Photo Credit – CDC PHIL
One of the more contentious topics among H5N1 researchers has been the argument over the `real’ CFR (Case Fatality Ratio) of the H5N1 virus in humans.
The `official’ number – a fatality rate of nearly 60% – is derived from the total known human infections by the virus (637 as of Aug 31st, 2013), and the total number of fatalities within that group (378)
Critics point out that only the sickest of the sick would end up in a testing environment, and that many mild cases would recover and never be counted. The numbers, they maintain, are badly skewed.
While I think most researchers would agree that the 60% CFR number is likely misleading, it has been difficult to put a `good’ number on the mortality rate of H5N1. The best way to get an idea of the uncounted number of people infected by a virus in a population is to conduct regional seroprevalence studies. You essentially check antibody levels against a specific virus in a representative group of the population.
Unfortunately, you don’t end up with a clear cut Infected/Not Infected reading from these tests. You get an antibody titer level, and that requires a subjective decision as to what level constitutes proof of a `previous infection’.
Set the bar too high, and you rule out possible cases whose antibodies have declined over time (or who were exposed to an antigenically different H5N1 strain).
Make it too low, and you may count people who were exposed to a non-H5 virus or who received such a low viral load as to not develop illness or immunity.
Over the years we’ve seen a number of seroprevalence studies on the H5N1 virus, and the results (and methods) have varied considerably.
In February of 2012 (see Science: Peter Palese On The CFR of H5N1), the journal Science published a meta-analysis by Taia T. Wang, Michael K. Parides & Peter Palese, that argued that we are likely missing a great many H5N1 infections (perhaps millions), and that the virus is far less lethal than has been assumed in the past.
This was published during a time of great debate over the safety and wisdom of conducting H5N1 gain of function (GOF) or Dual Use of Concern (DURC) research (see The Furor Over H5N1 Research Continues). GOF H5N1 research seeks to create in the laboratory H5N1 strains with increased virulence, transmission, or host range in hopes to better understand how pandemic viruses evolve.
These findings were used to argue that the H5N1 virus, and by extension Gain of Function research, were not nearly as dangerous as many feared.
That argument was quickly countered by CIDRAP director Michael T. Osterholm and Nick Kelley in an mBio article, where they found little serological evidence to suggest that we are missing `millions’ of uncounted H5N1 infections (see mBio: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective).
A few months later the journal Science published a response to the Palese study – authored by a truly impressive group of virologists and researchers – that also found little evidence to support the notion that `millions’ of mild infections have gone undetected.
A better understanding of the severity of H5N1 in humans is needed. Wang et al. (Brevia, 23 March 2012, p. 1463; published online 23 February 2012) over interpret the results of seroprevalence studies and take too little account of underlying uncertainties. Although the true risk of death from H5N1 infection will likely be lower than the 60% of reported laboratory-confirmed cases, there is little evidence of millions of missed infections.
Their entire rationale may be read here, and it strongly counters the assessment presented by Wang et al. in the original paper.
Meanwhile, the controversy over GOF research continues, which we looked at most recently in H7N9: Reigniting The `Gain Of Function’ Research Debate.
Today (h/t @Laurie_Garrett for the link) we’ve a new H5N1 seroprevalence study, this time conducted on poultry workers in Bangladesh who were exposed to infected chickens during laboratory confirmed bird flu outbreaks in 2009. Given their frequent and close contact to infected birds, they would be expected to have the highest risk of H5N1 infection.
Their findings are summed up in the last line of the abstract: Despite exposure to sick poultry, no farm or market poultry workers were seropositive for HPAI H5N1 virus antibodies (95% confidence interval 0–1%).
The entire study, which appears this month in the journal PloS One, may be accessed at the link below:
Sharifa Nasreen mail, Salah Uddin Khan, Eduardo Azziz-Baumgartner, Kathy Hancock, Vic Veguilla, David Wang, Mahmudur Rahman, A. S. M. Alamgir, Katharine Sturm-Ramirez, Emily S. Gurley, Stephen P. Luby, Jacqueline M. Katz, Timothy M. Uyeki
We conducted a cross-sectional study in 2009 to determine the seroprevalence and risk factors for highly pathogenic avian influenza A (H5N1) [HPAI H5N1] virus antibodies among poultry workers at farms and live bird markets with confirmed/suspected poultry outbreaks during 2009 in Bangladesh. We tested sera by microneutralization assay using A/Bangladesh/207095/2008 (H5N1; clade 2.2.2) virus with confirmation by horse red blood cell hemagglutination inhibition and H5-specific Western blot assays. We enrolled 212 workers from 87 farms and 210 workers from three live bird markets. One hundred and two farm workers (48%) culled poultry. One hundred and ninety-three farm workers (91%) and 178 market workers (85%) reported direct contact with poultry that died during a laboratory confirmed HPAI H5N1 poultry farm outbreak or market poultry die-offs from suspected HPAI H5N1. Despite exposure to sick poultry, no farm or market poultry workers were seropositive for HPAI H5N1 virus antibodies (95% confidence interval 0–1%).
While none of the poultry workers tested seropositive for the H5N1 virus (using thresholds established by WHO for serological testing), a small number did show mildly elevated titers – well below the threshold for positivity.
The authors explain:
It is difficult to interpret these low levels of HPAI H5N1 virus neutralizing antibodies in a cross-sectional study. First, low titers may indicate cross reactive antibodies from a previous influenza A virus infection with a different subtype rather than the presence of HPAI H5N1 virus-specific neutralizing antibodies [11,13]. Single or multiple-clade H5N1 influenza vaccines can generate cross-clade neutralizing antibodies in humans and mice [22,23]. Nevertheless, only HPAI H5N1 clade 2.2.2 viruses were identified among domestic poultry in Bangladesh during 2007–2009 . Second, these low titers could potentially reflect a limited neutralizing antibody response in some individuals with HPAI H5N1 virus infection. One study in Vietnam of persons with serologic evidence of clinically mild or asymptomatic HPAI H5N1 virus infection reported relatively lower neutralizing antibody titers compared with severely ill cases . Third, low titers may reflect past HPAI H5N1 virus infection with declining neutralizing antibody titers over time to when serum was sampled, to levels below our defined cut-off titer defining a seropositive result [24,25].
Admittedly, there have been other studies conducted in recent years that have come up with higher (although still low) levels of seropositivity for the H5N1 virus.
- Last year, in H5N1 Seroprevalence Among Jiangsu Province Poultry Workers, we saw a study that found across three locations tested (Gaochun, Jianhu and Gaoyou counties) the percentage of workers testing positive ranged from zero (Gaochun) to 5.38% (95%CI, 2.19%–10.78%) in Gaoyou.
- In 2011, a study (see Subclinical H5 & H9 Infections In Humans) tested 605 residents in and around Beijing China for antibodies to H5 and H9 avian flu viruses. Of these, just 5 (less than 1%) had antibodies to H9 avian influenza, and only 1 was positive for antibodies to H5.
- In May of 2009 (see Cambodian Study Finds Rare Asymptomatic H5N1 Infections) we saw a study published in the Journal of Infectious Diseases on more than 600 members of a Cambodian village where 2 human H5N1 cases were detected in 2006. Antibody titers showed that only 1% (7 of 674) of the villagers tested had contracted, and fought off, the H5N1 virus. A figure much lower than many had expected.
- In 2004 (see The Thailand Serological Study) 322 poultry farmers (in provinces where H5N1 had been detected) were tested. Researchers found that "no poultry workers had microneutralization titers >80, whereas 7 (2%) had lower titers that did not meet the WHO definition for seropositivity".
The debate over the true CFR of H5N1 continues, and no one really knows the answer. It is most likely substantially lower than 60%, but how much lower is the question. The great pandemic of 1918 carried a CFR of 2% or so for the United States and Europe, yet managed to kill tens of millions around the globe.
Proving that even if the true mortality rate of this avian flu is 1/20th of the `official’ CFR (ie. 3%) , an H5N1 pandemic could prove disastrous.