Clinico-epidemiological evaluation is required to guide diagnostic testing for Asian lineage A(H7N9) virus infections. In most H7N9 cases there is history of exposure to poultry in endemic areas, including visiting markets where poultry are sold live or slaughtered or through contact with backyard chickens, which can be useful in case recognition because the clinical and radiological features are non-specific and mimic other causes of viral and bacterial pneumonia.
If there is concern that a patient might be infected with Asian lineage A(H7N9) virus, recommended infection prevention and control precautions should be implemented as soon as possible, including patient isolation and the use of personal protective equipment by healthcare workers and family member carers (face mask, goggles, disposable gown, and gloves). Due to the potential to cause severe disease, suspected H7N9 infection is notifiable, and public health experts should be involved early. Positive laboratory results for human infection with any avian influenza A virus should also be reported to the World Health Organization (WHO) under the International Health Regulations.
Influenza disease in humans is caused primarily by infection of the respiratory tract by influenza viruses. Of four known types of influenza viruses, three types (A, B, C) are known to infect humans, with influenza A and B virus infections most clinically significant. Seasonal influenza epidemics during colder periods in temperate climates result in a spectrum of illness, from asymptomatic infection to upper respiratory tract illness with or without fever and exacerbation of chronic illness, and may progress to severe and fatal complications.
Patients with Asian lineage A(H7N9) virus infection can present with signs and symptoms of pneumonia similar to those caused by other pathogens (including influenza A[H1N1]pdm09 and other seasonal influenza A or B viruses). There is a wide spectrum of disease ranging from asymptomatic infection, to sub-clinical or only mild symptoms, to severe respiratory compromise and death. However, most patients with Asian lineage A(H7N9) virus infection have required hospitalisation for management of pneumonia and/or respiratory failure. In contrast to the late clinical presentation that is seen with highly pathogenic avian influenza (HPAI) A(H5N1) virus infection, some Asian lineage low-pathogenic avian influenza (LPAI) A(H7N9) virus-infected patients have presented to medical care soon after onset of symptoms. Similar to HPAI A(H5N1) cases, initiation of antiviral therapy has been delayed in many patients with LPAI A(H7N9) virus infection (median 6 days; range 0-15 days).
Given that human infection with Asian lineage A(H7N9) virus appears to be rare (even among people with high-risk exposures within China) diagnostic evaluation and therapy must consider alternative aetiologies.
The median incubation period of Asian lineage LPAI A(H7N9) viruses in infected humans following poultry exposures has been estimated to be between 3 to 4 days and 6 days (range: 1-10 days) in different studies. In all countries, Asian lineage A(H7N9) virus infection should be considered in patients who develop acute febrile respiratory illness within 10 days of potential exposure to the virus. Exposure risks include a history of travel within 10 days of symptom onset to an area where Asian lineage A(H7N9) viruses are known to be circulating in animals (e.g., poultry) or humans, or exposure to wild or domestic animals or having visited environments in affected areas, such as markets or farms where live animals (especially poultry) are kept, sold, or slaughtered. Asian lineage A(H7N9) virus infection should also be considered in healthcare workers and close contacts who develop compatible symptoms within 10 days of contact with a suspected or confirmed case of Asian lineage A(H7N9) virus infection. To date, all acquisition of A(H7N9) virus infection in humans has occurred in China. The WHO advises that clinicians in China and neighbouring countries should consider testing for Asian lineage A(H7N9) virus infection in hospitalised patients with severe unexplained acute respiratory illness. Similarly, because exported cases of Asian lineage A(H7N9) virus infection acquired in China have been identified in Taiwan, Malaysia, and Canada, a history of potential exposure to poultry should be asked of any patient who has recently travelled to China and presents with severe unexplained acute respiratory illness.
Early illness is manifested by signs and symptoms consistent with a febrile upper respiratory tract infection. A dry or productive cough and dyspnoea are common symptoms. Non-specific symptoms consistent with influenza-like illness have been reported (headache, sore throat, myalgia, and fatigue). Clinical progression to severe lower respiratory tract disease occurs in many patients during days 3 to 6 of illness. Clinically mild disease (fever and symptoms of upper respiratory infection) has been described. At admission, most patients have fever and clinical findings similar to community-acquired pneumonia. In a series of 111 patients, 13.5% reported diarrhoea or vomiting.
Most patients admitted to hospital with Asian lineage LPAI A(H7N9) virus infection have experienced severe lower respiratory tract disease, often with multi-organ dysfunction or failure (renal, respiratory, hepatic, and cardiac). Other reported complications include haemophagocytosis, shock requiring vasopressor support, and disseminated intravascular coagulation. Acute respiratory distress syndrome and/or multi-organ failure is a common feature of fatal cases. Clinical data for Asian lineage HPAI A(H7N9) virus infections are limited, due to the small number of cases identified and reported.
Physical examination findings in severe illness associated with Asian lineage A(H7N9) virus infection are usually similar to those seen in severe pneumonia due to other aetiologies. They typically include raised body temperature ≥38°C (≥100.4°F), tachypnoea, and abnormalities on chest auscultation (which may include rales, wheezing, and focal decreased breath sounds). Based on clinical experience of severe influenza A virus infections, clinicians should be aware of atypical presentations of Asian lineage A(H7N9) virus infection such as altered mental status, seizures, and febrile diarrhoeal illness progressing to pneumonia.
Mild illness with Asian lineage A(H7N9) virus infection may be indistinguishable from uncomplicated human influenza virus infection. Physical examination findings include upper respiratory tract and constitutional signs and symptoms such as fever, cough, headache, and malaise. In contrast to illness caused by other influenza viruses, initial conjunctivitis appears to be uncommon in Asian lineage A(H7N9) virus infection.
Because Asian lineage A(H7N9) virus infection is much less common than infection due to other respiratory viruses including seasonal influenza viruses, it is critical that diagnostic evaluation also includes work-up for a broad range of more common disease processes that may also present as febrile respiratory illness, and investigation for endemic pathogens from the region where infection may have occurred.
First-line evaluation of patients suspected of having Asian lineage A(H7N9) virus infection should include the following.
Laboratory tests, including at least an FBC with differential, basic chemistries, and hepatic enzymes: common findings in severe cases may include normal white cell count or mild leukopenia, lymphopenia, and mild to moderate thrombocytopenia, but these laboratory findings are not present in all cases and are unable to differentiate between illness caused by Asian lineage A(H7N9) virus and illness caused by other respiratory pathogens.
Chest radiograph: lung infiltrates may be present, but a normal chest radiograph does not exclude the possibility of Asian lineage A(H7N9) virus infection.
Pulse oximetry: should be performed in patients with dyspnoea to assess their oxygenation status, as well as arterial blood gas analysis if considered necessary.
Sputum Gram stain and bacterial culture, and blood culture: should be performed as part of the evaluation for community-acquired primary bacterial pneumonia and potential bacterial co-infection. Urinary antigen testing for Streptococcus pneumoniae and Legionella pneumophila may also be considered.
Respiratory virus testing depending upon local surveillance and epidemiological data (e.g., seasonal influenza A and B viruses): other respiratory virus testing may be indicated (e.g., for respiratory syncytial virus, parainfluenza virus, and multiple virus aetiologies in immunocompromised patients).
Patients presenting with atypical signs and symptoms (e.g., affecting gastrointestinal or neurological systems) should receive a suitable work-up directed at alternative aetiologies for those processes.
Local or national guidelines for safely obtaining and testing samples should be followed. Guidance is available from the WHO website if local/national guidelines are not immediately available. WHO: WHO information for molecular diagnosis of influenza virus - update. external link opens in a new window
We recommend that clinicians consider more common causes of influenza-like illness and community-acquired pneumonia whenever they encounter a patient they suspect has Asian lineage A(H7N9) virus infection. As always, work-up should be directed towards abnormal clinical findings. Other travel-associated infections relevant to the area visited should also be considered, as appropriate.
Specific viral testing
The recommended and definitive test for detecting Asian lineage A(H7N9) virus is reverse transcription polymerase chain reaction (RT-PCR) of respiratory specimens, including real-time or conventional RT-PCR, and using specific primers and probes. Asian lineage A(H7N9) virus strains have demonstrated genetic evolution over time, so testing by RT-PCR using up-to-date primers and probes is essential. However, RT-PCR for A(H7N9) viruses is usually not available in many clinical settings, where detection of non-subtyped influenza A virus is more typical. Many regional public health laboratories, most national laboratories, and some private laboratories can perform RT-PCR for A(H7N9) virus, or RT-PCR for avian A(H7) viruses with subsequent virus characterisation by genetic sequencing. If subtyping of a detected influenza A virus has been attempted locally, but seasonal A(H1) and A(H3) viruses could not be detected ('unsubtypable influenza A'), the sample should be referred to a reference laboratory for further characterisation.
In non-intubated patients, the preferred respiratory specimens are nasal, nasopharyngeal, or oropharyngeal swabs. Healthcare workers collecting clinical specimens from patients with suspected A(H7N9) virus infection should follow recommended infection control precautions and use appropriate personal protective equipment.
Specific swabs are available to optimise the diagnostic yield for respiratory virus sampling (e.g., flocked Dacron swabs with plastic shafts that are placed in sterile viral transport medium). Using swabs with cotton tips or wooden shafts is not recommended because they may interfere with the RT-PCR assay. Swab specimens placed in bacterial transport medium (e.g., Amies swabs) are inappropriate samples for virus detection. Ideally, multiple respiratory specimens for testing should be collected from multiple respiratory sites from patients with suspected Asian lineage A(H7N9) virus infection, including over multiple days, because testing of single specimens may fail to detect Asian lineage A(H7N9) virus.
Intubated patients should also have endotracheal aspirates collected for Asian lineage A(H7N9) virus detection. Bronchoscopy and thoracocentesis are not recommended procedures for the sole purpose of collecting clinical specimens, but if collected for other diagnostic purposes, bronchoalveolar lavage fluid specimens and pleural fluid can also be tested.
National public health agencies have many useful online resources to assist clinicians to determine whether a particular patient should have clinical specimens tested for Asian lineage A(H7N9) virus, and typically they have medical officers available to consult and assist clinicians in the evaluation, testing, and case management of suspected or confirmed human Asian lineage A(H7N9) virus infection. The RT-PCR assay may take several hours to produce preliminary results, but transport time and testing logistics may delay testing results. Viral culture (isolation) should only be performed by an experienced, biosafety level 3-enhanced laboratory or greater following recommended personal protective equipment and infection control precautions.
Currently available, point-of-care, rapid influenza diagnostic tests lack satisfactory sensitivity and specificity for detecting A(H7N9) virus and, therefore, should not be used for diagnosis of Asian lineage A(H7N9) virus infection. Molecular assays for influenza that are available in clinical settings have high sensitivity for detecting influenza A viruses in respiratory specimens, but cannot specifically identify or distinguish A(H7N9) virus from seasonal influenza A viruses.
Analysis of paired acute and convalescent sera, collected approximately 2 to 3 weeks apart and tested using specific serological assays, can potentially yield a retrospective diagnosis of Asian lineage A(H7N9) virus infection in a patient with clinically compatible illness, but cannot inform clinical management decisions. All positive tests on human clinical specimens for Asian lineage A(H7N9) virus should be confirmed by a designated public health reference laboratory. Positive laboratory results for human infection with any avian influenza A viruses (e.g., H7N9, H5N1, H5N6, H10N8 viruses) should be reported to the WHO under the International Health Regulations.
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