Tools
Avian Influenza
Introduction
Avian influenza, commonly known as "bird flu," is a zoonotic disease caused by avian influenza A viruses.[1] While these viruses primarily infect birds, they can occasionally transmit to humans, resulting in severe illness and potentially death. This disease has garnered significant global attention due to its potential to cause widespread, lethal outbreaks in poultry and severe infections in humans. Highly pathogenic strains are particularly concerning due to their ability to mutate rapidly and spread efficiently, thereby posing serious threats to public health and economic stability. As a result, healthcare providers must maintain high suspicion when identifying and managing cases to prevent rapid disease progression and severe outcomes.Influenza A viruses, part of the Orthomyxoviridae family,[2][3] are classified into subtypes based on 2 distinct surface glycoproteins—hemagglutinin (H), which has 16 known antigenic variations, and neuraminidase (N), with 9 variations. These subtypes are commonly identified by combinations such as H5N1 or H7N9.[4] The Orthomyxoviridae family also includes influenza B and C viruses, thogotovirus, and isavirus. While influenza B and C viruses can infect certain other species, only influenza A viruses are known to infect birds.[5]
Most human infections occur through contact with infected domestic poultry, either via secretions or contaminated environments. Wild aquatic birds, however, serve as the natural reservoir for these viruses. Human-to-human transmission is rare, but documented cases highlight the pandemic potential of these viruses if they acquire enhanced transmissibility.[6]
Although the exact modes of transmission between birds are not fully understood, the oral-fecal route is widely considered the primary method of transmission.[7] Avian influenza viruses in birds are categorized into 2 categories—highly pathogenic avian influenza (HPAI) viruses and low pathogenicity avian influenza (LPAI).[5] LPAI viruses are more common and typically cause minimal illness in birds, while HPAI strains are associated with severe systemic illness.
In humans, both HPAI and LPAI strains can trigger significant outbreaks, with HPAI often resulting in more severe cases. Notable examples include the H5N1 outbreak in Hong Kong in 1997 and the H7N9 outbreak in China in 2013, both characterized by high case fatality rates.[8] These events underscore the importance of surveillance, early diagnosis, and timely intervention to prevent widespread transmission of the disease. As new highly pathogenic strains of avian influenza continue to emerge across various regions, reflecting the growing genetic diversity of circulating viruses, ongoing research is essential to mitigate potential threats.
Due to the disease's potential severity in humans, healthcare professionals must remain vigilant when assessing patients with relevant exposure history and symptoms. Early recognition, timely laboratory confirmation, and appropriate management are critical for improving outcomes and reducing the risk of further transmission.
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
Avian influenza viruses have a segmented, single-stranded RNA genome, enabling genetic reassortment, antigenic drift, or both, which enhances their ability to evolve and adapt to new hosts.[9][10][11] These viruses naturally circulate in wild aquatic birds, such as ducks, geese, and shorebirds, which often carry the virus asymptomatically and act as reservoirs. These birds facilitate the spread of the virus to domestic poultry through direct contact or via contaminated water and environments.[12]
When domestic poultry, such as chickens and turkeys, become infected, they shed large quantities of the virus through their feces, respiratory secretions, and saliva. These secretions serve as a significant source of zoonotic transmission to humans. Human infection typically occurs through:
- Direct contact with infected birds.[12]
- Indirect exposure to virus-contaminated environments, such as live bird markets or processing facilities.[13]
- Handling raw poultry products under unsafe conditions.[14]
Avian influenza viruses are categorized into 2 groups based on their pathogenicity in birds:
- Highly pathogenic avian influenza virus: HPAI causes severe disease and high mortality in birds and can also lead to severe infections in humans.[12]
- Low pathogenicity avian influenza virus: LPAI generally causes mild illness in birds but has the potential to mutate into HPAI under certain conditions.[15]
Although rare, limited human-to-human transmission has been documented, raising concerns about the virus's potential to adapt for more efficient spread among humans.[6] Such adaptations could significantly increase the risk of a global pandemic, highlighting the importance of ongoing surveillance and research.
Epidemiology
Avian influenza primarily affects individuals in regions with frequent human-poultry contact, such as Southeast Asia, Africa, and the Middle East, where people are commonly exposed to infected birds.[16] Human infections occur across all age groups but vary based on exposure risks and geographic locations.
H5N1 infections are more commonly observed in younger individuals, whereas H7N9 infections are more prevalent in older adults, particularly in China.[17][18] Both strains show a higher prevalence in males, possibly due to occupational exposure in poultry farming, live bird markets, and bird processing facilities. Children, especially in endemic regions, are at an increased risk due to close contact with backyard poultry. Infections are most common among individuals aged 20 to 50, primarily due to occupational exposure in these age groups. Although older individuals are less frequently exposed, they often experience more severe symptoms if infected due to age-related health vulnerabilities.
Although multiple strains of avian influenza viruses have sporadically infected humans, the most well-known strains responsible for outbreaks are H5N1 and H7N9. From 2003 to 2023, the World Health Organization (WHO) documented 878 human cases of HPAI H5N1 infection, resulting in 458 fatalities (52.16%) across 23 countries.[12] H7N9 has caused human infections in China since 2013, with 5 waves of the epidemic occurring between March 2013 and September 2017. Over 1500 human cases have been reported globally, with a case fatality rate of approximately 40%.[19][20] Additionally, in March 2024, a single confirmed case of avian influenza virus infection (H5N1) was reported in the United States involving a dairy worker.[21]
Pathophysiology
The infective and pathogenic capabilities of avian influenza viruses are influenced by their tendency to attach to specific sialic acid receptors on host cells. The hemagglutinin proteins of these viruses preferentially bind to α-2,3–linked sialic acid receptors, primarily found in the gastrointestinal tracts of birds. In humans, the α-2,3–linked sialic acid receptors are predominantly located in the lower respiratory tract, including the terminal bronchi and alveoli, which may account for the severe pneumonia commonly observed in human cases of avian influenza.[22]
In contrast, human influenza viruses typically bind to α-2,6–linked sialic acid receptors, which are abundant in the upper respiratory tract, facilitating easier transmission between humans.[23] Interestingly, α-2,3-linked receptors, favored by avian influenza viruses such as H7N9, are also present in the human eye, potentially explaining the conjunctival symptoms often observed in avian influenza infections.[24]Once avian influenza viruses enter human host cells, their replication dynamics differ from those of human-adapted influenza viruses. Specific subtypes, such as H5N1, have shown prolonged viral replication in humans. For example, during the 1997 H5N1 outbreak, the median time from infection to viral detection was 6.5 days, with some cases showing detectable virus for up to 16 days.[25] The host immune response is crucial in disease severity, with elevated levels of inflammatory markers linked to more severe disease courses. Postmortem analyses have also revealed inflammatory cells in damaged alveoli, suggesting that an excessive immune response contributes to pathogenesis.[26]
Respiratory failure due to primary viral pneumonia is the most common cause of death, often resulting from diffuse alveolar damage and hemorrhage caused by viral replication and immune-mediated injury. Animal studies suggest that avian influenza viruses may also damage neurons in the pre-Bötzinger complex, which is responsible for generating respiratory rhythm. This damage could contribute to ataxic breathing and respiratory collapse in severe cases.[27]
History and Physical
The clinical features of avian influenza infection are typically observed in patients who require hospitalization. Routine testing for avian influenza is generally not performed unless the patient presents with more severe symptoms. Thus, limited data exist on the clinical features or prevalence of milder infections. Most hospitalized patients typically present 2 to 4 days after exposure, although symptoms can develop more than a week after transmission.[25]
Most cases of avian influenza present with symptoms similar to those of seasonal influenza and can rapidly progress to severe disease. The patient’s history includes recent exposure to live or culled poultry, wild birds, or contaminated environments, particularly in high-risk areas such as live bird markets or poultry farms.[28] Occupational exposure in poultry farming, slaughterhouses, or veterinary care increases the risk, as does travel to regions with ongoing outbreaks, such as Southeast Asia or Africa.[29] Early symptoms typically include fever, cough, sore throat, and myalgia, while progressive symptoms such as dyspnea, chest pain, and fatigue suggest lower respiratory tract involvement.
Certain avian influenza strains, such as H5N1, H5N6, and H7N9, are more frequently associated with severe illness.[28] Some subtypes, such as H7N9, are associated with conjunctivitis, while gastrointestinal symptoms, such as diarrhea and abdominal pain, are more commonly seen with H5N1 infections.[28][30][31] A characteristic feature of advanced disease is rapid symptom progression over a few days, particularly severe dyspnea.
Physical examination findings in avian influenza reflect both systemic and respiratory involvement. Patients often appear acutely ill, febrile, and sometimes dehydrated. Common vital sign abnormalities include fever, tachycardia, and tachypnea, with hypoxia and hypotension occurring in severe cases. Respiratory findings such as crackles or rales suggest diffuse alveolar damage or pneumonia, and in severe cases, reduced air entry may be observed due to lung consolidation or pleural effusion. Ocular findings such as conjunctival injection are especially characteristic of H7N9 infections. Cyanosis and altered mental status may indicate advanced respiratory failure or multiple organ dysfunction, highlighting the severity of the disease in its later stages.
Evaluation
The diagnosis of avian influenza involves clinical suspicion, laboratory testing, and imaging studies. A detailed history is essential to identify exposure risks, such as contact with live poultry, wild birds, or contaminated environments in endemic regions. Travel to areas with ongoing outbreaks, such as Southeast Asia, along with symptoms such as fever, cough, dyspnea, or conjunctivitis, should raise clinical suspicion.[28] Rapid progression of respiratory symptoms and a history of occupational exposure—particularly in poultry farms or live bird markets—reinforces the need for prompt diagnostic testing.
Laboratory confirmation is crucial, with reverse transcriptase polymerase chain reaction (RT-PCR) as the gold standard for detecting avian influenza virus subtypes, including H5N1 and H7N9. RT-PCR is highly sensitive and can yield results within hours, enabling timely management.[32] In severe cases, samples such as bronchoalveolar lavage or tracheal aspirates may be collected for testing. While viral culture is helpful for virus characterization, it is limited to specialized biosafety level-3 laboratories due to safety concerns. Serologic testing is generally reserved for retrospective diagnosis or research purposes.
Biomarker analyses, including elevated C-reactive protein, procalcitonin, and lymphopenia, may suggest severe disease or secondary bacterial infections.[33] Rapid antigen testing for avian influenza viruses is available but often results in false negatives in confirmed cases.[34] Given the high mortality risk associated with the infection, a negative rapid antigen test should not rule out avian influenza when there is strong clinical suspicion of the virus's presence.[25]
Imaging studies are essential for assessing disease severity. Chest radiographs frequently reveal bilateral infiltrates consistent with viral pneumonia. In more advanced cases, computed tomography (CT) scans often demonstrate diffuse ground-glass opacities or consolidation, hallmark findings of acute respiratory distress syndrome (ARDS).[35]
Treatment / Management
The treatment of avian influenza primarily focuses on supportive care and antiviral medications.[3][25] Management mainly addresses the complications and sequelae of the infection. For instance, patients with volume loss or potential electrolyte imbalances should receive appropriate volume resuscitation and treatments to correct these imbalances. Additionally, patients with persistent fever should be given antipyretic medications.(B3)
Patients with respiratory compromise should receive supplemental oxygen and be closely monitored for signs of deterioration, as they are at high risk of requiring intubation and mechanical ventilation.[3][25] Given that severe disease can lead to multiple organ dysfunction and failure, these signs should be vigilantly monitored and treated aggressively to prevent further decompensation. Early diagnosis and intervention are crucial for improving outcomes, especially in severe cases.(B3)
Antiviral Therapy
Neuraminidase inhibitors: Neuraminidase inhibitors are the primary antiviral medications used to treat avian influenza, and early administration is essential for effectiveness.
- Oseltamivir: This drug of choice should be initiated as early as possible, ideally within 48 hours of symptom onset.[36] In severe cases, higher doses or prolonged treatment courses may be necessary. (B3)
- Zanamivir: This drug can be used for patients who cannot tolerate oral oseltamivir, although it requires inhalation for administration.[37] An intravenous (IV) formulation of zanamivir has completed phase-3 clinical trials and has been approved by the European Medicines Agency (EMA) for treating hospitalized patients with influenza.[38]
- Peramivir: Peramivir is an IV neuraminidase inhibitor, providing an alternative for hospitalized patients or those unable to take oral or inhaled medications.[37]
Endonuclease inhibitors: Baloxavir marboxil, a cap-dependent endonuclease inhibitor, may be considered in select cases where oseltamivir resistance is suspected or confirmed in patients with avian influenza. This drug can also be used as part of combination therapy in severe cases of avian influenza to reduce viral load and improve outcomes. However, its effectiveness against avian influenza is still being studied, and further research is ongoing.[39]
Resistance considerations: Some avian influenza viruses have demonstrated resistance to neuraminidase inhibitors. In these cases, alternative treatments or combination therapy may be necessary to manage the infection effectively.[40]
Supportive Care
Respiratory support: Oxygen therapy is essential for managing hypoxemia, and mechanical ventilation is crucial for patients with respiratory failure. In severe cases of ARDS, extracorporeal membrane oxygenation (ECMO) may be considered a treatment option.[41](B3)
Complications management: Secondary bacterial infections should be closely monitored and treated with appropriate antimicrobials. The management of multiple organ dysfunction requires intensive care support tailored to the individual patient's needs.
Corticosteroids and immunomodulatory therapy: The use of corticosteroids in avian influenza remains controversial and is not routinely recommended due to potential adverse effects, such as prolonged viral shedding and an increased risk of secondary infections.[42] However, corticosteroids may be considered in select cases of refractory ARDS or cytokine storm, where other treatment options have proven insufficient.(A1)
Preventive Measures
Vaccination: Vaccines targeting specific avian influenza strains, such as H5N1, are available for high-risk populations, including poultry workers and healthcare providers in endemic areas.[8]
Infection control: Effective infection control measures, including isolating infected patients, using personal protective equipment (PPE), and ensuring proper hand hygiene, are crucial to preventing nosocomial transmission.
Postexposure prophylaxis: Neuraminidase inhibitors, such as oseltamivir, can be administered to close contacts of confirmed cases to reduce the risk of infection.[43] High-risk groups, such as household and close family contacts, should receive oseltamivir at a dosage of 75 mg daily for 7 to 10 days following the last known exposure. While moderate and low-risk groups are not as strongly advised to receive chemoprophylaxis, moderate-risk individuals should be assessed on a case-by-case basis.[44](B3)
Public health measures: These include surveillance and culling of infected birds within the population to reduce exposure during an outbreak.
Differential Diagnosis
Avian influenza shares clinical features with several respiratory illnesses, necessitating a thorough differential diagnosis to ensure accurate identification and management. Key conditions to consider include:
- Seasonal influenza typically has a shorter incubation period (1-4 days) and manifests with milder symptoms. In contrast, avian flu is more likely to involve severe lower respiratory tract symptoms, such as viral pneumonia or ARDS.
- COVID-19 has a distinguishing loss of taste or smell, which is not associated with avian influenza.
- Bacterial pneumonia is characterized by purulent sputum and lobar consolidation on chest x-rays. Avian influenza, however, often presents with diffuse infiltrates or ground-glass opacities, consistent with viral pneumonia.
- Atypical pneumonia caused by organisms such as Mycoplasma pneumoniae or Chlamydia pneumoniae is generally milder and does not rapidly progress to severe respiratory failure, as is common in avian influenza.
- Middle East respiratory syndrome (MERS) is associated with travel or residence in the Middle East and exposure to camels.
- Severe acute respiratory syndrome (SARS) is primarily associated with person-to-person transmission, while avian influenza typically requires direct exposure to infected birds.
- Hantavirus pulmonary syndrome (HPS) is primarily linked to exposure to rodent droppings and urine.
- Other viral respiratory infections, such as respiratory syncytial virus (RSV), adenovirus, and parainfluenza virus, are more common in children and immunocompromised individuals. These infections typically have distinct epidemiological patterns and exposure histories compared to avian influenza.
- Tuberculosis typically follows a chronic course and is often accompanied by symptoms such as night sweats and weight loss. Imaging findings such as cavitary lesions, common in tuberculosis, are not characteristic of avian influenza.
- Secondary bacterial infections can complicate avian influenza and are identified by elevated inflammatory markers and purulent sputum. Diagnosis is confirmed through blood cultures or sputum Gram stain.
Pertinent Studies and Ongoing Trials
Recent advancements in avian influenza vaccine research have emphasized mRNA-based platforms, demonstrating significant promise in preclinical and early-phase studies.[45][46] Early-phase human trials are evaluating the efficacy and safety of various mRNA vaccines. Currently, mRNA influenza vaccines developed by Moderna and Pfizer have progressed to phase-3 clinical trials, while those from Sanofi-Translate Bio and GlaxoSmithKline (GSK)-CureVac are undergoing phase-1 clinical trials.[47]
Antiviral treatments are crucial in managing avian influenza. Neuraminidase inhibitors, such as oseltamivir, are commonly used; however, rising concerns about resistance have driven the development of alternative therapies.[48] Baloxavir marboxil, an inhibitor of cap-dependent endonuclease, has demonstrated efficacy in reducing viral replication of H5N1 and H7N9.[49] Additionally, experimental antivirals such as favipiravir, which exhibit broad-spectrum activity against avian influenza strains, are currently under evaluation.[50]
Prognosis
In patients with avian influenza requiring hospitalization, the overall reported mortality rate exceeds 50% for all strains of avian influenza virus infection combined. More detailed data suggest that H7N9 infection has a lower mortality rate of 40%, compared to 52% for H5N1 infection.[12][19][20] Notably, not all individuals affected by the virus may seek hospital care, and many cases with milder symptoms likely go unreported, potentially lowering the overall mortality rate. Nevertheless, current evidence underscores the severity of avian influenza infections in humans, particularly in hospitalized cases with poor prognoses.
Complications
Avian influenza infections can lead to severe complications, including severe respiratory issues and the involvement of multiple organ systems.[28] Respiratory complications are particularly prominent, with major concerns including primary viral pneumonia, ARDS, and secondary bacterial pneumonia. ARDS, resulting from diffuse alveolar damage and hypoxemia, is a leading cause of mortality in most cases.
Other respiratory complications may include pleural effusion, which exacerbates breathing difficulties. Without timely intervention, many of these conditions necessitate advanced respiratory support, including mechanical ventilation and ECMO. Pregnant patients are especially vulnerable to severe respiratory compromise due to physiological changes, such as reduced lung capacity and increased oxygen demand, further worsening outcomes.[51]Avian influenza can also cause complications in multiple organ systems due to its systemic nature. Severe cases frequently involve cardiovascular complications such as myocarditis and septic shock.[52] Neurological complications may include encephalopathy, Guillain-Barré syndrome, and ataxic breathing due to either viral damage or immune-mediated responses.[53][54] Other significant concerns in avian influenza include renal involvement, often presenting as acute kidney injury, particularly in cases of multiple organ failure. Gastrointestinal symptoms, such as diarrhea and abdominal pain, are more common with strains such as H5N1 and can lead to dehydration and electrolyte imbalances. Liver dysfunction may also occur due to systemic inflammation or hypoperfusion, often evidenced by elevated liver enzymes.Severe hematological complications, such as disseminated intravascular coagulation (DIC) and thrombocytopenia, are often seen in severe cases, indicating a worsening clinical course.[55] Many patients develop multiple organ dysfunction syndrome in which respiratory, cardiovascular, renal, and hepatic systems fail simultaneously.[56] Long-term complications can include chronic respiratory impairment,[57] chronic kidney disease, and psychological effects such as anxiety or posttraumatic stress disorder.
Consultations
Any patient hospitalized with a suspected or confirmed diagnosis of avian influenza should receive an infectious disease consultation to guide care and minimize complications. While the general recommendations are essential for managing suspected avian influenza, an infectious disease specialist can offer tailored guidance based on the specific strain and help manage treatment and patient expectations more effectively. Additionally, in the United States, confirmed cases of avian influenza must be reported to the Centers for Disease Control and Prevention (CDC).
Deterrence and Patient Education
Minimizing the spread of avian influenza is essential to reducing its severity and impact during an outbreak. Although human-to-human transmission is rare, the focus should be on promoting proper sanitation practices, especially among those who work with birds or are involved in food preparation.
When an outbreak is identified, public health officials should focus on identifying at-risk populations and educating the public about risk factors and how to recognize infection. Clear messaging should highlight that specific populations are at low risk of contracting the virus to prevent unnecessary fear and panic. Individuals working with live or dead birds, including those handling poultry in restaurants, should be informed about the signs and symptoms of avian influenza in themselves and their coworkers. They should also receive guidance on contacting local health authorities and seeking medical evaluation if infection is suspected.
Pearls and Other Issues
Key points to keep in mind about avian influenza include:
-
Avian influenza is caused by avian influenza A viruses, particularly H5N1, H7N9, and other strains.
- Transmission is primarily zoonotic, transmitted from infected poultry (domestic or wild) to humans via respiratory secretions, feces, or contaminated environments. Human-to-human transmission is rare but possible, particularly in close-contact settings.
- Symptoms include fever, cough, myalgia, and sore throat. Severe symptoms can progress to dyspnea, chest pain, and fatigue.
- Disease progression can lead to pneumonia, ARDS, respiratory failure, and multiple organ failure.
- Individuals at high risk include those with occupational exposure, such as poultry workers, veterinarians, and those working in live bird markets.
- High-risk areas include Southeast Asia, Africa, and the Middle East.
- RT-PCR is the gold standard for diagnosing avian influenza.
- Oseltamivir is the first-line treatment, which is more effective when administered within 48 hours of symptom onset.
Enhancing Healthcare Team Outcomes
The management of avian influenza requires collaboration among healthcare professionals from various disciplines. Effective collaboration, clear communication, and adherence to evidence-based interventions are essential for optimizing patient outcomes, improving team performance, and minimizing disease transmission. Early identification and diagnosis are critical in reducing the spread and severity of avian influenza.
Physicians play a central role by maintaining a high index of suspicion in patients with relevant exposure histories, such as contact with live poultry or recent travel to outbreak-prone regions. Advanced practitioners and nurses contribute significantly by taking patient histories, monitoring symptoms, and escalating care for at-risk individuals. The integration of diagnostic modalities, such as RT-PCR for viral detection and imaging studies for assessing disease severity, helps confirm cases promptly. Rapid diagnosis enables early isolation, treatment, and infection control measures, which are crucial for preventing outbreaks. Effective coordination among healthcare professionals is crucial for providing patient-centered care in the treatment of avian influenza.
Pharmacists ensure the appropriate use of antiviral medications, such as neuraminidase inhibitors (such as oseltamivir and zanamivir) and investigational drugs (such as baloxavir marboxil), while also updating physicians on potential drug resistance and interactions. Nursing staff are crucial in administering medications, oxygen therapy, and fluid resuscitation. Respiratory therapists or pulmonologists are vital in managing advanced respiratory support for critically ill patients, including mechanical ventilation and ECMO for ARDS. Dietitians offer nutritional support tailored to the patient’s metabolic needs. Close monitoring of affected patients by the healthcare team helps prevent complications, such as secondary bacterial infections.
To reduce the risk of nosocomial transmission, strict adherence to isolation protocols, personal protective equipment, and vaccination programs for high-risk populations are essential. The healthcare team must collaborate with public health authorities for effective case reporting, contact tracing, and outbreak monitoring. Social workers and public health educators play a vital role in community outreach, promoting hygiene practices, safe poultry handling, and vaccination campaigns in areas with high exposure risk.
A multidisciplinary approach that integrates expertise from physicians, nurses, pharmacists, respiratory therapists, dietitians, and public healthcare officials significantly enhances the management of avian influenza. This approach improves patient outcomes, reduces disease transmission, and boosts healthcare team efficiency. The model is designed to be adaptable, ensuring preparedness for future outbreaks and safeguarding public health and healthcare systems.
References
Kang M, Wang LF, Sun BW, Wan WB, Ji X, Baele G, Bi YH, Suchard MA, Lai A, Zhang M, Wang L, Zhu YH, Ma L, Li HP, Haerheng A, Qi YR, Wang RL, He N, Su S. Zoonotic infections by avian influenza virus: changing global epidemiology, investigation, and control. The Lancet. Infectious diseases. 2024 Aug:24(8):e522-e531. doi: 10.1016/S1473-3099(24)00234-2. Epub 2024 Jun 12 [PubMed PMID: 38878787]
Level 2 (mid-level) evidenceLiang Y. Pathogenicity and virulence of influenza. Virulence. 2023 Dec:14(1):2223057. doi: 10.1080/21505594.2023.2223057. Epub [PubMed PMID: 37339323]
Lazarus R, Lim PL. Avian influenza: recent epidemiology, travel-related risk, and management. Current infectious disease reports. 2015 Jan:17(1):456. doi: 10.1007/s11908-014-0456-3. Epub [PubMed PMID: 25475382]
Fu X, Wang Q, Ma B, Zhang B, Sun K, Yu X, Ye Z, Zhang M. Advances in Detection Techniques for the H5N1 Avian Influenza Virus. International journal of molecular sciences. 2023 Dec 5:24(24):. doi: 10.3390/ijms242417157. Epub 2023 Dec 5 [PubMed PMID: 38138987]
Level 3 (low-level) evidenceAlexander DJ. An overview of the epidemiology of avian influenza. Vaccine. 2007 Jul 26:25(30):5637-44 [PubMed PMID: 17126960]
Level 3 (low-level) evidenceAbuBakar U, Amrani L, Kamarulzaman FA, Karsani SA, Hassandarvish P, Khairat JE. Avian Influenza Virus Tropism in Humans. Viruses. 2023 Mar 24:15(4):. doi: 10.3390/v15040833. Epub 2023 Mar 24 [PubMed PMID: 37112812]
Simancas-Racines A, Cadena-Ullauri S, Guevara-Ramírez P, Zambrano AK, Simancas-Racines D. Avian Influenza: Strategies to Manage an Outbreak. Pathogens (Basel, Switzerland). 2023 Apr 17:12(4):. doi: 10.3390/pathogens12040610. Epub 2023 Apr 17 [PubMed PMID: 37111496]
Shi J, Zeng X, Cui P, Yan C, Chen H. Alarming situation of emerging H5 and H7 avian influenza and effective control strategies. Emerging microbes & infections. 2023 Dec:12(1):2155072. doi: 10.1080/22221751.2022.2155072. Epub [PubMed PMID: 36458831]
Rabadan R, Robins H. Evolution of the influenza a virus: some new advances. Evolutionary bioinformatics online. 2008 Jan 30:3():299-307 [PubMed PMID: 19430605]
Level 3 (low-level) evidenceXie R, Edwards KM, Wille M, Wei X, Wong SS, Zanin M, El-Shesheny R, Ducatez M, Poon LLM, Kayali G, Webby RJ, Dhanasekaran V. The episodic resurgence of highly pathogenic avian influenza H5 virus. Nature. 2023 Oct:622(7984):810-817. doi: 10.1038/s41586-023-06631-2. Epub 2023 Oct 18 [PubMed PMID: 37853121]
European Food Safety Authority, European Centre for Disease Prevention, Control, European Union Reference Laboratory for Avian Influenza, Adlhoch C, Fusaro A, Gonzales JL, Kuiken T, Marangon S, Niqueux É, Staubach C, Terregino C, Aznar I, Muñoz Guajardo I, Baldinelli F. Avian influenza overview May - September 2021. EFSA journal. European Food Safety Authority. 2022 Jan:20(1):e07122. doi: 10.2903/j.efsa.2022.7122. Epub 2022 Jan 21 [PubMed PMID: 35079292]
Level 3 (low-level) evidenceCharostad J, Rezaei Zadeh Rukerd M, Mahmoudvand S, Bashash D, Hashemi SMA, Nakhaie M, Zandi K. A comprehensive review of highly pathogenic avian influenza (HPAI) H5N1: An imminent threat at doorstep. Travel medicine and infectious disease. 2023 Sep-Oct:55():102638. doi: 10.1016/j.tmaid.2023.102638. Epub 2023 Aug 30 [PubMed PMID: 37652253]
Raj S, Matsuyama-Kato A, Alizadeh M, Boodhoo N, Nagy E, Mubareka S, Karimi K, Behboudi S, Sharif S. Treatment with Toll-like Receptor (TLR) Ligands 3 and 21 Prevents Fecal Contact Transmission of Low Pathogenic H9N2 Avian Influenza Virus (AIV) in Chickens. Viruses. 2023 Apr 16:15(4):. doi: 10.3390/v15040977. Epub 2023 Apr 16 [PubMed PMID: 37112957]
Islam A, Islam S, Amin E, Shano S, Samad MA, Shirin T, Hassan MM, Flora MS. Assessment of poultry rearing practices and risk factors of H5N1 and H9N2 virus circulating among backyard chickens and ducks in rural communities. PloS one. 2022:17(10):e0275852. doi: 10.1371/journal.pone.0275852. Epub 2022 Oct 11 [PubMed PMID: 36219598]
Seekings AH, Howard WA, Nuñéz A, Slomka MJ, Banyard AC, Hicks D, Ellis RJ, Nuñéz-García J, Hartgroves LC, Barclay WS, Banks J, Brown IH. The Emergence of H7N7 Highly Pathogenic Avian Influenza Virus from Low Pathogenicity Avian Influenza Virus Using an in ovo Embryo Culture Model. Viruses. 2020 Aug 21:12(9):. doi: 10.3390/v12090920. Epub 2020 Aug 21 [PubMed PMID: 32839404]
Alkie TN, Lopes S, Hisanaga T, Xu W, Suderman M, Koziuk J, Fisher M, Redford T, Lung O, Joseph T, Himsworth CG, Brown IH, Bowes V, Lewis NS, Berhane Y. A threat from both sides: Multiple introductions of genetically distinct H5 HPAI viruses into Canada via both East Asia-Australasia/Pacific and Atlantic flyways. Virus evolution. 2022:8(2):veac077. doi: 10.1093/ve/veac077. Epub 2022 Aug 25 [PubMed PMID: 36105667]
Cowling BJ, Jin L, Lau EH, Liao Q, Wu P, Jiang H, Tsang TK, Zheng J, Fang VJ, Chang Z, Ni MY, Zhang Q, Ip DK, Yu J, Li Y, Wang L, Tu W, Meng L, Wu JT, Luo H, Li Q, Shu Y, Li Z, Feng Z, Yang W, Wang Y, Leung GM, Yu H. Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases. Lancet (London, England). 2013 Jul 13:382(9887):129-37. doi: 10.1016/S0140-6736(13)61171-X. Epub 2013 Jun 24 [PubMed PMID: 23803488]
Level 3 (low-level) evidenceQin Y, Horby PW, Tsang TK, Chen E, Gao L, Ou J, Nguyen TH, Duong TN, Gasimov V, Feng L, Wu P, Jiang H, Ren X, Peng Z, Li S, Li M, Zheng J, Liu S, Hu S, Hong R, Farrar JJ, Leung GM, Gao GF, Cowling BJ, Yu H. Differences in the Epidemiology of Human Cases of Avian Influenza A(H7N9) and A(H5N1) Viruses Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015 Aug 15:61(4):563-71. doi: 10.1093/cid/civ345. Epub 2015 May 4 [PubMed PMID: 25940354]
Level 2 (mid-level) evidenceLiu WJ, Xiao H, Dai L, Liu D, Chen J, Qi X, Bi Y, Shi Y, Gao GF, Liu Y. Avian influenza A (H7N9) virus: from low pathogenic to highly pathogenic. Frontiers of medicine. 2021 Aug:15(4):507-527. doi: 10.1007/s11684-020-0814-5. Epub 2021 Apr 16 [PubMed PMID: 33860875]
Level 2 (mid-level) evidenceCargnin Faccin F, Perez DR. Pandemic preparedness through vaccine development for avian influenza viruses. Human vaccines & immunotherapeutics. 2024 Dec 31:20(1):2347019. doi: 10.1080/21645515.2024.2347019. Epub 2024 May 28 [PubMed PMID: 38807261]
Abbasi J. Bird Flu Outbreak in Dairy Cows Is Widespread, Raising Public Health Concerns. JAMA. 2024 Jun 4:331(21):1789-1791. doi: 10.1001/jama.2024.8886. Epub [PubMed PMID: 38718040]
Webster RG, Govorkova EA. H5N1 influenza--continuing evolution and spread. The New England journal of medicine. 2006 Nov 23:355(21):2174-7 [PubMed PMID: 17124014]
Thompson CI, Barclay WS, Zambon MC, Pickles RJ. Infection of human airway epithelium by human and avian strains of influenza a virus. Journal of virology. 2006 Aug:80(16):8060-8 [PubMed PMID: 16873262]
Belser JA, Lash RR, Garg S, Tumpey TM, Maines TR. The eyes have it: influenza virus infection beyond the respiratory tract. The Lancet. Infectious diseases. 2018 Jul:18(7):e220-e227. doi: 10.1016/S1473-3099(18)30102-6. Epub 2018 Feb 21 [PubMed PMID: 29477464]
Beigel JH, Farrar J, Han AM, Hayden FG, Hyer R, de Jong MD, Lochindarat S, Nguyen TK, Nguyen TH, Tran TH, Nicoll A, Touch S, Yuen KY, Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. Avian influenza A (H5N1) infection in humans. The New England journal of medicine. 2005 Sep 29:353(13):1374-85 [PubMed PMID: 16192482]
Level 3 (low-level) evidencePeiris JS, Hui KP, Yen HL. Host response to influenza virus: protection versus immunopathology. Current opinion in immunology. 2010 Aug:22(4):475-81. doi: 10.1016/j.coi.2010.06.003. Epub 2010 Jun 30 [PubMed PMID: 20594815]
Level 3 (low-level) evidenceZhuang J, Zang N, Ye C, Xu F. Lethal avian influenza A (H5N1) virus induces ataxic breathing in mice with apoptosis of pre-Botzinger complex neurons expressing neurokinin-1 receptor. American journal of physiology. Lung cellular and molecular physiology. 2017 Nov 1:313(5):L772-L780. doi: 10.1152/ajplung.00145.2017. Epub 2017 Jul 20 [PubMed PMID: 28729347]
Uyeki TM, Peiris M. Novel Avian Influenza A Virus Infections of Humans. Infectious disease clinics of North America. 2019 Dec:33(4):907-932. doi: 10.1016/j.idc.2019.07.003. Epub [PubMed PMID: 31668198]
Writing Committee of the Second World Health Organization Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus, Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z, Hayden FG, Nguyen DH, de Jong MD, Naghdaliyev A, Peiris JS, Shindo N, Soeroso S, Uyeki TM. Update on avian influenza A (H5N1) virus infection in humans. The New England journal of medicine. 2008 Jan 17:358(3):261-73. doi: 10.1056/NEJMra0707279. Epub [PubMed PMID: 18199865]
Hui DS. Review of clinical symptoms and spectrum in humans with influenza A/H5N1 infection. Respirology (Carlton, Vic.). 2008 Mar:13 Suppl 1():S10-3. doi: 10.1111/j.1440-1843.2008.01247.x. Epub [PubMed PMID: 18366521]
. EMERGING PATHOGENS: INFLUENZA - H7N9. Disease-a-month : DM. 2017 Sep:63(9):251-256. doi: 10.1016/j.disamonth.2017.03.018. Epub 2017 Sep 12 [PubMed PMID: 29737282]
An SH, Kim NY, Heo GB, Kang YM, Lee YJ, Lee KN. Development and evaluation of a multiplex real-time RT-PCR assay for simultaneous detection of H5, H7, and H9 subtype avian influenza viruses. Journal of virological methods. 2024 Jun:327():114942. doi: 10.1016/j.jviromet.2024.114942. Epub 2024 Apr 24 [PubMed PMID: 38670532]
Shi J, Xie J, He Z, Hu Y, He Y, Huang Q, Leng B, He W, Sheng Y, Li F, Song Y, Bai C, Gu Y, Jie Z. A detailed epidemiological and clinical description of 6 human cases of avian-origin influenza A (H7N9) virus infection in Shanghai. PloS one. 2013:8(10):e77651. doi: 10.1371/journal.pone.0077651. Epub 2013 Oct 15 [PubMed PMID: 24143251]
Level 2 (mid-level) evidenceChen Y, Wang D, Zheng S, Shu Y, Chen W, Cui D, Li J, Yu H, Wang Y, Li L, Shang H. Rapid diagnostic tests for identifying avian influenza A(H7N9) virus in clinical samples. Emerging infectious diseases. 2015 Jan:21(1):87-90. doi: 10.3201/eid2101.140247. Epub [PubMed PMID: 25529064]
Wang XM, Hu S, Hu CH, Hu XY, Yu YX, Wang YF, Wang JL, Li GH, Mao XF, Tu JC, Chen L, Zhao WF. Chest imaging of H7N9 subtype of human avian influenza. Radiology of infectious diseases (Beijing, China). 2015 Mar:1(2):51-56. doi: 10.1016/j.jrid.2015.02.001. Epub 2015 Feb 27 [PubMed PMID: 32289064]
Smith JR, Rayner CR, Donner B, Wollenhaupt M, Klumpp K, Dutkowski R. Oseltamivir in seasonal, pandemic, and avian influenza: a comprehensive review of 10-years clinical experience. Advances in therapy. 2011 Nov:28(11):927-59. doi: 10.1007/s12325-011-0072-7. Epub 2011 Nov 1 [PubMed PMID: 22057727]
Level 3 (low-level) evidenceSarukhanyan E, Shanmugam TA, Dandekar T. In Silico Studies Reveal Peramivir and Zanamivir as an Optimal Drug Treatment Even If H7N9 Avian Type Influenza Virus Acquires Further Resistance. Molecules (Basel, Switzerland). 2022 Sep 12:27(18):. doi: 10.3390/molecules27185920. Epub 2022 Sep 12 [PubMed PMID: 36144655]
Tepper V, Nykvist M, Gillman A, Skog E, Wille M, Lindström HS, Tang C, Lindberg RH, Lundkvist Å, Järhult JD. Influenza A/H4N2 mallard infection experiments further indicate zanamivir as less prone to induce environmental resistance development than oseltamivir. The Journal of general virology. 2020 Aug:101(8):816-824. doi: 10.1099/jgv.0.001369. Epub 2019 Dec 19 [PubMed PMID: 31855133]
Guan W, Qu R, Shen L, Mai K, Pan W, Lin Z, Chen L, Dong J, Zhang J, Feng P, Weng Y, Yu M, Guan P, Zhou J, Tu C, Wu X, Wang Y, Yang C, Ling Y, Le S, Zhan Y, Li Y, Liu X, Zou H, Huang Z, Zhou H, Wu Q, Zhang W, He J, Xu T, Zhong N, Yang Z. Baloxavir marboxil use for critical human infection of avian influenza A H5N6 virus. Med (New York, N.Y.). 2024 Jan 12:5(1):32-41.e5. doi: 10.1016/j.medj.2023.11.001. Epub 2023 Dec 8 [PubMed PMID: 38070511]
Lou X, Yan H, Su L, Sun Y, Wang X, Gong L, Chen Y, Li Z, Fang Z, Mao H, Chen K, Zhang Y. Detecting the Neuraminidase R294K Mutation in Avian Influenza A (H7N9) Virus Using Reverse Transcription Droplet Digital PCR Method. Viruses. 2023 Apr 17:15(4):. doi: 10.3390/v15040983. Epub 2023 Apr 17 [PubMed PMID: 37112963]
Nie Q, Zhang DY, Wu WJ, Huang CL, Ni ZY. Extracorporeal membrane oxygenation for avian influenza A (H7N9) patient with acute respiratory distress syndrome: a case report and short literature review. BMC pulmonary medicine. 2017 Feb 14:17(1):38. doi: 10.1186/s12890-017-0381-y. Epub 2017 Feb 14 [PubMed PMID: 28196469]
Level 3 (low-level) evidenceYang JW, Fan LC, Miao XY, Mao B, Li MH, Lu HW, Liang S, Xu JF. Corticosteroids for the treatment of human infection with influenza virus: a systematic review and meta-analysis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2015 Oct:21(10):956-63. doi: 10.1016/j.cmi.2015.06.022. Epub 2015 Jun 27 [PubMed PMID: 26123860]
Level 1 (high-level) evidenceSchirmer P, Holodniy M. Oseltamivir for treatment and prophylaxis of influenza infection. Expert opinion on drug safety. 2009 May:8(3):357-71. doi: 10.1517/14740330902840519. Epub [PubMed PMID: 19355841]
Level 3 (low-level) evidenceSchünemann HJ, Hill SR, Kakad M, Bellamy R, Uyeki TM, Hayden FG, Yazdanpanah Y, Beigel J, Chotpitayasunondh T, Del Mar C, Farrar J, Tran TH, Ozbay B, Sugaya N, Fukuda K, Shindo N, Stockman L, Vist GE, Croisier A, Nagjdaliyev A, Roth C, Thomson G, Zucker H, Oxman AD, WHO Rapid Advice Guideline Panel on Avian Influenza. WHO Rapid Advice Guidelines for pharmacological management of sporadic human infection with avian influenza A (H5N1) virus. The Lancet. Infectious diseases. 2007 Jan:7(1):21-31 [PubMed PMID: 17182341]
Level 3 (low-level) evidenceFurey C, Scher G, Ye N, Kercher L, DeBeauchamp J, Crumpton JC, Jeevan T, Patton C, Franks J, Rubrum A, Alameh MG, Fan SHY, Phan AT, Hunter CA, Webby RJ, Weissman D, Hensley SE. Development of a nucleoside-modified mRNA vaccine against clade 2.3.4.4b H5 highly pathogenic avian influenza virus. Nature communications. 2024 May 23:15(1):4350. doi: 10.1038/s41467-024-48555-z. Epub 2024 May 23 [PubMed PMID: 38782954]
Wang Y, Ma Q, Li M, Mai Q, Ma L, Zhang H, Zhong H, Mai K, Cheng N, Feng P, Guan P, Wu S, Zhang L, Dai J, Zhang B, Pan W, Yang Z. A decavalent composite mRNA vaccine against both influenza and COVID-19. mBio. 2024 Sep 11:15(9):e0066824. doi: 10.1128/mbio.00668-24. Epub 2024 Aug 6 [PubMed PMID: 39105586]
He J, Kam YW. Insights from Avian Influenza: A Review of Its Multifaceted Nature and Future Pandemic Preparedness. Viruses. 2024 Mar 17:16(3):. doi: 10.3390/v16030458. Epub 2024 Mar 17 [PubMed PMID: 38543823]
Gubareva LV, Besselaar TG, Daniels RS, Fry A, Gregory V, Huang W, Hurt AC, Jorquera PA, Lackenby A, Leang SK, Lo J, Pereyaslov D, Rebelo-de-Andrade H, Siqueira MM, Takashita E, Odagiri T, Wang D, Zhang W, Meijer A. Global update on the susceptibility of human influenza viruses to neuraminidase inhibitors, 2015-2016. Antiviral research. 2017 Oct:146():12-20. doi: 10.1016/j.antiviral.2017.08.004. Epub 2017 Aug 10 [PubMed PMID: 28802866]
Shiraishi C, Kato H, Hagihara M, Asai N, Iwamoto T, Mikamo H. Comparison of clinical efficacy and safety of baloxavir marboxil versus oseltamivir as the treatment for influenza virus infections: A systematic review and meta-analysis. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2024 Mar:30(3):242-249. doi: 10.1016/j.jiac.2023.10.017. Epub 2023 Oct 20 [PubMed PMID: 37866622]
Level 1 (high-level) evidenceBonomini A, Zhang J, Ju H, Zago A, Pacetti M, Tabarrini O, Massari S, Liu X, Mercorelli B, Zhan P, Loregian A. Synergistic activity of an RNA polymerase PA-PB1 interaction inhibitor with oseltamivir against human and avian influenza viruses in cell culture and in ovo. Antiviral research. 2024 Oct:230():105980. doi: 10.1016/j.antiviral.2024.105980. Epub 2024 Aug 6 [PubMed PMID: 39117284]
Liu S, Sha J, Yu Z, Hu Y, Chan TC, Wang X, Pan H, Cheng W, Mao S, Zhang RJ, Chen E. Avian influenza virus in pregnancy. Reviews in medical virology. 2016 Jul:26(4):268-84. doi: 10.1002/rmv.1884. Epub 2016 May 17 [PubMed PMID: 27187752]
Hsieh YC, Wu TZ, Liu DP, Shao PL, Chang LY, Lu CY, Lee CY, Huang FY, Huang LM. Influenza pandemics: past, present and future. Journal of the Formosan Medical Association = Taiwan yi zhi. 2006 Jan:105(1):1-6 [PubMed PMID: 16440064]
Ng YP, Yip TF, Peiris JSM, Ip NY, Lee SMY. Avian influenza A H7N9 virus infects human astrocytes and neuronal cells and induces inflammatory immune responses. Journal of neurovirology. 2018 Dec:24(6):752-760. doi: 10.1007/s13365-018-0659-8. Epub 2018 Jul 9 [PubMed PMID: 29987581]
Boyd M, Clezy K, Lindley R, Pearce R. Pandemic influenza: clinical issues. The Medical journal of Australia. 2006 Nov 20:185(S10):S44-7 [PubMed PMID: 17115951]
Ahmad Malik J, Ahmed S, Shinde M, Almermesh MHS, Alghamdi S, Hussain A, Anwar S. The Impact of COVID-19 On Comorbidities: A Review Of Recent Updates For Combating It. Saudi journal of biological sciences. 2022 May:29(5):3586-3599. doi: 10.1016/j.sjbs.2022.02.006. Epub 2022 Feb 10 [PubMed PMID: 35165505]
Martin-Loeches I, Rodriguez A, Bonastre J, Zaragoza R, Sierra R, Marques A, Juliá-Narvaez J, Diaz E, Rello J, H1N1 SEMICYUC Working Group. Severe pandemic (H1N1)v influenza A infection: report on the first deaths in Spain. Respirology (Carlton, Vic.). 2011 Jan:16(1):78-85. doi: 10.1111/j.1440-1843.2010.01874.x. Epub [PubMed PMID: 20946335]
Wang Q, Jiang H, Xie Y, Zhang T, Liu S, Wu S, Sun Q, Song S, Wang W, Deng X, Ren L, Qin T, Horby P, Uyeki T, Yu H. Long-term clinical prognosis of human infections with avian influenza A(H7N9) viruses in China after hospitalization. EClinicalMedicine. 2020 Mar:20():100282. doi: 10.1016/j.eclinm.2020.100282. Epub 2020 Feb 19 [PubMed PMID: 32300739]
Level 2 (mid-level) evidence