Diagnosis and Treatment of Influenza: Rapid Tests and Antiviral Options
By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA, is Editor for Infectious Disease Alert.
Sources: Chartrand C, et al. Accuracy of rapid influenza diagnostic tests: a meta-analysis. Ann Intern Med 2012; 156:500-11.
Hsu J, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med 2012; 156:512-24.
Recent ACIP recommendations for the management of influenza virus infections include: "1) early antiviral treatment of suspected or confirmed influenza among persons with severe influenza (e.g., those who have severe, complicated, or progressive illness or who require hospitalization); 2) early antiviral treatment of suspected or confirmed influenza among persons at higher risk for influenza complications; and 3) either oseltamivir or zanamivir for persons with influenza caused by 2009 H1N1 virus, influenza A (H3N2) virus, or influenza B virus or when the influenza virus type or influenza A virus subtype is unknown; 4) oseltamivir may be used for treatment or chemoprophylaxis of influenza among infants aged <1 year when indicated; 5) local influenza testing and influenza surveillance data, when available, to help guide treatment decisions; and 6) consideration of antiviral treatment for outpatients with confirmed or suspected influenza who do not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset."1
These recommendations raise at least two important questions: how is the diagnosis of influenza virus infection best made; and what is the evidence that current antiviral therapies are effective? The role of point-of-care antigen detection tests was addressed in a metanalysis by Chartrand and colleagues. These investigators examined 159 studies involving 26 rapid immunochromatographic diagnostic tests (RIDT) designed to detect influenza antigens. The pooled specificity of the tests was excellent (98.2%; 95% CI, 97.5% to 98.7%), as was the positive likelihood ratio (38.1). In contrast, however, the sensitivity (62.3%; 95% CI, 57.9% to 66.6%), and negative likelihood ratio (0.38) were each unacceptably low. The sensitivity was higher in children than adults and higher for influenza A than for influenza B.
Having made the diagnosis, how effective are currently available antivirals? Hsu and colleagues examined 74 observational studies that compared single antiviral therapy with no therapy or with other antiviral therapy, or that had no comparator, in patients with influenza or influenza-like illness. Their metaanalysis was designed to determine whether the available evidence demonstrated benefit from therapy with amantadine, rimantidine, oseltamivir, or inhaled zanamivir of patients with influenza or influenza-like illness. The included studies were, in general, not of the highest quality and were generally limited by potential confounding, selection bias, and publication bias. There was low to very low confidence in the estimates of effect. The investigators, nonetheless, concluded that oseltamivir "may provide net benefit by reducing mortality and the duration of symptoms and complications from influenza". Thus, when compared to no treatment, the odds ratio (OR) for mortality for oseltamivir was 0.23 among high risk patients, while that for need of hospitalization was 0.29. Oseltamivir was associated with a mean reduction in duration of symptoms of 33 hours. Zanamavir administered by inhalation was associated with reduced hospitalizations and a mean 23 hour reduction in duration of symptoms, but with a greater number of complications compared to no treatment. Analysis of direct comparisons of oseltamivir to zanamivir found no apparent differences in outcomes. No study included in this metaanalysis involved the use of rimantidine and a single study suggested that amantadine therapy was associated with a reduction in mortality and pneumonia due to influenza A.
These valuable metanalyses represent an enormous amount of work and, to the clinician, there conclusions may be considered somewhat disappointing, albeit not surprising. The conclusions one can reach from these analyses are several. First, in agreement with previous CDC statements, RIDTs can "rule in", but they cannot rule out the presence of influenza virus infection. The gold standard for influenza diagnosis is now RT-PCR and, in circumstances where its use is feasible, this method of testing should be made available to the clinician. Second, treatment with either oseltamivir or inhaled zanamivir is likely to provide clinical benefit to patients with influenza infection caused by susceptible virus. The potential benefit is maximized by early initiation of therapy.
A more general conclusion was articulated by Hsu and colleagues: "We need high-quality evidence from randomized trials that address patient-important outcomes and include hospitalized patients with influenza". They point out that such trials will require collaboration among organizations caring for large numbers of patients together with preparedness to initiate such trials when epidemic infection is first recognized.
- CDC. Antiviral agents for the treatment and chemoprophylaxis of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Recommendations and Reports 2011; 60(RR01);1-24:http://1.usa.gov/oeURqF