Avian Influenza H5N1

7 Interesting Facts of Avian Influenza H5N1

Avian influenza of H5N1 type is a zoonotic infection with highly pathogenic avian influenza type A virus, subtype H5N1
Infection frequently presents with influenzalike symptoms, but it can be asymptomatic, mild, or have an aggressive clinical course with rapid deterioration
Real-time reverse transcription polymerase chain reaction testing on a pulmonary aspirate is the only test to definitely confirm diagnosis; H5N1 will test positive for influenza A by rapid antigen testing; notify the state or local public health laboratory that a respiratory, bronchoalveolar, or endotracheal aspirate is being sent for testing
- If results are positive, the specimen is sent to CDC for confirmation
Hospitalization is recommended for patients diagnosed with probable or confirmed infection until clinical stability has been achieved
Oseltamivir is the recommended therapy, plus supportive care (eg, oxygen if needed)
Complications include pneumonia, acute respiratory distress syndrome, septic shock, multiple organ dysfunction, and death
Prognosis is poor; H5N1 infection has more than 50% mortality

Pitfalls

Do not wait for confirmatory test results before administering oseltamivir to patients suspected of having H5N1

Avian influenza of H5N1 type is a zoonotic infection caused by highly pathogenic avian influenza type A virus, subtype hemagglutinin 5, neuraminidase 1
Highly infectious in birds; sporadic cases in humans have occurred in Africa, Asia, and the Middle East after prolonged and close contact with infected birds. Human-to-human spread is very rare
Presentation in humans ranges from mild conjunctivitis to severe respiratory illness with multiorgan involvement

Classification

CDC case definitions
- Used to provide treatment guidance
  - Confirmed case
    - Infection confirmed in CDC laboratory or CDC-certified public health laboratory using CDC-approved protocols or an FDA-authorized test that specifically detects H5N1
  - Probable case
    - Influenzalike illness in a patient who meets exposure criteria, and
    - Tested positive for influenza A, negative for H1, negative for H1pdm09 (common viral phenotype), negative for H3 using real-time reverse transcription polymerase chain reaction, and virus unable to be subtyped
  - Case under investigation
    - Influenzalike illness in a patient who meets exposure criteria, and
    - Confirmatory test results are unknown or pending
- CDC exposure criteria
  - Travel within 10 days of illness onset to areas where there are human cases of H5N1, or to areas where it is known to be circulating among animals, or
  - Unprotected exposure to H5N1 in a laboratory, or
  - Close contact with confirmed or suspected cases of human infection with H5N1 within 10 days of illness onset
    - Close contact is defined as coming within 2 meters of a person with confirmed or suspected H5N1 infection while the person was ill (includes the day before onset of illness, up to the time the illness resolves)
    - Includes the following populations:
      - Health care personnel providing care to a patient with a confirmed or suspected case
      - Family members of a patient with a confirmed or suspected case
      - Persons living with or who have stayed overnight with a patient with a confirmed or suspected case
      - Others with similar close contact

Clinical Presentation

History

Exposure history (as per CDC exposure criteria)
- Travel within 10 days to an area where human cases of H5N1 have been detected or where the virus is circulating among animals, or
- Close contact (within 10 days) of a person with suspected or confirmed H5N1, or
- Unprotected exposure to H5N1 in a laboratory
Incubation period is typically 7 days or fewer, but frequently is only 2 to 5 days
Presents in early infection with flulike symptoms, but may present with more severe lower respiratory illness along with alteration of consciousness and seizures
- Typical symptoms on presentation (occur in most cases) include:
  - Fever (typically higher than 38 °C)
  - Cough, with or without sputum (may be bloody)
  - Dyspnea
- Gastrointestinal symptoms are common early in the course of disease
  - Watery diarrhea, vomiting, and abdominal pain
- Upper respiratory tract symptoms are less common
  - Rhinorrhea and sore throat
- Myalgia
- Other less common symptoms
  - Hoarse voice
  - Chest pain
  - Headache
  - Epistaxis
  - Constipation

Physical examination

Signs in decreasing order of frequency
- Signs of respiratory distress
  - Tachypnea
  - Bilateral inspiratory crackles
  - Tachycardia
- Altered mental status
- Active seizures
- Bleeding gums
- Conjunctival injection

Causes

Infection with H5N1
- Human infection occurs via contact with infected birds or poultry
- Rarely, prolonged intimate contact with a severely ill patient has produced human-to-human transmission

Risk factors and/or associations

Age

89% of all cases have occurred in those younger than 40 years
52% of all cases have occurred in those younger than 20 years
Highest case fatality rate is 76%, for those aged 10 to 19 years
Lowest case fatality rate is 40%, for those older than 50 years

Sex

Increased complications in females have been attributed to increased female occupational exposure in recent outbreaks
- ICU admission: 3.7 times more likely
- Pneumonia: 3.03 times more likely
- Need for ventilator support: 2.94 times more likely
- Death: 1.75 times more likely

Other risk factors/associations

Travel to or residing in endemic areas, listed in decreasing order of risk:
- Vietnam
- Indonesia
- Thailand
- Egypt
- China
- Turkey
- Azerbaijan
- Cambodia
- Iraq
Most common risk factor is handling sick or dead poultry during the week before onset of symptoms
- Most patients acquire the infection from poultry they raise
Less common risk factors
- Slaughtering birds
- Plucking birds’ feathers
- Preparing poultry to eat
- Eating raw or undercooked poultry

Diagnostic Procedures

Primary diagnostic tools

Exposure criteria established by CDC (patient must meet 1 of these criteria)
- Travel within 10 days of illness onset to areas where there are human cases of H5N1 or to areas where the virus is known to be endemic in animal populations, or
- Close contact (within 2 meters) within 10 days of illness onset with confirmed or suspected cases of H5N1 while the patient was ill (beginning 1 day before illness and continuing until illness resolved), or
- Unprotected exposure to live H5N1 virus in a laboratory
When exposure criteria for H5N1 are met, the diagnosis is probable
- Diagnosis is made through recognition of an influenzalike illness (with atypical features) combined with confirmatory testing of an appropriately obtained respiratory, bronchoalveolar, or endotracheal aspirate
  - Bronchoscopy may be required to obtain aspirate for analysis in patients with lower respiratory disease, owing to a higher yield of organisms than with a nasotracheal or endotracheal aspirate
- Real-time reverse transcription polymerase chain reaction testing of the aspirate for H5N1 is the only test to definitively confirm diagnosis; H5N1 will test positive for influenza A by rapid antigen testing
CDC recommends that clinicians notify their state health departments when they suspect a patient is infected with H5N1
- Send specimens (ie, respiratory, bronchoalveolar, or endotracheal aspirates) first to the state or local public health laboratory (not to CDC), where FDA-cleared real-time reverse transcription polymerase chain reaction testing is done
- If test results are positive, notify CDC immediately and send specimen to CDC for confirmation
Obtain chest radiograph for all cases suspected to be caused by H5N1
Evaluate patients with pneumonia, considering other sources of community-acquired pneumonia as a secondary infection, including:
- Blood cultures
- Sputum Gram stain and culture
- Pleural fluid testing (if pleural effusion is present)
- Urinary antigen testing

Laboratory

Influenza real-time reverse transcription polymerase chain reaction diagnostic panel
- Obtain specimens as soon as possible after illness onset, ideally within 7 days
  - Multiple respiratory specimens from different sites are obtained from the same patient on at least 2 consecutive days, if possible, to increase potential for H5N1 detection
- Early after illness onset, provide a nasopharyngeal swab, a nasal aspirate or wash, or 2 swabs combined into 1 viral transport media vial (eg, nasopharyngeal and oropharyngeal swabs)
- If lower respiratory involvement is present, obtain test results on bronchoalveolar or endotracheal aspirates
- Place specimens into sterile viral transport media; immediately refrigerate with gel packs or in refrigerator at 4 °C
  - If specimen is to be examined within 72 hours, keep the specimen at 4 °C (2-8 °C) and ship on refrigerant gel packs
  - If specimen will not be examined for over 72 hours, store frozen at −70 °C or colder and ship on dry ice
- Identify the H5N1 subtype of influenza, which is diagnostic

Imaging

Chest radiography
- Pneumonic infiltrates begin with an interstitial pattern and progress to an interstitial/alveolar pattern in the late stages in most patients
- Further progression to diffuse bilateral confluent air space opacification can occur rapidly
- Lower lung fields are involved in most patients
- Not associated with pleural effusion

Procedures

Bronchofiberscope is passed through the nose or mouth, down the trachea, and into the lung
Lung tissue is visually examined
Sterile saline is injected into the lung, then aspirated and collected for analysis
Patients with significant lower respiratory tract disease and who need for sampling of deep secretions for analysis and identification of the causative microorganism, not adequately provided by an endotracheal aspirate
Visual examination of tracheal and alveolar tissue
Patient unable to support ventilation during procedure
Hemodynamic instability
Real-time reverse transcription polymerase chain reaction detection of H5N1 on bronchial aspirate confirms the diagnosis
A small amount of saline is instilled through an endotracheal tube; fluid is aspirated and examined
Patients infected with H5N1 are usually already intubated and ventilated for therapeutic purposes
Patients with lower respiratory tract infection who are intubated
Patients who are unstable (eg, recent myocardial infarction, unstable angina)
Real-time reverse transcription polymerase chain reaction detection of H5N1 in aspirate is confirmatory

Differential Diagnosis

Most common

Bacterial pneumonia
- Similar respiratory symptoms and fever that are not as severe as those of H5N1
- Associated with high WBC cell count on CBC (more than 11,000 WBC/mL); compares with reported tendency toward leukopenia, lymphocytopenia, and thrombocytopenia in patients with H5N1
- Chest radiography frequently shows lobar consolidation and pleural effusion in bacterial pneumonia
- Sputum Gram stain and culture are usually diagnostic for bacterial pneumonia
Seasonal influenza
- Similar symptoms as with H5N1 (eg, fever, myalgia, headache, sore throat, cough, rhinorrhea), although typically milder and occurring in annual outbreaks
- Patients usually have had no close exposure to poultry or other birds
- Gastrointestinal symptoms are usually not present
- Typically positive results on rapid influenza diagnostic tests; differentiate from H5N1 by real-time reverse transcription polymerase chain reaction testing if needed
Respiratory syncytial virus
- Respiratory symptoms similar to those of influenza, often with wheezing
- More common in children, but can occur at any age, especially in immunocompromised patients
- Rapid respiratory syncytial virus antigen testing can differentiate
COVID-19 infection
- Symptoms similar to those of H5N1 (eg, fever, myalgia, headache, sore throat, cough, dyspnea)
- May progress to severe illness with respiratory distress and shock
- Loss of taste or smell is highly suggestive
- Suggestive laboratory findings include lymphopenia, elevated levels of lactate dehydrogenase, and transaminases
- Chest imaging result is almost always abnormal, typically demonstrating bilateral infiltrates
- Real-time reverse transcription polymerase chain reaction testing for SARS-CoV-2 will differentiate

Least common

Avian influenza: H7N9
- Symptoms and risk factors identical, but no cases reported outside of China
- Real-time reverse transcription polymerase chain reaction testing for H7N9 will differentiate

Treatment Goals

Prevent severe complications and mortality associated with H5N1
Prevent the spread of H5N1 to asymptomatic household or family contacts of patients with confirmed or probable cases

Admission criteria

Owing to the rapid, aggressive clinical course, WHO recommends hospitalizing anyone believed to be in the initial stages of the disease in order to monitor clinical status until clinically stable

Criteria for ICU admission

Worsening respiratory symptoms despite oxygen supplementation, especially when endotracheal intubation and ventilatory support are required
Hemodynamic instability
Evidence of single-organ or multiorgan failure

Recommendations for specialist referral

Consult a critical care specialist if respiratory status is deteriorating despite oxygen supplementation, to prepare for more invasive respiratory support
Consult an infectious disease specialist for any patient with suspected, probable, or diagnosed H5N1 infection

Treatment Options

Hospitalized patients

Assess respiratory and hemodynamic status
- Initiate supplemental oxygen to maintain SaO₂ over 90%
  - Early intervention with invasive positive pressure ventilation is recommended using lung-protective low-pressure and low–tidal volume ventilation (to prevent barotrauma)
  - Oxygen for mild hypoxia can be delivered via nasal cannula; oxygen for severe hypoxia requires a face mask to accommodate high flow (eg, 10 L/minute)
  - Monitor using pulse oximetry
  - Administer supplemental oxygen to all patients in respiratory distress; ventilator support is recommended if condition does not improve with oxygen
- Maintain conservative fluid management
Provide adequate infection control because of risk of infectious aerosols
- Use particulate respirator (ie, N95, FFP2, or comparable), eye protection, gowns, gloves, airborne precautions, or negative pressure room
Initiate antiviral therapy with orally or enterically administered oseltamivir as soon as possible
- Do not wait for confirmatory test results before administering oseltamivir to patients suspected of having H5N1
- Inhaled zanamivir is not recommended for severely ill patients owing to a lack of substantiating data
- There are insufficient data regarding efficacy of IV peramivir for hospitalized patients
- There is insufficient evidence to recommend use of baloxavir in H5N1; however, baloxavir does have activity against influenza A viruses
- For patients who cannot tolerate or absorb oral or enterically administered oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of IV peramivir or investigational IV zanamivir should be considered
In a patient with suspected or probable H5N1 who presents with pneumonia, guidelines recommend empirical treatment of community-acquired pneumonia for the first few days until sputum and culture results are known
- Typical empiric antibiotics would include a respiratory fluoroquinolone or a combination of a β-lactam plus a macrolide
  - Chemoprophylaxis with an antibacterial agent is not indicated in cases where no pneumonia is seen on the chest radiograph and there are no clinical indications of pneumonia

Outpatients

For outpatients with severe, progressive, or complicated illness, oseltamivir is recommended
For other outpatients, oral oseltamivir, inhaled zanamivir, or IV peramivir may be used

Other exposures

Initiate antiviral therapy with oseltamivir for:
- Asymptomatic household member or close family member contacts of anyone with a confirmed or probable case
- Those with unprotected exposure in a laboratory

Drug therapy

Antiviral
- Neuraminidase inhibitors
  - Oseltamivir
    - Off-label use
    - Primary recommended antiviral treatment, especially in those who are severely ill
    - Oseltamivir Phosphate Oral suspension; Infants: 3 mg/kg/dose PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients. AAP recommends 3.5 mg/kg/dose PO twice daily for infants 9 to 11 months old.
    - Oseltamivir Phosphate Oral suspension; Children weighing 15 kg or less: 30 mg PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Oseltamivir Phosphate Oral suspension; Children weighing 16 to 23 kg: 45 mg PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Oseltamivir Phosphate Oral suspension; Children weighing 24 to 40 kg: 60 mg PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Oseltamivir Phosphate Oral suspension; Children weighing more than 40 kg and Adolescents: 75 mg PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Oseltamivir Phosphate Oral capsule; Adults: 75 mg PO twice daily for 5 days; consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - For immunosuppressed patients (ie, stem cell transplant recipients) and severely ill patients with lower respiratory tract disease, use of a higher dose (eg, 150 mg twice daily) for 10 days is recommended
    - Do not delay administering oseltamivir while laboratory test results are pending
    - Administer oseltamivir even if more than 48 hours have passed since onset of illness
    - Oseltamivir can be administered via orogastric or nasogastric tube in critically ill patients
  - Peramivir
    - Indicated for severe illness not responsive to orally or enterically administered oseltamivir
    - Peramivir Solution for injection; Neonates: 6 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Peramivir Solution for injection; Infants 30 to 90 days: 8 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Peramivir Solution for injection; Infants older than 180 days and Children 1 to 5 years: 10 to 12 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Peramivir Solution for injection; Children and Adolescents 6 to 17 years: 10 mg/kg/dose IV once daily (Max: 600 mg/dose) for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    - Peramivir Solution for injection; Adult outpatients with uncomplicated, mild-to-moderate illness: 600 mg IV as a single dose within 48 hours of symptom onset.
  - Zanamivir
    - Not recommended for patients with underlying airway disease
    - Can be used in outpatient care
    - Not indicated for severe illness owing to lack of data
    - Zanamivir Inhalation powder; Children and Adolescents 7 to 17 years: 10 mg by oral inhalation every 12 hours for 5 days starting within 48 hours of symptom onset.
    - Zanamivir Inhalation powder; Adults: 10 mg by oral inhalation every 12 hours for 5 days starting within 48 hours of symptom onset.

Nondrug and supportive care

Most hospitalized patients require supplemental oxygen owing to compromised respiratory effort and hypoxia
- Oxygen for mild hypoxia can be delivered via nasal cannula; oxygen for severe hypoxia requires a face mask to accommodate high flow (eg, 10 L/minute)
- Monitor using pulse oximetry
- Maintain oxygen saturation over 90%

Special populations

Pregnant patients are treated with oseltamivir using the same antiviral dosage as nonpregnant patients

Complications

Complications are generally worse with late presentation of the patient for care
Pneumonia
- Most patients with H5N1 infection have radiographic evidence of pneumonia at presentation
- Often leads to acute respiratory distress syndrome and death
- Empiric treatment with antibiotics is indicated using treatment guidelines for community-acquired pneumonia until definitive cause of pneumonia is known; antibiotic chemoprophylaxis is not otherwise recommended in patients without evidence of pneumonia
Acute respiratory distress syndrome
- Life-threatening inflammatory process in the lungs as a result of pulmonary injury or infection
- Often the precursor to death, acute respiratory distress syndrome has a high mortality rate in this disease
- Do not administer high-dose corticosteroids for prophylaxis of acute respiratory distress syndrome, because they are not effective and increase risk of patients with H5N1 acquiring opportunistic infections
Septic shock
- A subset of sepsis with circulatory and cellular/metabolic dysfunction associated with a higher risk of mortality
- Monitor blood pressure frequently and institute therapy for septic shock if patient is hypotensive despite adequate fluid resuscitation
Multiorgan dysfunction
- Frequently the result of septic shock and mainly affecting the lungs, kidneys, and liver
- Often the precursor to death in patients with H5N1
Secondary infection (bacterial and fungal)
- Less common complication; can be cause of significant morbidity and mortality
Encephalitis
- Rare, but can be precursor to death
- Unclear if caused by infection with the H5N1 virus, inflammatory response to H5N1, or another infection (eg, secondary bacterial pneumonia)
Death

Prognosis

Mortality rate over 50% out of confirmed human cases of H5N1 reported to WHO between 2003 and 2021

Screening and Prevention

Prevention

For the general population, avoid the following:
- Contact with ill or dead poultry, especially in countries where H5N1 is pandemic
- Contact with feces from wild or domestic birds
- Unprotected contact with soil, water, cages, tools, and other fomites that have touched feces and other secretions from wild or domestic birds in countries where H5N1 is pandemic
- Poultry farms and bird markets in countries where avian influenza has caused disease in birds or people
- Ingestion of or contact with contaminated water (fresh water that may contain feces from infected birds) in countries where H5N1 is endemic
Asymptomatic contacts of confirmed or probable cases
- Public health personnel will attempt to identify all close contacts of index cases
- Close contacts are monitored for 10 days for temperature of 38 °C or higher or any new respiratory symptoms
  - Evaluate patients who develop fever or symptoms and test for H5N1
- Asymptomatic close contacts are treated with antiviral chemoprophylaxis
  - If highest risk (recognized risk of transmission), antiviral chemoprophylaxis should be administered
  - If moderate risk (unknown risk of transmission), antiviral chemoprophylaxis could be considered
  - If low risk (transmission unlikely), chemoprophylaxis is not routinely recommended
  - Chemoprophylaxis preferably is started within 48 hours of exposure
  - Treatment dosage of oral oseltamivir or inhaled zanamivir (twice daily) is recommended instead of typical antiviral chemoprophylaxis regimen
  - Treatment duration of 5 days (time-limited, not ongoing exposure); if exposure ongoing (eg, in the household), 10 days of treatment is recommended
Unprotected exposure in a laboratory
- Persons with an unprotected exposure in a laboratory setting may have high-risk or moderate-risk exposure; should be evaluated case by case
  - If highest risk (recognized risk of transmission), antiviral chemoprophylaxis should be administered
  - If moderate risk (unknown risk of transmission), antiviral chemoprophylaxis could be considered
H5N1 vaccine
- National Prepandemic Influenza Vaccine Stockpile contains 4 vaccines against different strains of H5N1
- Vaccine is not available for commercial use
- United States maintains this vaccine for use in the event that the virus might mutate and become pandemic

References

Loeffelholz MJ: Avian influenza A H5N1 virus. Clin Lab Med. 30(1):1-20, 2010 Reference

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