Technical Report: Highly Pathogenic Avian Influenza A(H5N1) Viruses

Executive summary

A small number of sporadic human cases of A(H5N1) have been identified since 2022, despite the panzootic of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in wild birds and poultry. Nearly all reported human cases since 2022 were associated with poultry exposures, and no cases of mammal-to-human or human-to-human transmission of HPAI A(H5N1) virus have been identified. In a few cases, the source of exposure to HPAI A(H5N1) virus was unknown. To date, HPAI A(H5N1) viruses currently circulating in birds and poultry, with spillover to mammals, and those that have caused human infections do not have the ability to easily bind to receptors that predominate in the human upper respiratory tract. Therefore, the current risk to the public from HPAI A(H5N1) viruses remains low. However, because of the potential for influenza viruses to rapidly evolve and the wide global prevalence of HPAI A(H5N1) viruses in wild birds and poultry outbreaks, continued sporadic human infections are anticipated. Continued comprehensive surveillance of these viruses in wild birds, poultry, mammals, and people worldwide, and frequent reassessments are critical to determine the public health risk, along with ongoing preparedness efforts.

HPAI A(H5N1) viruses in wild birds and poultry

Since 2005, HPAI A(H5N1) viruses have undergone extensive genetic diversification including the formation of hundreds of genotypes following reassortment with other avian influenza A viruses. Clade 2.3.4.4b HPAI A(H5N1) viruses emerged in 2020 and were introduced into North America in late 2021 [1,2] and have spread to Central and South America, resulting in wild bird infections (in terrestrial, seabird, shorebird, and migratory species) and poultry outbreaks in many countries [3-8].

Globally, this 2.3.4.4b clade of HPAI A(H5N1) viruses has become widespread causing record numbers of bird outbreaks in wild, backyard, village, and farm birds. Over 17,000 animal outbreaks of HPAI A(H5N1) viruses were reported by 80 member countries to the World Organisation for Animal Health since January 2022.

In the United States, USDA APHIS monitors for avian influenza viruses in wild, commercial, and backyard birds. From January 2022 through September 2023, APHIS reported HPAI A(H5)/A(H5N1) virus detections in more than 7,200 wild birds in 50 states or territories and 840 commercial and backyard flocks in 47 states or territories.

HPAI A(H5N1) virus infections among mammals

Sporadic HPAI A(H5N1) virus infections of mammals have been reported since 2003-2004 during HPAI A(H5N1) virus outbreaks in poultry or wild birds [9-11]. HPAI A(H5) viruses are known to occasionally infect mammals that eat (presumably infected) birds or poultry and mammals that are exposed to environments with a high concentration of virus.

In the United States, from May 2022 through September 22, 2023, USDA APHIS reported HPAI A(H5N1) virus detections in 200 mammals comprising 20 different species in 26 states or territories. Globally, sporadic HPAI A(H5N1) virus infections have been reported in farmed mink in Spain and farmed foxes and other mammals in Finland, harbor and gray seals in the United States, sea lions in Peru, Argentina, and Chile, and in many other wild mammal species in several countries, including domesticated pets such as cats in Poland, France, South Korea, and the United States, and dogs in Italy.  The reports of HPAI A(H5N1) virus infections in mammals are not surprising given the widespread outbreaks of HPAI A(H5N1) virus infections in wild birds worldwide.

Genetic data have revealed that when some mammals are infected with HPAI A(H5N1) virus, the virus may undergo intra-host evolution resulting in genetic changes that allow the virus to replicate more efficiently in the lower respiratory tract [12-14].

Although these genetic changes may impact mammalian disease outcome, they have not been associated with enhanced transmissibility of the virus to humans. HPAI A(H5N1) viruses do not currently have the ability to easily infect and bind to α2,6-linked sialic acid receptors that are predominant in the human upper respiratory tract [2], which would be needed to increase the risk of transmission to people [15-16].

Human cases of A(H5N1)

While HPAI A(H5N1) viruses are currently circulating widely in wild birds and poultry in many geographic regions, relatively few human cases of A(H5N1) have been reported in recent years [Figure 1]. From January 2022 through September 2023, fifteen sporadic human cases of A(H5N1) were reported from eight countries, including six cases of severe disease and two deaths, two cases of mild illness, and seven asymptomatic cases [Table 1].

One human case of A(H5N1) was reported in the United States in April 2022. The individual reported fatigue without other symptoms and a low level of A(H5N1) viral RNA was detected in a single upper respiratory tract specimen. It is possible that detection of A(H5N1) viral RNA resulted from deposition of non-infectious viral material in the upper respiratory tract of the individual and did not represent true infection, similar to the environmental contamination that was attributed to the two asymptomatic cases in poultry workers reported in Spain [17]. Transient environmental deposition may also explain the detection of A(H5N1) viral RNA in cases of A(H5N1) reported in asymptomatic poultry workers in the U.K. that were investigated as part of a surveillance study [18-20].

Nearly all reported cases reported since January 2022 had recent exposure to sick or dead poultry, and no cases of human-to-human HPAI A(H5N1) virus transmission were identified. Six cases (three children, three adults) had severe disease, and two died. Twelve cases were associated with clade 2.3.4.4b HPAI A(H5N1) viruses, and two cases were associated with clade 2.3.2.1c HPAI A(H5N1) viruses; none of the HPAI A(H5N1) virus genetic sequences contained any known markers of reduced susceptibility to currently recommended FDA-approved influenza antiviral medications.

Table 1. Global reported A(H5N1) human cases, January 2022 through September 2023

Since 1997, a total of 898 sporadic human A(H5N1) cases have been reported from 22 countries, caused by different HPAI A(H5N1) virus clades [21], with a cumulative case fatality proportion of greater than 50%. Human A(H5N1) cases peaked in 2006 (115 cases, 9 countries) and 2015 (145 cases, 4 countries) primarily due to a large epidemic in Egypt with 136 cases [Figure 1].

Nearly all reported human A(H5N1) cases had poultry exposures, such as to sick or dead poultry or visiting live poultry markets. Rare, limited, and non-sustained instances of human-to-human HPAI A(H5N1) virus transmission likely occurred in a small number of family members following prolonged, close unprotected exposure with a symptomatic case-patient during 2004-2007 in multiple countries [22-25].

Active monitoring of persons exposed to HPAI A(H5N1) virus in the United States

Although few human cases have occurred recently, given widespread infection among poultry and wild birds, people who have job-related or recreational exposures to infected birds or sick or dead mammals might be at higher risk of infection.

CDC, in collaboration with state, territorial, and local public health partners, actively monitors people exposed to infected birds and poultry for 10 days after their last exposure, from February 2022 through September 2023:

• Total monitored: more than 6,500 people in 52 jurisdictions.
• Total illnesses reported among monitored persons: more than 165 people.
• Number positive for influenza A(H5N1) virus: 1 person.

Of the more than 165 people showing symptoms who were tested for novel influenza A and seasonal flu viruses along with other respiratory viruses, HPAI A(H5N1) virus genetic material was detected in a respiratory specimen from one person in Colorado who experienced fatigue without any other symptoms while participating in poultry culling activities. [See above section on “Human cases of A(H5N1).”]

U.S. influenza surveillance for human infections with novel influenza A viruses, including HPAI A(H5N1) virus

Human infection with a novel influenza A virus, including HPAI A(H5N1) virus, is a nationally notifiable condition (case definition: Novel Influenza A Virus Infections 2014 Case Definition | CDC)

Influenza testing is widely available in clinical laboratories and healthcare facilities. Assays in these settings would detect A(H5N1) virus infections as influenza A positive and a subset of assays would be able to also determine that they are not influenza A virus subtypes H1 or H3 that commonly circulate among humans. Specimens from persons possibly exposed to H5N1 virus or that test positive for an influenza A virus but negative for A(H1) and A(H3) subtypes should be forwarded to the appropriate state or local public health laboratory for further testing. Very few specimens have been submitted to CDC for H5 testing since January 2022.

• Seasonal influenza virus detection assays that can also detect novel influenza A viruses are used in 128 public health laboratories in all 50 U.S states.
• Specific diagnostic assays to detect current A(H5) viruses are available at 99 public health laboratories in all 50 states.

Per long-standing protocols, upon detection of a virus that tests positive for influenza A but is negative for human H1 or H3 genes the public health laboratory will rapidly contact CDC and ship the specimen to CDC.  Samples that are influenza A positive but negative for human H1 or H3 genes may also be tested for H5 by state public health laboratories and are rapidly sent to CDC for a diagnostic result.  An investigation of the case will be initiated, and a case report form submitted to CDC through the novel influenza A reporting module.

CDC and U.S. Government Preparedness Activities

Limitations of the Report

This report is subject to the following limitations.  First, the number of human infections with currently circulating clade 2.3.4.4b HPAI A(H5N1) viruses is small.  Conclusions regarding virus characterization analyses, transmissibility from animals to people, transmissibility among people, and clinical spectrum of illness in people should be interpreted in light of this small number.  Second, detailed exposure information was not available for all persons actively monitored for illness after exposure to HPAI A(H5N1) virus-infected birds and poultry in the United States. Thus, we were not able to assess the impact of exposure variables such as duration of exposure, nature of exposure (e.g., direct vs. indirect contact), and use of personal protective equipment on infection risk.

Conclusions

• To date, CDC analyses of clade 2.3.4.4b HPAI A(H5N1) viruses detected in wild birds, poultry, and sporadically in mammals since late 2021 indicate that these viruses all have a high degree of genetic identity with each other and no significant mammalian adaptive substitutions, insertions, or deletions have been identified, particularly in the HA gene, which is important for zoonotic and subsequent human-to-human transmission.
• Considering the high prevalence of HPAI A(H5N1) viruses detected in wild birds and poultry worldwide, spill over into mammals (particularly carnivores that may feed on infected avian species) and additional sporadic zoonotic infections among people with exposures to sick or dead poultry or wild birds are anticipated.
• HA clade 2.3.4.4b A(H5N1) viruses currently circulating in wild birds and poultry worldwide lack the ability to preferentially bind to the types of sialic acid receptors that are predominant in the upper respiratory tract of humans and therefore do not currently have the ability to easily infect or transmit among people.
• Despite extensive worldwide spread of influenza A(H5N1) viruses in wild birds and poultry in recent years, only a small number of sporadic human infections with 2.3.4.4b or clade 2.3.2.1c H5N1 viruses have been reported since 2022; all cases had recent exposure to poultry and no cases of human-to-human influenza A(H5N1) virus transmission were identified.

While CDC’s assessment is that the overall threat of HA clade 2.3.4.4b A(H5N1) viruses to public health is currently low, the widespread geographic prevalence of infected birds and poultry raises the potential for exposures of humans and other mammals that could result in viral evolution or reassortment events which might change the current risk assessment. Vigilance and ongoing surveillance of HPAI A(H5N1) viruses circulating in wild birds, poultry, and in sporadic infections of mammals and people worldwide is critical to monitor the public health risk and to detect genetic changes (particularly in the HA gene) that would change CDC’s risk assessment.

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Resources

Case Definitions for Investigations of Human Infection with Avian Influenza A Viruses in the United States

Interim Guidance on Influenza Antiviral Chemoprophylaxis of Persons Exposed to Birds with Avian Influenza A Viruses Associated with Severe Human Disease or with the Potential to Cause Severe Human Disease

Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses and Use of Antiviral Medications for Chemoprophylaxis

Brief Summary for Clinicians: Evaluating and Managing Patients Exposed to Birds Infected with Avian Influenza A Viruses of Public Health Concern

Interim Guidance on Testing and Specimen Collection for Patients with Suspected Infection with Novel Influenza A Viruses with the Potential to Cause Severe Disease in Humans

Interim Guidance for Infection Control Within Healthcare Settings When Caring for Confirmed Cases, Probable Cases, and Cases Under Investigation for Infection with Novel Influenza A Viruses Associated with Severe Disease | Avian Influenza (Flu) (cdc.gov)

Interim Guidance on the Use of Antiviral Medications for Treatment of Human Infections with Novel Influenza A Viruses Associated with Severe Human Disease

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