Vote Yay for Treating Flu A (Dr. Mehta)
We, as a nation, recently experienced an influenza epidemic that was the worst in 15 years in my state of Ohio. Questions reminiscent of the pre-pandemic era have resurfaced. A hospital leader recently asked me if oseltamivir even works for influenza, suggesting that the benefits might be minimal. This sentiment was echoed in a broader discussion among medical personnel outside the hospital, raising doubts about the efficacy of antiviral agents against influenza. However, is the presence of small efficacy a valid reason to withhold antivirals, especially when no alternative exists for hospitalized patients with influenza A? Should treatment hinge on whether symptoms begin within 48 hours—often with 12 of those hours spent in the ED—or should we adopt a blanket approach to treatment?
I firmly believe that every patient admitted to the hospital with active influenza A should receive antiviral treatment, regardless of when their symptoms begin. Both the latest Centers for Disease Control and Prevention and Infectious Diseases Society of America guidelines recommend initiating antiviral medications for hospitalized patients and those with high-risk features as soon as they are assessed. We have several antiviral agents available that can be administered orally, intravenously, or via inhalation.
While these guidelines are based on the absence of prospective, randomized, placebo-controlled trials of oral oseltamivir or inhaled zanamivir in hospitalized influenza patients, a pooled meta-analysis of observational studies involving individual-level data from more than 29,000 hospitalized patients (86% with laboratory-confirmed influenza, 14% clinically diagnosed) demonstrated a survival benefit from neuraminidase inhibitor (NAI) treatment, primarily oseltamivir, compared to no treatment. The benefit was significantly greater when treatment was initiated early (within two days of illness onset) compared to later initiation (more than two days after onset).1
Other observational studies in hospitalized influenza patients have shown that NAI treatment reduces hospitalization duration and the risk of mechanical ventilation in children, and improves survival in adults.2-4 The majority of observational studies, individual patient-level pooled analyses, and meta-analyses involving patients with lab-confirmed influenza report clinical benefits of NAI treatment (primarily oral oseltamivir) for hospitalized patients, including those at high risk for complications. These benefits extend even when treatment is initiated beyond 48 hours after illness onset. Although the greatest clinical benefit is seen with treatment started within two days of illness onset, evidence of benefit persists when treatment is initiated four to five days—and up to seven days—after illness onset.5
A recent study examined patients hospitalized with pneumonia and influenza (median age 71, with at least one non-immunocompromising risk factor—representative of the typical hospitalized patient). This study categorized patients by the timing of antiviral initiation from the day of admission and found a statistically significant increase in 30-day mortality as the delay in starting antiviral therapy increased.6 To address concerns about hospital metrics, another recent meta-analysis demonstrated a significant reduction in the length of stay (LOS) for patients treated with antivirals, with an average decrease of one day.7
Given this data and the evidence I have outlined, I firmly stand by the practice of initiating antiviral therapy for all hospitalized patients with influenza. I respectfully disagree with any approach that opts otherwise.
Oseltamivir for Influenza? Hold that Click. (Dr. Chang)
While I respect the opinion of my highly esteemed colleague from the great state of Ohio, I must temper his exuberant support for the use of oseltamivir in the treatment of hospitalized patients. I also recognize that he is hamstrung by the innate tendencies of his internal medicine training to “do something,” while those trained in the magical arts of pediatrics, grizzled veterans of the virus wars that we are, know that the best treatment is often tincture of time, with a swirl of honey.8
Why might you, dearest reader, be tempted to click on the oseltamivir order for your hospitalized patient? As Dr. Mehta has espoused, because everyone tells you to—the CDC, IDSA, AAP, and any number of reputable organizations. But drill down into these recommendations, and you might find that your palace of intervention is built on quicksand. Let’s take, for instance, the CDC Clinical Guidance, which states, “Antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications.”9 Yet a few flicks on your touchpad will bring you down to this statement: “No completed, sufficiently powered, randomized, placebo-controlled clinical trials have been conducted of monotherapy with neuraminidase inhibitors for treatment of influenza in hospitalized patients; studies supporting the licensure of oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavir were conducted in outpatients, primarily among previously healthy persons with uncomplicated illness.”
One might ask, why has there not been an appropriately powered RCT assessing the efficacy of oseltamivir in hospitalized patients? The phrase “don’t ask questions you don’t want the answers to” comes to mind. No doubt, Roche, which originally sought and obtained the U.S. Food and Drug Administration (FDA) approval for oseltamivir, is happy to have escaped the FDA-approval process with a win at all, given the controversy generated when Roche was found to have withheld complete trial datasets of oseltamivir for years.10 These were only obtained after the Cochrane Acute Respiratory Infections (ARI) Group refused to conclude oseltamivir’s effectiveness until Roche released the full data sets under massive public pressure from Cochrane, the BMJ, and even the U.K. parliament.11
Without the financial backing of Big Pharma powering RCTs of oseltamivir in hospitalized patients, well-meaning, curious researchers have attempted to take a lower-cost approach to answering this question, including a large Canadian retrospective cohort study and a prospective U.S. multicenter observational study, which show that oseltamivir treatment is associated with lower risk of in-hospital disease progression and mortality, earlier discharge, and lower readmission rates.12,13 But the results of retrospective cohort studies as massive as the one performed by our Canadian colleagues, even after the statistical hocus pocus of propensity score weighting, are suspect due to residual confounding, selection bias, and misclassification. In the case of the Canadian study, over a quarter of the patients in the “supportive care” group ultimately received oseltamivir, forcing the authors to perform a per-protocol analysis, which analyzed patients according to whether they had received oseltamivir at all, in addition to the modified intention-to-treat analysis. Per-protocol analyses, however, have their own problems, including selection bias and loss of generalizability. Additionally, the study relied on administrative coding rather than microbiological confirmation.
In the case of the study done by our U.S. colleagues, more statistical magic was needed to compensate for possible indication bias—clinicians may have treated sicker patients earlier and conversely may have withheld antivirals in less severe cases. These statistical adjustments for baseline severity and demographics cannot escape the clutches of possible residual confounding, however.
And then we have meta-analyses referenced by Dr. Mehta, which come to the same conclusions. This brings to mind another well-worn phrase—”garbage in, garbage out”. At the end of the day, there is no substitute for the causal certainty only RCTs can provide, the lack of which, given the financial means of Big Pharma, should leave our readers with suspicion.
These same ills plague studies attempting to discern whether oseltamivir benefits hospitalized children. A 2022 multicenter retrospective analysis of more than 55,000 children hospitalized with influenza found that those who received early oseltamivir (on hospital day 0 or one) had a reduced LOS, all-cause seven-day hospital readmissions, late ICU transfer, and composite outcome of death or ECMO use.14 The crutches of propensity score-weighting and use of administrative claims data (not microbiologic diagnosis) also propped up the efforts of these authors to make up for the lack of a true RCT.
So where does that leave the lonely hospitalist, long on admissions and short on time, cursor hovering over the checkbox for oseltamivir? I can’t offer them the interventional certitude that Dr. Mehta provides, nor can I offer them laissez-faire minimalism. The benefit/harm ratio makes oseltamivir treatment compelling for patients at the highest risk (over 65 years old with multiple or severe comorbidities, immunocompromise, pregnant/postpartum, extreme obesity, residents of nursing homes/chronic care facilities, critically ill patients, under 5 years old, children receiving long-term aspirin, and American Indian/Alaska Native populations).18 Those not in high-risk categories should be given, if feasible, the benefit of shared decision-making regarding the scarcity of RCTs showing benefit in hospitalized patients like themselves, versus the risk of harm in the form of gastrointestinal adverse effects, for which the number needed to harm is in the 20s for adults and children—not an insignificant number.15-17
As always, think critically and follow the conclusions you can draw from high-quality evidence performed by respected researchers.
Dr. Mehta
Dr. Chang
Dr. Mehta is the vice-chair of inpatient clinical affairs, medical director, and associate professor of medicine in the clinical core faculty for program valuation and improvement at the University of Cincinnati Medical Center in Cincinnati, and the associate editor of The Hospitalist. Dr. Chang is a pediatric and adult hospitalist at Baystate Medical Center and Baystate Children’s Hospital, Springfield, Mass., associate professor of pediatrics at the University of Massachusetts Medical School, Baystate, chief of pediatric hospital medicine, vice-chair for clinical affairs at Baystate Children’s Hospital, and editor of The Hospitalist.
References
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