Approach

There is no standardised approach for the clinical management of humans with Asian lineage A(H7N9) virus infection; supportive care and early initiation of neuraminidase inhibitor antiviral therapy are considered the mainstays of treatment, similar to the management of complicated seasonal influenza A and B, highly pathogenic avian influenza (HPAI) A(H5N1), and influenza A(H1N1)pdm09 virus infections.[141][142] Patients with severe illness due to Asian lineage A(H7N9) virus infection can present with clinical findings similar to those of pneumonia caused by other infectious aetiologies. Because human infection with Asian lineage A(H7N9) 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. Many local health departments can directly assist clinicians to determine which people need testing, to facilitate testing, and to assist with case management.

WHO: avian and other zoonotic influenza external link opens in a new window

Public Health England: avian influenza - guidance, data and analysis external link opens in a new window

CDC: information on avian influenza external link opens in a new window

CDC: avian influenza - information for health professionals and laboratorians external link opens in a new window

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 Asian lineage A(H7N9) virus exposure and the associated risk of developing infection. No prospective clinical trials exist to guide WHO antiviral chemoprophylaxis recommendations. The WHO does not recommend routine post-exposure antiviral chemoprophylaxis for Asian lineage A(H7N9) virus but states that it may be considered in asymptomatic individuals who have had substantial unprotected or prolonged exposure to an ill patient with Asian lineage A(H7N9) virus infection. Such individuals include those with risk factors for complications of influenza virus infection who have had close contact, and unprotected healthcare workers, especially those involved in aerosol-generating procedures.[143] Public Health England (PHE) and the Centers for Disease Control and Prevention (CDC) suggest that standard twice-daily treatment-dose regimens should be used for chemoprophylaxis, to decrease the risk of antiviral resistance developing.[144][145] When the decision is made to administer post-exposure antiviral chemoprophylaxis, it should be commenced as soon as possible following the potential exposure. The CDC recommends that 5 days of a neuraminidase inhibitor (twice-daily treatment dose) is administered when exposure was time-limited and not ongoing, but that 10 days (treatment dose) should be administered when exposure is likely to be ongoing (e.g., in a household setting). Regardless of whether or not antiviral chemoprophylaxis is administered, all close contacts should be monitored closely for signs and symptoms of influenza, and, if symptomatic, respiratory specimens should be collected for Asian lineage A(H7N9) virus testing as soon as possible.

Suspected human infection with Asian lineage A(H7N9) virus

When Asian lineage A(H7N9) virus infection is suspected, the appropriate course of action is to isolate the patient, and commence empirical neuraminidase inhibitor treatment as soon as possible (according to existing guidelines for seasonal influenza) while awaiting the results of specific diagnostic laboratory tests. Oral or enterically administered oseltamivir is the preferred primary treatment. Inhaled zanamivir might be used as an alternative regimen in non-intubated patients.[142] It is important to note that Asian lineage A(H7N9) virus infection of humans appears to be rare even among exposed individuals, and physicians must consider alternative diagnoses when evaluating patients with suspected Asian lineage A(H7N9) virus infection.

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.

Confirmed Asian lineage A(H7N9) virus infection

Most patients hospitalised with confirmed Asian lineage A(H7N9) virus infection have rapidly progressive viral pneumonia leading to acute respiratory distress syndrome (ARDS) with variable multi-organ failure.[37][116] Based on observational data from treatment of patients with seasonal influenza, A(H1N1)pdm09, or HPAI A(H5N1) virus infection, early recognition of disease and initiation of antiviral and supportive therapies may improve clinical outcomes. Local or national public health departments should be contacted for guidance.

There is no standardised approach for the clinical management of humans with Asian lineage A(H7N9) virus infection, and WHO management guidelines are in development. In the absence of specific guidance, experience from the treatment of HPAI A(H5N1) and severe A(H1N1)pdm09 virus infection is helpful. For HPAI A(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).[1][147] 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.[148]

Neuraminidase inhibitor antiviral therapy 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 Asian lineage A(H7N9) virus-infected patients, and observational data on the effectiveness of oseltamivir treatment for Asian lineage A(H7N9) virus-infected patients are very limited. One observational study reported that early initiation of neuraminidase inhibitor antiviral treatment shortened the duration of viral shedding and was associated with improved survival in A(H7N9) patients.[149] Another observational study reported that mortality was significantly lower in patients treated with a neuraminidase inhibitor within 5 days of illness onset.[150] One study reported that delayed initiation of neuraminidase inhibitor treatment was associated with prolonged A(H7N9) viral shedding.[151] PHE and the CDC strongly recommend that oseltamivir therapy is started as soon as possible for patients with suspected or confirmed A(H7N9) virus infection, based on the experience of treating patients with complicated influenza A(H1N1)pdm09 and HPAI A(H5N1).[146] Observational uncontrolled studies have suggested a survival benefit to early oseltamivir therapy in hospitalised A(H1N1)pdm09 and HPAI A(H5N1) virus-infected patients, especially when antivirals are started early in the clinical course, or before the onset of ARDS.[1][152][153][154][155][156][157][158][159] Treatment with oseltamivir for seasonal influenza virus infection in children under 1 year of age is recommended by the CDC and the WHO, and may be extrapolated to patients with Asian lineage A(H7N9) virus infection. The dosage for children is based on body weight. Serious adverse events were generally not reported during treatment of HPAI A(H5N1) virus-infected patients or in systematic reviews in adults with seasonal influenza. Inhaled zanamivir might be used as an alternative regimen in non-intubated patients.[142]

Clinicians can consider longer duration of oseltamivir treatment for patients with severe illness. To date, Asian lineage A(H7N9) virus isolates with de novo reduced susceptibility to oseltamivir (before oseltamivir exposure) have not been identified. De novo resistance to oseltamivir has been reported for A(H1N1)pdm09 and HPAI A(H5N1) virus infections, but appears to be rare. Emergence of oseltamivir, peramivir, and zanamivir resistance during treatment of patients with Asian lineage low-pathogenic avian influenza (LPAI) and HPAI A(H7N9) virus infections has been reported.[36][37][38][40][41][120][160] The Arg292Lys mutation, which has been the most commonly reported resistance mutation to date in Asian lineage A(H7N9) viruses, confers high-level resistance to oseltamivir and reduced susceptibility to zanamivir and peramivir. Where the clinical course remains severe or progressive despite at least 5 days of antiviral treatment, it is recommended that monitoring of Asian lineage A(H7N9) virus replication and shedding is performed, along with antiviral drug susceptibility testing. Combination oseltamivir and zanamivir treatment is not recommended for Asian lineage A(H7N9) virus infection because of potential mechanistic antagonism.[161] Data on use of investigational antivirals with different mechanisms of action than the neuraminidase inhibitors for treatment of patients with Asian lineage A(H7N9) virus infection are needed, but should be studied in clinical trials.

Giving M2 inhibitors (amantadine or rimantadine) or a cap-dependent endonuclease inhibitor (baloxavir marboxil) alone as a first-line therapy is not recommended. Virus isolates from humans demonstrate inherent resistance to M2 inhibitors. See Emerging treatments section for more detailed information on investigational antivirals.

Infection control procedures

Given the potential infectiousness and virulence of Asian lineage A(H7N9) virus, and because nosocomial transmission has been documented (e.g., patient-to-healthcare worker, and patient-to-patient)[12][13][14] enhanced infection prevention and control precautions are recommended. All infection prevention and control strategies include standard hand hygiene and respiratory precautions. There may be slight infection control recommendation differences between the WHO and some national public health organisations; therefore, if Asian lineage A(H7N9) virus infection is considered in a patient, it is recommended that clinicians consult national infection control guidelines. For example, the CDC recommends placement of a patient under investigation for Asian lineage A(H7N9) virus infection in an airborne infection isolation room and use of a respirator.[162]

For human infection with avian influenza A viruses, the WHO recommends using the following personal protective equipment before patient contact:[163]

  • 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

  • Eye protection: eye visor or goggles, or a face shield

  • Medical mask for routine care

  • Particulate respirator (FFP3 or N95 standard) for aerosol-generating procedures.

The recommended duration of the above precautions has not been defined for Asian lineage A(H7N9) virus-infected patients. However, for HPAI A(H5N1) virus infection, the recommended duration varies according to age group:

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

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

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

Corticosteroids

The WHO advises against the use of corticosteroids in the management of patients with Asian lineage A(H7N9) virus infection because of the potential for increased risk of prolonged virus shedding, emergence of antiviral resistant virus strains, ventilator-associated pneumonia, and higher mortality. A retrospective study of 288 H7N9 patients in China reported that high-dose corticosteroid treatment was associated with increased mortality and longer median duration of viral shedding.[164] Corticosteroid use was associated with prolonged detection of A(H7N9) viral RNA in hospitalised patients.[151] In seasonal influenza virus infection, studies have demonstrated that corticosteroid use is associated with persistent viral replication 7 days after symptom onset.[165] One study reported that early use of glucocorticoids is a risk factor for critical illness and death with A(H1N1)pdm09 virus infection.[166] Another study reported that corticosteroids increased superinfection and deaths when controlled for indications in patients with seasonal influenza virus infections.[159] Corticosteroids are not recommended for the treatment of any influenza virus infection, but may be indicated for other reasons (e.g., asthma or COPD exacerbation, adrenal insufficiency, preterm labour, refractory septic shock).

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