Clinical Causes Fifth Disease (Erythema Infectiosum) Miscellaneous viruses features Also causes aplastic anemia in pple with SSA, and fetal infections like hydrops fetalis

1st phase Important viruses from the Parvovirus family Viraemic phase B19 Virus Virus present in upper respiratory tract (site of shedding) Virology Virus Family Parvovirus Symptoms occur at the end of 1st week (constitutional symptoms) Very small virus (22 nm only) - Fever - Malaise Genotype - Myalgia Ss DNA - Chills Simplest DNA animal viruses. - Itching Negative strand DNA NO VIRION polymerase 2nd phase mediated by immune complexes Icosahedral capsid Rash in 1/3 of patients

Envelope “Slapped cheek” appearance Small, naked particles (NON ENVELOPED) Rash appears particularly on the face This is the most characteristic appearance Replicate autonomously in rapidly dividing cells Differential diagnosis is child abuse Virus that lives only in human is Parvovirus B19 Rash can also appear on the trunk Only one serotype Has a reticulated lacy appearance

Replicative After adsorption to host cell receptors, virion penetrates and moves to nucleus Pathogenesis cycle Replication occurs in nucleus Infects mainly 2 types of cells Single stranded genome DNA has hairpin loops at both ends providing double stranded areas for RBC precursors (erythroblasts) in the BONE MARROW ‰ aplastic anaemia cellular DNA polymerase to initiate synth of progeny genomes ENDOTHELIAL CELLS in blood vessels ‰ accounts in part for rash in erythema infectiosum

Viral mRNA is synth by cellular RNA polymerase from Double stranded DNA intermediate Immune complexes composed of virus and IgM or IgG also contribute to pathogenesis of rash and to arthritis seen in some adults infected by B19 Progeny virons are assembled IN THE NUCLEUS Infection provides LIFELONG immunity against infection B19 only replicates when cell is in S phase. Which explains why it is only replicating in RBC precursors, BUT not in mature RBCs Hydrops fetallis manifests as massive edema of the fetus This is secondary to congestive heart failure ppt by SEVERE ANEMIA caused by death of parvovirus Epidemiology Transmission B19 infected ERYTHROBLASTS in FETUS Transmitted mainly by o Body fluids o Blood o Vertically from mother to fetus (transplacental also occurs)

Mainly by respiratory route

Symptoms usually appear within 4 days to 2 weeks after exposure

Parvovirus infection is common in childhood Most infections are asymptomatic. B19 infection occurs worldwide About ½ the pple in US older than 18 have antibodies

Humans are natural reservoir Animals not a source of human infection

Printed with FinePrint - purchase at www.fineprint.com 4 main clinical presentations (5 if include chronic infection) Complications Special patients with B19 infection Disease Group affected Elaboration Erythema Children Mild disease primarily of childhood Because the B19 targets human erythroid progenitor cells infectiosum Char bright red rash most prominent on Cause lysis of cells leading to anaemia. cheeks Can also affect lymphocytes, granulocytes and platelets. Accompanied by Low grade fever Runny nose Hence must consider these patients Sore throat Especially in chronic anemia and pregnant women

Lacy less intense erythematous rash appears on body Patient group Complications Patients with chronic Can cause Transient Aplastic Crisis Symptoms resolve in about 1 wk haemolytic anaemia (e.g. Aplastic anemia due to the aplasia of erythroid progenitors sickle cell disease or Other rashes thalassemia Can cause reticulocytosis (reticulocytes are one of the cells in Measles erythrocyte development) Rubella SSA is more common in Scarlet fever the Negroid races This is because Chronic haemolytic anemia requires a physiological Roseola response to produce more red blood cells from the bone marrow. Thalassemia is more However, B19 can cause lysis of cells thus aggravating chronic common in Asian haemolytic anemic condtions) Aplastic Children with chronic anemia due Transient but severe aplastic anemia (aplastic anemia to SSA, thalassemia, crisis) when infected populations, might confer spherocytosis some protection against malaria. Pple with normal RBC do not have clinically apparent anemia, but RBC precursors are still affected Immunocompromised Can cause severe aplastic anemia patients st nd Fetal infections Woman infected in 1 or 2 Virus crosses placenta and infects fetus trimester of pregnancy Pregnant patients (1st Can cause severe anaemia in fetus (non-immune hydrops fetalis) Infection in 1st trimester trimester > 2nd trimester) Fetal death Fetus can go into severe cardiac failure (chronic cardiac failure) This leads to generalized chronic edema Not an important cause of congenital Leading to hydrops fetalis abnormalities because fetus dies when Leads eventually to spontaneous abortion infected early in preg Cancer patients This is because the bone marrow cells are trying to replicate to 2nd trimester replace the stuff that is destroyed by chemotherapy Hydrops fetalis

3rd trimester Not result in important clinical findings

Arthritis B19 infection in adults esp women Causes arthritis Involving small joints of hands and feet BILATERALLY Resembles rheumatoid arthrititis

Other infections that cause immune complex related arth 1. hep B 2. rubella

CHRONIC B19 Pple with immunodeficiencies esp • Chronic anemia

infections • HIV infection • Leukopaenia

• Chemotherapy • Thrombocytopaenia due to chronic • Tpt patients infection

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Printed with FinePrint - purchase at www.fineprint.com Lab diagnosis Viral culture and isolation is NOT possible Virus is difficult to grow. Can be isolated from throat swabs BUT not usually done

Serology Hence diagnosis depends on serology Usually dx by detecting IgM abs

IgM appears 4 - 7 days IgG appears 7 - 10 days later and persists for years (unsure if this gives long-term protection)

In the case of Pregnancy: Tests for mother Mother’s Serology IgM and IgG (rising titres)

PCR - detect B19 DNA in maternal serum

Tests for fetus Ultrasound screening for non-immune hydrops.

Percutaneous umbilical blood sampling (PUBS) – this is a more invasive procedure

Molecular methods ‰‰‰ PCR In immunocompromised, abs may not be detectable Hence can detect viral DNA in blood by PCR methods

Fetal infection can also be det by PCR analysis of amniotic fluid

Management Treatment and Control No known specific treatment (not needed in most cases) Pooled immune globulins may have beneficial effect in chronic infection with immunodeficient patients.

No chemoprophylaxis either

Blood transfusion for transient aplastic crisis

In the case of Fetal infection 1.Watchful waiting (conservative management) 2.High-dose IgG therapy 3.Intrauterine fetal transfusion

Vaccine Not available yet

PREVENTION IS THE SAFEST Avoid exposure during pregnancy

Printed with FinePrint - purchase at www.fineprint.com Pox virus induced diseases

Genus Virus Primary host Disease Orthopoxvirus Variola Smallpox Humans Ç

Vaccinia Ç Smallpox vaccination Humans This was very useful for vaccination against small pox

Monkey pox Monkey Human infections rare, localized lesions

Cowpox Cows

Parapoxvirus Orf Sheep Human infections rare Localized lesions Milker’s node Cows More important for Australia and New Zealand

Unclassified Molluscum Ç Many benign skin nodules contagiousm Humans

Tanapox Monkeys Human infections rare Localized lesions Yabapox Monkeys

Printed with FinePrint - purchase at www.fineprint.com Transmission Transmission Important Poxviruses Infection transmitted by respiratory route from Spread by direct contact or fomites (towels, lesions in respiratory tract swimming pools) Variola Virus (smallpox virus) Molluscum contagiosum Respiratory aerosols Virology Virus family May be transmitted from Poxviruses OR BY DIRECT contat with virus either in skin - Skin to skin Brick shaped particles containing double stranded DNA, a disk shaped core within a DOUBLE lesions or on fomites such as bedding - After sexual intercourse (sexually transmitted) membrane and a lipoprotein envelope - Tends to occur in children

Features of the virus Tm by close personal contact Large virus: 250 - 300 nm (the largest and most complex viruses known) Pathogenesis Small pox begins when virus infects upper Have been known about for centuries respiratory tract and local LN

Viral genome Then enters the blood (10 viraemia) Double-stranded DNA virus Has a DNA dependent RNA polymerase Internal organs are infected Replicates in the cytoplasm and does not have access to cellular RNA polymerase which is located in the nucleus Virus then REENTERS the blood and spreads to the skin Smallpox has a single stable serotype which was key to the success of the vaccine These EVENTS OCCUR DURING THE Easy to grow in the lab INCUBATION PERIOD. WHEN PATIENT IS STILL WELL. Poxviruses have their specific animal hosts Rash is a result of the viral replication in skin Characteristics of pox infection followed by damage by cytotoxic T cells attacking Infections mostly characterised by a rash virus infected cells

Important Antigen features Immunity following small pox is lifelong Antigenically, poxviruses are very complex, inducing both specific and cross-reacting antibodies Immunity following vaccination is 10 years

Epidemiology Smallpox has now been eradicated - the last Human disease of worldwide distribution Clinical Incubation period Incubation period: naturally occurring outbreak of smallpox was in This will be commonly seen in GP practice features During 12-day incubation, virus distributed to 1 week to 6 months Somalia on 26th October 1977. internal organs. Small papule that grows into WHO campaign - most outstanding example of During this period, there is a sudden onset of - Discrete what could be achieved through international prodromal symptoms such as fever and malaise. - Waxy cooperation and mass immunization - Smooth Biggest success story of the WHO This is followed by the rash - Dome-shaped - Pearly or flesh-coloured nodule. Not many diseases can be eradicated in such a RASH - Looks like a volcano from the top manner Rash appears suddenly - Viruses come out from the crater Found on the face and trunk and extremities (characteristic cup shaped crater with white Now there is a fear of use as bioterrorism agent Worse on the face and extremities than on the core NOT the same as warts which are trunk (centrifugal distribution) caused by HPV a member of papovavirus NOTE family ) There are virus stocks kept in the US and Russian Evolves through stages from macules ‰ papules labs. ‰vesicles ‰ pustules ‰ crusts in 2-3 weeks Usually 1 - 20 lesions, occasionally in hundreds Hope that no one ever takes possession of these Can be widespread in the immunocompromised stocks Papular ‰ initially the rash is popular ie raised Vesicular ‰ then fluid appears in the rash Children: trunk and proximal extremities NOTE Pustular‰ then pus appears in the rash Adults: trunk, pubic areas and thighs that you can synthesize the full length of the DNA Vesicles then burst leaving pink scars of the virus and transfect it into a susceptible cells Individual lesions persist for 2 months, disease (has infectious DNA) Severe infections with 20-50% mortality lasts 6 months The cell will then make the virus for you No need live virus stock All the vesicles will be of the same stage of Infection is usually benign and painless development In immunocompentent, lesions are self limited.

Spontaneous recovery (treatment for cosmetic reasons)

Printed with FinePrint - purchase at www.fineprint.com Variola Virus (smallpox virus) Molluscum contagiosum Lab diagnosis Can diagnose on the clinical signs and symptoms Can make diagnosis on characteristic clinical Why was eradication possible in the first place appearance Eradication of smallpox was possible for 3 In the past when disease occurred, dx made reasons: either by growing virus in cell culture or chick Confirmed by EM (semi-solid caseous material embryos or by detecting viral antigens in vesicular can be expressed from the lesions) 1) There is no other reservoir for VV but man fluid by IF (including primates) (c.f. Arboviruses) EM has characteristic appearance, has a very Hence because the virus only attacks humans. complex appearance NO reservoirs like in birdflu

Management Vaccination No vaccines available 2) VV causes only acute infections, from which the Poxvirus vaccines infected person either: "Variolation" = the administration of material from Treatment a) dies known smallpox cases to protect recipients Can treat by squeezing the nodule to remove the b) recovers with life-long immunity This was not a very effective practice. viruses (c.f. Herpesviruses) No latent period. Edward Jenner, 14th May 1796, used cowpox Can apply some iodine to the crater after Latent viruses are very successful viruses (Sarah Nemes) to "vaccinate" 8 year old James squeezing HIV has 10 years of latency Phipps, who he later challenged with variola virus and showed that he was protected. Removal of lesion by curettage or liquid nitro is 3) Vaccinia virus is an effective immunogen often effective Safe and immunogenic vaccine available for Vaccinia virus for vaccination is prepared from small pox. vesicular lesions produced in the skin of calves No established antiviral therapy and sheep, or it can be grown in chick embryos. But cidofovir may be useful for tx extensive “Search and containment”, i.e. isolation of cases lesions in immunocompromised patients. and the tracing and vaccination of contacts. NOTE THAT Vaccination with Vaccinia Associated with certain risks Note that not many other viral diseases fulfil this Complications range from mild reactions to fatal criteria for eradication encephalitis Polio is another target But this is a really big challenge eg Indonesia Overall incidence of complications was 1/800 Severe complications 15 per million (this is fairly Bioterrorism safe) In potential possibility of bioterrorism attack using small pox virus, US federal government Recent interest: vaccinia as a vector for programme to vaccinate first responders. immunisation against other viruses Exposed individual can be immunized as long as Renewed interest in the vaccine because of threat 4 days AFTER exposure and still be protected. of bioterrorism Hence if attack occurs, need to vaccinate pple who were exposed

Some military personnel and civilians have exp myocarditis following vaccination and because of this programme NOT advised to be expanded to general public

Rifampin inhibits viral DNA dep RNA polymerase BUT not used clinically against small pox

VIG containing high titer abs against vaccinia virus can be used to tx complications of vaccination

Methisazone was used to tx complications and may be useful again.

Printed with FinePrint - purchase at www.fineprint.com Virus moves by axonal tpt to the CNS Important Zoonoses o During tpt in the nerve, sheltered from immune system o Hence little if ANY immune response occurs

Definition of Zoonoses Virus multiplies in the CNS Zooneses are diseases of vertebrate animals that can be transmitted to man: either directly or indirectly through an insect Travels down the peripheral nerves to the salivary glands and other organs vector. From salivary glands, enters saliva to be tm by the bite When an insect vector is involved, the disease is also known as an arboviral disease. There is NO VIRAEMIC STAGE

Note that a lot of emerging diseases are zoonoses Clinical Rabies is an acute infection of the CNS which is almost invariably fatal Bird flu – original hosts: Birds features Must be introduced at the site of inoculation usually by an animal bite (bite of a rabid animal, usually a SARS - Original hosts: civet cats dog) Nipah virus Originally from civet cats Infectivity of rabies virus may be determined by the site and mode of transmission For example, the risk is low if the person is bitten on the foot Rabies Depends on the distance the virus has to travel from the site of inoculation to the brain Virology Virology Member of the Lyassavirus of the Rhabdoviridae Site of inoculation Risk Only medically important member of the rhabdovirus family Head and neck 60% risk Upper limb 15-40% risk Viral Genome Lower limb 3-10% risk ssRNA enveloped virus genome has negative polarity Incubation period varies according to location of the bite hence virion contains an RNA dependent RNA polymerase 2 wks -16 wks or longer Shorter when bites on head rather than on leg because of distance virus travels to reach CNS Viral structure Characteristic bullet-shaped appearance with 6-7 nm spike projections May also be inhaled (in bat-infested caves) Virion 130-240nm Possibly from the guano Has a single antigenic type From Levinson: Non bite rabies can also occur. Antigenicity resides in the envelope glycoprotein spikes o Most important example is exposure to aerosols of bat secretions containing rabies virus. o Another example is pple who died in when tpt with corneas taken from pple dying of undx rabies Epidemiology Epidemiology Prevalent in wildlife Within the CNS, encephalitis develops Has a broad host range. o Death of neurons Can infect all mammals, but only certain mammals are important sources of infection for humans o Demyelination

In urban areas where there are no immunization programs for animals, the domestic dog is the major o Infected neurons contain eosinophilic cytoplasmic inclusion called the Negri body which is impt source in the lab dx of rabies Elsewhere, wildlife may be responsible for human infection Because so few pple survive, no information regarding immunity to dz upon being bitten again Europe fox, bats Middle East wolf, dog Asia dog Africa dog, mongoose, antelope N America foxes, skunks, raccoons, insectivorous bats S America dog, vampire bats

Domestic dog is a major source of infection Rodents and rabbits do not tm rabies

Pathogenesis of Rabies Transmitted by the bite of a rabid animal that manifests aggressive biting behaviour induced by the viral encephalitis

The virus replicates in the striated or connective tissue at the site of inoculation Multiplies locally at the bite site

Enters the peripheral nerves through the neuromuscular junction. (no viraemia in this case) Spreads to the CNS in the endoneurium of the Schwann cells. Terminally, there is widespread CNS involvement

Printed with FinePrint - purchase at www.fineprint.com Complications 3 phases Management Postexposure Prophylaxis

Prodromal phase: Wound treatment Non specific symptoms presenting according to Levinson Bites and scratches should be thoroughly washed with soap and water. A day or two, marked by pain and paresthesias in the area of the bite This is to reduce the viral load Gastrointestinal and upper respiratory symptoms There may be increased salivation Experimentally, the incidence of rabies in animals can be reduced by local treatment alone.

Irritability No antiviral tx for rabies, only supportive Apprehension A sense of impending death Passive immunization Human rabies immunoglobulin around the area of the wound Hydrophobia – this is very characteristic for rabies This is to allow the antibodies introduced to bind and to neutralize the virus Most notable is the painful spasm of throat muscles on swallowing. This results in hydrophobia, an aversion to swallowing water because it is so painful To be supplemented with an i.m. dose to confer short term protection. This ensures that the antibodies will go into the bloodstream as well Excitation phase: - Hyperventilation Active immunization - Hyperactivity Injection site of active immunization must be different from the injection site of the passive immunization - Disorientation This is because rabies has a relatively long incubation period so you can actually get the host to make - Even seizures (disease progresses to seizures in several days) his own antibodies

Paralytic phase: CF Hep B children of Hep B positive mothers can also use both passive and active immunization - Lethargic and early paralysis - Particularly in those areas innervated by the cranial nerves Rabies Vaccines - In the somatic muscles, bladder, and bowels. The vaccines available for humans are inactivated whole virus vaccines.

- Gradual involvement of cardiac muscles and paralysis of respiratory muscles lead to death. Human Diploid Cell Vaccine (HDCV) Currently the best vaccine available Death is almost invariable - Efficacy rate of nearly 100% Life support does mean a few individuals survive - Rarely any severe reactions. - Most immunogenic vaccine compared to duck embryo Lab diagnosis Histopathology - No allergic encephalomyelitis as compared to nerve tissue derived vaccines which can cross react Negri bodies are pathognomonic on histology ( 70% of cases) with human myelin - These are eosinophilic inclusions in cytoplasm of neurons of the CNS of the DOG involved or possibly of the dead individual Can either have preexposure or post exposure - This is if you can find the dog that caused the bite Pre-exposure Rapid dx in the animal is usually made by examination of brain tissue using fluorescent abs or histo Given i.m. or s.c. into deltoid area of upper arm staining of negri bodies in cytoplasm of hippocampal neurons In five doses spaced at day 0, 3, 7, 14 and 30. Booster doses given as needed to maintain ab titer of 1:5 Rapid virus antigen detection Become widely used Preexposure should be given to individuals in HIGH risk groups eg vets zookeepers and travellers to Corneal impressions or neck skin biopsy. hyper-endemic areas Can detect with this method of Direct Fluorescent Antibody Test (commonly used) In humans, rabies can be dx by fluorescent ab staining of biopsy specimen Post-exposure Can also isolate virus from sources like saliva, spinal fluid or brain tissue Rabies vaccine is the ONLY vaccine that is routinely used POST EXPOSURE LONG incubation means that virus in vaccine can have sufficient time to induce immunity Negri bodies can also be seen in corneal scrapings of HUMAN or in autopsy specimens of HUMAN Give both vaccine and human rabies globulin obtained from HYPERIMMUNIZED persons. Plus brain immediate cleaning of the wound. Tetanus immunization should also be considered Virus cultivation The most definitive means of diagnosis is by virus cultivation from saliva and infected tissue. Note if the animal was captured, should also observe animal for 10 days and euthanize if symptoms Cell cultures may be used or more commonly develop. Brain of animal should be examined by immunofluorescence Specimen is inoculated intracerebrally into infant mice. Rarely offered by diagnostic laboratories. This takes too long to be useful in decision on whether to give vaccine

Serology Circulating antibodies appear slowly in the course of infection but they are usually present by the time of onset of clinical symptoms.

Can also do PCR for rapid diagnosis

Printed with FinePrint - purchase at www.fineprint.com Vaccines for Dogs Inactivated vaccines This makes sure that the dog is protected against rabies so it cannot become infected and spread it to people

Vaccines for Wild animals Live attenuated virus vaccines are on trial Release these vaccines into the wild to immunize foxes and wolves to prevent them from spreading rabies to pple

Control of Rabies Urban Canine rabies accounts for more than 99% of all human rabies.

Control measures against canine rabies include Stray dog control Vaccination of dogs Quarantine of imported animals

Wildlife On-going trials in Europe where bait containing rabies vaccine is given to foxes. Success had been reported in Switzerland.

Printed with FinePrint - purchase at www.fineprint.com Important slow virus diseases

Slow Virus Diseases Viruses causing progressive pathological processes involving mainly the central nervous system, with clinically silent incubation periods of many months or years.

Disease Virus Subacute Sclerosing panencephalitis (SSPE) Measles

o Slowly progressive disease char by inflammatory Levinson says that SSPE is due to persistent infection by lesions in many areas of the brain variant of measles virus that CANNOT COMPLETE o Rare disease of children who were infected by REPLCATION measles virus several years earlier o Begins with mild changes in personality Evidence is as follows o Ends with dementia and death 1. Inclusion bodies containing helical nucleocapsids which react to antibody to measles virus seen in infected neurons 2. Virus very similar to measles virus can be induced from these cells by co-cultivation with permissive cells in culture. The induced virus has a different matrix protein. This protein is impt in viral assembly 3. Patients have high titers of measles ab in blood and CSF 4. SSPE has virtually disappeared since onset of widespread immunization with vaccine

SSPE Congnital infection Rubella A progressive panencephalitis can also occur in pple with congenital rubella

Progressive Multifocal Leucoencephalopathy JC (Human polyomavirus)

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