PMID 16675815. ed.). New Delhi: Jaypee Brothers Medical Pub. pp. 391– [19] Singh, V; Aneja, S (March 2011). “Pneumonia – man- 394. ISBN 8184487495. agement in the developing world”. Paediatric respiratory [34] Maskell, Nick; Millar, Ann (2009). Oxford desk refer- reviews. 12 (1): 52–9. doi:10.1016/j.prrv.2010.09.011. ence. Oxford: Oxford University Press. p. 196. ISBN PMID 21172676. 9780199239122.

[20] Nair, GB; Niederman, MS (November 2011). [35] Murray and Nadel (2010). Chapter 37. “Community-acquired pneumonia: an unﬁnished battle”. The Medical clinics of North America. 95 (6): [36] Vijayan, VK (May 2009). “Parasitic lung infections”. 1143–61. doi:10.1016/j.mcna.2011.08.007. PMID Current Opinion in Pulmonary Medicine. 15 (3): 274– 22032432. 82. doi:10.1097/MCP.0b013e328326f3f8. PMID 19276810. [21] “Pneumonia (Fact sheet N°331)". World Health Organi- zation. August 2012. [37] ed. in chief Richard K. Root. Eds. Francis Waldvogel (1999). Clinical infectious diseases : a practical approach. [22] Darby, J; Buising, K (October 2008). “Could it be Le- New York, NY [u.a.]: Oxford Univ. Press. p. 833. ISBN gionella?". Australian family physician. 37 (10): 812–5. 978-0-19-508103-9. PMID 19002299. [38] Volume editors, Ulrich Costabel (2007). Diﬀuse [23] Ortqvist, A; Hedlund, J; Kalin, M (December 2005). parenchymal lung disease : ... 47 tables ([Online-Ausg.] “Streptococcus pneumoniae: epidemiology, risk factors, ed.). Basel: Karger. p. 4. ISBN 978-3-8055-8153-0. and clinical features”. Seminars in respiratory and critical care medicine. 26 (6): 563–74. doi:10.1055/s-2005- [39] Ranganathan, SC; Sonnappa, S (February 2009). “Pneu- 925523. PMID 16388428. monia and other respiratory infections”. Pediatric clinics of North America. 56 (1): 135–56, xi. [24] Murray and Nadel (2010). Chapter 32. doi:10.1016/j.pcl.2008.10.005. PMID 19135585.

[25] Lowe, J. F.; Stevens, Alan (2000). Pathology (2nd ed.). [40] Elsevier, Dorland’s Illustrated Medical Dictionary, Else- St. Louis: Mosby. p. 197. ISBN 0-7234-3200-7. vier. 104 CHAPTER 10. PNEUMONIA

[41] editors, Gary R. Fleisher, Stephen Ludwig ; associate edi- [52] Llamas-Álvarez, AM; Tenza-Lozano, EM; Latour-Pérez, tors, Richard G. Bachur [et at.] (2010). Textbook of pedi- J (February 2017). “Accuracy of Lung Ultrasonography atric emergency medicine (6th ed.). Philadelphia: Wolters in the Diagnosis of Pneumonia in Adults: Systematic Re- Kluwer/Lippincott Williams & Wilkins Health. p. 914. view and Meta-Analysis.”. Chest. 151 (2): 374–382. ISBN 1605471593. PMID 27818332.

[42] Hammer, edited by Stephen J. McPhee, Gary D. (2010). [53] Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Pathophysiology of disease : an introduction to clinical Campbell GD, Dean NC, Dowell SF, File TM Jr, Musher medicine (6th ed.). New York: McGraw-Hill Medical. DM, Niederman MS, Torres A, Whitney CG; Infectious pp. Chapter 4. ISBN 0071621679. Diseases Society of America; American Thoracic Society (1 March 2007). “Infectious Diseases Society of Amer- [43] Fein, Alan (2006). Diagnosis and management of pneu- ica/American Thoracic Society consensus guidelines on monia and other respiratory infections (2nd ed.). Caddo, the management of community-acquired pneumonia in OK: Professional Communications. pp. 28–29. ISBN adults”. Clinical Infectious Diseases. 44 (Suppl 2): S27– 1884735630. 72. doi:10.1086/511159. PMID 17278083.

[44] Kumar, Vinay (2010). Robbins and Cotran pathologic [54] Stedman’s medical dictionary. (28th ed.). Philadelphia: basis of disease. (8th ed.). Philadelphia, PA: Saun- Lippincott Williams & Wilkins. 2006. ISBN 978-0- ders/Elsevier. pp. Chapter 15. ISBN 1416031219. 7817-6450-6.

[45] Lynch, T; Bialy, L; Kellner, JD; Osmond, MH; [55] Dunn, L (June 29 – July 5, 2005). “Pneumonia: classifica- Klassen, TP; Durec, T; Leicht, R; Johnson, DW tion, diagnosis and nursing management”. Nursing stan- (2010-08-06). Huicho, Luis, ed. “A systematic re- dard (Royal College of Nursing (Great Britain) : 1987). view on the diagnosis of pediatric bacterial pneumo- 19 (42): 50–4. doi:10.7748/ns2005.06.19.42.50.c3901. nia: when gold is bronze”. PLoS ONE. 5 (8): e11989. PMID 16013205. doi:10.1371/journal.pone.0011989. PMC 2917358 . [56] organization, World health (2005). Pocket book of hospi- PMID 20700510. tal care for children : guidelines for the management of common illnesses with limited resources. Geneva: World [46] Ezzati, edited by Majid; Lopez, Alan D.; Rodgers, An- Health Organization. p. 72. ISBN 978-92-4-154670-6. thony; Murray, Christopher J.L. (2004). Comparative quantification of health risks. Genève: Organisation mon- [57] Anand, N; Kollef, MH (2009), “The alphabet soup of diale de la santé. p. 70. ISBN 978-92-4-158031-1. pneumonia: CAP, HAP, HCAP, NHAP, and VAP”, Semin Respir Crit Care Med, 30 (1): 3–9, doi:10.1055/s- [47] Rambaud-Althaus, C; Althaus, F; Genton, B; 0028-1119803, PMID 19199181. D'Acremont, V (April 2015). “Clinical features for diagnosis of pneumonia in children younger than 5 years: [58] American Thoracic Society; Infectious Diseases Soci- a systematic review and meta-analysis.”. The Lancet. ety of America (2005), “Guidelines for the management Infectious diseases. 15 (4): 439–50. doi:10.1016/s1473- of adults with hospital-acquired, ventilator-associated, 3099(15)70017-4. PMID 25769269. and healthcare-associated pneumonia”, Am J Respir Crit Care Med, 171 (4): 388–416, doi:10.1164/rccm.200405- [48] Lim WS, Baudouin SV, George RC, Hill AT, Jamieson 644ST, PMID 15699079. C, Le Jeune I, Macfarlane JT, Read RC, Roberts HJ, Levy ML, Wani M, Woodhead MA; Pneumonia Guide- [59] Jefferson, T; Di Pietrantonj, C; Rivetti, A; Bawazeer, lines Committee of the BTS Standards of Care Com- GA; Al-Ansary, LA; Ferroni, E (13 March 2014). mittee (October 2009). “BTS guidelines for the man- “Vaccines for preventing influenza in healthy adults.”. agement of community acquired pneumonia in adults: The Cochrane database of systematic reviews. 3: update 2009”. Thorax. 64 (Suppl 3): iii1–55. CD001269. doi:10.1002/14651858.CD001269.pub5. doi:10.1136/thx.2009.121434. PMID 19783532. PMID 24623315. [60] “Seasonal Influenza (Flu)". Center for Disease Control and [49] Saldías, F; Méndez, JI; Ramírez, D; Díaz, O (April 2007). Prevention. Retrieved 29 June 2011. "[Predictive value of history and physical examination for the diagnosis of community-acquired pneumonia in [61] Moberley, S; Holden, J; Tatham, DP; Andrews, adults: a literature review]". Revista medica de Chile. 135 RM (31 January 2013). “Vaccines for preventing (4): 517–28. PMID 17554463. pneumococcal infection in adults.”. The Cochrane database of systematic reviews. 1: CD000422. [50] Call, SA; Vollenweider, MA; Hornung, CA; Simel, doi:10.1002/14651858.CD000422.pub3. PMID DL; McKinney, WP (2005-02-23). “Does this pa- 23440780. tient have influenza?". JAMA: The Journal of the American Medical Association. 293 (8): 987–97. [62] “Pneumonia Can Be Prevented – Vaccines Can Help”. doi:10.1001/jama.293.8.987. PMID 15728170. Centers for Disease Control and Prevention. Retrieved 22 October 2012. [51] Helms, editors, William E. Brant, Clyde A. (2012-03-20). Fundamentals of diagnostic radiology (4th ed.). Philadel- [63] Jefferson, T; Demicheli, V; Di Pietrantonj, C; Rivetti, phia: Wolters Kluwer/Lippincott Williams & Wilkins. p. D (19 April 2006). “Amantadine and rimanta- 435. ISBN 9781608319114. dine for influenza A in adults.”. The Cochrane 10.12. REFERENCES 105

database of systematic reviews (2): CD001169. [73] Lassi, ZS.; Haider, BA.; Bhutta, ZA. (2010). “Zinc doi:10.1002/14651858.CD001169.pub3. PMID supplementation for the prevention of pneumo- 16625539. nia in children aged 2 months to 59 months.”. Cochrane Database Syst Rev (12): CD005978. [64] Jeﬀerson, T; Jones, MA; Doshi, P; Del Mar, CB; Hama, doi:10.1002/14651858.CD005978.pub2. PMID R; Thompson, MJ; Spencer, EA; Onakpoya, I; Mah- 21154362. tani, KR; Nunan, D; Howick, J; Heneghan, CJ (10 April 2014). “Neuraminidase inhibitors for prevent- [74] Bradley JS, Byington CL, Shah SS, Alverson B, Carter ing and treating inﬂuenza in healthy adults and chil- ER, Harrison C, Kaplan SL, Mace SE, McCracken GH dren.”. The Cochrane database of systematic reviews. Jr, Moore MR, St Peter SD, Stockwell JA, Swanson JT, 4: CD008965. doi:10.1002/14651858.CD008965.pub4. Pediatric Infectious Diseases Society and the Infectious PMID 24718923. Diseases Society of America (2011-08-31). “The Man- agement of Community-Acquired Pneumonia in Infants [65] Gray, DM; Zar, HJ (May 2010). “Community-acquired and Children Older Than 3 Months of Age: Clinical pneumonia in HIV-infected children: a global perspec- Practice Guidelines by the Pediatric Infectious Diseases tive”. Current Opinion in Pulmonary Medicine. 16 (3): Society and the Infectious Diseases Society of Amer- 208–16. doi:10.1097/MCP.0b013e3283387984. PMID ica”. Clinical Infectious Diseases. 53 (7): e25–76. 20375782. doi:10.1093/cid/cir531. PMID 21880587.

[66] Huang L, Cattamanchi A, Davis JL, den Boon S, Ko- [75] Yang, M; Yan, Y; Yin, X; Wang, BY; Wu, T; Liu, vacs J, Meshnick S, Miller RF, Walzer PD, Woro- GJ; Dong, BR (28 February 2013). “Chest phys- dria W, Masur H; International HIV-associated Oppor- iotherapy for pneumonia in adults.”. The Cochrane tunistic Pneumonias (IHOP) Study; Lung HIV Study database of systematic reviews. 2: CD006338. (June 2011). “HIV-associated Pneumocystis pneumo- doi:10.1002/14651858.CD006338.pub3. PMID nia”. Proceedings of the American Thoracic Society. 8 23450568. (3): 294–300. doi:10.1513/pats.201009-062WR. PMC [76] Zhang, Y; Fang, C; Dong, BR; Wu, T; Deng, JL 3132788 . PMID 21653531. (14 March 2012). Dong, Bi Rong, ed. “Oxy- gen therapy for pneumonia in adults”. Cochrane [67] Stern, A; Green, H; Paul, M; Vidal, L; Leibovici, Database of Systematic Reviews. 3: CD006607. L (1 October 2014). “Prophylaxis for Pneumocystis doi:10.1002/14651858.CD006607.pub4. PMID pneumonia (PCP) in non-HIV immunocompromised pa- 22419316. tients.”. The Cochrane database of systematic reviews. 10: CD005590. doi:10.1002/14651858.CD005590.pub3. [77] Chang, CC; Cheng, AC; Chang, AB (10 March PMID 25269391. 2014). “Over-the-counter (OTC) medications to reduce cough as an adjunct to antibiotics for acute [68] Taminato, M; Fram, D; Torloni, MR; Belasco, AG; pneumonia in children and adults.”. The Cochrane Saconato, H; Barbosa, DA (November–December 2011). database of systematic reviews. 3: CD006088. “Screening for group B Streptococcus in pregnant doi:10.1002/14651858.CD006088.pub4. PMID women: a systematic review and meta-analysis”. Re- 24615334. vista latino-americana de enfermagem. 19 (6): 1470– 8. doi:10.1590/s0104-11692011000600026. PMID [78] Haider, BA; Lassi, ZS; Ahmed, A; Bhutta, ZA (5 Oc- 22249684. tober 2011). Bhutta, Zulfiqar A, ed. “Zinc supplementation as an adjunct to antibiotics in the treat- [69] Darville, T (October 2005). “Chlamydia trachoma- ment of pneumonia in children 2 to 59 months of tis infections in neonates and young children”. Semi- age”. Cochrane Database of Systematic Reviews (10): nars in pediatric infectious diseases. 16 (4): 235–44. CD007368. doi:10.1002/14651858.CD007368.pub2. doi:10.1053/j.spid.2005.06.004. PMID 16210104. PMID 21975768. [79] Lutfiyya MN; Henley, E; Chang, LF; Reyburn, [70] Global Action Plan for Prevention and Control of Pneumo- SW (February 2006). “Diagnosis and treatment of nia (GAPP) (PDF). World Health Organization. 2009. community-acquired pneumonia” (PDF). Am Fam Physician. 73 (3): 442–50. PMID 16477891. [71] Roggensack, A; Jefferies, AL; Farine, D; Basso, M; Delisle, MF; Hudon, L; Mundle, WR; Murphy-Kaulbeck, [80] Eliakim-Raz, N; Robenshtok, E; Shefet, D; Gafter-Gvili, LC; Ouellet, A; Pressey, T (April 2009). “Management of A; Vidal, L; Paul, M; Leibovici, L (12 September meconium at birth”. Journal of obstetrics and gynaecology 2012). Eliakim-Raz, Noa, ed. “Empiric antibiotic Canada : JOGC = Journal d'obstetrique et gynecologie du coverage of atypical pathogens for community- Canada : JOGC. 31 (4): 353–4, 355–7. PMID 19497156. acquired pneumonia in hospitalized adults”. Cochrane Database of Systematic Reviews. 9: CD004418. [72] van der Maarel-Wierink, CD; Vanobbergen, JN; doi:10.1002/14651858.CD004418.pub4. PMID Bronkhorst, EM; Schols, JM; de Baat, C (6 March 2012). 22972070. “Oral health care and aspiration pneumonia in frail older people: a systematic literature review”. Gerodontology. [81] Lee, JS; Giesler, DL; Gellad, WF; Fine, MJ (9 30 (1): 3–9. doi:10.1111/j.1741-2358.2012.00637.x. February 2016). “Antibiotic Therapy for Adults Hos- PMID 22390255. pitalized With Community-Acquired Pneumonia: A 106 CHAPTER 10. PNEUMONIA

Systematic Review.”. JAMA. 315 (6): 593–602. Lancet. 379 (9832): 2151–61. doi:10.1016/S0140- doi:10.1001/jama.2016.0115. PMID 26864413. 6736(12)60560-1. PMID 22579125.

[82] Siemieniuk, RA; Meade, MO; Alonso-Coello, P; Briel, [95] Rudan, I; Boschi-Pinto, C; Biloglav, Z; Mulholland, K; M; Evaniew, N; Prasad, M; Alexander, PE; Fei, Y; Campbell, H (May 2008). “Epidemiology and etiology of Vandvik, PO; Loeb, M; Guyatt, GH (11 August 2015). childhood pneumonia”. Bulletin of the World Health Orga- “Corticosteroid Therapy for Patients Hospitalized With nization. 86 (5): 408–16. doi:10.2471/BLT.07.048769. Community-Acquired Pneumonia: A Systematic Review PMC 2647437 . PMID 18545744. and Meta-analysis.”. Annals of Internal Medicine. 163: 519–28. doi:10.7326/M15-0715. PMID 26258555. [96] Garenne M; Ronsmans, C; Campbell, H (1992). “The magnitude of mortality from acute respiratory infections [83] Wan, YD; Sun, TW; Liu, ZQ; Zhang, SG; Wang, LX; in children under 5 years in developing countries”. World Kan, QC (January 2016). “Eﬃcacy and Safety of Corti- Health Stat Q. 45 (2–3): 180–91. PMID 1462653. costeroids for Community-Acquired Pneumonia: A Sys- tematic Review and Meta-Analysis.”. Chest. 149 (1): [97] WHO (1999). “Pneumococcal vaccines. WHO position 209–19. doi:10.1378/chest.15-1733. PMID 26501852. paper”. Wkly. Epidemiol. Rec. 74 (23): 177–83. PMID 10437429. [84] Scalera NM; File, TM (April 2007). “How long [98] Weiss AJ, Wier LM, Stocks C, Blanchard J (June 2014). should we treat community-acquired pneumonia?". Cur- “Overview of Emergency Department Visits in the United rent Opinion in Infectious Diseases. 20 (2): 177– States, 2011”. HCUP Statistical Brief #174. Rockville, 81. doi:10.1097/QCO.0b013e3280555072. PMID MD: Agency for Healthcare Research and Quality. 17496577. [99] Feigin, Ralph (2004). Textbook of Pediatric Infectious [85] American Thoracic Society; Infectious Diseases So- Diseases (5th ed.). Philadelphia: W. B. Saunders. p. 299. ciety of America (February 2005). “Guidelines for ISBN 978-0-7216-9329-3. the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneu- [100] Stevenson, Angus (2010). Oxford Dictionary of English. monia”. Am J Respir Crit Care Med. 171 (4): 388–416. OUP Oxford. p. 1369. ISBN 9780199571123. doi:10.1164/rccm.200405-644ST. PMID 15699079. [101] Hippocrates On Acute Diseases wikisource link [86] Marik, PE (May 2011). “Pulmonary aspiration syndromes”. Current Opinion in Pulmonary Medicine. 17 (3): [102] Maimonides, Fusul Musa ("Pirkei Moshe"). 148–54. doi:10.1097/MCP.0b013e32834397d6. PMID [103] Klebs E (1875-12-10). "Beiträge zur Kenntniss der patho- 21311332. genen Schistomyceten. VII Die Monadinen" [Signs for [87] O'Connor S (2003). “Aspiration pneumonia and pneu- Recognition of the Pathogen Schistomyceten]. Arch. Exp. monitis”. Australian Prescriber. 26 (1): 14–7. Pathol. Pharmakol. 4 (5/6): 40–488. [104] Friedländer C (1882-02-04). "Über die Schizomyceten bei [88] Behera, D. (2010). Textbook of pulmonary medicine (2nd der acuten ﬁbrösen Pneumonie". Archiv für pathologische ed.). New Delhi: Jaypee Brothers Medical Pub. pp. 296– Anatomie und Physiologie und für klinische Medizin. 87 297. ISBN 9788184487497. (2): 319–324. doi:10.1007/BF01880516. [89] Cunha (2010). Pages6-18. [105] Fraenkel A (1884-04-21). "Über die genuine Pneumonie, [90] Rello, J (2008). “Demographics, guidelines, and clin- Verhandlungen des Congress für innere Medicin". Dritter ical experience in severe community-acquired pneumo- Congress. 3: 17–31. nia”. Critical care (London, England). 12 Suppl 6 (Suppl [106] Gram C (1884-03-15). "Über die isolierte Färbung 6): S2. doi:10.1186/cc7025. PMC 2607112 . PMID der Schizomyceten in Schnitt- und Trocken-präparaten". 19105795. Fortschr. Med. 2 (6): 185–9.

[91] Yu, H (March 2011). “Management of pleural eﬀusion, [107] edited by J.F. Tomashefski, Jr. []; et al. (2008). Dail empyema, and lung abscess”. Seminars in interventional and Hammar’s pulmonary pathology (3rd ed.). New York: radiology. 28 (1): 75–86. doi:10.1055/s-0031-1273942. Springer. p. 228. ISBN 978-0-387-98395-0. PMC 3140254 . PMID 22379278. [108] William Osler; Thomas McCrae (1920). The principles [92] Cunha (2010). Pages 250–251. and practice of medicine: designed for the use of practi- tioners and students of medicine (9th ed.). D. Appleton. [93] “Mortality and Burden of Disease Estimates for WHO p. 78. One of the most widespread and fatal of all acute Member States in 2002” (xls). World Health Organiza- diseases, pneumonia has become the “Captain of the Men tion. 2002. of Death”, to use the phrase applied by John Bunyan to consumption. [94] Liu, L; Johnson, HL; Cousens, S; Perin, J; Scott, S; Lawn, JE; Rudan, I; Campbell, H; Cibulskis, R; Li, M; Math- [109] Adams WG; Deaver, KA; Cochi, SL; et al. (January ers, C; Black, RE; Child Health Epidemiology Reference 1993). “Decline of childhood Haemophilus inﬂuenzae Group of WHO and, UNICEF (Jun 9, 2012). “Global, re- type B (Hib) disease in the Hib vaccine era”. JAMA. 269 gional, and national causes of child mortality: an updated (2): 221–6. doi:10.1001/jama.1993.03500020055031. systematic analysis for 2010 with time trends since 2000”. PMID 8417239. 10.13. EXTERNAL LINKS 107

[110] Whitney CG; Farley, MM; Hadler, J; et al. (May 2003). “Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine”. N. Engl. J. Med. 348 (18): 1737–46. doi:10.1056/NEJMoa022823. PMID 12724479.

[111] “World Pneumonia Day Oﬃcial Website”. World Pneu- monia Day Oﬃcial Website. Fiinex. Retrieved 13 August 2011.

[112] Hajjeh, Rana; Whitney, Cynthia G. (November 2012). “Call to Action on World Pneumonia Day”. Emerging Infectious Diseases. 18 (11): 1898–1899. doi:10.3201/eid1811.121217. PMC 3559175 . PMID 23092708.

[113] “Household Component Summary Data Tables”.

[114] “Household Component Summary Data Tables”.

[115] “One hospital charges $8,000 – another, $38,000”. The Washington Post.

[116] Welte T, Torres A, Nathwani D (January 2012). “Clin- ical and economic burden of community-acquired pneumonia among adults in Europe”. Thorax. 67 (1): 71–9. doi:10.1136/thx.2009.129502. PMID 20729232.

[117] Yakoob, MY; Salam, RA; Khan, FR; Bhutta, ZA (9 November 2016). “Vitamin D supplementation for preventing infections in children under ﬁve years of age.”. The Cochrane database of systematic reviews. 11: CD008824. doi:10.1002/14651858.CD008824.pub2. PMID 27826955.

Bibliography

• John F. Murray (2010). Murray and Nadel’s textbook of respiratory medicine (5th ed.). Philadelphia, PA: Saunders/Elsevier. ISBN 1416047107. • Burke A. Cunha, ed. (2010). Pneumonia essentials (3rd ed.). Sudbury, MA: Physicians’ Press. ISBN 0763772208.

10.13 External links

• Pneumonia at DMOZ Chapter 11

Rubella virus

Rubella virus (RuV) is the pathogenic agent of the dis- The E1 glycoprotein is considered immunodominant in ease rubella, and is the cause of congenital rubella syn- the humoral response induced against the structural pro- drome when infection occurs during the ﬁrst weeks of teins and contains both neutralizing and hemagglutinating pregnancy. determinants. Rubella virus is the only member of the genus Rubivirus [4] and belongs to the family of Togaviridae, whose members commonly have a genome of single-stranded RNA of positive polarity which is enclosed by an icosahedral 11.3 Genome capsid.

The molecular basis for the causation of congenital The genome has 9,762 nucleotides and encodes 2 non- rubella syndrome are not yet completely clear, but in vitro structural polypeptides (p150 and p90) within its 5′- studies with cell lines showed that rubella virus has an terminal two-thirds and 3 structural polypeptides (C, E2, apoptotic eﬀect on certain cell types. There is evidence [5] [1] and E1) within its 3′-terminal one-third. Both envelope for a p53-dependent mechanism. proteins E1 and E2 are glycosylated. There are three sites that are highly conserved in to- gaviruses: a stem-and-loop structure at the 5' end of the 11.1 Taxonomy genome, a 51-nucleotide conserved sequence near the 5' end of the genome and a 20-nucleotide conserved se- Group: ssRNA(+) quence at the subgenomic RNA start site. Homologous sequences are present in the rubella genome.[5] Order: Unassigned The genome encodes several non-coding RNA structures; among them is the rubella virus 3' cis-acting element, which contains multiple stem-loops, one of which has • Family: Togaviridae been found to be essential for viral replication.[6] The only signiﬁcant region of homology between rubella • Genus: Rubivirus and the alphaviruses is located at the NH2 terminus of non structural protein 3. This sequence has helicase and replicase activity. In the rubella genome these occur in • Rubella virus the opposite orientation to that found in the alphaviruses indicating that a genome rearrangement has occurred. [2] The genome has the highest G+C content of any currently known single stranded RNA virus (~70%).[7] Despite this high GC content its codon use is similar to that of its hu- 11.2 Structure man host.

The spherical virus particles (virions) of Togaviridae have a diameter of 50 to 70 nm and are covered by a lipid 11.4 Replication membrane (viral envelope), derived from the host cell membrane. There are prominent “spikes” (projections) The virus attach to the cell surface via speciﬁc receptors of 6 nm composed of the viral envelope proteins E1 and [3] and are taken up by an endosome being formed. At the E2 embedded in the membrane. neutral pH outside of the cell the E2 envelope protein Inside the lipid envelope is a capsid of 40 nm in diameter. covers the E1 protein. The dropping pH inside the en-

108 11.7. LITERATURE 109

dosome frees the outer domain of E1 and causes the fu- Genotype 1j has only been isolated from Japan and the sion of the viral envelope with the endosomal membrane. Philippines. Thus, the capsid reaches the cytosol, decays and releases Genotype 1E is found in Africa, the Americas, Asia and the genome Europe. The (+)ssRNA (positive, single-stranded RNA) at first Genotype 1G has been isolated in Belarus, Cote d'Ivoire only acts as a template for the translation of the non- and Uganda. structural proteins, which are synthesized as a large polyprotein and are then cut into single proteins. The se- Genotype 1C is endemic only in Central and South Amer- quences for the structural proteins are first replicated by ica. the viral RNA polymerase (Replicase) via a complemen- Genotype 2B has been isolated in South Africa. tary (-)ssRNA as a template and translated as a separate short mRNA. This short subgenomic RNA is additionally Genotype 2C has been isolated in Russia. packed in a virion.[8] Translation of the structural proteins produces a large polypeptide (110 Dalton). This is then 11.7 Literature endoproteolytically cut into E1, E2 and the capsid protein. E1 and E2 are type I transmembrane proteins • David M. Knipe, Peter M. Howley et al. (eds.): which are transported into the endoplasmatic reticulum Fields Virology 4. Auflage, Philadelphia 2001 (ER) with the help of an N-terminal signal sequence. From the ER the heterodimeric E1·E2-complex reaches • C.M. Fauquet, M.A. Mayo et al.: Eighth Report the Golgi apparatus, where the budding of new virions of the International Committee on Taxonomy of occurs (unlike alpha viruses, where budding occurs at Viruses, London San Diego 2005 the plasma membrane. The capsid proteins on the other hand stay in the cytoplasm and interact with the genomic RNA, together forming the capsid.[9] 11.8 References [4] [1] Megyeri K, Berencsi K, Halazonetis TD, et al. (June 1999). “Involvement of a p53-dependent pathway in 11.5 Capsid protein rubella virus-induced apoptosis”. Virology. 259 (1): 74– 84. doi:10.1006/viro.1999.9757. PMID 10364491.

[10] The capsid protein (CP) has diﬀerent functions. Its [2] ICTV. “Virus Taxonomy: 2014 Release”. Retrieved 15 main tasks are the formation of homooligomeres to form June 2015. the capsid, and the binding of the genomic RNA. Further is it responsible for the aggregation of RNA in the cap- [3] Bardeletti G, Kessler N, Aymard-Henry M (1975). “Mor- sid, it interacts with the membrane proteins E1 and E2 phology, biochemical analysis and neuraminidase activ- and binds the human host-protein p32 which is important ity of rubella virus”. Arch. Virol. 49 (2–3): 175–86. for replication of the virus in the host.[11] doi:10.1007/BF01317536. PMID 1212096. As opposed to alpha viruses the capsid does not undergo [4] “Viral Zone”. ExPASy. Retrieved 15 June 2015. autoprotolysis, rather is it cut oﬀ from the rest of the polyprotein by the signal-peptidase. Production of the [5] Dominguez G, Wang CY, Frey TK (July 1990). “Se- capsid happens at the surface of intracellular membranes quence of the genome RNA of rubella virus: evidence for genetic rearrangement during togavirus evolu- simultaneously with the budding of the virus.[12] tion”. Virology. 177 (1): 225–38. doi:10.1016/0042- 6822(90)90476-8. PMID 2353453.

11.6 Epidemiology [6] Chen, MH; Frey TK (1999). “Mutagenic analysis of the 3' cis-acting elements of the rubella virus genome”. J Virol. On the basis of differences in the sequence of the E1 pro- 73 (4): 3386–3403. PMC 104103 . PMID 10074193. tein, two genotypes have been described which differ by [7] Zhou Y, Chen X, Ushijima H, Frey TK (2012) Analysis 8 - 10%. These have been subdivided into 13 recognised of base and codon usage by rubella virus. Arch Virol genotypes - 1a, 1B, 1C, 1D, 1E, 1F, 1G, 1h, 1i, 1j, 2A, 2B and 2C. [8] “Togaviridae- Classification and Taxonomy”. For typing, the WHO recommends a minimum window [13] [9] Garbutt M, Law LM, Chan H, Hobman TC (May 1999). that includes nucleotides 8731 to 9469. “Role of rubella virus glycoprotein domains in assembly Genotypes 1a, 1E, 1F, 2A and 2B have been isolated in of virus-like particles”. J. Virol. 73 (5): 3524–33. PMC China. 104124 . PMID 10196241. 110 CHAPTER 11. RUBELLA VIRUS

[10] Chen MH, Icenogle JP (April 2004). “Rubella virus capsid protein modulates viral genome replication and virus infectivity”. Journal of Virology. 78 (8): 4314–22. doi:10.1128/jvi.78.8.4314-4322.2004. PMC 374250 . PMID 15047844.

[11] Beatch MD, Everitt JC, Law LJ, Hobman TC (August 2005). “Interactions between rubella virus capsid and host protein p32 are important for virus replication”. J. Vi- rol. 79 (16): 10807–20. doi:10.1128/JVI.79.16.10807- 10820.2005. PMC 1182682 . PMID 16051872.

[12] Beatch MD, Hobman TC (June 2000). “Rubella virus capsid associates with host cell protein p32 and local- izes to mitochondria”. J. Virol. 74 (12): 5569– 76. doi:10.1128/JVI.74.12.5569-5576.2000. PMC 112044 . PMID 10823864.

[13] “Standardization of the nomenclature for genetic characteristics of wild-type rubella viruses” (PDF). Wkly Epi- demiol Rec. 80 (14): 126–132. 2005. PMID 15850226.

11.9 External links

• Viralzone: Rubivirus 11.10. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 111

11.10 Text and image sources, contributors, and licenses

11.10.1 Text • Airborne disease Source: https://en.wikipedia.org/wiki/Airborne_disease?oldid=772006608 Contributors: Discospinster, Rich Farm- brough, Xezbeth, Bender235, Smalljim, Rjwilmsi, Saberwyn, Paul Erik, MacsBug, SmackBot, Da Vynci, Mini-Geek, Dl2000, Cryptic C62, Qwyrxian, Paste, TAnthony, Mcewan, Iceway12, Doc James, Kehrbykid, Escape Orbit, Masterblooregard, Addbot, CanadianLin- uxUser, Yobot, AnomieBOT, Materialscientist, Valleyofdawn, Quebec99, Mark Schierbecker, Erik9bot, Pinethicket, LegendFPS, Heavy Joke, Dcirovic, ZéroBot, Psykonautiks, Hazard-Bot, JonRichfield, Pfancher, ClueBot NG, LikeAnOutlaw79, Widr, BG19bot, Mark Arsten, CitationCleanerBot, Angkomarnicki, Anbu121, ChrisGualtieri, Alevántate, Frosty, Jamesx12345, Mxland, Reatlas, Epicgenius, Tentina- tor, Denili9, Monkbot, 3primetime3, TheOtherUnknown, Dnorton1434, L0st H0r!z0ns, Ghost1324576809, Marianna251, Ashu124421, PrimeBOT and Anonymous: 48 • Influenza A virus Source: https://en.wikipedia.org/wiki/Influenza_A_virus?oldid=769074824 Contributors: AxelBoldt, Mav, The Anome, Alex.tan, Pgdudda, Vanderesch, Earth, Gabbe, Yann, Karada, Kosebamse, CesarB, Ronabop, Ahoerstemeier, Jpatokal, Snoyes, Den fjättrade ankan~enwiki, DropDeadGorgias, Whkoh, Poor Yorick, Nikai, Kaihsu, Mxn, Conti, Paul Weaver, Fuzheado, Tpbradbury, Itai, Bevo, Dbabbitt, Wilke, Jason M, Pakaran, Johnleemk, Francs2000, Zandperl, Tomchiukc, Chris 73, Romanm, Yosri, Auric, Hadal, UtherSRG, Pps, Mushroom, ElBenevolente, Jooler, Dusik, Giftlite, Christopher Parham, Wizzy, Tom harrison, Peruvianllama, Everyking, Malbear, Jfdwolff, Bobblewik, Edcolins, Keith Edkins, Bact, Daen, Antandrus, HorsePunchKid, Kaldari, Jossi, OwenBlacker, Tothe- barricades.tk, Thincat, Norman Lloydbottom, Sam Hocevar, Joyous!, Adashiel, Trevor MacInnis, Dr.frog, Wfaulk, DanielCD, JTN, A- giau, Rich Farmbrough, Guanabot, Thematicunity, Qutezuce, Vsmith, Gallen01, LeeHunter, Mani1, Paul August, Bender235, Sunborn, 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FoCuSandLeArN, Rab1802, KlatschmohnAcker, Sriharsh1234, 24yulia, Thejeffyo, Snipergreg1345, Khanane, Melonkelon, Kingofaces43, Mrradiostar82, Dinnbray182, Monkbot, Jfoster71, Yaleblair, Felicity nayda, Matthew Ferguson 57, Robere04, Ken Linder, KasparBot, Adam9007, Zupotachyon, GreenC bot, Drluzhouliang and Anonymous: 315 • Tuberculosis Source: https://en.wikipedia.org/wiki/Tuberculosis?oldid=772466569 Contributors: AxelBoldt, TwoOneTwo, Kpjas, ClaudeMuncey, Eloquence, Mav, Koyaanis Qatsi, -- April, Alex.tan, Wayne Hardman, Andre Engels, Youssefsan, Danny, DWeir, Rmher- 112 CHAPTER 11. RUBELLA VIRUS

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TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 117

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• Meningitis Source: https://en.wikipedia.org/wiki/Meningitis?oldid=772477916 Contributors: Malcolm Farmer, Alex.tan, Rsabbatini, Ed- ward, Gabbe, Pandora, Ixfd64, Mac, Theresa knott, Angela, Jebba, Randomned, Rob Hooft, Bemoeial, Tpbradbury, Saltine, Raul654, Robbot, Gak, Altenmann, Kowey, Naddy, Caknuck, Hadal, Plandu, Psb777, Richy, Nunh-huh, Ævar Arnfjörð Bjarmason, Zigger, Michael Devore, Gamaliel, LLarson, Jfdwolff, Guanaco, Gadfium, Andycjp, DocSigma, Antandrus, BozMo, Alex Cohn, Seannyob, Vogon77, TonyW, Neutrality, Joyous!, Adashiel, Discospinster, Rich Farmbrough, Paul August, Bender235, JoeSmack, CanisRufus, Remember, Art LaPella, Peter Greenwell, Bobo192, Smalljim, Davidruben, Arcadian, TheProject, MPerel, Sam Korn, WMMartin, Nsaa, Jumbuck, Alansohn, Oliverlewis, Falsifian, Babajobu, Wouterstomp, Axl, Bart133, Carioca, LFaraone, Scott Gall, Alai, Oystertoadfish, 2004-12- 29T22:45Z, LOL, The Wordsmith, Kmg90, Bbatsell, John Hill, MarcoTolo, Dysepsion, Mandarax, Siqbal, Graham87, Jclemens, Men- daliv, Edison, Sjö, Solace098, Sjakkalle, Rjwilmsi, XP1, Mdanciu, MarnetteD, Remurmur, Yamamoto Ichiro, Titoxd, FlaBot, RobertG, Nihiltres, Wknight8111, Itinerant1, RexNL, Gurch, Karelj, Stevenfruitsmaak, King of Hearts, Chobot, DVdm, Cuahl, YurikBot, Wave- length, Borgx, Rxnd, Gaius Cornelius, CambridgeBayWeather, Eleassar, Polarlys, Rsrikanth05, Wimt, NawlinWiki, EgbertW, Wiki alf, Mccready, Nephron, Rmky87, Starryboy, Mgcsinc, Tony1, Mysid, Bota47, Andrewr47, DRosenbach, Rcinda1, Supalognon, User27091, Encephalon, Cbogart2, Colin, ZoFreX, JoanneB, Kungfuadam, Paul Erik, Jkpjkp, DVD R W, Steven Pounders, AndrewWTaylor, Isoxyl, Mathiasm~enwiki, A bit iffy, SmackBot, Espresso Addict, Federalist51, KnowledgeOfSelf, Unyoyega, Jagged 85, Jfurr1981, DTM, Delldot, Dlodge, Jwestbrook, Gilliam, Quadratic, Tim.spears, Scaife, Bluebot, KaragouniS, Persian Poet Gal, Švitrigaila, Anchoress, Gcummins, Uthbrian, Nbarth, Keysignal, DHN-bot~enwiki, Gracenotes, Mendelson~enwiki, Brideshead, Tsca.bot, NYKevin, Can't sleep, clown will eat me, Nick Levine, Scray, Geekboy72, Snowmanradio, Niels Olson, Landon, Edivorce, Mr.Z-man, Allison Stillwell, Krich, Hackmi- ester, Flyguy649, Husey, G716, Lord Mrakainus, The undertow, Speh, Silvem, Kuru, NewTestLeper79, Joelmills, Lazylaces, Sir Nicholas de Mimsy-Porpington, Minna Sora no Shita, CredoFromStart, Aleenf1, Joshua Scott, Bella Swan, Cerberus™, Noroom, Mr Stephen, Serephine, Doczilla, Spydercanopus, Ryulong, Hu12, Nehrams2020, Iridescent, Wjejskenewr, Sjb72, GDallimore, Igoldste, Wwallacee, DavidOaks, Chovain, Tawkerbot2, K.murphy, Fvasconcellos, JForget, CmdrObot, R0, Eggman64, Insanephantom, Leevanjackson, Gal- liasM, Kiswanson, Dgw, Jesse Viviano, WeggeBot, Richard Keatinge, AndrewHowse, Neonlife, Cydebot, Vanished user 45po45lr87gj, Khatru2, Anthonyhcole, Corpx, Quibik, DumbBOT, Chrislk02, Garik, UberScienceNerd, Thijs!bot, Epbr123, Supermood00d, Mojo Hand, Woody, Jimmymags, James086, AgentPeppermint, Natalie Erin, E!, AlefZet, Mentifisto, Cyclonenim, AntiVandalBot, The Obento Musubi, Luna Santin, Seaphoto, Opelio, QuiteUnusual, Dgerton, Fru1tbat, Quintote, Prolog, BigNate37, Scepia, Malcolm, Spencer, Ola Rosling, Castlemj, ClassicSC, Waverly, Arch dude, Dr. May, Awien, Roleplayer, Chickyfuzz123, East718, Wise dude321, Kerotan, LittleOldMe, Magioladitis, A12n, VoABot II, MastCell, JamesBWatson, WhatamIdoing, Theroadislong, Animum, Loonymonkey, All- starecho, P.B. 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RUBELLA VIRUS

Toby1285, Kfcjdjrbccsblv ndb, Barbara (WVS), We Them Boys, Assassinanup, Msilvestro63, SkyWarrior, Preethi.murthy, JoinHands, MereTechnicality, Sans2233 and Anonymous: 994

• Pneumonia Source: https://en.wikipedia.org/wiki/Pneumonia?oldid=769705118 Contributors: Kpjas, Alex.tan, Josh Grosse, Karen John- son, Heron, B4hand, Edward, D, Fred Bauder, Gabbe, Ixfd64, Paul Benjamin Austin, Dori, Minesweeper, Mdebets, Ahoerstemeier, Mac, CatherineMunro, Marumari, Julesd, Glenn, Tristanb, Oliver Crow, Mxn, Smack, Etaoin, Richard Avery, Saument, Andrewman327, Tp- bradbury, Ozuma~enwiki, Saltine, Topbanana, Pollinator, Slawojarek, Robbot, Fredrik, Chris 73, Gak, Donreed, Mayooranathan, Dmadeo, Yosri, Hadal, Xanzzibar, GreatWhiteNortherner, Unfree, Giftlite, Thv, Ian Maxwell, Nmg20, Haeleth, Nunh-huh, Peruvianllama, Ev- eryking, Capitalistroadster, Alison, Michael Devore, Davin (usurped), Jfdwolff, Silvermask, Stevietheman, SoWhy, Quadell, Antandrus, Bcameron54, PDH, Khaosworks, DragonflySixtyseven, Kevin B12, Bk0, Sam Hocevar, JHCC, Joyous!, Ta bu shi da yu, Freakofnurture, Haruo, JimJast, Discospinster, Patricknoddy, Rich Farmbrough, FT2, GeoEvan, Autiger, Paul August, Bender235, Mehrenberg, Sgeo, Appleboy, RJHall, Mr. Billion, Sfahey, Fenevad, DS1953, Aude, CDN99, Causa sui, Keane4, Bobo192, Smalljim, Davidruben, Viriditas, Richi, Arcadian, Valar, John Fader, Hagerman, Mareino, Knucmo2, Jumbuck, Schissel, Danski14, Alansohn, Gary, Anthony Apple- yard, Halsteadk, Andrewpmk, Wouterstomp, Riana, Lectonar, Axl, Ddlamb, Fritzpoll, Stillnotelf, Lee S. Svoboda, Knowledge Seeker, Evil Monkey, RainbowOfLight, Fantumphool, Gene Nygaard, Kazvorpal, Ceyockey, TigerShark, Nuggetboy, Mhearne, Rikek, Tabletop, Yegorm, Dysepsion, RichardWeiss, Graham87, Magister Mathematicae, Elvey, Bunchofgrapes, DePiep, Coneslayer, Rjwilmsi, Rogerd, Harro5, Vegaswikian, Oblivious, Ligulem, Cww, Sferrier, Brighterorange, The wub, Dolphonia, Bhadani, M A Mason, Ucucha, Fred Brad- stadt, Sango123, Avocado, FlaBot, Ian Pitchford, RobertG, AED, Nihiltres, Chanting Fox, RexNL, Gurch, Stevenfruitsmaak, BradBeattie, Chobot, Rewster, Gwernol, YurikBot, Koveras, Rob T Firefly, Cabiria, Arado, Pburka, WAvegetarian, Bergsten, Eleassar, Big Brother 1984, Herbertxu, NawlinWiki, Wiki alf, Bachrach44, Jaxl, Duran, Irishguy, Albedo, Nephron, Andersonblog, The Filmaker, Wolbo, Voidxor, Tony1, Digitylgoddess, Dissolve, Nescio, Cstaffa, WAS 4.250, Encephalon, JCipriani, Closedmouth, Nemu, Sariberi, Badgettrg, JLaTon- dre, Spliffy, Jacqui M, Ben D., RG2, John Broughton, Andrew73, Quadpus, SpLoT, SmackBot, Teenwriter, FloNight, Hydrogen Iodide, Pgk, InvictaHOG, Hswapnil, Delldot, Eskimbot, HalfShadow, Xaosflux, DaveThomas, Gilliam, ERcheck, Master Jay, RDBrown, W8IMP, Thumperward, DanF, MalafayaBot, SchfiftyThree, Moshe Constantine Hassan Al-Silverburg, Baa, VenomSnake, Darth Panda, A. 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• Rubella virus Source: https://en.wikipedia.org/wiki/Rubella_virus?oldid=762631921 Contributors: Azhyd, Rich Farmbrough, Arca- dian, Alansohn, Terrycojones, Rjwilmsi, Benlisquare, RussBot, Rsrikanth05, Bob247, BullRangifer, Scientizzle, Ben Moore, NonDucor, PhilKnight, Kuyabribri, J.delanoy, VolkovBot, DrMicro, StevenBrown, Doc James, Graham Beards, Flyer22 Reborn, ClueBot, Excirial, Jacoblang01, Thehelpfulone, XLinkBot, Trabelsiismail, Shunju-kun, Addbot, DOI bot, Ronhjones, Tcharvin, Martina Steiner, Luckas-bot, Vedran12, DemocraticLuntz, Materialscientist, Citation bot, Xqbot, Cureden, ArcadianOnUnsecuredLoc, Manitobamountie, GrouchoBot, Dylasn, Philippe Le Mercier, Sushiﬂinger, Dr alherezi, Citation bot 1, Pinethicket, Beyond My Ken, Dcirovic, Solomonfromﬁnland, Brand- meister, ClueBot NG, ChrisGualtieri, Harsh 2580, Dexbot, ComfyKem, Monkbot, Bervin61, Crobles0303, BU Rob13, Prahlad balaji and Anonymous: 28 11.10. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 119

11.10.2 Images

• File:3D_Influenza_virus.png Source: https://upload.wikimedia.org/wikipedia/commons/3/3b/3D_Influenza_virus.png License: Public domain Contributors: California Department of Health Services Original artist: National Institutes of Health; originally uploaded to en.wikipedia by TimVickers (25 October 2006), transferred to Commons by Quadell using CommonsHelper. • File:Airport_Thermographic_Camera.jpg Source: https://upload.wikimedia.org/wikipedia/commons/1/1c/Airport_Thermographic_ Etan Tal איתן טל :Camera.jpg License: CC BY 3.0 Contributors: Own work Original artist • File:Antigenic_drift_vs_shift.png Source: https://upload.wikimedia.org/wikipedia/commons/c/ca/Antigenic_drift_vs_shift.png License: Public domain Contributors: ? Original artist: U.S. Food and Drug Administration

• File:Bem_chickenpox_vannkopper_20140318.jpg Source: https://upload.wikimedia.org/wikipedia/commons/b/ba/Bem_chickenpox_ vannkopper_20140318.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Ronny Ager-Wick • File:CT_scan_of_the_chest,_demonstrating_right-sided_pneumonia.jpg Source: https://upload.wikimedia.org/wikipedia/ commons/7/7a/CT_scan_of_the_chest%2C_demonstrating_right-sided_pneumonia.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: James Heilman, MD • File:Carswell-Tubercle.jpg Source: https://upload.wikimedia.org/wikipedia/commons/0/03/Carswell-Tubercle.jpg License: Public domain Contributors: University of Glasgow Original artist: Robert Carswell (1793–1857) • File:Ceftriaxone_structure.png Source: https://upload.wikimedia.org/wikipedia/commons/0/0c/Ceftriaxone_structure.png License: Public domain Contributors: Own work Original artist: Edgar181 • File:Characteristic_rash_of_hand,_foot,_and_mouth_disease,_on_human_hands.jpg Source: https://upload.wikimedia.org/ wikipedia/commons/5/5c/Characteristic_rash_of_hand%2C_foot%2C_and_mouth_disease%2C_on_human_hands.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: James Heilman, MD • File:Charlotte_Cleverley-Bisman_Meningicoccal_Disease.jpg Source: https://upload.wikimedia.org/wikipedia/commons/2/29/ Charlotte_Cleverley-Bisman_Meningicoccal_Disease.jpg License: CC-BY-SA-3.0 Contributors: http://www.babycharlotte.co.nz/ photos6-12mths.html Original artist: Pam Cleverley, Perry Bisman, http://babycharlotte.co.nz • File:Chickenpox.png Source: https://upload.wikimedia.org/wikipedia/commons/0/09/Chickenpox.png License: CC BY-SA 4.0 Contrib- utors: Own work Original artist: BruceBlaus • File:Chickenpox_Adult_back.jpg Source: https://upload.wikimedia.org/wikipedia/commons/7/74/Chickenpox_Adult_back.jpg Li- cense: CC BY-SA 3.0 Contributors: Own work Original artist: F malan • File:Chickenpox_blister.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c3/Chickenpox_blister.jpg License: CC BY- SA 3.0 Contributors: Own work Original artist: F malan • File:ChineseFluInspectors.JPG Source: https://upload.wikimedia.org/wikipedia/commons/6/6d/ChineseFluInspectors.JPG License: CC BY-SA 3.0 Contributors: Own work Original artist: NocturneNoir • File:Colorized_transmission_electron_micrograph_of_Avian_influenza_A_H5N1_viruses.jpg Source: https://upload.wikimedia. org/wikipedia/commons/0/0d/Colorized_transmission_electron_micrograph_of_Avian_influenza_A_H5N1_viruses.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identiﬁcation number #1841. Original artist: • Photo Credit: Cynthia Goldsmith • Content Providers: CDC/ Courtesy of Cynthia Goldsmith; Jacqueline Katz; Sherif R. Zaki • File:Commons-logo.svg Source: https://upload.wikimedia.org/wikipedia/en/4/4a/Commons-logo.svg License: PD Contributors: ? Origi- nal artist: ? • File:Crackles_pneumoniaO.ogg Source: https://upload.wikimedia.org/wikipedia/commons/c/c7/Crackles_pneumoniaO.ogg License: CC BY-SA 3.0 Contributors: Own work Original artist: James Heilman, MD • File:EM_of_influenza_virus.jpg Source: https://upload.wikimedia.org/wikipedia/commons/a/a4/EM_of_influenza_virus.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identiﬁcation number #8160. Original artist: • Photo Credit: Cynthia Goldsmith • Content Providers(s): CDC/ Dr. Terrence Tumpey • File:Ferguson_influenza_generation_time_distribution.png Source: https://upload.wikimedia.org/wikipedia/commons/4/4f/ Ferguson_influenza_generation_time_distribution.png License: CC BY-SA 3.0 Contributors: Own work Original artist: Gak • File:Gnome-mime-sound-openclipart.svg Source: https://upload.wikimedia.org/wikipedia/commons/8/87/ Gnome-mime-sound-openclipart.svg License: Public domain Contributors: Own work. Based on File:Gnome-mime-audio-openclipart. svg, which is public domain. Original artist: User:Eubulides • File:H1N1_navbox.jpg Source: https://upload.wikimedia.org/wikipedia/commons/e/ea/H1N1_navbox.jpg License: CC BY-SA 3.0 Con- tributors: Transferred from en.wikipedia to Commons by The New Mikemoral using CommonsHelper. Original artist: Cybercobra (talk) • File:H1N1_versus_H5N1_pathology.png Source: https://upload.wikimedia.org/wikipedia/commons/b/b0/H1N1_versus_H5N1_ pathology.png License: Public domain Contributors: Own work Original artist: TimVickers • File:Hand_Foot_Mouth_Disease_Adult_36Years.jpg Source: https://upload.wikimedia.org/wikipedia/commons/5/5f/Hand_Foot_ Mouth_Disease_Adult_36Years.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: KlatschmohnAcker • File:Hand_foot_and_mouth_disease_on_child_feet.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c5/Hand_foot_ and_mouth_disease_on_child_feet.jpg License: CC BY-SA 3.0 Contributors: picutre of my son’s feet Original artist: Ngufra 120 CHAPTER 11. RUBELLA VIRUS

• File:Hilleman-Walter-Reed.jpeg Source: https://upload.wikimedia.org/wikipedia/commons/1/1c/Hilleman-Walter-Reed.jpeg License: Public domain Contributors: The photo is a cropped version of the original, which is Order Number B014616 in the National Library of Medicine. The date and author (below) are taken from the NLM’s MARC record. The photograph was published in 1958 by Walter Reed Army Medical Center. The photo has been cropped, healed to fix minor defects, and converted to JPEG (quality level 88), with the GIMP 2.6.6. Original artist: Walter Reed Army Medical Center • File:Influenza_Seasonal_Risk_Areas.svg Source: https://upload.wikimedia.org/wikipedia/commons/3/30/Influenza_Seasonal_Risk_ Areas.svg License: CC BY-SA 3.0 Contributors: • BlankMap-World6.svg Original artist: BlankMap-World6.svg: Canuckguy (talk) and many others (see File history) • File:Influenza_geneticshift.svg Source: https://upload.wikimedia.org/wikipedia/commons/d/d2/Influenza_geneticshift.svg Li- cense: CC-BY-SA-3.0 Contributors: This file was derived from Influenza geneticshift.jpg: Original artist: Influenza_geneticshift.jpg: Dhorspool at en.wikipedia • File:Influenza_nomenclature.svg Source: https://upload.wikimedia.org/wikipedia/commons/7/7a/Influenza_nomenclature.svg License: CC-BY-SA-3.0 Contributors: Own work Original artist: Burschik • File:Influenza_subtypes.svg Source: https://upload.wikimedia.org/wikipedia/commons/b/b8/Influenza_subtypes.svg License: Public domain Contributors: Own work Original artist: Fvasconcellos • File:Influenza_virus_research.jpg Source: https://upload.wikimedia.org/wikipedia/commons/8/86/Influenza_virus_research.jpg Li- cense: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #7988. Original artist: • Photo Credit: James Gathany • Content Providers(s): CDC • File:Koplik_spots,_measles_6111_lores.jpg Source: https://upload.wikimedia.org/wikipedia/commons/6/6b/Koplik_ spots%2C_measles_6111_lores.jpg License: Public domain Contributors: http://phil.cdc.gov/PHIL_Images/20040908/ 4f54ee8f0e5f49f58aaa30c1bc6413ba/6111_lores.jpg Original artist: CDC • File:Lock-green.svg Source: https://upload.wikimedia.org/wikipedia/commons/6/65/Lock-green.svg License: CC0 Contributors: en:File: Free-to-read_lock_75.svg Original artist: User:Trappist the monk • File:Lower_respiratory_infections_world_map-Deaths_per_million_persons-WHO2012.svg Source: https://upload.wikimedia. org/wikipedia/commons/d/d9/Lower_respiratory_infections_world_map-Deaths_per_million_persons-WHO2012.svg License: CC BY- SA 4.0 Contributors: Data from World Health Organization Estimated Deaths 2012 Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Chris55 • File:Lower_respiratory_infections_world_map_-_DALY_-_WHO2004.svg Source: https://upload.wikimedia.org/wikipedia/ commons/7/75/Lower_respiratory_infections_world_map_-_DALY_-_WHO2004.svg License: CC BY-SA 2.5 Contributors: • Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Lokal_Profil • File:MRSAPneumoCT.png Source: https://upload.wikimedia.org/wikipedia/commons/5/5d/MRSAPneumoCT.png License: CC BY- SA 4.0 Contributors: Own work Original artist: James Heilman, MD • File:Mantoux_tuberculin_skin_test.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/fa/Mantoux_tuberculin_skin_ test.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #6806. Original artist: Greg Knobloch • File:Measles.webm Source: https://upload.wikimedia.org/wikipedia/commons/2/25/Measles.webm License: CC BY-SA 4.0 Contributors: open.osmosis.org Original artist: Osmosis • File:Measles_Aztec_drawing.jpg Source: https://upload.wikimedia.org/wikipedia/commons/b/b1/Measles_Aztec_drawing.jpg License: Public domain Contributors: (2009) Viruses, Plagues, and History: Past, Present and Future, Oxford University Press, USA, p. 144 ISBN: 0- 19-532731-4. Original artist: Unknown • File:Measles_in_African_Child_4.JPG Source: https://upload.wikimedia.org/wikipedia/commons/e/e6/Measles_in_African_Child_4. JPG License: Public domain Contributors: Own work Original artist: Mike Blyth • File:Measles_vaccination_coverage_world.svg Source: https://upload.wikimedia.org/wikipedia/commons/f/f7/Measles_vaccination_ coverage_world.svg License: CC BY-SA 3.0 Contributors: • BlankMap-World8.svg Original artist: BlankMap-World8.svg: AMK1211 • File:Measles_virus.JPG Source: https://upload.wikimedia.org/wikipedia/commons/6/62/Measles_virus.JPG License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #8429. Original artist: • Photo Credit: Cynthia S. Goldsmith • Content Providers(s): CDC/ Courtesy of Cynthia S. Goldsmith; William Bellini, Ph.D. • File:Measles_world_map-Deaths_per_million_persons-WHO2012.svg Source: https://upload.wikimedia.org/wikipedia/commons/7/ 77/Measles_world_map-Deaths_per_million_persons-WHO2012.svg License: CC BY-SA 4.0 Contributors: Data from World Health Or- ganization Estimated Deaths 2012 Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Chris55 11.10. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 121

• File:Measles_world_map_-_DALY_-_WHO2004.svg Source: https://upload.wikimedia.org/wikipedia/commons/a/ac/Measles_ world_map_-_DALY_-_WHO2004.svg License: CC BY-SA 2.5 Contributors: • Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Lokal_Profil • File:Meningitis-Epidemics-World-Map.png Source: https://upload.wikimedia.org/wikipedia/commons/b/b1/ Meningitis-Epidemics-World-Map.png License: Public domain Contributors: • BlankMap-World-large.png Original artist: User:Leevanjackson • File:Meningitis_Histopathology.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/f9/Meningitis_Histopathology.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Marvin 101 • File:Meningitis_world_map-Deaths_per_million_persons-WHO2012.svg Source: https://upload.wikimedia.org/wikipedia/ commons/1/19/Meningitis_world_map-Deaths_per_million_persons-WHO2012.svg License: CC BY-SA 4.0 Contributors: Data from World Health Organization Estimated Deaths 2012 Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Chris55 • File:Meningitis_world_map_-_DALY_-_WHO2004.svg Source: https://upload.wikimedia.org/wikipedia/commons/c/ca/Meningitis_ world_map_-_DALY_-_WHO2004.svg License: CC BY-SA 2.5 Contributors: • Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Lokal_Profil • File:Merge-arrows.svg Source: https://upload.wikimedia.org/wikipedia/commons/5/52/Merge-arrows.svg License: Public domain Con- tributors: ? Original artist: ? • File:Morbillivirus_measles_infection.jpg Source: https://upload.wikimedia.org/wikipedia/commons/3/3c/Morbillivirus_measles_ infection.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #3168. Original artist: • Photo Credit: • Content Providers(s): CDC/Dr. Heinz F. Eichenwald • File:Mummy_at_British_Museum.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/cc/Mummy_at_British_Museum. jpg License: CC-BY-SA-3.0 Contributors: ? Original artist: ? • File:Mycobacterium_tuberculosis.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/cb/Mycobacterium_tuberculosis. jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Im- age Library (PHIL), with identification number #8438. Original artist: • Photo Credit: Janice Carr • Content Providers(s): CDC/ Dr. Ray Butler; Janice Carr • File:Neck_stiffness.jpg Source: https://upload.wikimedia.org/wikipedia/commons/5/54/Neck_stiffness.jpg License: Public domain Contributors: Sophian, Abraham: Epidemic cerebrospinal meningitis (1913), St. Louis, C.V Mosby (Scan from archive.org). Original artist: L.A. Marty, M.D, Kansas City • File:Neisseria_meningitidis.jpg Source: https://upload.wikimedia.org/wikipedia/commons/7/75/Neisseria_meningitidis.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #6423. Original artist: Dr. Brodsky • File:New_Pneumonia_cartoon.jpg Source: https://upload.wikimedia.org/wikipedia/commons/f/fb/New_Pneumonia_cartoon.jpg Li- cense: Public domain Contributors: ? Original artist: ? • File:Open_Access_logo_PLoS_transparent.svg Source: https://upload.wikimedia.org/wikipedia/commons/7/77/Open_Access_logo_ PLoS_transparent.svg License: CC0 Contributors: http://www.plos.org/ Original artist: art designer at PLoS, modified by Wikipedia users Nina, Beao, and JakobVoss • File:Pleural_effusion.jpg Source: https://upload.wikimedia.org/wikipedia/commons/e/e7/Pleural_effusion.jpg License: Public domain Contributors: • http://www.cdc.gov/ncidod/dvbid/dengue/slideset/spanish/set1/vi/slide08.htm Original artist: User InvictaHOG on en.wikipedia • File:Ploketes_d'_aiwe_dj3_costé.jpg Source: https://upload.wikimedia.org/wikipedia/commons/9/90/Ploketes_d%27_aiwe_dj3_ cost%C3%A9.jpg License: CC BY-SA 3.0 Contributors: Own work Original artist: Lucyin • File:Pneumonia.webm Source: https://upload.wikimedia.org/wikipedia/commons/8/8e/Pneumonia.webm License: CC BY-SA 4.0 Con- tributors: open.osmosis.org Original artist: Osmosis • File:PneumonisWedge09.JPG Source: https://upload.wikimedia.org/wikipedia/commons/a/ac/PneumonisWedge09.JPG License: CC BY-SA 3.0 Contributors: Own work Original artist: James Heilman, MD • File:RobertKoch.jpg Source: https://upload.wikimedia.org/wikipedia/commons/0/07/RobertKoch.jpg License: Public domain Contributors: https://ihm.nlm.nih.gov/images/B16691 Original artist: Unknown • File:RtPneuKidMark.png Source: https://upload.wikimedia.org/wikipedia/commons/c/c4/RtPneuKidMark.png License: CC BY-SA 4.0 Contributors: Own work Original artist: James Heilman, MD • File:Sida-aids.png Source: https://upload.wikimedia.org/wikipedia/commons/2/2f/Sida-aids.png License: CC-BY-SA-3.0 Contributors: User:FoeNyx © 2004 (artistic illustration) Original artist: User:FoeNyx © 2004 (artistic illustration) • File:Sneeze.JPG Source: https://upload.wikimedia.org/wikipedia/commons/7/77/Sneeze.JPG License: Public domain Contributors: CDC Public Health Image library ID 11162 Original artist: James Gathany 122 CHAPTER 11. RUBELLA VIRUS

• File:Streptococcus_pneumoniae.jpg Source: https://upload.wikimedia.org/wikipedia/commons/2/20/Streptococcus_pneumoniae.jpg License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #262. Original artist: • Photo Credit: CDC/Janice Carr • Content Providers(s): CDC/Dr. Richard Facklam • File:Symptoms_of_influenza.svg Source: https://upload.wikimedia.org/wikipedia/commons/9/9e/Symptoms_of_influenza.svg License: Public domain Contributors: All used images are in public domain. Original artist: Mikael Häggström. • File:Symptoms_of_pneumonia.svg Source: https://upload.wikimedia.org/wikipedia/commons/2/20/Symptoms_of_pneumonia.svg Li- cense: Public domain Contributors: All used images are in public domain. Original artist: Mikael Häggström. • File:TB_in_sputum.png Source: https://upload.wikimedia.org/wikipedia/commons/2/27/TB_in_sputum.png License: Public domain Contributors: This media comes from the Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #2128. Original artist: • The original uploader was TimVickers at English Wikipedia • File:TB_poster.jpg Source: https://upload.wikimedia.org/wikipedia/commons/8/8e/TB_poster.jpg License: Public domain Contributors: U.S. National Library of Medicine Transferred from en.wikipedia Original artist: Rensselaer County Tuberculosis Association. • File:Tango_Phone_medapp.svg Source: https://upload.wikimedia.org/wikipedia/commons/8/82/Tango_Phone_medapp.svg License: CC0 Contributors: Own work Original artist: CFCF • File:Tuberculosis-prevalence-WHO-2009.svg Source: https://upload.wikimedia.org/wikipedia/commons/e/e1/ Tuberculosis-prevalence-WHO-2009.svg License: Public domain Contributors: I made this map, starting with the map outline in File:BlankMap-World6, compact.svg, and then applying prevalence data taken from Annex 3 of: (2009) Global tuberculosis control: epidemiology, strategy, financing (PDF), World Health Organization Retrieved on 12 November 2009. ISBN: 978 92 4 156380 2. . A copy of the data I extracted is below. Original artist: Eubulides • File:Tuberculosis_symptoms.svg Source: https://upload.wikimedia.org/wikipedia/commons/2/2f/Tuberculosis_symptoms.svg License: Public domain Contributors: All used images are in public domain. Original artist: Mikael Häggström. • File:Tuberculosis_video.webm Source: https://upload.wikimedia.org/wikipedia/commons/b/b8/Tuberculosis_video.webm License: CC BY-SA 4.0 Contributors: open.osmosis.org Original artist: Osmosis • File:Tuberculosis_world_map-Deaths_per_million_persons-WHO2012.svg Source: https://upload.wikimedia.org/wikipedia/ commons/7/76/Tuberculosis_world_map-Deaths_per_million_persons-WHO2012.svg License: CC BY-SA 4.0 Contributors: Data from World Health Organization Estimated Deaths 2012 Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Chris55 • File:Tuberculosis_world_map_-_DALY_-_WHO2004.svg Source: https://upload.wikimedia.org/wikipedia/commons/b/b6/ Tuberculosis_world_map_-_DALY_-_WHO2004.svg License: CC BY-SA 2.5 Contributors: • Vector map from BlankMap-World6, compact.svg by Canuckguy et al. Original artist: Lokal_Profil • File:Tuberculous_epididymitis_Low_Power.jpg Source: https://upload.wikimedia.org/wikipedia/commons/8/8c/Tuberculous_ epididymitis_Low_Power.jpg License: CC BY-SA 4.0 Contributors: Government Medical College, Kozhikode Original artist: Department of Pathology, Calicut Medical college • File:Vaccination_US_Navy.jpg Source: https://upload.wikimedia.org/wikipedia/commons/c/c2/Vaccination_US_Navy.jpg License: Public domain Contributors: [1] Original artist: Joseph R Schmitt • File:Vicki_Pandit_-_Howrah_2014-04-06_9845.JPG Source: https://upload.wikimedia.org/wikipedia/commons/0/0a/Vicki_Pandit_ -_Howrah_2014-04-06_9845.JPG License: CC BY 3.0 Contributors: Own work Original artist: Biswarup Ganguly • File:Virus_Replication_large.svg Source: https://upload.wikimedia.org/wikipedia/commons/a/a0/Virus_Replication_large.svg License: CC-BY-SA-3.0 Contributors: Scaled up from Image:Virus Replication.svg by User:YK Times, who redrew from w:Image:Virusreplication. png using Adobe Illustrator. Original artist: User:YK Times • File:WHO_Rod.svg Source: https://upload.wikimedia.org/wikipedia/commons/d/d6/WHO_Rod.svg License: Public domain Contribu- tors: http://www.who.int/about/licensing/emblem/en/ Original artist: WHO • File:WPA_Pneumonia_Poster.jpg Source: https://upload.wikimedia.org/wikipedia/commons/7/77/WPA_Pneumonia_Poster.jpg Li- cense: Public domain Contributors: Work Projects Administration Poster Collection (Library of Congress). http://memory.loc.gov/service/ pnp/cph/3f00000/3f05000/3f05300/3f05391r.jpg Original artist: WPA Federal Art Project • File:W_curve.png Source: https://upload.wikimedia.org/wikipedia/commons/7/70/W_curve.png License: Public domain Contributors: Transferred from en.wikipedia to Commons by Leptictidium using CommonsHelper. Source: http://www.cdc.gov/ncidod/EID/vol12no01/ 05-0979.htm (fig. 2) - Taken from “1918 Influenza: the Mother of All Pandemics” Jeffery K. Taubenberger and David M. Morens Original artist: CDC is author • File:Wiki_letter_w_cropped.svg Source: https://upload.wikimedia.org/wikipedia/commons/1/1c/Wiki_letter_w_cropped.svg License: CC-BY-SA-3.0 Contributors: This file was derived from Wiki letter w.svg: Original artist: Derivative work by Thumperward • File:Wikibooks-logo.svg Source: https://upload.wikimedia.org/wikipedia/commons/f/fa/Wikibooks-logo.svg License: CC BY-SA 3.0 Contributors: Own work Original artist: User:Bastique, User:Ramac et al. • File:Wikinews-logo.svg Source: https://upload.wikimedia.org/wikipedia/commons/2/24/Wikinews-logo.svg License: CC BY-SA 3.0 Contributors: This is a cropped version of Image:Wikinews-logo-en.png. Original artist: Vectorized by Simon 01:05, 2 August 2006 (UTC) Updated by Time3000 17 April 2007 to use official Wikinews colours and appear correctly on dark backgrounds. Originally uploaded by Simon. 11.10. TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES 123

• File:Wikiquote-logo.svg Source: https://upload.wikimedia.org/wikipedia/commons/f/fa/Wikiquote-logo.svg License: Public domain Contributors: Own work Original artist: Rei-artur • File:Wikisource-logo.svg Source: https://upload.wikimedia.org/wikipedia/commons/4/4c/Wikisource-logo.svg License: CC BY-SA 3.0 Contributors: Rei-artur Original artist: Nicholas Moreau • File:Wikiversity-logo-Snorky.svg Source: https://upload.wikimedia.org/wikipedia/commons/1/1b/Wikiversity-logo-en.svg License: CC BY-SA 3.0 Contributors: Own work Original artist: Snorky • File:Wiktionary-logo-v2.svg Source: https://upload.wikimedia.org/wikipedia/commons/0/06/Wiktionary-logo-v2.svg License: CC BY- SA 4.0 Contributors: Own work Original artist: Dan Polansky based on work currently attributed to Wikimedia Foundation but originally created by Smurrayinchester

11.10.3 Content license

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