When it comes to safeguarding the health of the US, there is no one I trust more than Dr. Anthony Fauci, head of NIAHD/NIH (whom I was fortunate to interview on TWiV in 2013). So when Dr. Fauci says that 100,000 people could die in the SARS-CoV-2 outbreak just in the US, I take notice. What exactly does he mean? Can we put this in perspective with other outbreaks?
case fatality ratio
Ralph Baric joins TWiV to dissect the coronavirus pandemic caused by SARS-CoV-2, including discussion on community spread, asymptomatic infections, origin of the virus, transmission, vaccine development, and much more.
Become aÂ patronÂ ofÂ TWiV!
Show notes at microbe.tv
Driving the anxiety and uncertainty about the current outbreak of COVID-19 is the case fatality ratio (CFR) being thrown about carelessly by not just the press, but also WHO and other organizations. However the CFRÂ is not a one-size-fits all, and is influenced by many factors.
Health experts say itâ€™s not a question of whether SARS-CoV-2 will spread within the U.S., but when. A CDC official said yesterday, â€œWe are asking the American public to prepare for the expectation that this might be bad.â€ What exactly does that mean?
When virologists Fouchier and Kawaoka were isolating avian influenza H5N1 viruses that could transmit among ferrets by aerosol, there was consternation from some quarters that such viruses might escape from the laboratory and cause a pandemic in humans. Part of the fear came from the fact that the case fatality ratio for human infections with the H5N1 virus exceeds 50%. This number could be substantially higher than the lethality ratio, which is the number of symptomatic cases divided by the total number of infections. Divining the latter number has been difficult. Results of aÂ meta-analysis published in 2012 suggest that H5N1 seropositivity approaches 1-2% in certain populations. Others have concluded that these studies are flawed, clouded by false positives and cross-reacting antigens. Recently two additional studies have been published that contribute to this discussion.
The first paper is a case report of subclinical avian influenza H5N1 virus infection in a Vietnamese household in which family members were involved in slaughtering, preparing, and consuming chickens, and birds were permitted to roam freely in the sleeping area. Four chickens from this household were found to be positive for H5N1 virus by polymerase chain reaction (PCR) of throat and cloacal swab specimens. The 40-year old father died after a severe four day respiratory illness requiring hospitalization; H5N1 viral RNA was detected by PCR of a throat swab on day 3 of illness. A throat swab from his daughter, taken 6 days after she had killed a chicken, was positive by PCR, and H5N1 virus was recovered by inoculation of cell cultures. Her hemagglutination-inhibition (HI) titer, a measure of anti-viral antibodies, increased from <20 to 160, but she showed no signs of illness, perhaps because she was treated with oseltamivir from day 5 of her father’s illness.
The authors note the difficulty in detecting subclinical H5N1 infections:
…it is unclear whether serologic testing reliably detects subclinical cases. According to the World Health Organization,MN (microneutralization) titers >80 are indicative of infection but must be confirmed by a second serologic test because of the possibility of cross-reactivity. The interpretation of results from a single serum sample is limited by the specificity or sensitivity of serologic tests, and viral shedding times may mean that infected cases may be missed.
The second studyÂ examinedÂ seroprevalence of anti-H5N1 virus antibodies in poultry workers in Bangladesh. Sera were collected in 2009 from poultry workers on farms (212 from 87 farms) and live bird markets (210 from 3 markets). Some of the farm workers (91%) reported handling sick animals during laboratory-confirmed H5N1 outbreaks. Sera were screened for antibodies to H5N1 virus by two methods: microneutralization and hemagglutination-inhibition. None of the individuals were seropositive for anti-H5N1 virus antibodies.
I have several reservations about this study. Although H5N1 virus was identified on the poultry farms whose workers were sampled, the sera were drawn from 22 to 543 days after the onset of poultry deaths. If any of the workers had been infected with H5N1 virus, anti-viral antibody titers might have already declined by this time. Although the sera were examined for anti-viral antibodies by two different tests, paired sera were not used, as recommended by the authors of the first paper discussed above.
Therefore the answer to the question ‘what is the fatality rate of influenza H5n1 virus infections in humans?’ still cannot be answered. As the authors of the first paper conclude:
Estimating the incidence of asymptomatic influenza A(H5N1) virus infection in humans exposed to sick poultry or human case-patients requires further careful study using early collection of swab samples and paired acute and convalescent serum samples.
The lethality of avian influenza H5N1 infections in humans has been a matter of extensive debate. The >50% case fatality rate established by WHO is high, but the lethality of the virus might be lower if there are many infections accompanied by mild or no disease. One way to answer this question is to determine how many individuals carry antibodies to the virus in populations that are at risk for infection. A number of such studies have been done, and some have concluded that the results imply a low but substantial level of infection (even less than one percent of millions of people is a lot of infections). The conclusion of aÂ new meta-analysis of H5N1 serosurveys is that most of the studies are flawed, and that the frequency of H5 infections appears to be low.
Twenty-nine different H5N1 serological studies were included in this meta-analysis. None of these are particularly satisfactory according to the authors:
None of the 29 serostudies included what we would consider to be optimal, blinded unexposed controls in their published methodologies, i.e., including in the serology runs blinded samples from individuals with essentially no chance of H5N1 infection. Serological assays can easily produce misleading results, especially when paired sera are not available.
Some of the problems identified in the serological surveys include the possibility that many H5N1 positive sera are the result of false positives, that is, cross reaction with antigens from other influenza virus strains. In addition, many studies utilized H5N1 strains that are no longer circulating.
It is clear that most of the H5N1 serosurveys have not been done as well as they should have been. The authors conclude that â€œit is essential that future serological studies adhere to WHO criteria and include unexposed control groups in their laboratory assays to limit the likelihood of misinterpreting false positive results.â€
Letâ€™s not forget that a completely different way of assessing H5N1 infection – by looking for virus-specific T cells – has been reported. The results provide further evidence for subclinical H5N1 infection and are not subject to the caveats noted here for antibody surveys.
I come away from this meta-analysisÂ with an uneasy sense that the authors are not being sufficiently objective, and that they firmly believe that there are no mild or asymptomatic H5N1 infections. One reason is the authorsâ€™ use of â€˜onlyâ€™ to describe their findings. For example: â€œOf studies that used WHO criteria, onlyÂ [italics mine] 4 found any seropositive results to clades/genotypes of H5N1 that are currently circulatingâ€. The use of â€˜onlyâ€™ in this context implies a judgement, rather than an objective statement of fact. Furthermore, despite the authors stated problems with all H5N1 serosurveys, they nonetheless conclude that there is little evidence for asymptomatic H5N1 infection. If the studies are flawed, how can this conclusion be drawn?
My concern about the authorsâ€™ objectivity is further heightened by the fact that they are members of the Center for Biosecurity at the University of Pittsburgh. These are individuals whose job it is to find dangerous viruses that could be used as weapons. On the front pageÂ of the website for the Center for Biosecurity is a summary of the meta-analyis article which concludes that â€œIn the article, Assessment of Serosurveys for H5N1, Eric Toner and colleagues discuss their extensive review of past studies and conclude that there is little evidence to suggest that the 60% rate is too high.â€
I would argue that if the H5N1 serosurveys are flawed, then do them properly; it is incorrect to simply assume that the H5N1 virus is as lethal as WHO suggests. The World Health Organization should call for and coordinate a study that satisfies criteria established by virologists and epidemiologists for a robust analysis of human H5N1 exposure.