Influenza laboratory findings

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohammad Braizat, M.S. [2]

Influenza Laboratory Findings

This microchapter covers influenza-specific diagnostic testing and routine (nonspecific) laboratory abnormalities observed in patients with influenza. It does not cover imaging findings or the clinical features of influenza (see History and Symptoms, Physical Examination).

Influenza-Specific Diagnostic Testing

When to Test

Diagnostic testing for influenza should be considered when results will inform clinical management or infection control decisions. Per the Infectious Diseases Society of America (IDSA) and CDC, testing is recommended in the following scenarios:

• Hospitalized patients with suspected influenza (molecular assays preferred)
• Outpatients for whom a diagnosis of influenza will change clinical management (e.g., antiviral prescribing, antibiotic stewardship)
• Institutional outbreaks (nursing homes, hospitals, cruise ships) where results will guide infection control measures
• Patients not improving on antiviral therapy or those at high risk for complications

Most patients with uncomplicated influenza-like illness during periods of known community influenza circulation do not require testing for empiric clinical management. Empiric antiviral treatment should not be delayed while awaiting test results in priority groups (hospitalized patients, those with severe/progressive illness, high-risk outpatients).

Specimen Collection

• Preferred specimens: Nasopharyngeal swab or aspirate; mid-turbinate nasal swab or combined nasal and throat swabs are acceptable alternatives depending on the assay.
• Timing: Specimens should be collected as close to illness onset as possible, ideally within 4 days of symptom onset. Viral RNA may be detectable for longer periods in young children and immunocompromised patients.
• Lower respiratory tract specimens (BAL, endotracheal aspirate, sputum) should be tested in hospitalized patients with respiratory failure if upper respiratory specimens are negative.
• Transport: Specimens should be placed in viral transport medium or sterile container and transported at room temperature (or on wet ice for culture) within 24 hours.
• Specimen type impact: RIDT sensitivity varies by specimen type: nasopharyngeal swabs > nasal swabs > throat swabs. Anterior nares swabs are acceptable for some assays but may have lower sensitivity.

Diagnostic Testing Methods

Nucleic acid amplification tests (NAATs), including RT-PCR, are considered the gold standard for influenza virus detection due to their high sensitivity and specificity. The IDSA/ASM 2024 guidelines and the IDSA 2018 clinical practice guidelines recommend:

• Rapid molecular assays (nucleic acid amplification, results in 15–30 minutes) for outpatient/point-of-care settings
• RT-PCR and multiplex molecular assays (results in 1–8 hours) for hospitalized patients

The following table summarizes available influenza testing methods:

Testing Category	Method	Viruses Detected	Distinguishes Influenza A Subtypes	Time to Results	Performance
Rapid molecular assay	Nucleic acid amplification	Influenza A or B viral RNA	No	15–30 min	High sensitivity; high specificity
Rapid influenza diagnostic test (RIDT)	Antigen detection	Influenza A or B virus antigens	No	10–15 min	Moderate sensitivity (higher with analyzer reader device); high specificity
Direct/indirect immunofluorescence	Antigen detection	Influenza A or B virus antigens	No	2–4 h	Moderate sensitivity; high specificity
Molecular assays (including RT-PCR)	Nucleic acid amplification	Influenza A or B viral RNA	Yes, if subtype primers used	1–8 h	Very high sensitivity; very high specificity
Multiplex molecular assays	Nucleic acid amplification	Influenza A or B RNA + other targets	Yes, if subtype primers used	1–2 h	High sensitivity; high specificity
Rapid cell culture (shell vials)	Virus isolation	Influenza A or B virus	Yes	1–3 days	High sensitivity; high specificity
Viral tissue cell culture	Virus isolation	Influenza A or B virus	Yes	3–10 days	High sensitivity; high specificity

Adapted from IDSA/AAP/CDC guidance. Specificities are generally >90% for all methods compared with RT-PCR.

Rapid Influenza Diagnostic Tests (RIDTs)

RIDTs are immunochromatographic antigen-detection assays that provide results in 10–15 minutes. Key performance characteristics:

• Sensitivity: Pooled sensitivity for influenza A is approximately 54% (traditional RIDTs), 80% (digital immunoassays/DIAs), and 92% (rapid NAATs); for influenza B, approximately 53%, 77%, and 95%, respectively. Sensitivities are higher in children than adults by 12–32 percentage points.
• Specificity: Uniformly high (>98%) across all rapid test categories.
• RIDTs may perform poorly in detecting certain strains (e.g., pandemic H1N1, swine-associated H3N2 variants).
• Negative RIDTs should not be used to rule out influenza, particularly during peak influenza activity. Confirmation with a molecular assay is recommended when clinical decisions depend on the result.

Interpreting Results in the Context of Prevalence

• Low prevalence periods (beginning/end of influenza season): False-positive results are more likely; positive predictive value (PPV) is reduced. Positive results should be interpreted cautiously and confirmed if clinically important.
• High prevalence periods (peak season): False-negative results are more likely; negative predictive value (NPV) is reduced. A negative RIDT should not exclude influenza in a clinically compatible case.

Multiplex Assays

Multiplex molecular assays that simultaneously detect influenza A, influenza B, SARS-CoV-2, and/or RSV are widely available and particularly useful when multiple respiratory viruses are cocirculating. These assays aid in:

• Identifying coinfections (influenza + SARS-CoV-2)
• Guiding pathogen-specific antiviral therapy
• Antimicrobial stewardship

Over-the-counter at-home multiplex antigen tests (influenza A/B + SARS-CoV-2) are available under FDA emergency use authorization for symptomatic individuals aged ≥2 years. Independent testing data show influenza A sensitivity of OTC lateral flow assays ranges from 0.64–0.85 in field studies; negative results should not definitively exclude influenza in symptomatic patients during peak season.

Avian Influenza A Subtyping

Most clinical influenza tests do not distinguish avian influenza A(H5) from seasonal influenza A. When an influenza A–positive specimen cannot be subtyped as seasonal A(H1) or A(H3), further testing at a public health laboratory should be pursued within 24 hours to evaluate for influenza A(H5), per CDC guidance (January 2025).

Serologic Testing

Serologic testing requires paired acute and convalescent sera, does not provide timely results for clinical decision-making, and is not recommended for routine diagnosis. It is reserved for vaccine studies and epidemiological investigations. Single-specimen serology is not interpretable due to high rates of prior vaccination and natural exposure.

Viral Culture

Viral culture (3–10 days for conventional; 1–3 days for rapid shell vial) does not yield timely results for clinical management but remains essential for antigenic characterization, antiviral resistance surveillance, and candidate vaccine virus development.

Routine (Nonspecific) Laboratory Findings

Routine laboratory values in influenza are often normal in uncomplicated cases. Abnormalities are more common in severe, complicated, or hospitalized cases and may serve as markers of disease severity rather than diagnostic tools.

Hematologic Findings

• Leukopenia: White blood cell count may be normal or mildly decreased in seasonal influenza. Leukopenia is more pronounced in avian influenza (H5N1, H7N9). Neutropenia has also been reported in hospitalized patients, particularly in children.
• Lymphopenia: Present in >50% of hospitalized patients with influenza pneumonia, regardless of bacterial coinfection. Lymphopenia and thrombocytopenia were prognostic indicators for ARDS and death in H5N1 and H7N9 case series.
• Thrombocytopenia: Reported in up to 73% of H7N9 patients. In seasonal influenza, severe cytopenias (hemoglobin ≤9 g/dL, platelets <100,000/µL, or absolute lymphocyte count <600/µL) occur in approximately 21% of hospitalized patients and are independently associated with respiratory failure and death. These thresholds correspond to the hematologic criteria used in the HLH-04 diagnostic framework, though meeting one cytopenia criterion does not equate to a diagnosis of hemophagocytic lymphohistiocytosis.

Biochemical Findings

• Elevated lactate dehydrogenase (LDH): LDH >225 U/L was independently associated with poor outcomes in hospitalized adults.
• Elevated transaminases (AST, ALT): Transient hepatic transaminase elevations occur in 16–26% of patients with seasonal influenza and in up to 66% of patients with avian influenza (H7N9). Liver injury correlates with disease severity, hypoxemia, and systemic inflammation rather than direct hepatotropism. Cholestatic markers (bilirubin, GGT) are typically not elevated.
• Elevated creatine kinase (CK): Reflects myositis or rhabdomyolysis, reported in approximately 8–22% of cases. Rhabdomyolysis was present in ~10% of H7N9 patients.
• Electrolyte abnormalities: Hyponatremia, hypokalemia, and hypocalcemia have been described in severe cases, particularly avian influenza.
• Hypoalbuminemia: Common in severe cases, reflecting systemic inflammation and capillary leak.

Inflammatory Markers

• C-reactive protein (CRP): Frequently elevated, particularly in pneumonia. CRP levels correlate with disease severity. One study of H1N1 pneumonia found that a CRP cutoff of ~86.5 mg/L had sensitivity of 82% and specificity of 59% for distinguishing bacterial coinfection from primary influenza pneumonia; however, these cutoffs are from a single small study and should be interpreted with caution.
• Procalcitonin (PCT): Typically low (<0.25 μg/L) in pure viral infection, but may be elevated in severe viral illness. No single PCT threshold perfectly discriminates viral from bacterial coinfection in influenza; pooled sensitivity for PCT in distinguishing bacterial from viral pneumonia is only 0.55 (95% CI 0.43-0.66) with specificity of 0.76 (95% CI 0.68-0.82). In a study of 2,075 patients with pure viral infection versus 179 with bacterial coinfection, PCT was a better indicator of disease severity than bacterial coinfection; after matching for severity, specificity dropped from 72% to 61%. PCT should not be used in isolation to rule out bacterial coinfection.
• Erythrocyte sedimentation rate (ESR): May be elevated but is nonspecific.
• Ferritin: Markedly elevated in severe cases, particularly those with hypertransaminasemia, suggesting systemic inflammatory involvement.

Coagulation Abnormalities

Prolonged PT and APTT, elevated D-dimer concentrations, and decreased fibrinogen have been described in severe influenza, particularly avian strains, and may indicate disseminated intravascular coagulation (DIC) or hemophagocytic lymphohistiocytosis (HLH).

Clinically Actionable Recommendations

1. For hospitalized patients with suspected influenza, use molecular assays (RT-PCR or multiplex NAAT) rather than RIDTs. 2. For outpatients, rapid molecular assays (15–30 min) are preferred over RIDTs when available. If only RIDTs are available, confirm negative results with molecular testing during peak influenza activity. 3. Interpret all test results in the context of community influenza prevalence. A negative RIDT during peak season does not exclude influenza; a positive RIDT during low-prevalence periods warrants confirmation. 4. Routine laboratory tests (CBC, metabolic panel, LDH, CRP) are not diagnostic for influenza but may help assess severity in hospitalized patients. Lymphopenia, thrombocytopenia, elevated LDH, and elevated transaminases are associated with worse outcomes. 5. Procalcitonin should not be used in isolation to rule out bacterial coinfection in influenza, as it may be elevated in severe viral illness and has limited discriminative ability. 6. For suspected avian influenza A(H5), if an influenza A–positive specimen is not subtypable as seasonal H1 or H3, notify public health authorities and pursue testing at a public health laboratory within 24 hours.

Common Pitfalls

• Relying on a negative RIDT to exclude influenza during peak season, leading to missed diagnoses and delayed antiviral therapy.
• Ordering viral culture for clinical decision-making — culture results take 3–10 days and cannot guide acute management.
• Using procalcitonin alone to rule out bacterial coinfection in a patient with severe influenza — PCT has limited discriminative ability and may be elevated in severe viral illness.
• Failing to consider avian influenza A(H5) when an influenza A specimen does not subtype as seasonal H1 or H3, particularly in patients with poultry/animal exposure.
• Interpreting a positive RIDT as definitive during low-prevalence periods without considering the reduced positive predictive value.
• Not testing lower respiratory specimens in intubated patients with negative upper respiratory testing.

Areas of Uncertainty

• Optimal procalcitonin and CRP cutoffs for distinguishing bacterial coinfection from primary influenza pneumonia remain poorly defined, with modest sensitivity and specificity across studies.
• Performance of RIDTs varies by circulating strain, and sensitivity estimates from meta-analyses may not reflect performance against novel or drifted strains in any given season.
• Lower respiratory tract testing: The incremental yield of BAL or endotracheal aspirate testing when upper respiratory specimens are negative is supported by expert opinion and limited observational data rather than randomized trials.