The Next Influenza Pandemic: Not If, but When

Abstract & Commentary

Synopsis: Two of the 3 conditions required for the next human pandemic of influenza are in place.

Source: World Health Organization Executive Board. EB114/6 114th Session 8 April 2004 Provisional Agenda Item 4.5. Avian Influenza and Human Health. Report by the Secretariat.

Avian influenza has created an economic disaster in parts of Asia. While the number of associated identified human infections has, to date, not reached 100 cases, the possibility of a public health disaster looms since the outbreak of avian influenza may be setting the stage for the next human influenza pandemic.

While 15 distinct subtypes of influenza virus are known to infect birds, all avian outbreaks of the highly pathogenic form have been caused by influenza A viruses of subtypes H5 and H7. All avian species (ducks, geese) are at risk of infection, but domestic poultry, especially chickens and turkeys, are particularly susceptible to epidemics associated with rapid fatality, with mortality rates of 50% or greater. Infection of migratory waterfowl, the natural reservoir of avian influenza viruses, is, in contrast, mildly symptomatic or asymptomatic. Direct or indirect contact of domestic flocks with wild migratory waterfowl has been implicated as a frequent cause of epidemics. Live bird markets have also played an important role in the spread of epidemics.

Outbreaks in poultry caused by these highly pathogenic strains have previously been uncommon, with only 21 identified worldwide between 1959 and 2003.1 Control of these outbreaks with measures such as culling, quarantine, disinfection, restriction in animal movement, and strict biosecurity on farms, has been successful, but has required as long as 3 years of application. Of importance, these control measures have previously been largely successful in preventing geographic dissemination of the infection. Such measures are, however, difficult to apply in countries such as many in Asia, where as much as four-fifths of poultry production occurs on small rural farms and in the backyards of individual dwellings, with birds often ranging freely.

Additional factors related to the virus itself and its niche in nature, are illustrative of the difficulties confronted in bringing it under control. Avian influenza virus can survive in cool temperatures in manure for at least 3 months, and can survive for up to 4 days in water at 22° C, and for more than 30 days at 0° C. International spread may occur via international trade in live poultry, and migratory birds may carry the virus great distances, excreting it in their droppings.

The current crisis began with an outbreak of avian influenza in poultry caused by the highly pathogenic H5N1 influenza strain reported in the Republic of Korea in December 2003. This was followed by outbreaks confined to poultry in Cambodia, China, Indonesia, Japan, Laos, Thailand, and Vietnam. While of great potential economic significance to the affected countries, the alarm bells truly went off when the first human cases of H5N1 infection were reported in Thailand and Vietnam in January 2004. As of April 4, 2005, Thailand has reported 17 human cases to the World Health Organization, while Vietnam has reported 60 and Cambodia has reported 2. Forty-nine (62%) of the total 79 reported cases have been fatal. It is widely believed, however, that many more cases, undetected and unreported, have occurred.

Avian influenza viruses do not normally infect species other than birds and pigs. The 1997 Hong Kong outbreak, in which 18 human cases (6 fatal) were identified, demonstrated the potential human infectivity of H5N1. Fortunately, human-to-human transmission appeared to be absent during that outbreak, accounting for the self-limited nature of the human cluster. Recently, however, evidence of probable person-to-person transmission of H5N1, within a family in Thailand, has been reported.2 In contrast, however, serological surveys have failed to detect asymptomatic infection among health care workers potentially exposed to H5N1 in the current outbreak.3

Two of the 3 prerequisites for the emergence of a human influenza pandemic are now in place. The human population is immunologically virginal in relation to H5N1, and no protective vaccine is available. In addition, the virus is capable of replicating in humans and causing disease. Only lacking is the ability of the virus to be efficiently transmitted between humans. Sequencing of the H5N1 virus from 5 affected individuals demonstrated that all its genes are of avian origin, with no evidence of reassortment between avian and human viruses. Human-to-human transmission could result from a future resassortment event occurring in swine or humans simultaneously infected with H5N1 and a circulating influenza virus already adapted to human-to-human transmission. Mutation is theoretically another means for H5N1 to acquire this capability. Thus, the extent of the current avian influenza outbreak in an environment of extensive avian-human contact could constitute a perfect storm that vastly increases the probability of such a genetic event.

Besides measures aimed at controlling the epidemic in poultry, effective surveillance for human cases is key to the early detection of events that might be indicative of a coming human pandemic. The capability for early detection, reporting, and investigation of clusters of human cases, followed by aggressive containment measures, includes tracing and management of contacts, targeted prophylactic use of antivirals, and travel-related measures in some of the currently affected areas is uncertain.

The rapid production of a vaccine protective against H5N1 is problematic.4 The current standard approach to the production of influenza vaccines for human use each year utilizes reassortment viruses with relevant haemagglutinin and neuraminidase genes together with the 6 remaining gene segments from A/Puerto Rico/8/34 (H1N1). The vaccine stock is grown in chicken eggs; unfortunately, highly pathogenic H5 (and H7) viruses may be lethal to chicken embryos, precluding large scale productivity. Cultivation in non-avian cell lines may be an effective alternative, and an inactivated H5N1 vaccine is undergoing a Phase I evaluation in 450 adults in Baltimore, Los Angeles, and Rochester, NY, designed to evaluate safety and immunogenicity.

Table 1
Interim Recommendations for Infection Control in HealthCare Facilities Caring for Patients with Known or Suspected Avian Influenza
Patients with a history of travel within 10 days to a country with avian influenza activity and are hospitalized with a severe febrile respiratory illness, or are otherwise under evaluation for avian influenza, should be managed using isolation precautions identical to those recommended for patients with known Severe Acute Respiratory Syndrome (SARS). These include:
  • Standard Precautions
  • Contact Precautions
  • Use gloves and gown for all patient contact
  • Use dedicated equipment such as stethoscopes, disposable blood pressure cuffs, disposable thermometers, etc.
  • Eye protection (ie, goggles or face shields)
  • Wear when within 3 feet of the patient
  • Pay careful attention to hand hygiene before and after all patient contact or contact with items potentially contaminated with respiratory secretions


Epidemiological models developed by the CDC suggest that a new pandemic is likely to result in 2-7.4 million deaths globally. The WHO has stated that the following could be expected when the next human influenza pandemic occurs.

  • Given the high level of global traffic, the pandemic virus may spread rapidly, leaving little or no time to prepare.
  • Vaccines, antiviral agents, and antibiotics to treat secondary infections will be in short supply and will be unequally distributed. It will take several months before any vaccine becomes available.
  • Medical facilities will be overwhelmed.
  • Widespread illness may result in sudden and potentially significant shortages of personnel to provide essential community services.
  • The effect of influenza on individual communities will be relatively prolonged when compared to other natural disasters, as it is expected that outbreaks will reoccur.

The CDC5 suggests that testing of hospitalized patients for influenza A (H5N1) infection is indicated when both of the following exist: 1) radiographically confirmed pneumonia, acute respiratory distress syndrome (ARDS), or other severe respiratory illness for which an alternative diagnosis has not been established, and 2) a history of travel within 10 days of symptom onset to a country with documented H5N1 avian influenza infections in poultry or humans (CDC. 2004). Testing for influenza A (H5N1) should also be considered on a case-by-case basis in consultation with state and local health departments for hospitalized or ambulatory patients with all of the following: 1) documented temperature of > 100.4°F (> 38°C); 2) cough, sore throat, or shortness of breath; and 3) history of contact with poultry or domestic birds (eg, visited a poultry farm, a household raising poultry, or a bird market) or a known or suspected patient with influenza A (H5N1) in an H5N1-affected country within 10 days of symptom onset. While these guidelines stress the evaluation of febrile patients with respiratory symptoms, documented fatal H5N1 infection has occurred in the absence of the latter, with the clinical syndrome being that of encephalitis instead.6 Table 1 lists recommended infection control measures for patients with possible H5N1 infection.

Sequencing and phenotypic testing have demonstrated that the virus is resistant to the adamantines, amantadine, and rimantadine, but susceptible to the neuraminidase inhibitor, oseltamivir.


  1. World Health Organization Executive Board. EB114/6 114th Session April 8, 2004. Provisional Agenda Item 4.5. Avian Influenza and Human Health Report by the Secretariat.
  2. Ungchusak K, et al. Probable Person-to-Person Transmission of Avian Influenza A (H5N1). N Engl J Med. 2005;352:333-340.
  3. Apisarnthanarak A, et al. Seroprevalence of Anti-H5 Antibody Among Thai Health Care Workers After Exposure to Avian Influenza (H5N1) in a Tertiary Care Center. Clin Infect Dis. 2005;40:16-18.
  4. Wood JM, et al. Confronting the Avian Influenza Threat: Vaccine Development for a Potential Pandemic. Lancet. 2004;4:499-509.
  5. CDC. Outbreaks of Avian Influenza A (H5N1) in Asia and Interim Recommendations for Evaluation and Reporting of Suspected Cases—United States, 2004. MMWR 2004;53:97-100.
  6. de Jong MD, et al. Fatal Avian Influenza A (H5N1) in a Child Presenting With Diarrhea Followed By Coma. N Engl J Med. 2005;352:686-691.

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