Avian influenza: Clinical manifestations and diagnosis

INTRODUCTION — The clinical manifestations of avian influenza are determined in part by the pathogenicity of the virus and subtype. The classification of avian influenza viruses as high pathogenicity avian influenza (HPAI) or low pathogenicity avian influenza (LPAI) viruses is based on specific molecular criteria and pathogenicity in birds [1]. Both HPAI and LPAI viruses are capable of causing caused a wide range of human disease. Avian influenza virus subtypes H5N1 and H7N9 have been associated with the greatest public health impact, numerically as well as in terms of disease severity.

The clinical manifestations and diagnosis of avian influenza will be reviewed here. The epidemiology, transmission, treatment, and prevention of avian influenza are discussed separately. (See "Avian influenza: Epidemiology and transmission" and "Avian influenza: Treatment and prevention" and "Avian influenza vaccines".)

EPIDEMIOLOGY AND RISK FACTORS — Risk factors for human infection with avian influenza viruses include [2] (see 'Whom to test' below):

●Close exposure or direct contact with infected live poultry (well appearing or sick) or poultry products

●Close, unprotected exposure to a person with avian influenza virus infection and respiratory illness

Issues related to transmission are discussed further separately. (See "Avian influenza: Epidemiology and transmission", section on 'Transmission'.)

CLINICAL MANIFESTATIONS

Incubation period — The incubation period for human infection with avian influenza H5N1 and H7N9 viruses is generally three to five days but may be as long as 7 to 10 days [3-7].

General principles — The spectrum of manifestations associated with avian influenza infection is broad and depends on the specific virus as well as host characteristics. Infected individuals may be asymptomatic or present with a range of manifestations including mild focal illness (such as conjunctivitis), uncomplicated upper respiratory illness, or fulminant pneumonitis with multiorgan failure [1].

Signs and symptoms may include fever, cough, dyspnea, chest pain, and myalgia; malaise, headache, diarrhea, and sore throat can occur but are less common. Gastrointestinal manifestations such as abdominal pain, vomiting, and diarrhea are variable.

Complications may include pneumonia, respiratory failure, acute kidney injury, rhabdomyolysis, disseminated intravascular coagulation, meningoencephalitis, and coinfection with bacterial or fungal pathogens.

Avian influenza H5N1 — H5N1 infection can result in mildly symptomatic illness to life-threatening disease. The clinical presentation may depend on several factors including the nature of the exposure and the virus clade [8-11]. Important features of prior H5N1 outbreaks include the predominance of children and young adults and the high mortality rate [12,13].

Signs and symptoms — Most common clinical presentations include fever and cough; other manifestations may include sore throat, nasal congestion, headache, myalgia, or diarrhea; uncommonly, conjunctivitis or bleeding gums may be observed [11,14,15]. Patients with gastrointestinal or central nervous system involvement in the absence of respiratory symptoms have also been described [16]. There have been several case reports of children with fatal encephalitis confirmed by polymerase chain reaction (PCR) detection of H5N1 virus in cerebrospinal fluid, usually in association with concurrent respiratory disease [16-18].

The following observations illustrate the range of findings:

●In the 1997 H5N1 outbreak in Hong Kong including 18 patients, 8 patients were <12 years of age and all but one had relatively mild disease [11,19]. The most severe infections occurred in patients >12 years of age.

●In a study including 67 hospitalized patients in Vietnam with clade 1 H5N1 influenza infection between 2004 and 2006, the median age was 25 [20]. Common manifestations were fever (75 percent), cough (89 percent), dyspnea (81 percent), bilateral pulmonary infiltrates (72 percent), lymphopenia (73 percent), and elevated aminotransferases concentrations (aspartate aminotransferase [AST], 69 percent; alanine aminotransferase [ALT], 61 percent). Diarrhea and mucosal bleeding at presentation were more common among patients who died. The risk of death was highest among individuals ≤16 years of age.

Risk factors associated with severe disease include delayed hospital admission and the presence of bilateral pneumonia [9-11,21]. In one study including 67 patients, neutropenia and increased ALT concentration at presentation were predictive of a fatal outcome [20].

Complications include multiorgan failure with renal dysfunction and cardiac compromise, pulmonary hemorrhage, pneumothorax, and pancytopenia [14,15]. Most deaths have been related to respiratory failure.

Laboratory and radiographic findings — Patients with severe disease often have leukopenia, neutropenia, lymphopenia, and thrombocytopenia on hospital admission [9-11,19-23]. Other laboratory abnormalities may include elevated levels of aminotransferases (AST>ALT) [9,10,20], lactate dehydrogenase, creatine kinase [9], and hypoalbuminemia [10].

Radiographic findings of H5N1 avian influenza include diffuse, multifocal, or patchy infiltrates, interstitial infiltrates, and segmental or lobular consolidation [15]. Pleural effusions are usually not seen [9,10]. Progression to respiratory failure is associated with diffuse bilateral ground-glass infiltrates [21].

Avian influenza H7N9

Signs and symptoms — Signs and symptoms may include fever, cough, dyspnea, headache, myalgia, and malaise [6,24-26]. Respiratory tract infection may progress to severe pneumonia [27,28].

●Severe disease − In case reports and case series, clinical features of severe include fulminant pneumonia, respiratory failure, acute respiratory distress syndrome (ARDS), septic shock, multiorgan failure, rhabdomyolysis, disseminated intravascular coagulation, and encephalopathy [5,25,29,30].

Various series have described cases of severe avian influenza A H7N9 infection [5,6,24,31-34].

In one study including 111 patients hospitalized with avian influenza A H7N9 infection in China, 77 percent were admitted to an intensive care unit and 27 percent died [24]. The most common presenting clinical manifestations were fever (100 percent) and cough (90 percent). The majority of patients had sputum production (56 percent) and shortness of breath (56 percent). Some (14 percent) had diarrhea or vomiting. At the time of admission, 97 percent had findings consistent with pneumonia. No patients had conjunctivitis, in contrast with past outbreaks of avian influenza H7 infection in the Netherlands and elsewhere. (See "Avian influenza: Epidemiology and transmission".)

The most common complications were moderate to severe ARDS (in 71 percent), shock (26 percent), acute kidney injury (16 percent), and rhabdomyolysis (10 percent) [24]. The median time from onset of illness to ARDS was 7 days (range 1 to 19 days) and from illness onset to shock was 8 days (range 3 to 55 days). Of the 79 patients with ARDS, 65 required mechanical ventilation, and, of these, 20 went on to receive extracorporeal membrane oxygenation. On multivariate analysis, the presence of a coexisting medical condition was the only independent risk factor for the development of moderate to severe ARDS (odds ratio 3.4, 95% CI 1.2-9.7).

●Mild or moderate disease − Most patients described with avian influenza A H7N9 infection have been severely ill; however, mild and moderate disease also occurs.

Using China's national sentinel surveillance system in outpatient clinics and emergency departments of 554 sentinel hospitals across 31 provinces, a subset of patients with influenza-like illness underwent testing for avian influenza A H7N9 via reverse transcription-PCR of nasopharyngeal swabs [35]. Among 130 individuals with laboratory-confirmed infection, 4 percent were detected using the sentinel surveillance system. The mean age of these patients was 13 years (range 2 to 26) and none had any underlying medical conditions. All presented with fever and most had upper respiratory tract symptoms; one had pneumonia. Only two of the five patients required hospitalization and all recovered uneventfully.

●Asymptomatic infection – Most reports have shown that individuals in Asia generally lack pre-existing immunity to avian influenza A H7N9 [36-40]; however, some data suggest immunity in a subset of poultry workers [41,42]. In a surveillance study among 1129 individuals in H7N9 outbreak areas of China, no seropositivity for avian-origin H7N9 virus was observed; however, among 396 poultry workers, 6 percent had hemagglutination inhibition antibody titers ≥80, suggesting past or subclinical infection [41].

Laboratory and radiographic findings — In a study of 111 hospitalized patients with avian influenza A H7N9 infection, 88 percent had lymphopenia and 73 percent had thrombocytopenia [24]. The white blood cell count was normal or slightly decreased in most patients. Elevated levels of AST, ALT, lactate dehydrogenase, creatine kinase, and C-reactive protein have been reported [24,34].

On chest radiograph and computed tomography (CT) scanning, patients with pneumonia have had multilobar patchy consolidations and diffuse ground-glass opacities (image 1 and image 2) [24,25,43-45]. Other CT findings may include air bronchograms, interlobular septal thickening, centrilobular nodules, reticular opacities, cystic changes, bronchial dilatation, and subpleural linear opacities [43].

Other avian influenza strains

●Avian influenza H5N6 − Avian influenza H5N6 viruses have been isolated from several individuals in China since 2014; patients have presented with a spectrum of clinical manifestations ranging from mild respiratory symptoms to severe pneumonia and death [46-50].

●Avian influenza H6N1 − Avian influenza H6N1 was isolated from a previously healthy 20-year-old woman with who presented with lower respiratory symptoms and pneumonia [51].

●Avian influenza H7 − Avian influenza H7N7 and H7N3 appear to have a predilection for conjunctival epithelium and may present with isolated conjunctivitis following direct contact with poultry or contaminated material (such as feathers, feces, or eggs) [52-54]. In one survey of poultry workers and their families potentially exposed during the 2003 Netherlands H7N7 outbreak, 349 individuals had conjunctivitis (among whom 83 cases of avian influenza H7N7 were confirmed), while 90 individuals had symptoms of influenza-like illness (among whom 5 cases of avian influenza H7N7 were confirmed) [52].

●Avian influenza H9N2 − Children infected with avian H9N2 influenza viruses have presented with mild, self-limited upper respiratory illnesses [50,55-57].

●Avian influenza H10 – Avian influenza H10N3, H10N7, and H10N8 have been isolated from individuals presenting with respiratory symptoms ranging from self-limiting mild upper respiratory tract illness to fatal, severe rapidly progressive pneumonia [58-61].

DIAGNOSIS

Case definitions — The United States Centers for Disease Control and Prevention (CDC) has outlined the following case definitions for avian influenza [62]:

●Confirmed Case – A person with laboratory confirmed avian influenza A virus infection.

●Suspected Case (also called Case Under Investigation) – A person meeting clinical and epidemiologic criteria for avian influenza A virus infection (see 'Whom to test' below) and for whom confirmatory laboratory test results are unknown or pending.

●Probable Case – A person meeting clinical and epidemiologic criteria for avian influenza A virus infection (see 'Whom to test' below) and for whom laboratory test results do not provide sufficient level of detail to confirm avian influenza virus infection.

Whom to test — The diagnosis of avian influenza should be suspected in patients who present with clinical criteria and epidemiologic criteria as outlined below [62]. Patients being evaluated for avian influenza should begin empiric antiviral treatment and be placed on appropriate infection control precautions. (See "Avian influenza: Treatment and prevention".)

●Clinical criteria − Clinical criteria include any of the following [62]:

•Mild flu-like illness (cough, sore throat, fever or feeling feverish, rhinorrhea, fatigue, myalgia, arthralgia, headache) or conjunctivitis (red eye, discharge from eye)

•Moderate to severe illness including shortness of breath or difficulty breathing, altered mental status, seizures

•Complications including pneumonia, respiratory failure, acute respiratory distress syndrome, multiorgan failure, or meningoencephalitis

●Epidemiologic criteria – Epidemiologic criteria include any of the following [62]:

•Exposure to infected birds – Recent (within ten days of illness onset), close (within two meters), and unprotected (without use of respiratory and eye protection) exposure to sick or dead birds with confirmed avian influenza virus infection by A(H5), A(H7), or A(H9) viruses; birds include including poultry, wild aquatic birds, or captive birds of prey that have had contact with aquatic birds. Exposure includes any of the following [63]:

-Handling, slaughtering, defeathering, butchering, culling, or preparation of birds for consumption

-Direct contact with surfaces contaminated by infected bird secretions, excretions, or remains

-Visiting a live poultry market with confirmed bird infection or associated with a case of human infection [64]

•Exposure to an infected person − Recent (within 10 days of illness onset), close (within two meters), and unprotected (without use of respiratory and eye protection) exposure to a person who is a confirmed, suspected, or probable case of avian influenza virus. (See 'Case definitions' above.)

•Exposure to secretions of an infected person – Direct, unprotected (without use of respiratory and eye protection) exposure to secretions from an infectious patient (beginning one day prior to symptom onset and continuing until symptoms resolve).

Choice of test

Preferred approach — Testing for suspected avian influenza should be performed via real-time reverse-transcriptase polymerase chain reaction (RT-PCR) on a respiratory specimen [2]. The specimen should be sent to the state or regional health laboratory for RT-PCR to detect influenza virus ribonucleic acid (RNA) and to distinguish between seasonal and avian influenza. In the United States, specimens may be sent to the CDC for confirmatory testing.

Commercially available influenza tests are not capable of distinguishing between seasonal influenza A viruses (circulating among humans) and zoonotic avian influenza A viruses.

Initial diagnostic testing may be negative; RT-PCR testing should be repeated if there is a high index of suspicion [9,64]. The sensitivity and specificity of RT-PCR for diagnosis of avian influenza are 95 to 99 percent [65,66].

●Specimen type – An upper respiratory tract specimen should be obtained; acceptable specimens include [2]:

•A nasopharyngeal swab, or

•A nasal aspirate or wash, or

•A nasal or nasopharyngeal swab combined with an oropharyngeal swab into one transport media vial

If it is not possible to obtain one of the above specimen types, a single nasal swab or oropharyngeal swab may be used.

For patients with lower respiratory tract involvement, a lower respiratory tract specimen (eg, an endotracheal aspirate or bronchoalveolar lavage fluid) should be obtained.

●Specimen collection − Respiratory specimens should be obtained using a swab with a synthetic tip (eg, polyester or Dacron) and an aluminum or plastic shaft; swabs with calcium alginate or cotton tips are not recommended [64].

Specimens should be placed in sterile viral transport medium and shipped immediately (on ice or frozen at -70°C and then shipped on dry ice) to the biosafety level 3 laboratory.

Specimens from patients with suspected avian influenza must be handled and processed using appropriate biosafety precautions. Clinicians must alert laboratory personnel to ensure samples are processed at the appropriate facility [64,67]. Detailed recommendations for specimen handling can be found on the CDC website.

Other tests

●Serologic testing – In general, serologic testing is not helpful for diagnosis of avian influenza in acute clinical settings [68]. In such cases, serologic testing may be performed as an alternative approach if other diagnostic testing methods are not available.

Serologic testing may be useful for epidemiologic surveillance studies and retrospective diagnosis, via hemagglutinin-inhibition or microneutralization assays that detect an increase in specific antibodies in serum collected during the acute and convalescent phases of infection. A positive result consists of a fourfold or greater increase in antibody titer between a sample obtained as soon as possible after the onset of symptoms and another obtained after at least 14 days.

●Antigen tests – Rapid antigen detection assays should not be used for diagnosis of patients with suspected avian influenza [64,69]. These tests are less sensitive than RT-PCR and lack specificity in differentiating between seasonal and avian influenza [9,10,15,21].

●Viral culture – Viral culture is not recommended.

DIFFERENTIAL DIAGNOSIS

●Respiratory viral infection − Signs and symptoms of influenza frequently overlap with those of other respiratory viral infections and may be clinically indistinguishable in the absence of diagnostic testing.

•Seasonal influenza – Seasonal influenza is characterized by abrupt onset of fever, cough, and myalgia when influenza virus is circulating (in northern hemisphere, typically September to April; in southern hemisphere, typically April to September). The preferred diagnostic tool is a molecular assay (nucleic acid amplification test). (See "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Seasonal influenza in children: Clinical features and diagnosis".)

•Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) – It can be difficult to distinguish between influenza and COVID-19 based on clinical manifestations alone [70,71]. The diagnosis of COVID-19 is established via nucleic acid amplification testing or antigen testing. A positive test result for either influenza or COVID-19 does not rule out coinfection when both viruses are circulating. (See "COVID-19: Clinical features" and "COVID-19: Diagnosis".)

•Respiratory syncytial virus – Respiratory syncytial virus causes seasonal outbreaks of respiratory tract illness throughout the world, usually during the winter season. It is common among children but is also an important and often unrecognized cause of respiratory tract infection in older adults and immunocompromised patients. The diagnosis is established via a polymerase chain reaction-based assay. (See "Respiratory syncytial virus infection: Clinical features and diagnosis in infants and children".)

•Common cold − The common cold can be caused by several different viruses, including rhinoviruses, parainfluenza, and coronaviruses. Compared with influenza, cold symptoms are usually milder, nasal congestion is more common, and colds rarely result in serious health problems or complications. The diagnosis is based on clinical manifestations. (See "The common cold in adults: Diagnosis and clinical features".)

•Middle East respiratory syndrome coronavirus − Middle East respiratory syndrome coronavirus is a coronavirus causing severe respiratory illness that emerged in 2012 in Saudi Arabia and continues to cause infections, primarily on the Arabian peninsula. The diagnosis is established via nucleic acid amplification testing. (See "Middle East respiratory syndrome coronavirus: Clinical manifestations and diagnosis".)

●Bacterial pneumonia − Bacterial pneumonia may present as a complication of influenza or independently. Patients with bacterial pneumonia typically present with fever, dyspnea, cough, and sputum production. (See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Bird flu (avian influenza) (The Basics)")

SUMMARY

●Introduction − The clinical manifestations of avian influenza are determined in part by the pathogenicity of the virus. Avian influenza virus subtypes H5N1 and H7N9 have been associated with the greatest public health impact. (See 'Introduction' above.)

●Incubation period – The incubation period for human infection with avian influenza H5N1 and H7N9 viruses is generally three to five days, but may be as long as 7 to 10 days. (See 'Incubation period' above.)

●Diagnosis − The diagnosis of avian influenza should be suspected in patients who present with clinical and epidemiologic criteria as outlined below. Patients being evaluated for avian influenza should begin empiric antiviral treatment and be placed on appropriate infection control precautions. (See 'Diagnosis' above and "Avian influenza: Treatment and prevention".)

●Clinical criteria – Clinical criteria include any of the following (see 'Whom to test' above):

•Mild flu-like illness (cough, sore throat, fever, rhinorrhea, fatigue, myalgia, arthralgia, headache) or conjunctivitis

•Moderate to severe illness including shortness of breath or difficulty breathing, altered mental status, seizures

•Complications including pneumonia, respiratory failure, acute respiratory distress syndrome, multiorgan failure, or meningoencephalitis

●Epidemiologic criteria − Epidemiologic criteria include any of the following (see 'Whom to test' above):

•Exposure to infected birds − Recent (within 10 days of illness onset), close (within two meters), and unprotected (without use of respiratory and eye protection) exposure to sick or dead birds with confirmed avian influenza virus infection by A(H5), A(H7), or A(H9) viruses; birds include including poultry, wild aquatic birds, or captive birds of prey that have had contact with aquatic birds. Exposure includes any of the following:

-Handling, slaughtering, defeathering, butchering, culling, or preparation of birds for consumption

-Direct contact with surfaces contaminated by infected bird secretions, excretions, or remains

-Visiting a live poultry market with confirmed bird infection or associated with a case of human infection

•Exposure to an infected person − Recent (within 10 days of illness onset), close (within two meters), and unprotected (without use of respiratory and eye protection) exposure to a person who is a confirmed, suspected, or probable case of avian influenza virus. (See 'Case definitions' above.)

•Exposure to secretions of an infected person – Direct, unprotected (without use of respiratory and eye protection) exposure secretions from an infectious patient (beginning one day prior to symptom onset and continuing until symptoms resolve).

●Choice of test − Testing should consist of obtaining a respiratory specimen for reverse-transcriptase polymerase chain reaction to detect influenza virus RNA and to distinguish between seasonal and avian influenza. Such testing should be performed at a state or regional health laboratory; commercially available influenza tests are not capable of distinguishing between seasonal and avian influenza. Acceptable specimens are described above. (See 'Choice of test' above.)