Influenza in Hospitalized Adults: Gaining Insight into a Significant Problem

Influenza virus infection results in >226,000 excess hospital admissions, 3.1 million hospitalized days, and $5 billion of excess economic costs associated with these hospitalizations annually in the United States [1, 2]. Hospitalization appears to occur most frequently among very young and elderly persons, with enhanced admission rates among those with underlying medical conditions, such as pulmonary disease, cardiovascular disease, diabetes, and compromised immunity [1, 3]. Morbidity among hospitalized patients remains high [1–3]. Despite this significant burden of disease, influenza is frequently not considered by many admitting clinicians, and anti-influenza treatment is often not initiated early, if at all. Additionally, influenza and its management has been best studied among ambulatory adults [4–9]; data for hospitalized patients remain limited [10–20] In their prospective, observational study of all adults admitted with acute febrile respiratory illness and documented influenza over 1 calendar year in a single Hong Kong hospital published in this issue of the Journal Lee et al [21] have contributed to our understanding of the expected course of influenza viral shedding in this population. As part of routine care at their hospital, all patients who were diagnosed with influenza within 2 days of onset of symptoms were administered a standard dosage of oseltamivir (75 mg twice daily for 5 days); decisions to treat other patients was at the discretion of the treating physician. Daily nasal swabs were obtained and symptom assessments were conducted until 1 week after resolution of symptoms. Respiratory samples were tested by standard culture and polymerase chain reaction (PCR) to detect and quantify the amount of virus present Many of the findings of this study are consistent with prior, mostly retrospective studies of influenza among hospitalized adults. In general, most of the admitted patients were old (76% were aged >65 years), and many (64%) had comorbidities (table 1). Sixty percent of patients required supplemental oxygen and 80% had influenza-related complications at initial evaluation. Two-thirds of the patients were treated with antivirals. Overall, 1.4% of patients died during the course of therapy Summary of Key Findings of Selected Epidemiologic Studies of Influenza in Hospitalized Adults This was the first study of hospitalized patients to perform careful and serial sampling of the respiratory tract to monitor the duration of viral shedding and to correlate these findings with clinical symptoms. Although the primary data are not presented in the article, the authors state that the initial viral concentration as measured by PCR had a positive correlation with 4-point symptom scores. Patients with major comorbidities had a statistically significantly (∼1 log) higher viral load than those without such comorbidities; interestingly, although there was a trend toward higher viral loads in patients aged >65 years and in female patients, underlying chronic lung disease and influenza vaccination did not correlate with baseline viral loads. Prolonged viral shedding was documented, with 68.5% and 32.7% of patients shedding virus at symptom day 5 and 7, respectively. Presence of comorbidity, older age, and use of systemic corticosteroids were associated with a significantly higher proportion of shedding at 1 week, whereas the use of oseltamivir within 48 h (adjusted odds ratio, 0.10) and within 96 h (adjusted odds ratio, 0.30) were associated with reduced viral shedding at 1 week. Virus clearance was associated with a shorter time to hospital discharge This study was conducted at a single center in a region with heightened sensitivity to recognizing, diagnosing, and treating influenza. Additionally, the decision to treat patients presenting >48 h after symptom onset was deferred to the attending physician; this may have resulted in a bias to treating more symptomatic patients and those with greater comorbidity. The authors did not provide data to assess the severity of illness (baseline symptom scores), nor did they provide data on the proportion of patients admitted to the intensive care unit. Although the authors correlated the initial symptom scores with viral concentration, they did not assess whether this correlation persisted over time. Likewise, although the authors state that virus culture was associated with a lower rate of positive results than did reverse-transcriptase PCR, they did not provide longitudinal data on the 2 assays or on the degree of correlation. Additionally, there was no assessment of how many patients were admitted to their hospital with influenza diagnosed by a method other than specimen immunofluorescence at admission Despite these limitations, this study moves our understanding of influenza in hospitalized adults forward. Additionally, taken in context with the few other previous studies involving hospitalized patients (table 1), it is possible to begin to understand the differences between clinical presentation and course of influenza in ambulatory and hospitalized adults. Patients with influenza who are admitted to the hospital have different clinical presentations, clinical and virological courses, and responses to antiviral therapy than do previously healthy ambulatory adults. Although not shown in this study, other studies have demonstrated that patients are admitted with a wide range of diagnoses, including many nonrespiratory diagnoses. Similarly, typical symptoms, including fever, myalgias, sore throat, and cough may be muted or absent at the time of admission [15, 16]. Patients typically are admitted later in the course of illness; previous studies have documented that patients present between 1 and 5.4 days after the onset of infection [11, 13, 21–23]. Most of these individuals still have evidence of viral replication [14–16, 18, 21] Among ambulatory, previously healthy adults, viral shedding typically ceases within 3–6 days, with rapid improvement in clinical signs and symptoms [6]. Among ambulatory adults, antiviral therapy initiated within 48 h after onset of symptoms is associated with reductions in the time to alleviation of symptoms, shortening of viral shedding, and reduction in complications that require antibiotics [4, 5, 8, 9, 24–26]. On the basis of these data, antiviral therapy is typically only used in previously healthy ambulatory adults if started within 48 h after the onset of influenza symptoms. In those studies of hospitalized patients that have analyzed the impact of antiviral therapy, all have associated use of antiviral treatment with improved clinical outcomes; all have shown a reduced mortality, whereas some have documented positive effects on prescriptions for antibacterials, in terms of either total duration or use, as well as reduced duration of hospitalization. This impact appears to be clinically significant even if antivirals are started beyond 48 h after the onset of symptoms. Lee et al [21] moved our understanding of the clinical course of influenza in hospitalized patients forward by modeling the impact of antiviral therapy on viral shedding and correlating presenting symptoms with initial viral loads Although this study advances our understanding of influenza clinical epidemiology and clinical course, there still remain significant questions that need to be answered. We now recognize that patients admitted to the hospital can present with a wide range of diagnoses. Because of the risk of spreading influenza among other patients, routine contact and droplet precautions are recommended for all hospitalized patients with influenza [27]. Physicians should have a very low threshold for testing patients admitted to the hospital; by doing so, they may be able to institute therapy that could have a positive impact on the patient’s clinical course and could prevent transmission to other patients. Hospitalized patients shed virus for a prolonged period of time. Molecular diagnostics have superior sensitivity compared with culture, but there is concern that PCR may be detecting noninfectious viral particles at the end of the course of illness [18, 21, 23]. Studies are needed to determine the risk of transmission in those patients who are PCR positive but culture negative, to inform infection control practices We also need to better define optimal screening for influenza through prospective studies involving all patients admitted to the hospital, to get a clearer sense of the burden of disease in this population. We need studies to define prognostic features present at hospital admission that identify which patients will benefit from antiviral therapy. Likewise, we need to conduct prospective studies to define the optimal agent, dosage, route, and duration of antiviral therapy for hospitalized patients. In the current era of complex resistance in circulating strains [28, 29], there are even more complicated questions, including the safety and efficacy of zanamivir monotherapy or combination therapy in hospitalized patients. These studies are challenging; placebo is likely not an acceptable study arm because of the biologic plausibility and the current level of evidence that antiviral therapy has some benefit in this population. In addition, the optimal end points for such studies have yet to be defined. Symptoms are often muted in the hospitalized patient population, and some patients may be too ill to provide information about their current symptoms. Predictors of responses that have been developed for other disease entities, such as pneumonia, may not be appropriate to use in patients with influenza [20]. Discharge from the hospital is dependent on a number of features that may not correlate with the antiviral efficacy of a anti-influenza agent. This study clearly documents that clinical symptoms and signs at presentation correlate with baseline viral load and define the expected course of viral decay in hospitalized patients. If clinical course can be correlated with viral load over the course of illness, virologic end points may become reasonable and reliable surrogates to use in future studies of antiviral therapy in patients hospitalized with influenza. A number of other objective potential end points could include time to return to usual activity or changes in pulmonary function testing These studies are also challenging to conduct because they enroll patients with a wide range of baseline degrees of severity of illness and comorbidities. As a result, only 2 prospective studies have been conducted to date to investigate the treatment of influenza in hospitalized patients [10, 20]. The present report provides more robust virologic and clinical data that may allow design of studies to better define the optimal treatment of influenza in hospitalized adults. Answers to these challenges need to be addressed because they will inform the optimal design for studies to define screening and treatment interventions to optimize outcomes of influenza among hospitalized adults and children