Approach

There is no standardized approach for the clinical management of humans with Asian lineage A(H7N9) virus infection. Optimal supportive care and prompt initiation of antiviral therapy are considered the mainstays of treatment.

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 etiologies. 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 etiologies.

Avian influenza A virus infection of humans is a notifiable disease. Local or national public health departments should be contacted for guidance.[111][112]​ Many local health departments can directly assist clinicians to determine which people need testing, to facilitate testing, and to assist with case management.

Antiviral chemoprophylaxis for close contacts

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.

The Centers for Disease Control and Prevention (CDC) recommends post-exposure antiviral chemoprophylaxis with oral oseltamivir or inhaled zanamivir for asymptomatic close contacts of a confirmed or probable case, according to their risk of exposure. A close contact is defined as a person within approximately 6 feet (2 meters), or within the room or care area, of a confirmed or probable case for a prolonged period of time, or a person who has had direct contact with infectious secretions from the case while they were likely to be infectious (i.e., 1 day prior to illness onset until resolution of illness).[128]

Highest-risk exposure groups

  • Household or close family member contacts with unprotected, prolonged close contact to a confirmed or probable case.

  • Chemoprophylaxis is recommended.

Moderate-risk exposure groups

  • Healthcare workers with unprotected close contact with a confirmed or probable case, or nonhousehold members with prolonged unprotected close contact with a confirmed or probable case outside of a healthcare facility.

  • Chemoprophylaxis may be considered.

Low-risk exposure groups

  • Other people who have had social contact of a short duration with a confirmed or probable case in a nonhospital setting (e.g., community or workplace environment).

  • Chemoprophylaxis is not routinely recommended.

The decision to start chemoprophylaxis in low- or moderate-risk groups should be based on clinical judgment, consideration of the type of exposure, and whether the contact is at high risk for complications.[128]

Oral oseltamivir is recommended for people of any age, including newborn infants. Inhaled zanamivir is recommended for people ≥5 years of age for chemoprophylaxis, but is not recommended for people with underlying airway disease.[128]

Administration should begin as soon as possible, within 48 hours after possible exposure.[128]

  • Treatment should continue for 5 or 10 days. 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.

  • The CDC recommends that chemoprophylaxis should be given twice daily (i.e., the treatment dosing frequency) rather than once daily (i.e., the typical seasonal influenza antiviral chemoprophylaxis dose) because of the potential that Asian lineage A(H7N9) virus infection may have already occurred. However, the dose may vary depending on location, and local guidelines should be consulted.

Contacts should be monitored closely for signs and symptoms of illness for up to 10 days following exposure. If the person develops a compatible illness during this time, the person should be treated as a possible case.

  • If a close contact becomes symptomatic during or after use of chemoprophylaxis, appropriate infection prevention and control measures should be instituted and respiratory specimens collected for testing as soon as possible.[128]

  • If a close contact tests positive and has been taking oseltamivir chemoprophylaxis for ≥3 days before becoming symptomatic, oseltamivir should be stopped and inhaled zanamivir or oral baloxavir initiated, as some novel influenza A viruses may rapidly become oseltamivir-resistant.[128]

Chemoprophylaxis may be considered for people who are exposed to birds with avian influenza A virus infection. The decision to initiate chemoprophylaxis should be based on clinical judgment, with consideration given to the type and duration of exposure, time since exposure, known infection status of bird(s), and whether the exposed person is at higher risk for complications.[129]

The World Health Organization (WHO) does not currently offer any recommendations for chemoprophylaxis.[130]

Infection prevention and control

Patients with suspected, probable, or confirmed Asian lineage A(H7N9) virus infection should be isolated and local infection control recommendations followed. If an airborne infection isolation room is not available, the patient should be isolated in a private room.[119]

Given the potential infectiousness and virulence of Asian lineage A(H7N9) virus, enhanced infection control precautions are recommended, including airborne and contact precautions (with the use of eye protection), in addition to standard precautions.[119]

There may be slight infection control recommendation differences between national public health organizations; therefore, if Asian lineage A(H7N9) virus infection is considered in a patient, it is recommended that clinicians consult national infection control guidelines.

Patients may be treated as outpatients or in hospital depending on disease severity and clinical presentation.

Antiviral treatment

Antiviral treatment is recommended as soon as possible for suspected, probable, or confirmed cases of Asian lineage A(H7N9) virus infection, even if more than 48 hours has elapsed since onset of symptoms, and regardless of disease severity.[131] Antiviral therapy can be discontinued in patients who are not hospitalized and who test negative for Asian lineage A(H7N9) virus infection (or other influenza viruses).

Antiviral treatment should not be delayed by diagnostic specimen collection or laboratory testing.[131]

Neuraminidase inhibitors are widely available and active against all currently circulating zoonotic influenza A viruses. There are four commercially available neuraminidase inhibitors (depending on location), and they vary by administration, dosing and duration of treatment, contraindications, and adverse effects.[130]

  • Oseltamivir

  • Zanamivir

  • Peramivir

  • Laninamivir.

Oral oseltamivir is the most widely studied and available, and it is recommended first-line in all patients.

  • The WHO recommends oseltamivir as the preferred treatment for people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on low-quality evidence.[130]

  • The CDC recommends oseltamivir as soon as possible for all hospitalized patients with suspected or confirmed novel influenza A virus infection associated with severe disease (e.g., H5N1, H5N6, H7N9) regardless of time since onset of illness, and all outpatients (i.e., any patient in the ambulatory care setting, including emergency departments, urgent care, and other clinics) including those with severe, progressive, or complicated illness. Oseltamivir is the only treatment for influenza recommended in outpatients if more than 48 hours have elapsed since onset of symptoms. For untreated outpatients with uncomplicated disease and no fever where symptoms are nearly resolved, the decision to start antiviral treatment should be based on clinical judgment.[131]

  • Oseltamivir is recommended for people of any age, including newborn infants. It is the preferred option in pregnant women.[132]

Inhaled zanamivir may be an alternative option in nonintubated patients who do not have underlying airway disease (e.g., COPD, asthma).

  • The WHO suggests not administering zanamivir to people with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence. The recommendation is based on the very low certainty of benefit on critical outcomes of mortality, hospitalization, or intensive care unit admission, rather than on evidence of harm. The WHO acknowledges that this recommendation does not apply to situations where the causative strain is known or at high risk of being resistant to oseltamivir.[130]

  • The CDC recommends zanamivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population.[131]

Other neuraminidase inhibitors may be available in certain jurisdictions.

  • The WHO suggests not administering intravenous peramivir or inhaled laninamivir to patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence.[130]

  • The CDC recommends intravenous peramivir only in outpatients with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms. It is not recommended in hospitalized patients due to a lack of safety and efficacy data in this population; however, it may be considered as an alternative to oseltamivir for patients who cannot tolerate or absorb oral oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding.[131]

  • Intravenous zanamivir may be available in some countries for hospitalized patients with severe or critical illness.

  • Asian lineage A(H7N9) virus isolates appear to be sensitive to laninamivir in vitro.[94] However, little is known about the clinical efficacy of laninamivir against Asian lineage A(H7N9) virus infection.[133]

  • Combination therapy with more than one neuraminidase inhibitor is not recommended because of the potential for antagonism.[134]

Neuraminidase inhibitor treatment with oseltamivir, peramivir, or zanamivir has been used for severely ill people infected with A(H7N9) viruses, but their effectiveness has not been determined.[131] No published controlled clinical trial data are available on the efficacy of neuraminidase inhibitors in treating Asian lineage A(H7N9) virus-infected patients, and observational data 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.[135] One study reported that delayed initiation of neuraminidase inhibitor treatment was associated with prolonged A(H7N9) viral shedding.[136]

  • Another observational study reported that mortality was significantly lower in patients treated with a neuraminidase inhibitor within 5 days of illness onset.[137]

  • Observational uncontrolled studies have suggested a survival benefit with early treatment with oseltamivir in hospitalized A(H1N1)pdm09 and highly pathogenic avian influenza (HPAI) A(H5N1) virus-infected patients, especially when antivirals are started early in the clinical course, or before the onset of acute respiratory distress syndrome (ARDS).[1][138][139][140][141][142][143][144][145]

Oral baloxavir is a newer antiviral agent with a different mechanism of action to neuraminidase inhibitors (selective inhibitor of influenza cap-dependent endonuclease).

  • The WHO does not currently recommend baloxavir for patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness due to a lack of data in this population; however, it acknowledges that clinical trials in this population are ongoing.[130]

  • The CDC recommends baloxavir only in outpatients ≥5 years of age with uncomplicated mild to moderate illness presenting within 2 days of onset of symptoms.[131][132]​

  • Inhibition of replication of avian A(H7N9) viruses has been demonstrated in vitro and in vivo, but there are no data on efficacy in infected humans.[146]

M2 inhibitors (amantadine or rimantadine) are not recommended for the treatment of novel influenza A virus infections, including Asian lineage A(H7N9) virus infection, due to the risk of resistance.[131]

Supportive care

Most patients hospitalized with confirmed Asian lineage A(H7N9) virus infection have rapidly progressive viral pneumonia leading to ARDS with variable multi-organ failure.[33][110] 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.

While there is no standardized approach for the clinical management of humans with Asian lineage A(H7N9) virus infection, the WHO recommends that supportive care follows published evidence-based guidelines for the clinical syndrome present (e.g., septic shock, respiratory failure, and ARDS).[1][147]

The WHO suggests not administering corticosteroids to patients with suspected or confirmed influenza virus infection (including zoonotic influenza) with or at risk of severe illness, based on very low-quality evidence. This recommendation is based on observational studies, and acknowledges the signal for increased risk of mortality with corticosteroids (although this finding is confounded by indication and time-dependent biases). However, corticosteroids should still be considered for other concurrent indications, when consistent with other recommendations (e.g., septic shock, asthma exacerbations, COPD).[130]

  • One 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.[148]

  • Corticosteroid use was associated with prolonged detection of A(H7N9) viral RNA in hospitalized patients.[136]

Antiviral resistance

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.[32][33][34][36][37][114][149] 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 antiviral treatment, it is recommended that monitoring of Asian lineage A(H7N9) virus replication and shedding is performed, along with antiviral drug susceptibility testing. Contacting local or national public health departments for guidance is highly recommended.

Use of this content is subject to our disclaimer