Case Fatality Rate CFR - birdflustocks.com

Given the global population and the current dynamics of population movement around the world, an H5N1 pandemic, even with a relatively low case-fatality rate, would be a truly catastrophic event.

Source: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

The Data

As of May 2023 the case fatality rate was 52.3%. The official WHO statistics can be found here. All seven countries with ten or more cases have reported a CFR of at least one third, 33.3%. This is mostly true on yearly basis as well, with 10.3% (4/39) in Egypt in 2009 being an outlier, followed by 28.7%. The data is quite consistent and based on confirmed H5N1 cases only.
Egypt and Indonesia have reported 64.4% of the cases and 62.8% of the fatalities. However, the CFR for Indonesia is 84.0% while the CFR for Egypt is 33.4%. Taking the available data at face value, we could assume that Indonesia is under-reporting the number of cases. With Indonesia excluded, the CFR would be 43.4%.

The Estimates

H5N1 is poorly adapted to infect mammals. This can lead to false positives due to contamination of nose or mouth without infection. Another aspect are very high doses of viral material in animal experiments, but also in the context of human cases like poultry workers. Those doses are higher than what we would expect in case of a pandemic. The CFR is a complex topic, but unfortunately far from being a statistical artifact.

Indonesia has reported a H5N1 CFR of 84% and 200 cases. The seasonal influenza has a CFR around 0.1%. A comparable H5N1 CFR of 0.084% would require 200.000 H5N1 cases. There was actually a study in Jakarta searching for H5N1 cases in patients with influenza-associated severe acute respiratory infections, but they found only one case of H5N1. Extrapolating from the study and all influenza-associated severe acute respiratory infections, this would result in 91 H5N1 SARI cases per year, while 5 per year were reported during the study period. Those estimates are not reliable and the number of all H5N1 infections is far too small to be conclusive. But this is a real phenomenon, not a lack of reporting.

All countries with significant case numbers report a CFR above 33%. While it is consensus that the "true" CFR, meaning IFR, of the current H5N1 virus is likely lower than 50%, it is mostly expected to be in the double-digits.

Compared to the 1918 pandemic, the most severe influenza pandemic in recent times, those estimates are very high. However, the 1918 influenza pandemic or "Spanish Flu" mostly killed younger people, while typically influenza infections are most lethal for old people. The best explanation for this is a similar virus circulating decades before 1918, leading to immunity in older people. For an H5 virus this is not the case.

Delays in the delivery of appropriate care to human cases of avian influenza H5N1 in Indonesia appear related to delays in diagnosis rather than presentation to health care settings. Either cases are not suspected of being H5N1 cases until nearly one week after presenting for medical care, or viral testing and/or antiviral treatment is not available where patients are presenting for care.

Source: Human influenza A H5N1 in Indonesia: health care service-associated delays in treatment initiation

Detection of avian influenza in poultry workers can follow contamination of the nose and throat from breathing in material on the affected farm or can be true infection. It can be difficult to distinguish these in people who have no symptoms.

Source: UK Health Security Agency

"There's going to definitely be some people with the disease that were either asymptomatic or subclinical, that really didn't come up on radar," Sandrock said. "I think 50% is going to be the high end. How much it's going to drop, I don't know. What we'd like to see is that it goes from 50% to 3%. But, I think what we may see is that it goes from 50% to 40%, or 50% to 30%, which is still a phenomenally high mortality."

Source: Overestimating Avian Flu

While the real H5N1 CF rate could be lower than the current estimate of 60%, it is unlikely that it will be at the 0.1-0.4% level currently embraced by many pandemic plans. We suggest that, based on surveillance and seroprevalence studies conducted in several countries, the real H5N1 CF rate should be closer to 14-33%.

Source: Finding the real case-fatality rate of H5N1 avian influenza

The available seroepidemiologic data for human H5N1 infection support the current WHO-reported case-fatality rates of 30% to 80%

Source: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

During October 2011–September 2014, we screened respiratory specimens for seasonal and avian influenza A(H5N1) virus infections among outpatients with influenza-like illness and inpatients with severe acute respiratory infection (SARI) in East Jakarta, an Indonesia district with high incidence of H5N1 virus infection among poultry. (...) Although 28% (2,810/10,135) of case-patients reported exposure to poultry, only 1 SARI case-patient with an H5N1 virus infection was detected.

Source: Seasonal Influenza and Avian Influenza A(H5N1) Virus Surveillance among Inpatients and Outpatients, East Jakarta, Indonesia, 2011–2014

Extrapolations for age-specific death rate have been made for four different scenarios, giving lower and upper boundaries for what might have happened if nobody had been immune when the 1918–1920 pandemic started. For the first (lower boundary) scenario the age-specific death rate is increasing up to the age of 30 and is assumed (very unrealistically) to be constant thereafter. For the second scenario the age-specific death rate is monotonically increasing as a function of age according to an almost cubic functionality. For the third (upper boundary) scenario the age-specific death rate is increasing exponentially with age. For the third scenario the mortality of the world population becomes 0.3. Thus 30% of the world population could have been killed by the Spanish flu virus, had nobody been immune when the pandemic started. For the fourth scenario the mortality by age due to the virus mimics the traditional mortality by age in a population. The fifth scenario is identical with scenario 3, except that it is also counterfactually assumed that the wave 2 virus came first. For this scenario, it is found that as much as 80% of the total world population in 1918 might have been killed by the Spanish flu virus. (...) For the scenario where the mortality by age mimics the common mortality by age in a population the mortality becomes 8%.

Source: The Spanish flu as a worst case scenario?

Seroevidence and Contamination

Seroevidence, blood samples with antibodies reacting to H5N1, indicates infections not included in the official WHO statistic. Infections included in that statistic have to fulfill uniform standards and a certain amount of infections not observed or reported is to be expected. While a lower CFR would be good news, seropositivity is not always a confirmation of the past or present presence of the virus. For many technical reasons, a small percentage of the blood samples being close to the threshold may not be significant. The human immune system is complex and has a long history of contact with influenza viruses. The results could be caused by heterosubtypic immunity, a immune response to similar influenza viruses. There is also BTN3A3, a very recently discovered part of the human immune system targeting avian influenza viruses, which shows that our understanding is incomplete.

Recently a study about workers on a poultry market in Bangladesh has been published, where workers live and work in the worst possible conditions regarding H5N1 prevention. Despite widespread H5N1 contamination and zero preventive measures, no fatalities have occurred. In fact all the workers with positive H5N1 respiratory swabs continued to work and didn't develop any H5N1 antibodies.

There is serologic evidence from the 1997 Hong Kong outbreak that can't be disputed so easily. It is however assumed that the virus has changed significantly since then. While there may be asymptomatic cases where human exposure to the H5N1 virus resembled a vaccination with a live attenuated virus, there is no conclusive evidence of that. Additional infections are not confirmed beyond doubt and the issue remains controversial.

What matters most is what an H5N1 pandemic would look like. And for a pandemic to happen, the virus would have to change to become a lot more infectious. And the more infectious virus may be less virulent.

Eight (3.7%) of 217 exposed and 2 (0.7%) of 309 nonexposed HCWs were H5N1 seropositive (P=.01). The difference remained significant after controlling for poultry exposure (P=.01). This study presents the first epidemiologic evidence that H5N1 viruses were transmitted from patients to HCWs.

Source: Risk of influenza A (H5N1) infection among health care workers exposed to patients with influenza A (H5N1), Hong Kong

Also, the fatal cases that have been reported are most likely caused by mega-doses of H5 virus inhaled by the patients, who are living in very close contact with infected poultry. (...) two studies report no seropositivity and the other eight report rates ranging from 0.2% to 5.6%; the studies are mostly conducted in rural areas where H5 infections have been previously documented. Even if only a low percentage of the rural population is asymptomatically/subclinically infected, the case fatality rate that is offered by the WHO—and that is driving this controversy—is likely orders of magnitude too high.

Source: H5N1 influenza viruses: Facts, not fear

Given the fact that most H5N1 infections in poultry and in humans occur in resource-poor areas where access to health care is often arduous and expensive to obtain, we hypothesized that many people with H5N1 virus infection would not have been examined by a health provider to allow formal H5N1 disease confirmation. In addition, persons who are seropositive for H5N1 infection often report no history of influenza-like illness, and subclinical or mild H5N1 infections are not recognized under the WHO criteria for confirmed cases.

Source: Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis

With WHO criteria, we performed subanalyses of study participants who were specifically employed as poultry workers (N = 2729). This analysis revealed a seropositivity rate of about 1.4%.

Source: Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis

The data were compiled from 12,677 study participants in 20 studies. They show that avian H5N1 viruses can cause a rate of mild or subclinical infections in humans that is not currently accounted for; thus, the true fatality rate for H5N1 influenza viruses is likely to be less than the frequently reported rate of more than 50%.

Source: Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis

Particular laboratory issues that must be rectified include lack of standardization of assay format and performance, variability in criteria used to define seropositivity, cross-reactions in persons exposed to seasonal influenza vaccine or infection, and virus strains other than the avian H5N1 strain currently circulating. (...) Therefore, we suggest that no data are presented in Wang et al. that can reasonably be used to establish a lower bound for the proportion of individuals exposed in the general population of countries affected by H5N1.

Source: Comment on “Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis”

Over the many decades that H5N1 viruses have been circulating in poultry, millions of people have likely been infected. (...) We strongly disagree with the statement by Van Kerkhove et al. that existing studies likely overestimate the H5N1 antibody seroprevalence rates. (...) The WHO criteria could result in under-documentation of H5N1 infections by several orders of magnitude; random calculations such as the one made by Van Kerkhove et al. have little value in discussions related to H5N1 viruses in humans.

Source: Response to Comment on “Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis”

Moreover, previous infections of humans with seasonal influenza viruses are likely to induce heterosubtypic immunity that would offer some protection against the development of severe disease. It has been shown that mice and ferrets previously infected with an A/H3N2 virus are clinically protected against intranasal challenge infection with an A/H5N1 virus.

Source: Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets

Heterosubtypic immunity (HSI) is defined as cross-protection to infection with an influenza A virus serotype other than the one used for primary infection. Although HSI has been thought to be mediated by serotype cross-reactive cytotoxic T lymphocytes (CTL) that recognize conserved epitopes of structural proteins, recent studies suggest that antibodies (Abs) may make a significant contribution.

Source: Heterosubtypic Immunity to Influenza A Virus Infection Requires a Properly Diversified Antibody Repertoire

Villagers were asked about poultry exposures in the past year and tested for H5N1 antibodies. Despite frequent, direct contact with poultry suspected of having H5N1 virus infection, none of 351 participants from 93 households had neutralizing antibodies to H5N1. H5N1 virus transmission from poultry to humans remains low in this setting.

Source: Low Frequency of Poultry-to-Human H5N1 Transmission, Southern Cambodia, 2005

Although available evidence supports the fact that asymptomatic infections with H5N1 can occur in persons exposed to the virus, the evidence does not suggest that asymptomatic infections are common or that the case-fatality rate for H5N1 has been significantly overestimated. There is no evidence to support the statement by Palese and Wang that “the case-fatality rate that is offered by the WHO—and that is driving this controversy—is likely orders of magnitude too high”.

Source: H5N1 influenza virus seroepidemiological studies: The facts revisited

Across both investigations, we collected 161 poultry specimens; 58 (36%) had detectable A(H5) viral RNA, 9 (6%) had A(H9), 8 (5%) had both A(H5) and A(H9), and 15 (9%) had influenza A unsubtypeable viral RNA detected. Of the 98 environmental swabs collected, 34 (35%) tested positive for A(H5) and 18 (18%) had influenza A unsubtypeable viral RNA detected.

Source: Interpretation of molecular detection of avian influenza A virus in respiratory specimens collected from live bird market workers in Dhaka, Bangladesh: Infection or contamination?

During both investigations, we identified 1,273 workers with ILI, with a median age of 28 years (...). Of those 1,273, 167 (13%) had influenza A viral RNA detected in their respiratory swabs, with relatively high Ct values (median Ct values: 37, IQR: 36.1 – 38). 90 (7%) had AIV RNA [34 (38%) had A(H5), 56 (62%) had A(H9)] (...) None of the workers with detectable influenza A viral RNA developed severe illness requiring hospitalization and the workers continued working during their illnesses. The frequency of ILI symptoms was similar between LBM workers with and without detectable AIV RNA (Table 3).

Source: Interpretation of molecular detection of avian influenza A virus in respiratory specimens collected from live bird market workers in Dhaka, Bangladesh: Infection or contamination?

None of the cases had evidence of seroconversion against the respective AIVs detected. (...) Taken together, these findings suggest that the detection of AIV RNA at low levels in respiratory specimens from asymptomatic and symptomatic LBM workers in Bangladesh may have represented exposure to AIVs and environmental contamination rather than AIV infection. During 2012, when ILI surveillance detected AIV RNA in respiratory specimens collected from some LBM workers in Bangladesh, there was suspicion that these detections did not represent true human infections, in part because workers were pauci-symptomatic. Multiple lines of evidence from subsequent investigations suggested that these detections likely did not represent true infections, including the lack of seroconversion among workers tested, and lack of detection of the same AIVs in follow-up respiratory specimens of individuals who initially tested positive for AIVs with high Ct values. Based on the available evidence from these investigations, no further human A(H5N1) or A(H9N2) cases were reported to the WHO from the Government of Bangladesh after the first three reports.

Source: Interpretation of molecular detection of avian influenza A virus in respiratory specimens collected from live bird market workers in Dhaka, Bangladesh: Infection or contamination?

Some researchers have stated that, because of the specificity of the WHO case definition, milder or asymptomatic H5N1 cases have been missed by traditional case-based surveillance and therefore a small fraction of the total number of infected cases has been accounted for under the WHO surveillance system. (...) However, all of the data presented above suggest that the number of mild infections that have been missed is likely relatively small.

Source: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

They identified 89 poultry farms that had confirmed H5N1 outbreaks from December 2007 to June 2009 and three live-bird markets in Dhaka where poultry deaths exceeded 5% to 10% for 2 consecutive days in 2008. From January to July of 2009, the investigators identified 422 workers at those sites (212 farm workers, 210 from markets) and collected serum samples, demographic information, and data about poultry exposures. The team used a microneutralziation assay to detect antibodies to a 2008 Bangladeshi strain of H5N1 virus, using a titer of 1:40 as their threshold for a positive result. Both farm and market workers reported many tasks that involved poultry exposures, such as feeding, collecting eggs, cleaning stalls, slaughtering, and evisceration. Despite these exposures, none of the workers tested positive for H5N1 antibodies, the report says.

Source: No sign of missed H5N1 cases in Bangladesh study

WHO criteria for serologic confirmation (titer of ≥1:80)

Source: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

The five studies, which included 2,629 participants, found that no participants had evidence of previous infection based on the WHO criteria for serologic confirmation and only 13 (0.49%) had neutralization titers between 1:10 and 1:40.

Source: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective

We have been conducting field and surveillance studies for avian influenza in Egypt since 2008. Our most recent efforts were focused on studying potential transmission and spill-over routes of avian influenza in live bird markets. (...) Between February 2022 and March 2023, we obtained written consent from and enrolled 394 adult market workers. Of those, 230 were sampled only once while 164 were available for multiple sampling. A total of 830 serum samples were collected. Sera obtained from those workers were tested for antibodies against A/Duck/Egypt/BA20361C/2022 (H5N1) a clade 2.3.4.4b virus. Thirty-eight (4.6%) of the samples had neutralising antibodies with titres ranging from 1:40 to 1:320.

Source: We are underestimating, again, the true burden of H5N1 in humans

We detected high titers of cross-reactive neuraminidase inhibition antibodies to influenza A(H5N1) virus clade 2.3.4.4b in 96.8% (61/63) of serum samples from healthy adults in Hong Kong in 2020. In contrast, antibodies at low titers were detected in 42% (21/50) of serum samples collected in 2009. Influenza A(H1N1)pdm09 and A(H5N1) titers were correlated.

Source: Avian Influenza A(H5N1) Neuraminidase Inhibition Antibodies in Healthy Adults after Exposure to Influenza A(H1N1)pdm09

The presence of these antibodies suggests that some individuals living near migratory sites may have been exposed to H5. There is a spatial and environmental overlap between individuals displaying high H5 binding and the distribution of migratory birds.

Source: Serological analysis in humans in Malaysian Borneo suggests prior exposure to H5 avian influenza

The Outlook

The idea of a "true CFR", meaning the infection fatality rate IFR, is a bit misleading as the CFR discussed is about the current form of the virus. What we really want to know is the IFR of a future virus that has adapted to infecting the upper airways of humans. Since there are no gain-of-function experiments with humans, we can only speculate based on the current CFR and animal studies.
The good news is that all ferrets from the Fouchier et al. gain-of-function study survived the infection. Infections of the upper respiratory tract also tend to be less dangerous than infections deep in the lungs. However, H5N1 has the tendency to spread from the nasal epithelial cells to the central nervous system and cause neurological issues.

One of eight inoculated animals died upon intranasal inoculation (Table 1). In previously published experiments, ferrets inoculated intranasally with WTA/Indonesia/5/2005 virus at a dose of 1 × 106 TCID50 showed neurological disease and/or death (39, 40). It should be noted that inoculation of immunologically naïve ferrets with a dose of 1 × 106 TCID50 of A/H5N1 virus and the subsequent course of disease is not representative of the natural situation in humans. Importantly, although the six ferrets that became infected via respiratory droplets or aerosol also displayed lethargy, loss of appetite, and ruffled fur, none of these animals died within the course of the experiment.

Source: Airborne Transmission of Influenza A/H5N1 Virus Between Ferrets

From 1 dpi onwards, ferrets developed clinical signs including anorexia, diarrhea, and lethargy, as well as neurological signs. Neurological signs consisted of unsteady gait and uncontrolled movements. All eight ferrets had lost between 13% and 24% of their original body weight by 7 dpi. Two ferrets were found dead, at 5 dpi and at 7 dpi. One ferret was euthanized at 6 dpi because of the presence of severe clinical signs, in accordance with animal welfare regulations.

Source: Pathogenesis of Influenza A/H5N1 Virus Infection in Ferrets Differs between Intranasal and Intratracheal Routes of Inoculation

Intranasal inoculation with wild-type H5N1 virus revealed extensive replication in the olfactory mucosa, from which it spread to the olfactory bulb and the rest of the CNS, including the cerebrospinal fluid (CSF). (...) Several studies have shown that the central nervous system (CNS) is the most common extrarespiratory site of replication after experimental intranasal inoculation. (...)

Source: The Multibasic Cleavage Site in H5N1 Virus Is Critical for Systemic Spread along the Olfactory and Hematogenous Routes in Ferrets

The clinical presentation of the disease in red foxes, skunks, and mink was mostly neurologic, resembling clinical and pathologic features described in seals and foxes that were naturally infected with HPAI H5N8 viruses.

Source: Characterization of neurotropic HPAI H5N1 viruses with novel genome constellations and mammalian adaptive mutations in free-living mesocarnivores in Canada

Highly pathogenic avian influenza (HPAI) H5Nx viruses can cause neurological complications in many mammalian species, including humans. Neurological disease induced by HPAI H5Nx viruses in mammals can manifest without clinical respiratory disease. HPAI H5Nx viruses are more neuropathogenic than other influenza A viruses in mammals. Severe neurological disease in mammals is related to the neuroinvasive and neurotropic potential of HPAI H5Nx viruses. Cranial nerves, especially the olfactory nerve, are important routes of neuroinvasion for HPAI H5Nx viruses. HPAI H5Nx viruses have a broad neurotropic potential and can efficiently infect and replicate in various CNS cell types. Vaccination and/or antiviral therapy might in part prevent neuroinvasion and neurological disease following HPAI H5Nx virus infection, although comprehensive studies in this area are lacking.

Source: The neuropathogenesis of highly pathogenic avian influenza H5Nx viruses in mammalian species including humans

While both 1918 reassortant viruses also were highly pathogenic, the H5N1 virus was exceptional for the extent of tissue damage, cytokinemia, and interference with immune regulatory mechanisms, which may help explain the extreme virulence of HPAI viruses in humans.

Source: Early and sustained innate immune response defines pathology and death in nonhuman primates infected by highly pathogenic influenza virus

The Data

The Estimates

Seroevidence and Contamination

The Outlook

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