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Meta-Analyses Support Influenza Antivirals, Diagnostic Tests

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Meta-Analyses Help Position Antivirals, RIDTs

The meta-analysis on the efficacy of oseltamivir and zanamivir for treating influenza, especially in severely infected or high-risk patients, is very important. The controlled clinical trials for these drugs excluded hospitalized patients, pregnant women, and patients at very high risk for complications. But these are precisely the patients who face the greatest risk from influenza and need effective therapy. Because it is unlikely that placebo-controlled, randomized trials of these drugs will ever be done in these populations, our only recourse is to use observational studies for guidance on whether these drugs work in these critical settings.

The observational studies reviewed in this report show the consistent finding that antiviral treatment of influenza infections in patients who need hospitalization or are pregnant prevented death and ICU admissions. The results of these studies, individually, had already led to recommendations for using antivirals in these patients from the Centers for Disease Control and Prevention and from the Infectious Diseases Society of America (Clin. Infect. Dis. 2009;48:1003-32). The new meta-analysis highlights these benefits in a more detailed way. More importantly, the new analysis provides evidence that treating high-risk patients infected with influenza with one of these drugs prevents the outcomes that we care about the most: death, hospitalization, and complications.

Observational studies are always subject to more limitations than properly controlled randomized trials, but the consistency of the evidence and the attempts to control for bias in the meta-analysis improve the quality of the evidence.

I believe that most clinicians are already aware of the CDC recommendations on antiviral use for influenza. In recent years we have seen improved rates of treatment of high-risk patients with an antiviral, but too many patients remain untreated. I worry that some clinicians have only heard the message that the results from randomized trials showed only modest benefits in otherwise healthy influenza patients. These new meta-analysis results should reassure them that there is solid evidence for benefit in high-risk patients.

The meta-analysis of RIDTs involved data that, I think, were generally better known to flu experts. The meta-analysis deals with a wide range of test types and flu seasons, and that is both a strength and weakness of the analysis.

The results show that the relatively low sensitivity of the RIDTs is a consistent finding from year to year and in study to study, and that this produces a low negative predictive value. An important message from this new analysis is that RIDT sensitivity is consistently lower among adult patients. During the 2009 H1N1 pandemic, we saw that many clinicians did not appreciate that a negative test did not rule out influenza. Since then, the CDC has issued statements on how to best use RIDTs in practice, but I’m not sure how much of this misuse has changed.

It is reassuring to see that the positive predictive value of RIDTs is consistently high according to the meta-analysis. RIDTs can be very useful when positive for limiting additional testing and avoiding the use of antibiotics. Results from several studies showed that clinicians change their behavior when they get a positive RIDT result. The low negative predictive value of these tests means that a negative RIDT result should not be the reason to not use antiviral treatment. That is a major shortcoming of RIDTs. The role of RIDT on management of patients with suspected influenza would be greater if and when a more sensitive, point-of-care test becomes available.

ANDREW T. PAVIA, M.D., is a professor and chief of the division of pediatric infectious diseases at the University of Utah in Salt Lake City. He said that he has no disclosures. He made these comments in an interview.


 

FROM ANNALS OF INTERNAL MEDICINE

The meta-analysis of RIDTs included 159 studies that assessed the accuracy of 26 commercially marketed RIDTs; 119 of the studies compared one or more RIDTs against either of the two reference standards for influenza infection, viral culture, or reverse transcriptase-polymerase chain reaction. The analysis showed that specificity rates ranged from 51% to 100%, and that sensitivity rates ranged from 4% to 100%. The pooled sensitivity was 62%, and the pooled specificity was 98%, reported Dr. Caroline Chartrand, a pediatrician at CHU Sainte-Justine in Montreal, and her associates.

"Overall, RIDTs have high specificity, with modest and highly variable sensitivity," the authors concluded. "This means that a positive test is unlikely to be a false positive result." In the presence of a positive RIDT result, "a clinician can confidently make the diagnosis of influenza and begin appropriate infection-control measures and antiviral therapy, if indicated, while forgoing unnecessary additional diagnostic testing and antibiotic prescription. However, a negative RIDT result has a reasonable likelihood of being a false negative and should be confirmed by other laboratory diagnostic tests if the result is likely to affect patient management."

The analysis also showed that RIDTs performed better in children than in adults, with approximately 13% higher sensitivity in children. "This is plausible because young children have higher viral loads and longer viral shedding than adults," the authors said. RIDTs also showed higher sensitivity for detecting influenza A compared with influenza B.

"Overall, no commercial brand of RIDT seemed to perform markedly better or worse than the others, but this finding should be interpreted cautiously because head-to-head comparisons were not done in most studies. Administration of the RIDT by personnel other than a trained laboratory technician does not seem to adversely influence the performance of these tests," they added.

"The most important advantage of RIDTs is their rapid turnaround time. RIDTs fill a void at the point of care that no other test is likely to fill in the near future. As long as clinicians understand the limitations of RIDTs, namely that a negative result is unreliable and should be confirmed by using culture or RT-PCR, RIDTs could enable clinicians to institute prompt infection-control measures, begin antiviral treatment in high-risk populations, and make informed decisions about further diagnostic interventions," the authors concluded.

The meta-analysis results "support the notion that a positive rapid test result is much more helpful to the clinician than a negative result," commented Dr. Peters. "Positive test results can prompt early, appropriate initiation of neuraminidase inhibitor therapy. A negative result may occur in an influenza-infected patient at high risk for severe disease, especially in adults who shed less virus [than children] when infected. Clinicians should be especially suspicious of negative test results at times when they are seeing a lot of influenza disease, and they should be prepared to initiate early neuraminidase inhibitor therapy when their clinical suspicion for influenza is high despite a negative test result," Dr. Peters said.

Dr. Schünemann and his associates, Dr. Chartrand and her associates, and Dr. Peters said that they had no disclosures.

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