Unanswered questions about the 1918 influenza pandemic: origin, pathology, and the virus itself

Oxford, John S et al.
The Lancet Infectious Diseases, 2018

• “…Studies of the resurrected 1918 virus showed it to be somewhat more virulent than contemporary H1N1 epidemic viruses in animal models, but not enough to be the sole factor in the high mortality rates…..”
• “…A cytokine storm, together with previous immune history, were important factors in explaining both enhanced pathology and protection from death….”

CDC

CDC

The Influenza Risk Assessment Tool (IRAT) is an evaluation tool conceived by CDC and further developed with assistance from global animal and human health influenza experts. The IRAT is used to assess the potential pandemic risk posed by influenza A viruses that are not currently circulating in people. Input is provided by U.S. government animal and human health influenza experts. Information about the IRAT is available at Influenza Risk Assessment Tool (IRAT) Questions and Answers(https://www.cdc.gov/flu/pandemic-resources/national-strategy/risk-assessment.htm).

H1N1: [North American avian H1N1 [A/duck/New York/1996]

Avian influenza A viruses are designated as highly pathogenic avian influenza (HPAI) or low pathogenic avian influenza (LPAI) based on molecular characteristics of the virus and the ability of the virus to cause disease and death in chickens in a laboratory setting. North American avian H1N1 [A/duck/New York/1996] is a LPAI virus and in the context of the IRAT serves as an example of a low risk virus.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the low risk category (less than 3). Similarly the average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission also falls into the low risk range (less than 3).

H3N2 Variant:[A/Indiana/08/11]

Swine-origin flu viruses do not normally infect humans. However, sporadic human infections with swine-origin influenza viruses have occurred. When this happens, these viruses are called “variant viruses.” Influenza A H3N2 variant viruses (also known as “H3N2v” viruses) with the matrix (M) gene from the 2009 H1N1 pandemic virus were first detected in people in July 2011. The viruses were first identified in U.S. pigs in 2010. In 2011, 12 cases of H3N2v infection were detected in the United States. In 2012, 309 cases of H3N2v infection across 12 states were detected. The latest risk assessment for this virus was conducted in December 2012 and incorporated data regarding population immunity that was lacking a year earlier.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate risk category (less than 6). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low-moderate risk category (less than 5).

H3N2: [A/canine/Illinois/12191/2015]

The H3N2 canine influenza virus is an avian flu virus that adapted to infect dogs. This virus is different from human seasonal H3N2 viruses. Canine influenza A H3N2 virus was first detected in dogs in South Korea in 2007 and has since been reported in China and Thailand. It was first detected in dogs in the United States in April 2015(https://www.cdc.gov/flu/news/canine-influenza-update.htm). H3N2 canine influenza has reportedly infected some cats as well as dogs. There have been no reports of human cases.

Summary: The average summary risk score for the virus to achieve sustained human-to-human transmission was low risk (less than 4). The average summary risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low risk range (less than 4). For a full report, click here[186 KB, 4 pages](https://www.cdc.gov/flu/pandemic-resources/pdf/cdc-irat-virus-canine-h3n2.pdf).

H5N1 clade 1: [A/Vietnam/1203/2004]

The first human cases of highly pathogenic avian influenza (HPAI) H5N1 virus were reported from Hong Kong in 1997. Since 2003, highly pathogenic H5N1 avian influenza viruses have caused over 850 laboratory-confirmed human cases; mortality among these cases was high. A risk assessment of this H5N1 clade 1 virus was conducted in 2011 soon after the IRAT was first developed and when 12 hemagglutinin (HA) clades were officially recognized.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate risk category (less than 6). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the high-moderate risk category (less than 7).

H5N1: [A/American green winged teal/Washington/1957050/2014]

In December 2014, an H5N1 highly pathogenic avian influenza virus was first isolated from an American green-winged teal in the state of Washington. This virus is a recombinant virus containing four genes of Eurasian lineage (PB2, HA, NP and M) and four genes of North American lineage (PB1, PA, NA and NS).In February 2015, the Canadian government reported isolating this virus from a backyard flock in the Fraser Valley. When this risk assessment was conducted in 2015, these were the only reported isolations of this virus. There have been no reports of human cases.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the low risk category (less than 4). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low-moderate risk category (less than 5).

H5N2: [A/Northern pintail/Washington/40964/2014]

In December 2014, an H5N2 highly pathogenic avian influenza virus was first reported by the Canadian government from commercial poultry in the Fraser Valley.Subsequently this virus was isolated from wild birds, captive wild birds, backyard flocks and commercial flocks in the United States.This virus is a recombinant virus composed of five Eurasian lineage (PB2, PA, HA, M and NS) genes and three North American lineage (PB1, NP and NA) genes. There have been no reports of human cases.

Summary: The average summary risk score for the virus to achieve sustained human-to-human transmission was low risk (less than 4).The average summary risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the low-moderate risk range (less than 5).

H5N6: [A/Yunnan/14564/2015 (H5N6-like)]

Between January 2014 and March 2016, there have been 10 human cases of H5N6 highly pathogenic avian influenza reported. Nine reportedly experienced severe disease and six died. Avian outbreaks of this virus were first reported from China in 2013. Subsequently avian outbreaks have been reported in at least three countries (China, Vietnam and Lao PDR) through 2015.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate range (less than 6).The average summary risk score for the virus to significantly impact on public health if it were to achieve sustained human-to-human transmission fell in the moderate range (less than 7).

H5N8: [A/gyrfalcon/Washington/41088/2014]

In December 2014, an H5N8 highly pathogenic avian influenza virus was first isolated from a sample collected in the United States from a captive gyrfalcon.Subsequently this virus was isolated from wild birds, captive wild birds, backyard flocks and commercial flocks in the United States.This virus (clade 2.3.4.4) is similar to Eurasian lineage H5N8 viruses that have been isolated in South Korea, China, Japan, the Netherlands, the United Kingdom and Germany in late 2014-early 2015.There have been no reports of human cases.

Summary: The average risk score for the virus to achieve sustained human-to-human transmission was in the low-moderate range< (less than 5). The average summary risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission fell in the low-moderate range (less than 5).

H7N7: [A/Netherlands/219/03]

In 2003 the Netherlands reported highly pathogenic avian influenza (HPAI) in approximately 255 commercial flocks.Coinciding with human activities around these infected flocks, 89 human cases of H7N7 were identified.Cases primarily reported conjunctivitis, although a few also reported mild influenza-like illness.There was one death.

Summary: The summary average risk score for this virus to achieve sustained human-to-human transmission was in the low-moderate risk range (less than 5). The summary average risk score for this virus to significantly impact the public’s health if it were to achieve sustained human-to-human transmission fell in the moderate risk range (less than 7).

H7N8: [A/turkey/Indiana/1573-2/2016]

In January 2016, a highly pathogenic avian influenza (HPAI) virus of North American lineage was identified in a turkey flock in Indiana. Putative low pathogenic avian influenza (LPAI) viruses similar to A/turkey/Indiana/1573-2/2016 were subsequently isolated from 9 other turkey flocks in the area. There were no reports of human cases associated with this virus at the time of the IRAT scoring.

Summary: A risk assessment of this LPAI virus was conducted in July 2017. The overall IRAT risk assessment score for this virus falls into the low risk category (< 4). The summary average risk score for the virus to achieve sustained human-to-human transmission is in the low risk category (3.4). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was also in the low risk category (3.9).

H7N9: [A/Hong Kong/125/2017]

Low pathogenic avian influenza (LPAI) H7N9 viruses were first reported from China in March 2013. These viruses were first scored using the IRAT in April 2013, and then annually in 2014, 2015, and 2016 with no change in overall risk scores. Between October 2016 and May 2017 evidence of two divergent lineages of these viruses was detected – the Pearl River Delta lineage and the Yangtze River Delta lineage. The IRAT was used to assess LPAI H7N9 [A/Hong Kong/125/2017], a representative of the Yangtze River Delta viruses.

Summary: A risk assessment of H7N9 [A/Hong Kong/125/2017] was conducted in May 2017. The overall IRAT risk assessment score for this virus falls into the moderate-high risk category and is similar to the scores for the previous H7N9 viruses. The summary average risk score for the virus to achieve sustained human-to-human transmission is in the moderate risk category (less than 7). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the moderate-high risk category (less than 8).

H7N9: Avian H7N9 [A/Shanghai/02/2013]

On 31 March 2013, the China Health and Family Planning Commission notified the World Health Organization (WHO) of three cases of human infection with influenza H7N9. As of August 2016, the WHO has received reports of 821 cases, 305 have died. This low pathogenic avian influenza virus was rescored most recently in April 2016 with no substantive change in risk scores since May 2013.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate risk category (less than 7). The average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission fell in the high-moderate risk range (less than 8).

H7N9: Low Pathogenic North American avian [A/chicken/Tennessee/17-007431-3/2017]

Surveillance conducted in March 2017 during the investigation of a highly pathogenic avian influenza (HPAI) A(H7N9) virus in commercial poultry in Tennessee revealed the contemporaneous presence of North American lineage low pathogenic avian influenza (LPAI) A(H7N9) virus in commercial and backyard poultry flocks in Tennessee and three other states. The outbreak in poultry appeared limited with no further detections in subsequent surveillance. There were no reports of human cases associated with this virus.

Summary:  A risk assessment this North American lineage LPAI A(H7N9) virus was conducted in October 2017. The overall IRAT risk assessment score for this virus falls into the low risk category (< 4). The summary average risk score for the virus to achieve sustained human-to-human transmission was in the low risk category (score 3.1).  The average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was between the low to low-moderate range (score 3.5). For a full report, click here[228 KB, 4 pages](https://www.cdc.gov/flu/pandemic-resources/pdf/cdc-irat-virus-lpai.pdf).

H7N9: High Pathogenic North American avian [A/chicken/Tennessee/17-007147-2/2017]

In March 2017, the U.S. Department of Agriculture (USDA) reported the detection of a highly pathogenic avian influenza (HPAI) A(H7N9) virus in 2 commercial poultry flocks in Tennessee. Full genome sequence analysis indicated that all eight gene segments of the virus were of North American wild bird lineage and genetically distinct from the lineage of influenza A(H7N9) viruses infecting poultry and humans in China since 2013. The outbreak investigation revealed that a related North American low pathogenic avian influenza A(H7N9) was circulating in poultry prior to the detection of the HPAI A(H7N9). There were no reports of human cases associated with this virus.

Summary:  A risk assessment this North American lineage HPAI A(H7N9) virus was conducted in October 2017. The overall IRAT risk assessment score for this virus falls into the low risk category (< 4). The summary average risk score for the virus to achieve sustained human-to-human transmission is in the low risk category (2.8). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was also in the low risk category (3.5). For a full report, click here[225 KB, 4 pages](https://www.cdc.gov/flu/pandemic-resources/pdf/cdc-irat-virus-hpai.pdf).

H9N2: Avian H9N2 G1 lineage [A/Bangladesh/0994/2011]

Human infections with influenza AH9N2 virus have been reported sporadically, cases reportedly exhibited mild influenza-like illness. Historically these low pathogenic avian influenza viruses have been isolated from wild and domestic birds. In response to these reports, a risk assessment of this H9N2 influenza virus was conducted in 2014.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate risk category (less than 6). The summary average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission also fell in the moderate risk range (less than 6).

H10N8: Avian H10N8 [A/Jiangxi-Donghu/346/2013]

Two human infections with influenza A(H10N8) virus were reported by the China Health and Family Planning Commission in 2013 and 2014 (one each year). Both cases were hospitalized and one died. Historically low pathogenic avian influenza H10 and N8 viruses have been recovered from birds. A risk assessment of the H10N8 influenza was conducted in 2014.

Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was low-moderate (less than 5). The average risk score for the virus to significantly impact public health if it were to achieve sustained human-to-human transmission was in the moderate risk range (less than 7).

CIDRAP

• “The more I learn about flu, the less I know,” said Michael Osterholm PhD, MPH, director of the University of Minnesota’s Center for Infectious Disease Research and Policy
• More people will die from the non-pandemic aspects of such a global health crisis.
• The US economy is so inextricably linked to other countries, especially China’s, that a pandemic would paralyze supply chains for both consumer and medical goods.
• A pandemic would bring “unprecedented employee absenteeism,” Osterholm said.
• Consider that 30 of the most common generic medicines currently used in the United States are wholly or partially manufactured in China. “Look at what happened with saline bags in Puerto Rico,” said Osterholm.
• Arnold Monto, MD, from the University of Michigan:  Modern tools, including the flu vaccine, would mean it’s unlikely the 1918 pandemic could ever be repeated.
• Luciana Borio, MD, of the White House National Security Council, confirmed that China is not currently sharing flu vaccine strain information nor any progress made on its development of a universal flu vaccine.
• Trust for America’s Health (TFAH’s) annual readiness report, “Ready or Not?” :  TFAH President and CEO John Auerbach, MBA, said no states were completely prepared for a pandemic (based on 11 criteria, and ranked from 1 to 10). Only five states had a preparedness ranking of 8 or 9, and half sat at a 5 or lower. The report was published in December.
• Dwindling public health department budgets are a problem
• Nancy Messonnier, MD, head of CDC’s National Center for Immunization and Respiratory Diseases, said that despite gaps in preparedness, the CDC is better equipped to handle a flu pandemic now than it was in 2009, when a novel H1N1 flu strain first emerged. Technologies, including mobile apps that help consumers find flu shots, and antivirals are putting the power to prevent and fight flu into patients’ hands.

Homeland Security Today

• James Lawler is “…a retired Navy commander whose experience includes serving as director for medical preparedness policy on the National Security Council and director for biodefense policy on the White House’s Homeland Security Council…”
• “….Kenneth Luongo, president and founder of the Partnership for Global Security, echoed that the U.S. “remains woefully underprepared” for a biological attack or a “new intensity level” of pathogens…..”
• “….Former USAID Director Andrew Natsios, director of the Scowcroft Institute of International Affairs, told the panel that the country is “a lot more fragile than we realize” when it comes to emergency response….”

FAO

March 2018, Rome – A United States-FAO partnership working to strengthen the capacity of developing countries to manage outbreaks of diseases in farm animals has in just 12 months succeeded in training over 4,700 veterinary health professionals in 25 countries in Africa, Asia and the Middle East.

The FAO-provided technical trainings covered a gamut of key competencies, including disease surveillance and forecasting, laboratory operations, biosafety and biosecurity, prevention and control methods and outbreak response strategies.

All told, 3,266 vets in Asia, 619 in West Africa, 459 in East Africa, and 363 in the Middle East benefitted. They are on the front line of the effort to stop new diseases at their source. (Full list below)

“Over the course of this relationship we’ve learned that there are many mutually beneficial areas of interest between the food and agricultural community and the human health community,” said Dennis Carroll, Director of USAID’s Global Health Security and Development Unit.

“A partnership with FAO not only enables us to protect human populations from future viral threats, but also to protect animal populations from viruses that could decimate food supplies. It’s not just a global health, infectious disease issue, but also a food security, food safety, and economic growth issue,” Carroll added.

“Some 75 percent of new infectious diseases that have emerged in recent decades originated in animals before jumping to us Homo sapiens, a terrestrial mammal. This is why improving adequately discovering and tackling animal disease threats at source represents a strategic high-ground in pre-empting future pandemics,” said Juan Lubroth, FAO Chief Veterinary Officer

“A proactive approach is absolutely critical, and for that, the world needs well-trained, up-to-speed professionals — biologists, ecologists, microbiologists, modellers, physicians and veterinarians — which is why the United States’ consistent support for building up that kind of capacity has been invaluable,” Lubroth said.

Viral risks

Population growth, agricultural expansion and environmental encroachment, and the rise of inter-continental food supply chains in recent decades have dramatically altered how diseases emerge, jump species boundaries, and spread, FAO studies have shown.

A new study just published by USAID’s Dennis Carroll and experts from several institutions including FAO suggests that just  0.01 percent of the viruses behind zoonotic disease outbreaks are known to science.  The authors have proposed an international partnership, The Global Virome Project, aimed at characterizing the most risky of these. Doing so would allow more proactive responses to disease threats, with benefits not only for public health but also for the livelihoods of poor, livestock-depending farming communities.

Partnering for global health security

The close FAO-USAID partnership on animal health goes back over a decade.

Experts from the two organizations are meeting in Rome this week to review progress achieved in the past year and how to respond to threats like species-jumping zoonotic illnesses and the growing trends of antimicrobial resistance and options for intervention measures in food production and protection of public health.

In addition to trainings, via the USAID- Emerging Pandemic Threats (EPT) programme, FAO conducts research and advises on policy in order to help countries increase their resilience to disease emergence and protect animal and human health.

And to enable rapid responses by governments to disease events FAO has leveraged USAID support to work with the United Nations Humanitarian Response Depots to establish a series of emergency equipment and gear stockpiles in 15 countries that facilitate rapid and adequate responses to outbreaks.

FAO is also key player and advisor to the Global Health Security Agenda (GHSA), a growing partnership of over 60 countries, NGOs and international organizations working to improve early detection of and responses to infectious disease threats. USAID support under the GHSA umbrella is helping FAO engage with 17 countries in Africa and Asia to strengthen capabilities to detect and respond to zoonotic diseases.

Thanks to USAID support for the EPT and GSHA, FAO is actively tackling disease issues and building national capacities in over 30 countries

Economic impacts as well as health consequences

Beyond the risks posed to human health, animal diseases can cost billions of dollars and hamstringing economic growth.

The most damaging outbreaks of high impact disease in recent decades all had an animal source, including H5N1 highly pathogenic avian influenza, H1N1 pandemic influenza, Ebola, severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS).

For example, the H5N1 outbreak of the mid-2000s caused an estimated $30 billion in economic losses, globally; a few years later, H1N1 racked up as much as $55 billion in damages.

Not to mention that for millions of the world’s poorest people, animals are their primary capital assets — “equity on four legs”. Losing them can push these families out of self-reliance and into destitution.

Note to editors.  The countries where the trainings took place were: Bangladesh, Burkina Faso, Cambodia, Cameroon, China, Democratic Republic of the Congo, Egypt, Ghana, Guinea, Indonesia, Jordan, Kenya, Laos People’s Democratic Republic , Liberia, Mali, Myanmar, Nepal, Senegal, Sierra Leone, United Republic of Tanzania, Uganda and Viet Nam.

EMS1

Flu season and pandemic planning: Ethical epidemic response

Triage and ethical considerations in prioritizing care for healthcare professionals and the public in an influenza pandemic

Feb 28, 2018

WHO

List of Blueprint priority diseases

2018 annual review of the Blueprint list of priority diseases

For the purposes of the R&D Blueprint, WHO has developed a special tool for determining which diseases and pathogens to prioritize for research and development in public health emergency contexts. This tool seeks to identify those diseases that pose a public health risk because of their epidemic potential and for which there are no, or insufficient, countermeasures. The diseases identified through this process are the focus of the work of R& D Blueprint. This is not an exhaustive list, nor does it indicate the most likely causes of the next epidemic.

The first list of prioritized diseases was released in December 2015.

Using a published prioritization methodology, the list was first reviewed in January 2017.

The second annual review occurred 6-7 February, 2018. Experts consider that given their potential to cause a public health emergency and the absence of efficacious drugs and/or vaccines, there is an urgent need for accelerated research and development for*:

• Crimean-Congo haemorrhagic fever (CCHF)
• Ebola virus disease and Marburg virus disease
• Lassa fever
• Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS)
• Nipah and henipaviral diseases
• Rift Valley fever (RVF)
• Zika
• Disease X

Disease X represents the knowledge that a serious international epidemic could be caused by a pathogen currently unknown to cause human disease, and so the R&D Blueprint explicitly seeks to enable cross-cutting R&D preparedness that is also relevant for an unknown “Disease X” as far as possible.

A number of additional diseases were discussed and considered for inclusion in the priority list, including: Arenaviral hemorrhagic fevers other than Lassa Fever; Chikungunya; highly pathogenic coronaviral diseases other than MERS and SARS; emergent non-polio enteroviruses (including EV71, D68); and Severe Fever with Thrombocytopenia Syndrome (SFTS).

These diseases pose major public health risks and further research and development is needed, including surveillance and diagnostics. They should be watched carefully and considered again at the next annual review. Efforts in the interim to understand and mitigate them are encouraged.

Although not included on the list of diseases to be considered at the meeting, monkeypox and leptospirosis were discussed and experts stressed the risks they pose to public health. There was agreement on the need for: rapid evaluation of available potential countermeasures; the establishment of more comprehensive surveillance and diagnostics; and accelerated research and development and public health action.

Several diseases were determined to be outside of the current scope of the Blueprint: dengue, yellow fever, HIV/AIDs, tuberculosis, malaria, influenza causing severe human disease, smallpox, cholera, leishmaniasis, West Nile Virus and plague. These diseases continue to pose major public health problems and further research and development is needed through existing major disease control initiatives, extensive R&D pipelines, existing funding streams, or established regulatory pathways for improved interventions. In particular, experts recognized the need for improved diagnostics and vaccines for pneumonic plague and additional support for more effective therapeutics against leishmaniasis.

The experts also noted that:

• For many of the diseases discussed, as well as many other diseases with the potential to cause a public health emergency, there is a need for better diagnostics.
• Existing drugs and vaccines need further improvement for several of the diseases considered but not included in the priority list.
• Any type of pathogen could be prioritised under the Blueprint, not only viruses.
• Necessary research includes basic/fundamental and characterization research as well as epidemiological, entomological or multidisciplinary studies, or further elucidation of transmission routes, as well as social science research.
• There is a need to assess the value, where possible, of developing countermeasures for multiple diseases or for families of pathogens.

The impact of environmental issues on diseases with the potential to cause public health emergencies was discussed. This may need to be considered as part of future reviews.

The importance of the diseases discussed was considered for special populations, such as refugees, internally displaced populations, and victims of disasters.

The value of a One Health approach was stressed, including a parallel prioritization processes for animal health. Such an effort would support research and development to prevent and control animal diseases minimising spill-over and enhancing food security. The possible utility of animal vaccines for preventing public health emergencies was also noted.

Also there are concerted efforts to address anti-microbial resistance through specific international initiatives. The possibility was not excluded that, in the future, a resistant pathogen might emerge and appropriately be prioritized.

*The order of diseases on this list does not denote any ranking of priority.