Pathogenesis, Clinical Features and Diagnosis
Diagnosis of influenza
The accuracy of diagnosis of influenza tends to be strongly dependent on the physician's awareness of whether or not there is influenza activity in the local community. In clinical trials, accuracy of diagnosis during epidemics reached 62%, but may be as reliable as near-patient rapid testing (see below) when influenza is known to be circulating in the local community. Given the non-specific clinical presentation, the accuracy of diagnosis during epidemics is quite good. However, outside epidemic periods diagnostic accuracy may be less than 10%. Thus, it is important that primary-care physicians be aware of local influenza surveillance data (see list of websites in
The differential diagnosis of an influenza-like illness (ILI) includes a variety of viruses (e.g. respiratory syncytial virus, parainfluenza virus, rhino- and coronaviruses, adenoviruses) and bacteria (e.g. mycoplasma, chlamydia, rickettsia).
Proper and rapid diagnosis is essential to control influenza infection by antiviral treatment and to avoid the inappropriate use of antibiotics – the latter is a perennial problem, particularly in southern European countries. Accurate diagnosis is also very important for selection of vaccine virus strains and for the purposes of influenza surveillance.
Table 7 lists the criteria for purposes of clinical diagnosis of influenza that have been used in trials of antiviral drugs. Additional criteria are used in epidemiological studies to estimate attack rates and vaccine effectiveness, and to define clinical case definitions during the peak influenza period. 29 x KL Nichol, P Mendelman. Influence of clinical case definitions with differing levels of sensitivity and specificity on estimates of the relative and absolute health benefits of influenza vaccination among healthy working adults and implications for economic analyses. Virus Res 103 (2004) (3 - 8) Crossref. The most specific clinical case definition of influenza is “febrile upper respiratory illness” (URI), defined as 2 days of URI symptoms (runny nose, sore throat, cough) with two or more symptoms on at least 1 day and fever on at least 1 day.
Table 7 source: Reproduced from Nicholson KG. Managing Influenza in Primary Care, 1999 with permission from Blackwell Publishing.
|Criteria for clinical diagnosis of influenza|
|Fever (≥ 37.8°C) and/or feverishness|
References in context
Table 7 lists the criteria for purposes of clinical diagnosis of influenza that have been used in trials of antiviral drugs.
Go to context
A case definition of intermediate sensitivity and specificity is “any URI”, defined as 2 days of at least one URI symptom (runny nose, sore throat, cough). The most sensitive clinical case definition of influenza is “any URI symptom”, defined as any 1 day with at least one symptom (fever, runny nose, sore throat, cough, headache, muscle aches, chills, tiredness/weakness). The specificity of these case definitions is highly dependent on the attack rates of influenza in the community.
Thus, in conclusion, up-to-date tracking and awareness of circulating influenza in the local community is the single most important factor in the diagnostic accuracy of influenza as the cause of an acute respiratory tract illness.
Diagnostic tests available for influenza include virus isolation and culture, antigen or viral RNA detection, and serology. However, the sensitivity and specificity vary widely, and the positive and negative predictive value of these tests is highly dependent on whether or not influenza is circulating in the local community – the contribution of these tests to clinical diagnosis thus needs to be carefully considered. 30 x TM File. Community-acquired pneumonia. Lancet 362 (2003) (1991 - 2001) Crossref. Rapid influenza tests have been developed but have some limitations (see below under “Antigen detection”). Appropriate samples for influenza testing include nasopharyngeal or throat swabs, nasal wash or nasal aspirates, depending on which type of test is used. Samples should be collected within the first 4 days of illness. Acute and convalescent serum samples can be tested for influenza antibodies. Viral culture or reverse transcriptase–polymerase chain reaction (RT-PCR) remains essential for determining the influenza subtypes and strains causing illness.
Influenza viruses cause agglutination of erythrocytes due to the capacity of the viral HA to bind to sialic acid residues on the red blood cell surface (see
Virus isolation and culture
The influenza virus can be propagated from clinical specimens on cultured cells or in embryonated chicken eggs. Because influenza may not produce cytopathic effects in cell culture, the haemagglutinating activity of the virus (see above) in the culture supernatant is used as a measure to screen for viral replication. Also in eggs, virus replication produces haemagglutinating activity. The entire process of virus culture and detection takes about 4–5 days, although more rapid (less sensitive) methods are available.
Antigen can be detected by a variety of immunological techniques, including direct immunofluorescence of respiratory secretions, indirect antibody staining of exfoliated nasal epithelium or commercially available rapid influenza diagnostic tests. The latter differ in their ability to detect and distinguish between influenza A and B virus infections, methodologies, processing time and cost. The sensitivities of the rapid tests are lower than viral culture of respiratory specimens and may be comparable to symptom-defined illness when influenza is known to be circulating in the local community; a negative result might not exclude influenza virus infection. Rapid influenza tests provide results within 24 hours, while viral culture takes 4–5 days.
RNA detection by PCR
Although labour-intensive and usually slower than other tests, RT–PCR is used to type and subtype influenza infections. 31 x KE Templeton, SA Scheltinga, MF Beersma, AC Kroes, EC Claas. Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza A and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. J Clin Microbiol 42 (2004) (1564 - 1569) Crossref. Either clinical or cell culture specimens can be used. Multiplex PCR can differentiate between influenza A and B, parainfluenza 1, 2 and 3, and respiratory syncytial virus (RSV) with a very high degree of specificity (98%) and sensitivity (100%).
Influenza diagnosis in primary care
The diagnosis of influenza can be a particular challenge in the absence of surveillance data. Thus, the recommended approach for the patient who presents with an acute respiratory illness is to first determine whether or not a viral aetiology is likely according to the symptom criteria, and whether or not influenza is circulating in the local community. During an influenza outbreak, the primary-care physician can make the diagnosis of influenza based on clinical diagnostic criteria with similar diagnostic accuracy to that provided by the current rapid diagnostic tests. However, these tests may be helpful in the early stage of an influenza outbreak to identify sentinel cases. In addition, the collection of patient samples for virus culture and identification is critical to maintaining the network for influenza surveillance that determines the onset, peak and resolution of an influenza activity in the community. 32 x TJ Meerhoff, A Meijer, WJ Paget. Methods for sentinel virological surveillance of influenza in Europe – an 18-country survey. Eur Surveill 9 (2004) (1 - 4) The primary mode of influenza prevention is vaccination (see
References in context
|KL Nichol, P Mendelman.||Influence of clinical case definitions with differing levels of sensitivity and specificity on estimates of the relative and absolute health benefits of influenza vaccination among healthy working adults and implications for economic analyses. Crossref.||Virus Res 103 (2004) (3 - 8)||2004|
References in context
|TM File.||Community-acquired pneumonia. Crossref.||Lancet 362 (2003) (1991 - 2001)||2003|
|KE Templeton, SA Scheltinga, MF Beersma, AC Kroes, EC Claas.||Rapid and sensitive method using multiplex real-time PCR for diagnosis of infections by influenza A and influenza B viruses, respiratory syncytial virus, and parainfluenza viruses 1, 2, 3, and 4. Crossref.||J Clin Microbiol 42 (2004) (1564 - 1569)||2004|
References in context
|TJ Meerhoff, A Meijer, WJ Paget.||Methods for sentinel virological surveillance of influenza in Europe – an 18-country survey.||Eur Surveill 9 (2004) (1 - 4)||2004|
|CW Potter.||Chronicle of influenza pandemics.||KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, Oxford, 1998) (3 - 18)||1998|