Six waves of the same feather

According to the WHO, the risk to humans increases “when the virus becomes established in small backyard flocks”. The H5N1 will have met all the requirements to start a global epidemic (pandemic) when it enhances its “transmissibility” to spread easily and in a sustainable fashion from person-to-person. This enhancement could take place by an “evolution” of the virus. This is why scientists are looking for evidence for “person-to-person transmission” besides tracking the “evolution of H5N1”. Let us discuss two important journal papers on these topics.

Person-to-person transmissibility

Recently, The New England Journal of Medicine (NEJM) carried the first account on probable secondary human transmission of any avian influenza virus leading to fatality. In its January 27 issue (pp. 333-340), Kumnuan Ungchusak et al reported “probable person-to-person transmission in a family cluster of the disease in Thailand”.

It is extremely difficult to present convincing scientific evidence for person-to-person transmission because family members are usually exposed to each other, and to the same animal and environmental sources. In this case though, the index patient was cared for in the hospital by her mother who “came from a distant city and had no recognised exposure to poultry”.

Unfortunately, the mother “died from pneumonia after providing unprotected nursing care”. An aunt, who also provided unprotected nursing care, had fever and pneumonia. “Autopsy tissue from the mother and swabs from the aunt were positive for H5N1,” said the paper.

The points to note are that: (a) we cannot be certain even with this kind of “evidence”, and (b) person-to-person transmissions of H5N1 have occurred in association with outbreaks (albeit rarely), and are not a cause for alarm per se if they don’t spread beyond a first generation of close contacts. This is indeed the case with the NEJM paper. The WHO reminds us that incidents like this will not change its overall assessment of the pandemic risk.

Evolution of H5N1

Evolution can occur through “adaptive mutation” or a genetic recombination mechanism called “reassortment”. The former is relatively slow, leading to “small clusters of cases with some evidence of human-to-human transmission”. The latter can occur between human and bird viruses during co-infection of a human or pig, and is of greater concern because it could give “a sudden surge of cases with explosive spread”.

The difficulties lie not just in finding evidence for evolution, but in determining if and how it would enhance transmissibility. Members of the WHO’s Global Influenza Programme (and their collaborators) have published arguably the most comprehensive research on this. Their paper (“Evolution of H5N1 avian influenza viruses in Asia”) appeared in the October 2005 issue of Emerging Infectious Diseases, a journal published by the American Centers for Disease Control and Prevention (CDC).

These authors have analysed H5N1 viruses from the 2004-2005 outbreak and found no evidence that the H5N1 isolates have acquired “non-avian influenza genes by reassortment”. They have correctly emphasised the importance of continued surveillance because “the segmentation of the H5N1 genome into 8 separate RNA molecules allows frequent genetic exchange by segment reassortment — which may facilitate the evolution of viruses with increased virulence or expanded host range”.

This paper also reported that “several amino acids located near the receptor-binding site are undergoing change, some of which may affect antigenicity or transmissibility”. Studies like this are important to determine if these variants could “compromise the efficacy of the candidate vaccine or increase the efficiency of transmission”, but we cannot jump to hasty conclusions on transmissibility. Why?

Firstly, mutations at the receptor-binding site (even those involving the substitution of more mammalian-like amino acids) may not become fixed in the circulating viruses. According to the WHO, recent studies show that mutations detected in human viruses isolated in 2005 (and in a virus isolated from Turkey’s outbreak last month) were indeed “transient”. Secondly, even if mutations became fixed (as with viruses circulating in at least some species of wild birds), how it will affect transmissibility isn’t fully understood.

With “no convincing evidence that mutations have altered the epidemiology of the disease in humans”, the WHO has reassured the public that there “is no evidence, at present, from any outbreak site that the virus has increased its ability to spread easily from one person to another”.

So, what should we have for breakfast?

Will there be a flu pandemic? We are probably closer to a pandemic than at any time since 1968. The WHO pandemic alert has entered “phase 3” (out of 6, see graphic).

Can we predict the pandemic? Influenza viruses are inherently unstable, and specific mutations and evolution in them cannot be predicted. Therefore, neither the timing nor the severity of the next pandemic “can be predicted with any certainty”.

Should we panic? Absolutely not. As seen above, global efforts are underway to prevent the H5N1 threat from progressing through phases 4-5 to eventually become a pandemic (which is phase 6). Hopefully, the gentle reader is persuaded that there are no quick answers and that scientists are doing their best.

Leaving journals aside and switching to daily life: should we avoid poultry or eggs? There is no scientific evidence that these can be a source of infection for avian influenza viruses if all parts of the food are cooked above 70 degrees Celsius. So, I am afraid the toast soldiers will have to wait until it is absolutely safe to take a dip in the runny yolk!

S.S. Vasan is visiting senior scientist at the WHO Collaborating Centre for Vectors, IMR, Kuala Lumpur