GENERAL MEDICINE KY Yuen

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World HealthOrganization(WHO) severe syndrome acuterespiratory (SARS), neuraminidase(NA), like illness(ILI), influenza- humanimmunodeficiency virus(HIV), haemagglutinin(HA), fluid (CSF), h lsiiaino nlez iue,theseare the HA the classificationofinfluenza A viruses, Two ofthegeneproducts in are important segments). into eightsegments(exceptinfluenza Cwhichhasseven sense RNAgenomeofthe influenza virusesisdivided Thesingle-stranded negative andC. B, Influenza virus A, andthree generaofinfluenzaviruses, Thogotovirus, thetick-borne (infectious salmonanaemiavirus), The family THE VIRUSES and mortality. significantmorbidity carrying and perhaps pandemics, infections have ahighpropensity tocauseepidemics, these two diseases (withthepossibleexceptionofHIV), Unlike mostotherzoonotic viral economic impacts. bothmedically andfor their throughout theworld, influenza andSARS–have becomemajorconcerns two emergingzoonoticviralinfections –avian years, Inthepasteight filoviruses ofmore recent memory. toHIVand been known tomankindsinceancient times, andrabieswhichhave monkeypox, range from cowpox, These been known for centuries(zoonoticinfection). humans (withouttheneedfor anarthropod vector) has Direct transmissionofviralinfections from animalsto DECLARATION OFINTERESTS LIST OF ABBREVIATIONS KEYWORDS to humantransmission. ormutationsreassortment conferring theviruscapability ofefficienthuman preparedness for acominginfluenzapandemicwhich may occurwithgenetic crude fatalityrateof50%inhumanshave triggered aglobalresponse of Theglobalisationofthisavian birds andthe epidemicby migratory precautions. droplet andairborne Infection control measures shouldincludecontact, investigated andempirically treated for H5N1infection. should beisolated, ofcontactwithsickordeadbirdscommunity-acquired pneumoniawithahistory patientspresenting as Inendemicareas, health care workers andfamily contact. Human-to-humantransmissionisstillinefficientbuthasoccurred in transmission. Mostofthecasesare causedby poultry-to-human as early manifestations. Acuteencephalitisoracutegastroenteritis were occasionally reported secretions. inaddition totherespiratory cerebrospinal fluid, serum, spleen, in theintestine, Viruscanbedetected lymphopenia andimpaired liver functions. with leukopenia, by arapidly progressive community-acquired pneumoniaandfrequently diarrhoea The humandiseaseischaracterised South East Asia andisspreading toEurope. outbreaks andsporadiccasesinhumanscontinue tooccurin poultry vaccination, ABSTRACT Avian influenzainhumans Department ofMicrobiology, UniversityPathologyBuilding,QueenMaryHospital,HongKong Yuen KY Behind theMedicalHeadlines Behind theMedicalHeadlines Despite control of the poultry outbreakDespite control by cullingandsometimes ofthepoultry va nlez,ifcincnrl neuraminidaseinhibitors. infection control, Avian influenza, Orthomyxoviridae omnt-curdpemna(A) cerebrospinal community-acquired pneumonia(CAP), No conflictofinterests declared. includes theIsavirus may result inpandemicsofinfluenza. thelatterofwhich ofthe RNAfragments), reassortment or antigenicshift(majorchangesasaresult of (relatively minorchangesasaresult ofgeneticmutations) Suchchangesmay involve antigenicdrift rapid paces. changes (mainly attheHAandNAantigens)fairly are well known for theirabilitytoundergo antigenic Influenzaviruses any combinationsofHAandNAtypes. andindividualviralstrainsmay have types are recognized, 16HAandnineNA To date, envelope oftheviruses. and NAwhichare surfaceproteins found onthe only rarely human infections duetoavian influenzahadbeenreported Priorto1997, the avian influenzaviruses. Theseare collectively known as of influenza A viruses. aquatic birds which containsalltheHAandNAtypes butthelargestnaturalreservoir isthe of animals, serotypes ofinfluenza virusescanbefound inavariety Other viruses beingencountered lessfrequently. withH1N2andH2N2 by H3N2andH1N1viruses, Human influenza A nowadays ismostcommonly caused HUMAN INFLUENZAOUTBREAKS or laboratory-acquired or laboratory-acquired – anupdate – eitherasaresult of naturaltransmission © 2005Royal CollegeofPhysicians ofEdinburgh Published online Published Correspondence to to Correspondence Department of Microbiology, of Department J RCollPhysicians Edinb University Pathology Building, Pathology University Queen Mary Hospital, Hong Kong Hong Hospital, Mary Queen tel. tel. – fax. fax. oftenpresenting as e-mail e-mail +852 2855 4892 2855 +852 +852 2855 1241 2855 +852 [email protected] November 2005 November KY Yuen, KY 2005; 35: 317–320 317

GENERAL MEDICINE KY Yuen

TABLE 1 Management of patients with ILI or CAP.

Patient characteristics ILI with no signs of Mild CAP not requiring Moderate to severe CAP pneumonia hospital admission requiring hospital admission+ 1. History of touching dead or 1. Outpatient follow-up for 1.Amoxicillin-clavulanate 1.Amoxicillin-clavulanate and sick bird including poultry deterioration (admit if there is azithromycin (levofloxacin in a positive contact history) adult if the patient is allergic to beta-lactams) 2. Family members with 2. Oseltamivir 2. Outpatient follow-up and 2. Oseltamivir suspected or confirmed H5N1 chest radiograph for influenza deterioration (admit if there is a positive contact history)

GENERAL MEDICINE 3. Health care workers caring 3. Personal hygiene 3. Oseltamivir 3. Contact isolation with for suspected or confirmed droplet precaution H5N1 influenza patients

4. Laboratory workers handling 4. Microbiological work up for 4. Personal hygiene 4. Microbiological work up for specimens or viral cultures influenza A H5N1 in those with influenza A H5N1 virus from such patients positive exposure

5. Microbiological work-up for 5. Intensive care support and influenza A H5N1 is indicated if mechanical ventilation if exposure or travel history is clinically indicated positive

• Wear standard surgical mask at home with frequent handwashing especially after handling respiratory secretion. • Avoid aspirin in children <16 years of age. • Oxygen therapy by nasal cannula. • High-flow oxygen mask or nebulizers should be avoided to minimise risk of nosocomial spread. • High flow oxygen mask, non-invasive ventilation should only be used with strict infection precautions.

conjunctivitis and caused by influenza A H7N7. The The fulminant nature of the infection could be related first major outbreak of human infections due to avian to extrapulmonary systemic dissemination to blood, influenza occurred in Hong Kong in 1997 when the CSF, spleen and intestine and a highly pro-inflammatory influenza A H5N1 virus caused massive deaths in the response to the infection, the so-called ‘cytokine poultry with 18 documented human cases, six of whom storm’. Whether co-administration of an effective died. The epidemic was halted after 1·5 million poultry antiviral agent with immunomodulators will result in a were slaughtered in the farms and markets throughout better treatment outcome might warrant further Hong Kong. studies. Despite extensive slaughtering of tens of millions of poultry in the affected areas, cases of animal Since 1997, sporadic cases of H5N1 infection have and human infections due to H5N1 are still reported in occurred in humans and poultry in Hong Kong and the Eurasian region to date. southern China. From late 2003 to early 2004, the largest epidemic of avian influenza in history occurred Another major outbreak of human infections due to in a number of southeast Asian countries, extending as avian influenza occurred in the Netherlands in 2003. far north as South Korea and Japan and as far south as The causative virus was influenza A H7N7, and 87 Indonesia. In 2005, this avian virus genotype Z has virologically documented cases were found, with one extended its geographical range to Russia, Romania and death in a veterinarian. A recent study using a Turkey. This outbreak was caused mainly by the H5N1 modified haemagglutination-inhibition test, however, Z genotype and was characterised by a high mortality suggested that the actual number of people infected rate. As of 15 October 2005, 117 human cases of H5N1 could be much higher, with seroprevalence of H7 infection had been documented in the affected areas antibodies among household contacts of an infected with 60 fatalities, giving a crude overall case-fatality rate poultry worker approximating 59%. Unlike the H5N1 of 50% (WHO, accessed on 11 January 2005; outbreak in Asia, the H7N7 outbreak was www.who.int/csr/disease/avian_influenza/country/cases characterised by a lower mortality and many of the _table_2005_01_07/en/). Most of these human case presented with conjunctivitis and/or an ILI. infections occurred in Thailand, Indonesia and Vietnam Similarly, influenza A H9N2 is the third avian influenza as three different waves. A clear contact history with virus which has been shown to be transmissible to infected poultry was present in most of the patients. humans in Hong Kong.

CLINICAL IDENTIFICATION OF DISEASE airborne precautions for patients with documented avian influenza infections. The two most common clinical manifestations of avian influenza infections are conjunctivitis (mainly seen with SPREAD AND DRUG RESISTANCE H7N7) and respiratory symptoms (H7N7 and H5N1). Respiratory symptoms range from an uncomplicated ILI To date, there is at least serological evidence that avian to severe and fatal pneumonia. To date, all human H9N2 influenza viruses (H5N1 and H7N7) are capable of infections have presented as uncomplicated ILI while both human-to-human transmission. Unlike human influenza H7N7 and H5N1 infections may result in severe disease, viruses, interpersonal transmission does not appear to especially with the latter. Mortality associated with Reye be very efficient. Nevertheless, the possibility of genetic syndrome has also been described in H5N1 infections reassortment between human and avian viruses in following the use of aspirin and other nonsteroidal anti- humans or other permissive animals (e.g. swine) is a inflammatory drugs in the 1997 Hong Kong outbreak. constant threat to the genesis of a highly pathogenic GENERAL MEDICINE Gastrointestinal manifestations including diarrhoea has virus that is readily transmissible from person to person. also been noted in the 1997 Hong Kong outbreak and The readiness of influenza viruses to undergo genetic 2004 Vietnam outbreak. Unusual manifestations including changes is also evidenced by the evolution of a highly encephalitis, hepatic impairment, renal failure unrelated to pathogenic H5N1 genotype Z that has become the rhabdomyolysis, and pancytopenia were also described. predominant genotype in Asia, which accounts for the Factors associated with severe disease included older major Asian outbreak of avian influenza in 2003–2004. age, delay in hospitalisation, lower respiratory tract The current epidemic strain of H5N1 also acquired involvement, and a low total peripheral white blood cell resistance to the antiviral agent amantadine through a count or lymphopenia at admission. The median time to mutation in the M2 protein. This worrying finding death from the onset of illness was nine days (range, six implied that for practical purposes, the neuraminidase to 17) in the recent Vietnam outbreak. inhibitors (e.g. oseltamivir) are the only viable antiviral alternative for treatment and chemoprophylaxis of Since there are no pathognomonic signs and symptoms of human infections. Though the avian influenza viruses are human avian influenza apart from contact history with susceptible to neuraminidase inhibitors, their role in infected birds, early diagnosis and commencement of clinical management still awaits further studies. In antiviral therapy remains the cornerstone of therapy if human influenza, these antivirals are most active if given severe complications are to be avoided. Patients are within 48 hours of onset of disease. If this is also true defined as having ILI if they have a clinically unexplained for avian influenza infections, then in practice the elevated temperature of 37·8°C or higher, and systemic antivirals may not have significant impact on the diseases symptoms such as myalgia and fatigue (with or without course in endemic areas, since most patients in chills, headache), or respiratory symptoms such as cough developing countries are unlikely to receive this (with or without rhinorrhoea, sore throat). During the relatively expensive antiviral agent at the outset of the peak flu season, the combination of fever, cough, fatigue, disease. Resistance to the neuramindase inhibitor and myalgia has a sensitivity of around 30% and specificity oseltamvir due to the mutation H274Y is beginning to of around 80%. Patients with ILI are then screened by emerge in patients on prophylaxis or treatment for physical examination of the chest for signs of H5N1 infection. This is expected because 18 per cent consolidation (crepitations, decreased air entry, bronchial of the H3N2 infection in Japanese children on treatment breathing, or increased dullness) and/or chest radiograph. with oseltamivir has developed resistance. A higher Those with positive signs are managed as cases of acute dose of oseltamivir up to 500mg bid and/or combination community-acquired pneumonia. They are also screened with inhaled zanamivir are being considered to improve for the epidemiological risk factor of exposure to possibly clinical outcome and minimise resistance. High doses of infected chickens and risk factors of poor prognosis. oseltamivir are well tolerated in adult volunteers but the Subsequent investigations and management are systemic absorption or lung distribution of inhaled summarised in Table 1. zanamivir could be highly variable. As the H5N1 virus is found in blood, cerebrospinal fluid, spleen and intestine, CONTROL OF SPREAD a very low level of zanamvir may help to promote resistance at these sites and at consolidated lung where Though avian influenza appears to be less infectious than the inhaled zanamvir may not reach. At the moment human influenza or SARS, infection control measures oral oseltamivir at an increased dose should be the must be strictly adhered to in all confirmed or suspected treatment of choice. An extended duration of therapy cases. Droplet and contact precautions are the basis for to two weeks should be given till neutralising antibody preventing hospital cross-infection in patients admitted has developed. with undiagnosed ILIs. Although there is no evidence to suggest that avian influenza virus could spread by the airborne route, current WHO guidelines do recommend

FUTURE CONTROL KEYPOINTS • Avian influenza and SARS are two zoonotic (spread Despite intensive research and some phase one clinical directly from animal to humans) viral infections trials, there is still no commercially available vaccines capable of causing epidemics or pandemics with against avian influenza viruses for human use. The efficacy serious mortality. of such vaccines, if they were eventually available, may be • The influenza viruses (A, B and C) have an RNA hampered by the rapid antigenic changes which are genome and belong to the Orthomyxoviridae family of common to all influenza viruses. Prevention of human viruses. The largest natural reservoir of influenza A infections due to avian influenza ultimately depends on virus is in aquatic birds and these viruses are the control of the disease among the poultry. Proper avian influenza viruses. biosecurity measures in animal husbandry, surveillance of • Influenza viruses readily undergo antigenic change the disease, segregation of humans and animals, and making the effectiveness of vaccines short-lived. slaughtering of flocks in cases of outbreaks. These

GENERAL MEDICINE • Most outbreaks of human infection have occurred in measures, unfortunately, are largely not practised in parts South East Asia, but an outbreak has also occurred of the world where the disease is endemic. A coordinated in the Netherlands. international and regional effort is necessary to prevent, • Early recognition of avian influenza is important, but or at least delay, avian influenza as the next influenza there are no specific features of the illness other pandemic. All countries should have their plan for than a history of contact with infected birds. pandemic preparedness. Stockpiles of antiviral, diagnostic Anyone with an unexplained temperature above tests and vaccine stored under WHO should be sent to 37·50C, respiratory symptoms, or systemic the site where first cases of human to human symptoms such as aching muscles, should be transmission are detected in order to halt a pandemic. regarded as having an ILI. • Avian influenza viruses do not yet pass readily from Disease control in poultry is central to the control of one human to another, but this may not always be human disease. No vaccines are available currently, and the case and WHO recommendations should be rapid viral genetic change may limit the value of any followed. developed.

FURTHER READING Virology. 5th ed. Chichester: John Wiley & Sons; 2004. • Tran TH, Nguyen TL, Nguyen TD et al. WHO International Avian • Cheung CY, Poon LL, Lau AS et al. Induction of proinflammatory Influenza Investigative Team. Avian influenza A (H5N1) in 10 cytokines in human macrophages by influenza A (H5N1) viruses: patients in Vietnam. N Engl J Med 2004; 350:1179–88. a mechanism for the unusual severity of human disease? Lancet • Webster RG, Geraci J, Petursson G, Skirnisson K. Conjunctivitis 2002; 360:1831–7. in human beings caused by influenza A virus of seals. N Engl J Med • Koopmans M,Wilbrink B, Conyn M et al. Transmission of H7N7 1981; 304:911. avian influenza A virus to human beings during a large outbreak • Yuen KY,Chan PK, Peiris M et al. Clinical features and rapid viral in commercial poultry farms in the Netherlands. Lancet 2004; diagnosis of human disease associated with avian influenza A 363:587–93. H5N1 virus. Lancet 1998; 351:467–71 • Li KS, Guan Y,Wang J et al. Genesis of a highly pathogenic and • Yen HL, Monto AS,Webster RG, Govorkova EA. Virulence may potentially pandemic H5N1 influenza virus in eastern Asia. determine the necessary duration and dosage of oseltamivir Nature 2004; 430:209–13. treatment for highly pathogenic A/Vietnam/1203/04 influenza • Potter C. Influenza. In: Zuckerman AJ, Banatvala JE, Pattison JR, virus in mice. J Infect Dis 2005; 192(4):665–72. Griffiths PD, Schoub BD (editors). Principles and Practice of Clinical