Treatment With Neuraminidase Inhibitors for ... - Oxford Journals

EDITORIAL COMMENTARY

“Late” Treatment With Neuraminidase Inhibitors for Severely Ill Patients With Influenza: Better Late Than Never? Nelson Lee1 and Michael G. Ison2 1

Division of Infectious Diseases, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong; and 2Divisions of Infectious Diseases and Organ Transplantation, Departments of Medicine and Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois

(See the Major Article by Louie et al on pages 1198–204.)

It has been estimated that, globally, seasonal influenza epidemics result in 3–5 million severe infections, excessive hospitalizations, and 250 000 − 500 000 deaths each year [1]. During the pandemic in 2009, there were increased hospitalizations, and a recent study estimated that about 284 400 (range 151 700−575 400; respiratory and cardiovascular) deaths had occurred worldwide in the first 12 months [2]. Not only do severe, complicated influenza infections occur in young children, older adults, and those with underlying medical conditions, evidence also documents severe disease in obese persons, pregnant women, and adults 40% of patients with seasonal influenza who require hospitalization actually present >48 hours after symptom onset, with a median delay of about 2 days [4–6]; in patients with A/H1N1pdm09 influenza, the median time delay is about 3–4 days [3, 7–10]. Patients who develop critical illness requiring ICU care commonly have the longest delay in presentation (median, 5–7 days) [8, 10–13]. It is unclear what constitutes optimal management in patients with severe influenza, particularly in the large proportion of individuals who present later in their course of illness. To date, there are few data from randomized, controlled trials in this population group [14]. Based on accumulating experiences and emerging reports on the potential benefits (and side effects) of antiviral treatment, weighed against patients’ high morbidity and mortality, experts have earlier recommended neuraminidase inhibitor (NAI) treatment in all hospitalized patients with influenza, regardless

of time from illness onset [15, 16]. In practice, however, many clinicians do not intend to prescribe antivirals and may withhold such treatment if patients present after >48 hours after onset. A recent study documented that only 51%–57% of hospitalized adults in the United States with laboratory-confirmed influenza received antivirals during the prepandemic era, and treatment was given immediately or within the first day of admission in only 47%–55% [17]. During the pandemic, more hospitalized patients received antivirals, 75% and 82% during the first and second waves, respectively, but still less than half (38% and 47%, respectively) were treated within 48 hours of onset, and delay until the second day of admission or beyond was common (>40%) [8, 17, 18]. In comparison, 73%–79% of patients received antibacterial therapy, 93%–95% in the first 1–2 days of admission, reflecting a higher reluctance of clinicians to prescribe antivirals rather than antibacterials [8, 16, 18]. Further data to inform clinical decisions are clearly necessary. In this issue of Clinical Infectious Diseases, a study by Louie and colleagues on the survival of hospitalized patients with influenza sheds further light on the optimal management of this unique population [19]. Using California Department of Public Health surveillance


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data, the authors studied antiviral treatment and outcomes in 1859 critically ill patients with A/H1N1pdm09 influenza. The median time from symptom onset to hospital admission was 3 days (range, 0–42 days), transfer to the ICU occurred in 0 days (range, 0–13 days), and the time lag between symptom onset and NAI treatment was 4 days (range, 0–52 days). The overall mortality was 26%. Compared with untreated patients (about 10% of the overall study population), those who received NAI treatment had significantly better survival. Notably, “late” treatment, up to 4–5 days after symptom onset, was shown to improve survival, although the best prognosis was still observed in patients treated within 2 days. Bacterial superinfection (which occurred evenly in 9%–10% of NAI-treated and untreated patients) and antiviral resistance did not seem to confound the results. These findings are in line with other observational studies that showed a net benefit of timely NAI treatment (eg, reducing lower respiratory tract complications, hospitalizations, duration of illness, mortality) over no treatment, in a range of patient groups, including the immunocompromised, pregnant women, and the critically ill [20–26]. Most importantly, however, the results suggest that antivirals started >48 hours after symptom onset may still provide some benefit in severe infections. In contrast to mild seasonal influenza, in which active viral replication is largely controlled by the host within 48 hours, viral replication is much more prolonged in severe infections and pneumonia, which typically affect persons who are immunologically naive to the invading virus or have impaired immune defense [3, 27, 28]. Previous studies have shown that antiviral treatment started within 3–4 days in these severe cases can still affect (accelerate) viral clearance [29–31]. Improved outcomes with NAI treatment started within 4 or 4–6 days have been reported in patients hospitalized with

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seasonal influenza [4, 5, 30] or A/ H1N1pdm09 influenza, respectively [7, 12, 32–35]. The “time window” for therapeutic benefits seems to be longest in H5N1 influenza, up to 6–8 days from symptom onset [36]. Taken together, these data suggest that if there are ongoing symptoms and evidence of active viral replication, antiviral treatment should still be considered in hospitalized patients who present after the first 48 hours. However, it must be pointed that treatment benefits actually drop progressively with time, starting from the day of illness onset. Earlier studies on seasonal influenza have shown that treatment on day 1 of illness is associated with shorter total durations of symptoms and viral shedding (best if treatment is started within hours), compared with treatment started on day 2 or 3 [29, 37]; the duration of hypoxemia is longer and mortality higher with treatment started on day 3–4, though this is still better than no treatment [4, 5]. Recent studies on A/H1N1pdm09 influenza have similarly shown longer total durations of viral shedding and illness (hospitalization) with each day of delay in treatment [31, 38, 39]; and in 2 independent studies, risk of adverse outcomes (death, ICU admission) in the first week of illness was shown to increase by about 20% with each day of treatment delay, as a continuum [7, 33]. In A/H5N1 influenza, patients who received NAI after onset of respiratory failure had nearly 20 times higher fatality risk, compared with those treated earlier [40]. It is possible that in the advanced stage of disease, when there is excessive inflammation and tissue damage (together with the development of noninfective complications, eg, cardiovascular events or renal failure), antiviral treatment alone is insufficient to reverse the processes [3, 4, 40, 41]. Thus, based on the growing, consistent body of evidence, therapeutic intervention should still occur at the earliest time point in all patients with influenza, and any further


delay within the healthcare setting should be avoided [41]. Improving access to antivirals and efficient delivery of therapy to patients are important goals to consider in the management of severe influenza; areas suggested for further research include the use of clinical triage tools, rapid diagnostic testing (such as polymerase chain reaction–guided treatment or empirical treatment), and the impact of evaluating antimicrobial initiation time in patients hospitalized with influenza in addition to bacterial pneumonia [3, 5, 15, 16, 42, 43]. There are inherent limitations in all observational studies. Commonly, the comparison “no treatment” group presents a heterogeneous population of patients who are perceived to have milder diseases or noninfective medical conditions or are moribund [4, 5, 20]. As a result, the estimated therapeutic effect is likely to be imprecise. There are also issues of confounders, such as disease stage and comorbidity, as well as survival duration– related selection bias or time bias [41]. A recent meta-analysis showed that the reported effects of “late” NAI treatment vary considerably across different population groups, probably owing to differences in study setting, the comparison groups involved, and the outcomes being measured (eg, mortality vs length of stay) [5, 20, 23, 33, 39]. Nevertheless, the study by Louie et al provides a unique opportunity to assess the effect of antiviral treatment on survival in a large, specific population of critically ill patients, with some of the potential biases addressed. Ideally, prospective, randomized, placebo-controlled trials should be used to resolve such controversy; however, given the high mortality of severe influenza, ethical considerations make this approach improbable [44]. Therefore, data to guide antiviral use in these severely ill patients will probably be drawn from well-designed observational studies, or controlled trials comparing new antiviral agents (alone or in combination with the standard of care) with the standard of care [14, 20, 44]. Although

comparative trials may provide further insights into the relative efficacy of early versus late treatment as well as other important treatment-related issues, such as optimal dosage and duration, newer study designs and consensual end points are also urgently needed to address these questions and meet the regulatory requirements [14, 41]. In summary, accumulating data suggest that in cases of severe influenza, benefits of antiviral treatment may not be limited to that initiated within the first 48 hours. Therefore, it should be considered in all patients requiring hospitalization, even if they present later in the course of illness. Since shorter onsetto-treatment interval is associated with greater therapeutic effects, every effort should be made to make early therapy possible. The overall impacts of NAI treatment in hospitalized patients with influenza, the exact time interval when it will stop providing benefit, and ways to guide these treatment decisions remain unclear, and controlled studies to address these questions are urgently required to provide a stronger evidence base for intervention. Note Potential conflicts of interest. N. L. has received grant support from F. Hoffmann–La Roche for principal investigator–initiated clinical influenza research, paid to the Chinese University of Hong Kong; an honorarium for consultancy work for GlaxoSmithKline; and conference support from Sanofi-Aventis Hong Kong, MSD (Asia) and Pfizer Hong Kong, paid to the Chinese University of Hong Kong. M. G. I. has received research support, paid to Northwestern University Feinberg School of Medicine, from BioCryst, Cellex, Genentech/Roche, and GlaxoSmithKline. He is a paid member of a data and safety monitoring board for NexBio and has provided remunerated consultation to Abbott, Crucell, and Genentech/Roche; he has also provided unremunerated consultation to Adamas, Alios, BioCryst, Biota, Cellex, Clarassance, GlaxoSmithKline, MediVector/Toyama, TheraClone, and Visterra. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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