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

Executive summary

A small number of sporadic human cases of highly pathogenic avian influenza (HPAI) A(H5N1) have been identified worldwide since 2022, amidst a panzootic of these viruses in wild birds and poultry. Nearly all human cases reported globally since 2022 were associated with poultry exposures, and no cases of human-to-human transmission of HPAI A(H5N1) virus have been identified. One human case of HPAI A(H5N1) virus infection in a farm worker reported in April 2024 in the United States and was attributed to exposure to presumptively infected dairy cattle. One previous human case was reported in the United States in 2022. In a few cases, the source of exposure to HPAI A(H5N1) virus has been unknown. To date, HPAI A(H5N1) viruses currently circulating most commonly in birds and poultry, with spillover to mammals and humans do not have the ability to easily bind to receptors that predominate in the human upper respiratory tract. This is a major reason why 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 and following the identification and spread among dairy cattle in the United States, additional 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 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]. In Fall 2023, the first detections of HPAI A(H5N1) viruses in birds in the Antarctica region were reported [9]. 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.

In the United States, USDA APHIS monitors for avian influenza viruses in wild, commercial, and backyard birds. From January 2022 through April 25, 2024, APHIS reported HPAI A(H5)/A(H5N1) virus detections in more than 9,200 wild birds in 50 states or territories and more than 1,100 commercial and backyard flocks affecting more than 90 million birds in 48 states.

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 [10-12]. 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.

Globally, sporadic HPAI A(H5N1) virus infections and outbreaks in a wide range of mammal species were reported by countries in different regions of the world to the World Organisation for Animal Health since January 2022. HPAI A(H5N1) virus infections of mammals have included a polar bear in the United States, 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, elephant seals in Argentina, baby goats in the United States, and domesticated pets such as cats in Poland, France, South Korea, and the United States, and dogs in Italy. In March and April 2024, the United States reported HPAI A(H5N1) virus infections of dairy cattle at farms in multiple states. Spread from dairy farm-to-dairy farm was reported [292KB, 6 pages], and routes of transmission are under investigation. In the United States, from May 2022 through April 25, 2024, USDA APHIS reported HPAI A(H5N1) virus detections in wild mammals comprising a wide range of different species in 28 states.

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 HPAI A(H5N1) have been reported in recent years [Figure 1]. From January 2022 through April 25, 2024, 26 sporadic human cases of A(H5N1) were reported from eight countries, including 14 cases of severe or critical illness, and seven deaths, four cases of mild illness, and eight asymptomatic cases [Table 1].

One human case of HPAI 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 two asymptomatic cases in poultry workers reported in Spain [13]. 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 [14-16].

One human case of A(H5N1) was reported in the United States in April 2024 in an adult dairy farm worker. The individual worked at a farm with sick cows presumed to be infected with HPAI A(H5N1) virus in an area in which cows at other dairy farms were confirmed with HPAI A(H5N1) virus infection. The worker only experienced conjunctivitis without any other signs or symptoms of illness. HPAI A(H5N1) virus was detected in conjunctival and nasopharyngeal swab specimens, and sequence data confirmed clade 2.3.4.4b, genotype B3.13, and close genetic relatedness to viruses detected in other dairy cattle farms in Texas. Oseltamivir was provided for treatment of the individual and for post-exposure prophylaxis of household contacts. Conjunctivitis resolved without other symptoms and household contacts remained well.

Nearly all human cases of HPAI A(H5N1) 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. Fourteen cases (7 children, 7 adults) had severe or critical illness, and seven (3 children, 4 adults) died. Thirteen cases were associated with clade 2.3.4.4b HPAI A(H5N1) virus in 7 countries, and eleven cases were associated or assumed to be associated with clade 2.3.2.1c HPAI A(H5N1) viruses in Cambodia and Vietnam. None of the HPAI A(H5N1) virus genetic sequences contained any known markers of reduced susceptibility to currently recommended FDA-approved influenza antiviral medications.

Genetic data have revealed that when some mammals, including humans, are infected with HPAI A(H5N1) virus, the virus may undergo intra-host evolution resulting in genetic changes that allow more efficient replication in the lower respiratory tract or extrapulmonary tissues [17-19]. Some HPAI A(H5N1) viruses that have infected humans in 2023 and 2024 have also shown the same or similar genetic changes as those identified in wild and captive mammals. For example, sequencing of viruses from specimens collected from human cases identified in Cambodia during October and November 2023, in Vietnam in 2024 and in the dairy farm worker in Texas revealed the presence of the polymerase basic protein 2 (PB2) 627K marker, which is often associated with mammalian adaptation during infection [20]. The HPAI A(H5N1) virus sequenced from the human case in Chile identified in March 2023 had different genetic changes (PB2 591K and 701N) that are also associated with mammalian adaptation [21].

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 [22,23].

Table 1. Global reported A(H5N1) human cases, January 2022 through April 25, 2024

Since 1997, a total of 909 sporadic human A(H5N1) cases have been reported from 23 countries, caused by different HPAI A(H5N1) virus clades [24,25], 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 [26-29].

Figure 1. Epidemic Curve of Human Cases of A(H5N1) by Illness Onset Date, 1997-2024 by Country (N=909)

Monitoring of persons exposed to HPAI A(H5N1) viruses 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 are at higher risk of infection.

CDC, in collaboration with state, territorial, and local public health partners, has monitored people exposed to infected birds and poultry, cattle, or other animals beginning with their first exposure and for 10 days after their last exposure, from February 2022 through April 25, 2024:

• Total monitored: more than 8,800 people in 52 jurisdictions.
• Total illnesses reported among monitored persons: nearly 200 people.
• Number positive for influenza A(H5N1) virus: 2 people.

Of the nearly 200 people showing symptoms who were tested for novel influenza A and seasonal influenza 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 illness signs or symptoms while participating in poultry culling activities, and in one person in Texas who experienced conjunctivitis without any other illness signs or symptoms while working with sick dairy cattle presumed to be infected with HPAI A(H5N1) virus. [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 health care 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 HPAI A(H5N1) virus or that test positive for 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. CDC should be notified immediately in the event that any clinical specimens from suspected cases test positive for a novel influenza A virus or if the testing results of clinical specimens from suspected cases are inconclusive. Human infection with a novel influenza A virus is a nationally notifiable condition, and currently confirmatory testing is being done only at CDC. 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 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 will be 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 reported human infections with 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 exposed persons or for those being monitored for illness after exposure to HPAI A(H5N1) virus-infected wild birds, poultry, backyard flocks, and other animals, including dairy cattle in the United States. As of the date of this report, understanding of HPAI A(H5N1) virus infections of cattle is very limited. Thus, we are 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 among persons with confirmed HPAI A(H5N1) virus infection or those being monitored after exposures to any animals confirmed or suspected with HPAI A(H5N1) virus infection.

Conclusions

• To date, CDC analyses of clade 2.3.4.4b HPAI A(H5N1) viruses detected in wild birds, poultry, and sporadically in mammals, including in dairy cattle, 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, spillover into mammals (including carnivores that may feed on infected animals) and additional sporadic zoonotic infections are anticipated among people with exposures to infected sick or dead poultry, wild birds, or other infected animals.
• 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; nearly all cases had recent exposure to poultry and no cases of human-to-human influenza A(H5N1) virus transmission have been 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 and infections 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

• How CDC is monitoring influenza data among people to better understand the current avian influenza A (H5N1) situation | Avian Influenza (Flu)
• Highly Pathogenic Avian Influenza A(H5N1) Virus in Animals: Interim Recommendations for Prevention, Monitoring, and Public Health Investigations | Avian Influenza (Flu) (cdc.gov)
• Case Definitions for Investigations of Human Infection with Avian Influenza A Viruses in the United States
• Recommendations for Worker Protection and Use of Personal Protective Equipment (PPE) to Reduce Exposure to Novel Influenza A Viruses Associated with Severe Disease in Humans | Avian Influenza (Flu) (cdc.gov)
• 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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