There is no standardised approach for the clinical management of humans with highly pathogenic avian influenza (HPAI) H5N1 virus infection; supportive care and neuraminidase inhibitor antiviral therapy are considered the mainstays of treatment.[86] Patients with severe illness due to H5N1 virus infection can present with clinical findings similar to those of pneumonia caused by other infectious aetiologies. Given that human infection with HPAI H5N1 virus is rare (even among people with high-risk exposures), diagnostic evaluation and therapy should also consider alternative aetiologies.

Many local and national health departments, and the World Health Organization (WHO), have excellent online guidance documents:

WHO: avian and other zoonotic influenza

CDC: avian influenza - information for health professionals and laboratorians

Many local health departments can directly assist clinicians to determine which people need testing, to facilitate testing, and to assist with case management.

Unprotected exposure to a suspected or confirmed case: antiviral chemoprophylaxis

The decision to use antiviral chemoprophylaxis should be considered on a case-by-case basis and guided by the nature of HPAI H5N1 virus exposure and subsequent risk of developing infection. No prospective clinical trials exist to guide WHO antiviral chemoprophylaxis recommendations.[87][88] Guidelines are based on observational data for HPAI H5N1 virus cases and studies of patients with seasonal influenza.[88]

Close observation and post-exposure oseltamivir or zanamivir chemoprophylaxis is recommended for healthcare workers after unprotected close exposure to a symptomatic, suspected, or confirmed HPAI H5N1 case (within 2 m) in the healthcare setting, as well as for household members and close contacts of a person with suspected or confirmed HPAI H5N1 virus infection. Local or national public health departments should be contacted for guidance. If post-exposure antiviral chemoprophylaxis is administered, it should be given twice daily (treatment dosing frequency) rather than once daily because of potential that HPAI H5N1 virus infection may have already occurred.[89] If exposure was time-limited and not ongoing, chemoprophylaxis is recommended for 5 days from the last known exposure. If exposure is likely to be ongoing (e.g., household setting), 10 days is recommended.[89]

Suspected HPAI A (H5N1) virus infection

When HPAI H5N1 virus infection is highly suspected, isolating the patient and treating early with empiric neuraminidase inhibitor according to existing guidelines while waiting for the results of specific laboratory tests is appropriate. Oral or enterically-administered oseltamivir is the preferred primary treatment. Inhaled zanamivir might be used as an alternative regimen in non-intubated patients.[87] It is important to note that HPAI H5N1 virus infection of humans appears to be very rare, and physicians must consider alternative diagnoses when evaluating patients with suspected HPAI H5N1.

Contacting local or national public health departments for guidance is highly recommended. Antiviral therapy should not be delayed by diagnostic specimen collection or laboratory testing. Available evidence suggests that early diagnosis is associated with improved clinical outcomes.[90]

Confirmed avian influenza A (H5N1) virus infection

Most patients admitted to the hospital with HPAI H5N1 virus infection have rapidly progressive viral pneumonia leading to ARDS and multi-organ failure.[17] Patients with early recognition of disease and initiation of antiviral and supportive therapies may have improved clinical outcomes. Local or national public health departments should be contacted for guidance.

While there is no standardised approach for the clinical management of humans with HPAI H5N1 virus infection, the WHO recommends that supportive care follow published evidence-based guidelines for the clinical syndrome present (e.g., septic shock, respiratory failure, and ARDS).[17][91] According to the WHO, patients who have severe or progressive clinical illness, including viral pneumonitis, respiratory failure, and ARDS due to influenza virus infection, should not be given systemic corticosteroids unless indicated for other reasons (e.g., adrenal insufficiency, refractory septic shock) or as part of an approved research protocol.[87]

If exposure risk factors are present or suspected, empiric antiviral therapy should be initiated as early as possible. Antiviral therapy (neuraminidase inhibitors) should not be delayed by diagnostic specimen collection or laboratory testing. Oral or enterically-administered oseltamivir is the preferred primary treatment. No published controlled clinical trial data are available on efficacy of oseltamivir in treating HPAI H5N1 patients. Nevertheless, the WHO strongly recommends oseltamivir therapy for patients with HPAI H5N1 virus infection based on retrospective data.[88] Observational uncontrolled studies have suggested a survival benefit to early oseltamivir therapy in these patients, especially when antivirals are started early in the clinical course, or before the onset of ARDS.[17][22][24][41][62][92][93] Treatment with oseltamivir for HPAI H5N1 virus infection in children aged under 1 year is recommended by the US Centers for Disease Control and Prevention (CDC) and the WHO. The dosage for children is based on weight. Children may experience unique cutaneous, behavioural, and neurological adverse events; therefore, extra caution should be used in this population. Serious adverse events were generally not reported during treatment of HPAI H5N1 patients or in systematic reviews in adults with seasonal influenza. Inhaled zanamivir might be used as an alternative regimen in non-intubated patients.[87]

Where the clinical course remains severe or progressive, despite ≥5 days of antiviral treatment, the WHO recommends monitoring of virus replication and shedding, and antiviral drug susceptibility testing, if possible. Emergence of oseltamivir resistance during treatment of patients with HPAI H5N1 virus infection has been reported.[94][95] Additionally, HPAI A (H5N1) virus infection with de novo reduced susceptibility to oseltamivir (before oseltamivir exposure) has been reported.[96] In 2010, none of the HPAI H5N1 virus isolates tested by the WHO had neuraminidase mutations known to predict resistance to oseltamivir.[18] Combination oseltamivir and zanamivir treatment is not recommended because of the potential for antagonism.[97]

Giving M2 inhibitors (amantadine or rimantadine) alone as a first-line therapy is not recommended. According to the WHO, a combination of a neuraminidase inhibitor and an M2 inhibitor should be considered if local surveillance data show that the HPAI H5N1 virus is known or likely to be susceptible, but this should be done only in the context of research or prospective data collection.[88] Clinicians should carefully determine which patients could receive combination therapy.[88]

Infection control procedures

Given the potential infectiousness and virulence of HPAI H5N1 virus, enhanced infection control precautions are recommended. All infection control strategies include standard hand hygiene precautions. There may be slight infection control recommendation differences between the WHO and some national public health organisations; therefore, if HPAI H5N1 virus infection is considered in a patient, it is recommended that clinicians consult national infection control guidelines.

The WHO recommends using the following personal protective equipment before patient contact:[98]

  • Clean, non-sterile, long-sleeved gown; if cloth gowns are used, a plastic apron should be added if splashing of blood or body fluids is anticipated

  • Clean, non-sterile gloves

  • Face protection: either (1) medical mask and eye visor or goggles, or (2) a face shield.

The duration of the above precautions depends on the age of the HPAI H5N1 patient:

  • Patients aged ≥12 years: 7 days after fever resolves

  • Patients aged <12 years: up to 21 days after symptom onset.

If the patient leaves the hospital before this time, continued home quarantine is recommended.

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