There are three types of influenza viruses: A, B & C. Humans can be infected by all the three types whereas wild birds are the natural hosts for the influenza A. Influenza A viruses are further classified by subtype on the basis of the two main surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA.)

Influenza viruses are normally highly species-specific, meaning that viruses that infect an individual species (humans, certain species of birds, pigs, or horses) stay “true” to that species, and only rarely spill over to cause infection in other species. Since 1959, instances of human infection with an avian influenza virus have been documented on only 10 occasions. Of the hundreds of strains of avian influenza A viruses, only four are known to have caused human infections: H5N1, H7N3, H7N7, and H9N2. In general, human infection with these viruses has resulted in mild symptoms and very little severe illness, with one notable exception: the highly pathogenic H5N1 virus.

Avian influenza is an infectious disease of birds caused by type A strains of the influenza virus. The disease occurs worldwide. While all birds are thought to be susceptible to infection with avian influenza viruses, many wild bird species carry these viruses with no apparent signs of harm.

All 16 HA (haemagluttinin) and 9 NA (neuraminidase) subtypes of influenza viruses are known to infect wild waterfowl, thus providing an extensive reservoir of influenza viruses perpetually circulating in bird populations. In wild birds, routine testing will nearly always find some influenza viruses. The vast majority of these viruses cause no harm. To date, all outbreaks of the highly pathogenic form of avian influenza have been caused by viruses of the H5 and H7 subtypes. Not all virus strains of the H5 and H7 subtypes are highly pathogenic, but most are thought to have the potential to become so

The current outbreaks of highly pathogenic avian influenza, which began in South-East Asia in mid-2003, are the largest and most severe on record. Never before in the history of this disease have so many countries been simultaneously affected, resulting in the loss of so many birds. The causative agent, the H5N1 virus, has proved to be especially tenacious The H5N1 virus is also of particular concern for human health

The widespread persistence of H5N1 in poultry populations poses two main risks for human health.

1. The first is the risk of direct infection when the virus passes from poultry to humans, resulting in very severe disease. Of the few avian influenza viruses that have crossed the species barrier to infect humans, H5N1 has caused the largest number of cases of severe disease and death in humans. Unlike normal seasonal influenza, where infection causes only mild respiratory symptoms in most people, the disease caused by H5N1 follows an unusually aggressive clinical course, with rapid deterioration and high fatality. Primary viral pneumonia and multi-organ failure are common. In the present outbreak, more than half of those infected with the virus have died. Most cases have occurred in previously healthy children and young adults.
2. A second risk, of even greater concern, is that the virus – if given enough opportunities – will change into a form that is highly infectious for humans and spreads easily from person to person. Such a change could mark the start of a global outbreak (a pandemic).

Direct contact with infected poultry, or surfaces and objects contaminated by their faeces, is presently considered the main route of human infection. To date, most human cases have occurred in rural or periurban areas where many households keep small poultry flocks, which often roam freely, sometimes entering homes or sharing outdoor areas where children play. As infected birds shed large quantities of virus in their faeces, opportunities for exposure to infected droppings or to environments contaminated by the virus are abundant under such conditions. Moreover, because many households in Asia depend on poultry for income and food, many families sell or slaughter and consume birds when signs of illness appear in a flock, and this practice has proved difficult to change. Exposure is considered most likely during slaughter, defeathering, butchering, and preparation of poultry for cooking.

No. Though more than 100 human cases have occurred in the current outbreak, this is a small number compared with the huge number of birds affected and the numerous associated opportunities for human exposure, especially in areas where backyard flocks are common. It is not presently understood why some people, and not others, become infected following similar exposures.

A pandemic can start when three conditions have been met: a new influenza virus subtype emerges; it infects humans, causing serious illness; and it spreads easily and sustainably among humans. The H5N1 virus amply meets the first two conditions: it is a new virus for humans (H5N1 viruses have never circulated widely among people), and it has infected more than 100 humans, killing over half of them. No one will have immunity should an H5N1-like pandemic virus emerge.

All prerequisites for the start of a pandemic have therefore been met save one: the establishment of efficient and sustained human-to-human transmission of the virus. The risk that the H5N1 virus will acquire this ability will persist as long as opportunities for human infections occur. These opportunities, in turn, will persist as long as the virus continues to circulate in birds, and this situation could endure for some years to come.

The risk of pandemic influenza is serious. With the H5N1 virus now firmly entrenched in large parts of Asia , the risk that more human cases will occur will persist. Each additional human case gives the virus an opportunity to improve its transmissibility in humans, and thus develop into a pandemic strain. The recent spread of the virus to poultry and wild birds in new areas further broadens opportunities for human cases to occur. While neither the timing nor the severity of the next pandemic can be predicted, the probability that a pandemic will occur has increased.

In many patients, the disease caused by the H5N1 virus follows an unusually aggressive clinical course, with rapid deterioration and high fatality. Like most emerging disease, H5N1 influenza in humans is poorly understood. Clinical data from cases in 1997 and the current outbreak are beginning to provide a picture of the clinical features of disease, but much remains to be learned. Moreover, the current picture could change given the propensity of this virus to mutate rapidly and unpredictably.

The incubation period for H5N1 avian influenza : 2- 8 days, possibly as long as 17 days .

The main clinical manifestations of avian influenza infections depend on the viral subtype causing the disease. In the H5N1 outbreak,:

•  An influenza-like-illness typically appears early in the course of the disease

•  Conjunctivitis may be seen in some patients.

•  Some patients may have prominent GI symptoms with abdominal pain, diarrhea and vomiting.

•  Patients may progress to pneumonia or eventually die due to ARDS or multiorgan failure.

•  Rye 's syndrome and pulmonary hemorrhage are the likely complications.

Advanced age, a longer symptomatic period before admission, pneumonia, leucopenia and lymphopenia were the risk factors associated with severe disease.

Onset of disease occurred at a median of 3 to 4 days after exposure. In H5N1 infection reports from Vietnam , the main presenting syndrome was community acquired pneumonia and fever was universally present.

• Lymphopenia and thrombocytopenia were common findings in all patients; these were prognostic indicators for ARDS and death.
• All patients had abnormal chest radiographic findings with features of interstitial infiltration, lobar infiltration, collapse/consolidation, and air bronchograms.
• Pneumothorax occurred in patients who received mechanical ventilation.
• Post-mortem findings in two patients in Hong Kong due to HSNI infection showed multiorgan damage, disseminated intravascular coagulation, lymphoid tissue necrosis and atrophy and the expected pulmonary pathology of diffuse alveolan damage.
• Hemophagocytic syndrome was a prominent feature.
• Viral RNA has been detected in the lungs, intestine and spleen but active viral replication was limited to the lungs and the intestine. Intestinal involvement by HSNI virus may explain the common occurrence of diarrhea.

There are no pathognomonic signs and symptoms of A/H5N1 infections. The clinical, laboratory, and radiologic findings are not distinguishable from other causes of influenza-like illness, severe community acquired pneumonia, or ARDS. The only feature that raises the suspicion of avian influenza infection is the epidemiologic linkage to endemic areas and the history of contact with poultry. The frontline clinicians should therefore always try to elicit a detailed history of travel and exposure to animals in suspected patients. Those with a positive travel or contact history should receive appropriate radiologic and microbiological investigations, together with proper infection control precautions. Patients with mild influenza-like illness may be isolated and closely observed while waiting for results of laboratory investigations. A chest radiograph should be performed to exclude pulmonary involvement. The decision for hospitalization is based on a clinical assessment of disease severity, whether the patient can be readily followed up, and the likelihood of having avian influenza infection. Those with severe pneumonia pneumonia and risk factors for avian influenza should initially be empirically treated with oseltamivir in addition to broad-spectrum antibiotics ( eg , ß-lactam plus a macrolide).

Two drugs (in the neuraminidase inhibitors class), oseltamivir (Antiflu) and zanamivir can reduce the severity and duration of illness caused by seasonal influenza. The efficacy of the neuraminidase inhibitors depends, among others, on their early administration (within 48 hours after symptom onset). For cases of human infection with H5N1, the drugs may improve prospects of survival, if administered early, but clinical data are limited. The H5N1 virus is expected to be susceptible to the neuraminidase inhibitors.

So far, most fatal pneumonia seen in cases of H5N1 infection has resulted from the effects of the virus, and cannot be treated with antibiotics. Nonetheless, since influenza is often complicated by secondary bacterial infection of the lungs, antibiotics could be life-saving in the case of late-onset pneumonia. WHO regards it as prudent for countries to ensure adequate supplies of antibiotics in advance.

Limited evidence suggests that some antiviral drugs, notably oseltamivir (Antiflu) , can reduce the duration of viral replication and improve prospects of survival, provided it is administered within 48 hours following symptom onset. However, prior to the outbreak in Turkey , most patients have been detected and treated late in the course of illness. For this reason, clinical data on the effectiveness of oseltamivir are limited. Moreover, oseltamivir and other antiviral drugs were developed for the treatment and prophylaxis of seasonal influenza, which is a less severe disease associated with less prolonged viral replication.

In suspected cases, Antiflu should be prescribed as soon as possible (ideally, within 48 hours following symptom onset) to maximize its therapeutic benefits. However, given the significant mortality currently associated with H5N1 infection and evidence of prolonged viral replication in this disease, administration of the drug should also be considered in patients presenting later in the course of illness.

The recommended dose of Antiflu for the treatment of influenza, in adults and adolescents 13 years of age and older, is 150 mg per day, given as 75 mg twice a day for five days. The recommended oral dose of Antiflu for prophylaxis of influenza in adults and adolescents 13 years and older following close contact with an infected individual is 75 mg once daily for at least 10 days . Safety and efficacy have been demonstrated for up to 6 weeks. Antiflu is not indicated for the treatment of children younger than one year of age. Dose adjustment is required in patients with renal impairment.

As the duration of viral replication may be prolonged in cases of H5N1 infection, clinicians should consider increasing the duration of treatment to seven to ten days in patients who are not showing a clinical response. In cases of severe infection with the H5N1 virus, clinicians may need to consider increasing the recommended daily dose or the duration of treatment, keeping in mind that doses above 300 mg per day are associated with increased side effects. For all treated patients, consideration should be given to taking serial clinical samples for later assay to monitor changes in viral load, to assess drug susceptibility, and to assess drug levels. These samples should be taken only in the presence of appropriate measures for infection control.

The most frequently reported events with Oseltamivir are nausea, vomiting, diarrhoea and dizziness.

In severely ill H5N1 patients or in H5N1 patients with severe gastrointestinal symptoms, drug absorption may be impaired. This possibility should be considered when managing these patients.

Zanamavir is an orally inhaled powdered drug that is approved for the treatment of influenza in persons aged 7 years and older. The dose is 10 mg twice daily.

Vaccines effective against a pandemic virus are not yet available. Vaccines are produced each year for seasonal influenza but will not protect against pandemic influenza. Although a vaccine against the H5N1 virus is under development in several countries, no vaccine is ready for commercial production and no vaccines are expected to be widely available until several months after the start of a pandemic.

1. www. cdc .gov/ flu
2. www.who.int/csr/disease/ avian _ influenza /en/
3. Chest 2006;129: 156-168