What is Avian Influenza?Avian influenza (AI) is an RNA virus ofthe Orthomyxoviridae family. Theinfluenza viruses are classified as A, Band C. Avian influenza belongs to type A.Avian influenza was first identified inbirds in Italy in 1878. Avian influenza iscommonly also known as “bird flu”.

Avian influenza viruses are furt h e rclassified according to theirpathogenicity, i.e., the ability to causeillness. There are the less harmful lowpathogenic avian influenza (LPAI) strainsand the more virulent and dangerousstrains known as highly pathogenic avianinfluenza (HPAI). Low pathogenic avianinfluenza becomes highly pathogenicavian influenza through gene mutationand re-assortment. HPAI has numeroussubtypes. The most pathogenic sub-types identified to date are the HPAIH5N1 and the HPAI H7N1 subtypes.

Avian Influenza and Birds andOther AnimalsAvian influenza is naturally-occurring inb i rds and other animals, e.g., ducks,chickens, geese, turkeys, wild andm i g r a t o ry birds, especially waterf o w l

and shorebirds, pigeons, cats, horses,pigs, and sea mammals. Some of thebird species are carriers of the virus intheir intestines and do not get sick orexhibit signs or symptoms. Bird flu isvery contagious among domestic poultrysuch as chickens and ducks oftenresulting in serious illness and death.

Transmission map of influenza viruses

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Avian Influenza and Humans Avian influenza virus strains have onlyrecently been identified as the cause ofhuman disease. Humans can also beinfected by avian influenza although avast majority of avian influenza virusesdo not infect humans. The only avianinfluenza strain to repeatedly causesevere disease in humans is the H5N1serotype, first diagnosed in humans inHong Kong in 1997.

Pandemic InfluenzaAn influenza pandemic is a globaloutbreak of influenza among the humanpopulation, which can spread easily fromperson-to-person causing serious illness.

Global experts predict and fear thepotential of the H5N1 virus evolving toform a new pandemic virus strain. Oncethis adaptation occurs, it will no longerbe an avian/bird virus, it will be a newhuman influenza virus. The pandemicH5N1 strain will cause massive fatalitiesto occur as the virus inevitably spreadsglobally. As a result of this significantt h reat, national, regional and globalp re p a redness & response plans arebeing developed for this possibility.

Difference Between Seasonal Influenza andPandemic Influenza Seasonal influenza outbreaks occur ina predictable pattern annually causedby subtypes of influenza viruses thata l ready circulate among people whoa l ready have some immunity, andfor which we have vaccines. Theyoung, elderly, and sick are usuallythose most at risk of developing severe

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complications from seasonal influenza.As a result, the impact of seasonalinfluenza every year is moderate. On theother hand, pandemic influenza iscaused by new virus subtypes, whichoccur very rarely, and to which no, orextremely few, humans have immunity.S u fficient quantities of effective andc o m m e rcially available vaccines willunlikely be available during the earlystages of a pandemic. Every o n e ,including healthy adults, will be at risk ofdeveloping severe complications frompandemic influenza. As a re s u l t ,significant morbidity and mort a l i t ywould be expected, causing a majorimpact on national and global society.

Basic VirologyInfluenza A and B viruses are envelopedviruses with a segmented genome madeof eight single-stranded negative RNAsegments. They are spherical orfilamentous in structure, ranging from 80to 120 nm in diameter. On the basis ofthe antigenicity of the surf a c eglycoproteins, haemagglutinin (HA) andneuraminidase (NA), influenza A virusesare further divided into sixteen H (H1-H16) and nine N (N1-N9) subtypes. HA is

the major antigen for neutralisingantibodies, and is involved in the bindingof the virus to host cell receptors. NA isconcerned with the release of progenyvirions from the cell surface.

Influenza virus

H5N1 Transmission toHumans

So far, the number of human cases hasf o rtunately been relatively low. Thesource of infection of confirmed cases ofhuman H5N1 influenza so far around the

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Haemagglutinin

Neuraminidase

world have been identified as having ahistory of contact with infected poultry.There has been no confirmed human-to-human transmission. H5N1 infectiontransmission is considered to be throughone or more of the following methodsduring 7 – 10 days before onset ofsymptoms:

l Direct and unprotected contact withbirds:

l Close contact (within 1 metre) withlive, sick, or dead birds;

l P reparing birds duringslaughtering or for meals;

l Playing with birds;

l Having worked in a laboratorywhere samples from animals orhumans suspected of having H5N1are being tested.

l Indirect contact:l E x p o s u re to settings where

domestic poultry were or had beenconfined in the previous 6 weeks;

l Infected materials, surfaces;

l History of travel to a country orterritory with reported HPAI due toH5N1 in animals;

l Eating undercooked or rawinfectious birds’ meat, eggs orblood.

l Possible risk from contaminated water

l Intake of contaminated water byswimming, drinking, or gettingcontaminated water in the eyes

l U n c e rtain risk of person-to-personspread

l Face-to-face contact without properprecautions;

l Touching or within 1 metre ofsuspected or diagnosed H5N1patient without proper precautions;

l Touching or being within 1 meter(without proper precautions) of aperson who has severe pneumoniaor dies from an acute respiratoryillness.

H5N1 Incubation Period inHumans

The precise incubation period isunknown, but is likely to be 2 – 8 days,but may be longer. The incubation periodfor H5N1 may be longer than forseasonal influenza – up to 17 days.

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Period of H5N1Communicability

The infectious period is 7 days afterresolution of fever in adults and 21 daysafter onset of illness in childre n .Communicability increases with theseverity of disease and degree of directexposure.

The virus is known to survive in coldt e m p e r a t u re and in contaminatedmanure of birds for up to three months.In water it may survive up to 4 days at 22degree Celsius (72 degrees Fahrenheit)and more than 30 days at zero degreeCelsius (32 degree Fahrenheit). The virus

can be killed by heat, i.e., meat cooked tointernal temperature of 70 degree Celsius(154 degree Fahrenheit) is not infective.

Signs and Symptoms of H5N1Infection in Humans

The clinical manifestations of H5N1influenza infection in humans are notwell-defined as current knowledge isbased on the description of a fewhospitalised patients. The spectru mranges from asymptomatic infection tofatal pneumonitis and multiple org a nfailure. Initial symptoms include:

l High Fever ( typically >38oC/101

oF);

l Respiratory symptoms, e.g., cough,sore throat, rhinitis (although upperre s p i r a t o ry symptoms may beabsent);

l Malaise, myalgia, headache;

l More rare: gastrointestinal manifesta-tions, e.g., frequent watery diarrhoea,abdominal pain and vomiting; andconjunctivitis.

All these symptoms are however non-specific and may also be associated with

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c u rrently circulating human influenzavirus subtypes, H1N1 and H3N2. Waterydiarrhoea may be present well beforepulmonary symptoms develop. Anotherreport describes a four-year-old boy withsevere diarrhoea, followed by seizures,coma, and death, suggesting the clinicaldiagnosis of encephalitis, although H5N1avian influenza was later detected incerebrospinal fluid, faecal, throat, ands e rum specimens. Due to the non-specificity of “flu-like” symptomspotentially indicating H5N1 influenzainfection, it is important to consider awide differential diagnosis which shouldbe guided by the patient’s history, whichincludes, travel, occupational exposure,

contact with poultry, wild birds or sickindividuals, history of symptoms, as wellas the local epidemiology of disease.

L a b o r a t o ry findings of patients withs e v e re H5N1 influenza includeleucopenia, lymphopenia, impaired liverfunction with elevated liver enzymes,p rolonged clotting times, and re n a limpairment.

The pro g ression of severe H5N1infection seems to be different from thatof severe diseases observed duringearlier influenza pandemics. None of thepatients with the severe disease reportedf rom Hong Kong and Vietnam hadevidence of secondary bacterialpneumonia, suggesting that fataloutcome was due to overw h e l m i n gp r i m a ry viral pneumonia. The clinicalcourse may include:

l Shortness of breath (dyspnea);l Clinical pneumonia with variable x-ray

findings (almost all develop this);

l Acute respiratory distress syndrome(ARDS);

l Multi-organ failure;l Encephalitis;l High case fatality rate.

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Diagnosis of H5N1Accurate and rapid diagnosis ofsuspected cases of H5N1 infection byl a b o r a t o ry diagnosis is of paramounti m p o rtance in the initiation andcontinuation of appropriate tre a t m e n tand infection control measures. Isolationof virus from specimens of suspectedcases of avian influenza should beconducted in specialised re f e re n c elaboratories with at least biosafety level3 facilities.

Specimens for virus detection orisolation should be collected within 3

days after the onset of symptoms andrapidly transported to the laboratory. An a s o p h a ryngeal aspirate, nasal swab,nasal wash, nasopharyngeal swab, orthroat swab are all suitable for diagnosis.However a nasopharyngeal aspirate isthe specimen of choice. In cases wherepatients are intubated, a transtrachealaspirate and a bronchoalveolar lavagecan be collected. At the same time, acuteand convalescent serum samples shouldbe collected for serological diagnosis.Swabs should be transported in virust r a n s p o rt medium to pre v e n tdesiccation. All specimens should arriveat the laboratory as soon as possible toavoid any degradation. Transportation invirus transport medium on ice or withrefrigeration at 2-8 degree Celsius (36-47degree Fahrenheit) is recommended ifany delay in transportation is expected.

Blood (whole blood serum) specimensare collected for the purpose of antibodyserology (determining the presence ofantibodies to influenza). Sero l o g i c a ldiagnosis has little value in diagnosingacute influenza; however it may havevalue in diagnosing recently infectedpatients. In order to diagnose acuteinfection, an at least four-fold rise in titre

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needs to be demonstrated, whichre q u i res both an acute and aconvalescent serum sample to be taken14 – 21 days apart.

D i ff e rent methods exist for dire c tdetection of influenza viruses. Rapididentification of the infecting agent as aninfluenza A virus can be performed byo rd i n a ry influenza rapid tests thatd i ff e rentiate between types. Therevolution in rapid diagnosis of influenzawas brought about by the developmentof rapid antigen assays (most of whichwork on an enzyme immunoassay (EIA)or immunochromatography principle).These assays enable the diagnosis ofinfluenza within 10 – 30 minutes. Someof these tests are easy to perf o rmallowing non-laboratory personnel toconduct them. However commerc i a lrapid chromatographic methods have asensitivity of only 70% for avianinfluenza compared to culture. EIAs anddirect immunofluorescence methods caneither detect both influenza A and B ordifferentiate between types (influenza Aor B), but cannot exclude H5N1 infectiondue to lack of sensitivity. The only directtechnique that has the potential to

differentiate between subtypes (i.e. onthe basis of haemagglutinin andneuraminidase) is RT-PCR. Detection ofinfluenza A/H5 by RT-PCR offers a rapidand highly sensitive method to diagnoseH5N1 infection and should therefore beused.

Management and treatmentof H5N1 InfluenzaThere is no known specific treatment forH5N1 influenza. Patients with suspectedH5N1 influenza should promptly receivea neuraminidase inhibitor pending theresults of laboratory testing. Oseltamivir(e.g., Tamiflu®) is currently regarded asthe drug of choice. However, the optimaldosage and schedule for treatment ofH5N1 influenza is unknown. It isrecommended however that theseasonal influenza treatment regime isadjusted as indicated below. Notehowever, that resistance to treatment hasbeen experienced in some H5N1patients.

Efficacy of Oseltamivir has been provenonly with early administration – within48 hours of illness onset. However,

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t reatment with Oseltamivir may bebeneficial even when initiated as late aseight days after the onset of symptoms,if there is evidence of ongoing viralreplication.

The active metabolite of Oseltamivir(Oseltamivir phosphate) inhibitsneraminidases (NA) of influenza viruses.F u rt h e rm o re, it also inhibits influenzav i rus growth in vitro and inhibitsinfluenza virus replication andpathogenicity in vivo. Lastly, the activemetabolite reduces shedding of influenzav i ruses by inhibiting the release ofinfectious virus from infected cells.

Ribavirin, interf e ron alpha and otherimmunomodulatory drugs have all beenused, but without convincing results andshould therefore not be used. Moreover,adverse reactions such as anaemia arefrequent and may further compromisethe patient.

In severe cases, hospitalize patientsunder appropriate infection contro lp recautions. Provide supportive care .Monitor oxygen saturation and tre a tdesaturation with supplemental oxygenas required. As nebulizers and high-air-flow oxygen masks have been potentially

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Oseltamivir (e.g., Tamiflu®) TreatmentDosage for H5N1 Influenzal Longer treatment (7 to 10 days) orl Higher doses (150mg twice a day for adults)

Oseltamivir (e.g., Tamiflu®) TreatmentDosage for Seasonal Influenza

Adults (above 13 years): 75 mg twice a day for 5 daysChildren <1 year: not adequately studiedChildren < 15 kg: 30 mg twice a day for 5 dayChildren >15 kg to <23 kg: 45 mg twice a day for 5 daysChildren >23 kg to <40 kg: 60 mg twice a day for 5 daysChildren >40 kg: 75 mg twice a day for 5 days

Form of drug:Available in tablet and powder/suspension form

Special Precautions:u Consider risks versus benefitsu Adjust dose for people with kidney disease u Insufficient evidence on use by pregnant or

nursing females. Is likely to be excreted inmilk. Therefore should be used only whenpotential benefits justify the potential risks.

Effect of drug:u Reduces influenza symptoms in 1 - 3 daysu Reduces lower respiratory tract

complications, pneumonia, andhospitalization

Side effects of drug:u Nausea u Vomitingu Skin rash

implicated in the nosocomial spread ofsevere acute respiratory syndrome, usethese measures only if clinically justifiedand apply them under strict infectioncontrol, including airborne transmissionprecautions.

If a case is assessed as not requiringhospitalization, educate the patient andhis or her family on personal hygieneand infection control measures (e.g.hand-washing, use of a paper or surgicalmask by the ill person, and restriction ofsocial contacts), and instruct the patientto seek prompt medical care if thecondition worsens. Follow up all non-hospitalized patients.

The lymphocyte count appears to be themost valuable parameter foridentification of patients who are at riskof pro g ression to severe illness.Laboratory findings include:

l Drop in lymphocytes (white bloodcell count) - (<1 x 109/litre);

l Mild to moderate drop in bloodplatelet count;

l Mild to moderate increase inaminotransferase and aspartatetransaminase (liver enzymes).

Infection control measuresInfection control measures include theapplication of standard precautions to allpatients receiving care in hospitals. If thediagnosis of H5N1 influenza infection isbeing considered on the basis of clinicalfeatures, additional precautions shouldbe implemented until the diagnosis canbe ruled out. Although there is currentlyno evidence that the H5N1 virus istransmitted among humans, the WorldHealth Organization (WHO) recommendsthe following precautions:

l Patients to use high-efficiency masks(European CE approved respirators orUS NIOSH certified N-95) in additionto droplet and contact precautions;

l Patients should be housed in anegative pressure room;

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l Patients should be isolated to a singleroom. If a single room is not available,c o h o rt patients separately indesignated multi-bed rooms or wards;In these rooms/wards beds should beplaced more than 1 metre apart andpreferably be separated by a physicalbarrier (e.g. partition, curtain);

l Restrict the number of visitors andp rovide them with appro p r i a t epersonal protective equipment andinstruct them on their use;

l Dispose of waste properly by placingin sealed, impermeable containerswhich should be clearly labelled" b i o h a z a rd" and incinerated. Linenand reusable materials that have beenin contact with patients should behandled separately and disinfected.

To protect healthcare workers (HCWs)and other hospital personnel, thefollowing recommendations should befollowed:

l Designated HCWs should all beproperly trained in infection controlprecautions;

l Use of a high efficiency mask(European CE approved respirators orUS NIOSH certified N-95), gown, face

shield or goggles, and gloves whencoming into contact with patients;

l Limit the number of HCWs who haved i rect contact with the patient(s);these HCWs should not look afterother patients;

l The number of other hospitalemployees (cleaners, laboratorypersonnel etc.) with access to theenvironment of these patients shouldalso be limited;

l HCWs with direct patient contact mustmonitor their own temperature twicedaily and report any fever to theirs u p e rvisor and facility authorities.HCWs who have a fever of >38

oC

( 1 0 1oF), and who have had dire c t

patient contact, should be tre a t e dimmediately.

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l O ffer post-exposure pro p h y l a x i s(described below) to any HCW whohas had potential un-pro t e c t e dcontact with droplets from asuspected patient.

l HCWs who are unwell should not beinvolved in direct patient care sincethey are more vulnerable and may bemore likely to develop severe illnesswhen exposed to influenza A (H5N1)viruses.

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Items of personal protective equipment (PPE)

Transmission Prophylaxis

As soon as a case of human H5N1infection is suspected, precautions needto be taken to minimise nosocomialspread. If the diagnosis is confirmed,possible contacts of the index case mustbe identified to be put under observationduring the incubation period and tofacilitate early intervention with antiviraltherapy, in order to reduce morbidity andmortality and limit further spread of thedisease. For the purpose of prevention,Oseltamivir is also used at the dosage ofonce daily for 7–10 days after lastexposure (initiated within 48 hours ofexposure).

In general, prophylaxis is more likely top revent serious complications fro minfluenza than treatment. However, useof antivirals for prophylactic purposesre q u i res a significantly larger dru gsupply at very high costs. Therefore, it isemphasized that antiviral use is fort reatment only with the exception ofp r i o r i t y, high-risk, essential serv i c ep roviders, e.g., outbreak investigationteams, personnel involved in poultryculling, and laboratory and medicalpersonnel.

All HCWs should be vaccinated againstseasonal influenza annually. Ani m p rovement in vaccination coveragelevels might help to protect HCWs, theirpatients, and communities; impro v ep revention of influenza-associateddisease and patient safety; and reducedisease burden.

Notification

Immediate notification of suspectedcases of H5N1 influenza infection iscrucial to protecting life and controllingthe spread of disease. More o v e r,notification to the World HealthOrganization (WHO) of avian influenza,as a public health emergency ofi n t e rnational concern, is mandatoryunder the revised International HealthRegulations (2005). Information onsuspected cases should be immediatelycommunicated through the local healthofficials to:

l Director of Disease Control, DGHS;

l D i rector of the Institute ofE p i d e m i o l o g y, Disease Control andResearch (IEDCR); and

l District Civil Surgeon.

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