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Original Research: CHEST INFECTIONS |

Timing of Oseltamivir Administration and Outcomes in Hospitalized Adults With Pandemic 2009 Influenza A(H1N1) Virus InfectionOseltamivir Timing and Outcome in Pandemic A(H1N1) FREE TO VIEW

Diego Viasus, MD; José Ramón Paño-Pardo, MD, PhD; Jerónimo Pachón, MD, PhD; Melchor Riera, MD, PhD; Francisco López-Medrano, MD, PhD; Antoni Payeras, MD, PhD; M. Carmen Fariñas, MD, PhD; Asunción Moreno, MD, PhD; Jesús Rodríguez-Baño, MD, PhD; José Antonio Oteo, MD, PhD; Lucia Ortega, MD, PhD; Julián Torre-Cisneros, MD, PhD; Ferrán Segura, MD, PhD; Jordi Carratalà, MD, PhD,; for the Novel Infl uenza A(H1N1) Study Group of the Spanish Network for Research in Infectious Diseases (REIPI)
Author and Funding Information

From the Departments of Infectious Diseases from the Hospital Universitari de Bellvitge-IDIBELL, University of Barcelona (Drs Viasus and Carratalà), Barcelona; Hospital Universitario La Paz-IDIPAZ (Dr Paño-Pardo), Madrid; Hospital Universitario Virgen del Rocío (Dr Pachón), Sevilla; Hospital Universitario Son Dureta (Dr Riera), Palma de Mallorca; Hospital Universitario 12 de Octubre (Dr López-Medrano), Madrid; Hospital Son Llàtzer (Dr Payeras), Palma de Mallorca; Hospital Universitario Marqués de Valdecilla (Dr Fariñas), Santander; Hospital Universitario Clinic (Dr Moreno), Barcelona; Hospital Universitario Virgen Macarena (Dr Rodríguez-Baño), Sevilla; Hospital San Pedro-CIBIR (Dr Oteo), Logroño; SCIAS-Hospital de Barcelona (Dr Ortega), Barcelona; Hospital Universitario Reina Sofía-IMIBIC, University of Córdoba, (Dr Torre-Cisneros) Córdoba; and Hospital Parc Tauli (Dr Segura), Sabadell, Spain.

Correspondence to: Jordi Carratalà, MD, PhD, Department of Infectious Diseases, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain; e-mail: jcarratala@ub.edu


A list of the study group members is available in e-Appendix 1.

Funding/Support: This study was supported by Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Programa de Investigación sobre gripe A/H1N1 (grant GR09/0014), and Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III. It was cofinanced by the European Regional Development Fund “A way to achieve Europe,” Spanish Network for Research in Infectious Diseases (REIPI RD06/0008). Dr Viasus is the recipient of a research grant from the Institut d´Investigació Biomèdica de Bellvitge (IDIBELL).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(4):1025-1032. doi:10.1378/chest.10-2792
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Background:  Data on the clinical effectiveness of oseltamivir in patients with pandemic 2009 influenza A(H1N1) (A[H1N1]) virus infection are scarce. We aimed to determine the effect of timing of oseltamivir administration on outcomes in hospitalized adults with A(H1N1).

Methods:  Observational analysis of a prospective cohort of adults hospitalized with laboratory-confirmed A(H1N1) was performed at 13 Spanish hospitals. Time from onset of symptoms to oseltamivir administration was the independent variable. Outcomes were duration of fever, hospital length of stay (LOS), need for mechanical ventilation, and mortality during hospitalization. Multivariate logistic regression was used to describe the association between the independent variable and the outcomes.

Results:  Five hundred thirty-eight hospitalized patients with A(H1N1) were studied. The median time from onset of symptoms to oseltamivir administration was 3 days (interquartile range [IQR], 2-5 days). With regard to outcomes, the median duration of fever was 2 days (IQR, 1-3 days), the median LOS was 5 days (IQR, 3-8 days), 49 patients (9.1%) underwent mechanical ventilation, and 11 patients (2%) died during hospitalization. In univariate analysis, prolonged duration of fever (above the median), prolonged LOS (above the median), need for mechanical ventilation, and mortality all increased with time to oseltamivir administration (χ2 test for trend P = .001, P ≤ .001, P = .008, and P = .001, respectively). After adjustment for confounding factors, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with a prolonged duration of fever (OR, 1.10; 95% CI, 1.02-1.19), prolonged LOS (OR, 1.07; 95% CI, 1.00-1.15), and higher mortality (OR, 1.20; 95% CI, 1.06-1.35).

Conclusions:  Timely oseltamivir administration has a beneficial effect on outcomes in hospitalized adults with A(H1N1), even in those who are admitted beyond 48 h after onset of symptoms.

Pandemic 2009 influenza A(H1N1) (A[H1N1]) virus emerged in Mexico during the spring of 2009 and spread rapidly worldwide,1 resulting in the first influenza pandemic of the current century. The majority of patients with A(H1N1) virus infection have self-limited mild to moderate uncomplicated disease. Risk factors for severe A(H1N1) are similar to those identified for seasonal influenza.2 A higher risk for severe A(H1N1) virus infection also has been reported in individuals who are obese (particularly in those with morbid obesity)3 and among certain indigenous populations.4,5 Conversely, it has been suggested that early antiviral therapy is associated with a lower risk of complications.69

Because no effective vaccine was available during the first months of the pandemic, antiviral drugs (oseltamivir and zanamivir) were the primary weapons for improving the clinical outcomes of patients with A(H1N1) virus infection. The guidelines recommend that healthy patients with uncomplicated illness should not be treated with antivirals, but in patients with initially severe presentations and those who have risk factors for complications or require hospital admission, treatment with antiviral drugs should commence as soon as possible.2

However, most available data on the use of antiviral drugs come from randomized trials in healthy adult patients and outpatients with seasonal influenza treated within 48 h of symptom onset.1012 In addition, two meta-analyses10,11 recently showed that data on the effectiveness of neuraminidase inhibitors for decreasing complications and mortality in patients with seasonal influenza are unclear. Notably, randomized trials of neuraminidase inhibitor treatment of hospitalized patients with influenza are limited.13 Additionally, information about antiviral treatment and outcomes in hospitalized patients with A(H1N1) virus infection are scarce.69,14 Consequently, there is a need for additional clinical, virologic, and timing of antiviral administration studies to assess neuraminidase inhibitor effectiveness for hospitalized patients with A(H1N1).15 The present study aimed to determine the effect of timing of oseltamivir administration on outcomes in hospitalized adults with laboratory-confirmed A(H1N1) virus infection.

Study Design and Study Population

This observational analysis was of a prospective cohort of adults aged > 15 years hospitalized with confirmed A(H1N1) virus infection at 13 Spanish university hospitals between June 12, 2009, and November 10, 2009. All patients had an influenza-like illness with laboratory-confirmed A(H1N1) virus infection by real-time reverse-transcription polymerase chain reaction (RT-PCR) or viral culture.16 Cases were identified at the ED by attending physicians or investigators when the microbiology results were available or by the daily reviewing by investigators of the microbiology-positive results of the RT-PCR for typing (A/B) and subtyping (1H/1H 2009/H3/H5) influenza virus. In these latter cases, the RT-PCR results were typically available in < 48 h after hospital admission. Patients with missing data on time from symptom onset to oseltamivir administration were excluded. The study was approved by the Institutional Review Board (number PR182/09) of the coordinating center (Hospital Universitari de Bellvitge; Barcelona, Spain), and informed consent was obtained from patients.

Clinical Assessment and Follow-up

Hospital and ICU admission criteria and treatment decisions were not standardized and were applied or made by attending physicians. Patients were seen during their hospital stay by one or more of the investigators at each participating hospital, who recorded clinical data in a standardized, computer-assisted protocol. Data were collected on demographic characteristics, comorbidities, BMI, clinical signs and symptoms, biochemical analysis, chest radiograph findings, antiviral and antibacterial therapy, concomitant and secondary bacterial pneumonia or infection, duration of fever during hospitalization, complications, and in-hospital mortality. For time from onset of symptoms to antiviral administration, the day of onset of symptoms was considered day 0.

Study Variables and Definitions

Time from onset of symptoms to oseltamivir administration was the independent variable. The time interval between the fever or malaise onset (as reported by the patient) and the oseltamivir administration was calculated for each patient. The outcomes of interest were duration of fever, hospital length of stay (LOS), need for mechanical ventilation, and mortality during hospitalization. Fever was defined as axillary temperature > 37.8°C and LOS as discharge date minus admission date. Mechanical ventilation was defined as need for endotracheal intubation or noninvasive mechanical ventilation and mortality as death from any cause during hospitalization.

Underlying medical conditions were assessed according to the Charlson Comorbidity Index.17 Other comorbidities, such as immunosuppression, neuromuscular disorders, and sickle cell disease, also were recorded. Morbid obesity was defined as a BMI ≥ 40 kg/m2 or a subjective assessment by the physician if weight and height data were not available.

Because hospital criteria decisions were not standardized in the present study, it is likely that factors other than disease severity may have contributed to site-of-care decisions. Therefore, we defined patients with progressive, severe, or complicated illness at hospital admission when any of the following were present on admission2: (1) signs and symptoms of lower respiratory tract disease (wheezing, intercostal retractions, tachypnea, pneumonia on chest radiographs, Pao2/Fio2 < 300, or arterial saturation < 90%), (2) altered mental status, (3) hypotension (systolic BP ≤ 90 mm Hg), or (4) bacterial coinfection based in laboratory testing.

Statistical Analyses

All proportions were calculated as percentages of the patients with available data. For continuous variables, the median and interquartile range (IQR) are reported. Crude outcomes for time from onset of symptoms to oseltamivir administration were reported by time-to-treatment groups (group 1, ≤ 2 days; group 2, 3-4 days; group 3, 5-6 days; and group 4, ≥ 7 days). Linear trend analysis was used to account for multiple comparisons of crude outcomes (univariate analysis). Multivariate logistic regression was used to describe the association between time from onset of symptoms (+ 1-day increase) to oseltamivir administration and each of the clinical outcomes. Significant variables detected in the univariate analysis were entered into the multivariate analysis. Variables entered in the univariate analysis were age, male sex, comorbidities, prior seasonal influenza and pneumococcal vaccination, obesity, morbid obesity, hypotension, tachypnea (respiratory frequency ≥ 24/min), altered mental status, pleural effusion, pneumonia on chest radiographs, bacterial coinfection, and ICU admission. Results derived from the logistic regression models were expressed as OR and 95% CI. An a priori subgroup analysis was performed in patients with progressive, severe, or complicated illness at hospital admission. The results were analyzed using SPSS version 15.0 (SPSS Inc; Chicago, Illinois) statistical software. Statistical significance was established at α = .05. All reported P values are two tailed.

Patient Characteristics

Of the 585 hospitalized patients with laboratory-confirmed A(H1N1), 47 with missing data on time from symptom onset to oseltamivir administration were excluded. Excluded patients did not present significant differences with regard to age, signs and symptoms, and outcomes compared with patients included in the study. Among the 538 patients analyzed in the present study, the median time from onset of symptoms to hospital arrival was 3 days (IQR, 2-5 days). The median age was 39 years (IQR, 28-52 years). Just more than one-half (52.4%) of the patients were men. Comorbidities were present in 304 patients (56.5%) as mainly chronic pulmonary diseases (29.7%), immunossuppression (14.5%), diabetes mellitus (11%), and chronic heart diseases (7.1%). Furthermore, 170 patients (31.6%) were current smokers, and 27 (5%) were morbidly obese. Seventy-seven patients (14.3%) were pregnant women. No patient was vaccinated for A(H1N1) or received oseltamivir prior to hospitalization. Pneumonia on chest radiograph was found in 224 patients (41.6%) and bacterial coinfection in 36 (16%) of them. Regarding treatment, all patients received oseltamivir (35 patients at a dose of 150 mg bid), and one patient also received inhaled zanamivir; antibacterial treatment was administered to 396 patients (73.6%) (all patients with bacterial coinfection received antibacterial treatment) and corticosteroids to 152 (28.3%). The median duration of oseltamivir therapy was 5 days (IQR, 5-5 days). No patient received IV peramivir or zanamivir.

Effect on Outcomes of Time From Onset of Symptoms to Oseltamivir Administration

The median time from onset of symptoms to oseltamivir administration was 3 days (IQR, 2-5 days). Of the 538 patients, 202 (37.5%) were included in time-to-treatment group 1, 160 (29.7%) in group 2, 87 (16.2%) in group 3, and 89 (16.5%) in group 4. Regarding outcomes, the median duration of fever during hospitalization was 2 days (IQR, 1-3 days), the median LOS was 5 days (IQR, 3-8 days), 49 (9.1%) patients underwent mechanical ventilation, and 11 (2%) died during hospitalization. The median time from hospital admission to death was 5 days (IQR, 3.5-19.5 days). Causes of death were respiratory failure or ARDS (three of 11 patients), shock or multiorgan failure (four patients), decompensated comorbid condition (three patients), and nosocomial infection (one patient).

Crude outcomes stratified by time-to-treatment groups are shown in Table 1. In univariate analysis, duration of fever (above the median > 2 days) during hospitalization, LOS (above the median > 5 days), need for mechanical ventilation, and mortality increased with time to oseltamivir administration (χ2 test for trend P = .001, P ≤ .001, P = .008, and P ≤ .001, respectively). After adjustment for confounding factors, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with prolonged duration of fever (Table 2), prolonged LOS (Table 3), and higher mortality during hospitalization (Table 4). However, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was not related to the need for mechanical ventilation (Table 5).

Table Graphic Jump Location
Table 1 —Crude Outcomes Stratified by Groups of Time From Onset of Symptoms to Oseltamivir Administration in All Hospitalized Patients With A(H1N1): Univariate Analysis

Data are presented as median (IQR) or No. (%). A(H1N1) = pandemic 2009 influenza A(H1N1); IQR = interquartile range; LOS = length of stay.

a 

χ2 test for trend P = .001.

b 

χ2 test for trend P ≤ .001.

c 

χ2 test for trend P = .008.

d 

χ2 test for trend P ≤ .001.

Table Graphic Jump Location
Table 2 —Factors Associated With Prolonged Duration of Fever (Above the Median of 2 d) in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 3 —Factors Associated With a Prolonged Length of Hospital Stay (Above the Median of 5 d) in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 4 —Factors Associated With Mortality in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 5 —Factors Associated With the Need for Mechanical Ventilation in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Patients With Progressive, Severe, or Complicated Illness

Three hundred seventy-seven patients had at least one criterion of progressive, severe, or complicated illness at hospital admission (signs and symptoms of lower respiratory tract disease in 371 patients, altered mental status in 13, hypotension in 15, and bacterial coinfection in 44). Crude outcomes stratified by time-to-treatment groups in hospitalized patients with progressive, severe, or complicated illness are shown in Table 6. In the univariate analysis, duration of fever (above the median > 2 days), LOS (above the median > 6 days), and mortality during hospitalization increased with time to oseltamivir administration (χ2 test for trend P = .003, P = .005, and P = .006, respectively). No association was found between timing of oseltamivir administration and need for mechanical ventilation in univariate analysis in this subgroup of patients. In the multivariate logistic regression analysis, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was associated with prolonged duration of fever (OR, 1.11; 95% CI, 1.01-1.20), prolonged LOS (OR, 1.10; 95% CI, 1.01-1.20), and higher mortality (OR, 1.19; 95% CI, 1.05-1.36). However, time from onset of symptoms to oseltamivir administration also was not associated with the need for mechanical ventilation in the multivariate analysis (OR, 1.04; 95% CI, 0.94-1.14).

Table Graphic Jump Location
Table 6 —Crude Outcomes Stratified by Groups of Time >From Onset of Symptoms to Oseltamivir Administration in Hospitalized Patients With Progressive, Severe, or Complicated Illness: Univariate Analysis

Data are presented as median (IQR). See Table 1 legend for expansion of abbreviations.

a 

χ2 test for trend P = .003.

b 

χ2 test for trend P = .005.

c 

χ2 test for trend P = .07.

d 

χ2 test for trend P = .006.

Effect on Outcomes of Time From Arrival to the Hospital to Oseltamivir Administration

There was concern that previous results may reflect differences in the time from onset of symptoms until hospitalization. Therefore, a post hoc analysis was performed to evaluate the effect on outcomes of delay of oseltamivir administration after arrival to the hospital (Table 7). Of the 538 hospitalized patients, 127 received oseltamivir treatment after the first 24 h after arrival. In these patients, the RT-PCR results were more frequently available after the first day since the arrival to the hospital (47.2% vs 25.1%; P ≤ .001). Compared with patients who received oseltamivir within the first 24 h, the delay of oseltamivir administration (> 24 h) was independently associated with prolonged duration of fever (adjusted OR, 1.67; 95% CI, 1.03-2.72), prolonged LOS (adjusted OR, 1.67; 95% CI, 1.06-2.63), more-often need for mechanical ventilation (adjusted OR, 3.13; 95% CI, 1.56-6.27), and higher mortality (adjusted OR, 4.29; 95% CI, 1.25-14.63).

Table Graphic Jump Location
Table 7 —Effect on Outcomes of Delay of Oseltamivir Administration After Arrival to the Hospital in All Hospitalized Patients With A(H1N1)

See Table 1 legend for expansion of abbreviations.

a 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, age (< 50 y), pleural effusion, pneumonia, and bacterial coinfection.

b 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, age (< 50 y), comorbidities, pleural effusion, pneumonia, bacterial coinfection, and ICU admission.

c 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, comorbidities, morbid obesity, pleural effusion, pneumonia, and bacterial coinfection.

d 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, age (< 50 y), and comorbidities.

In this large, prospective cohort study of hospitalized patients with laboratory-confirmed A(H1N1) virus infection, time from onset of symptoms to oseltamivir administration (+ 1-day increase) was independently associated with a prolonged duration of the fever, prolonged LOS, and higher mortality during hospitalization. Moreover, we performed a subgroup analysis in patients with progressive, severe, or complicated illness at hospital admission because hospital criteria decisions were not standardized in the present study and because it was likely that mild cases had been admitted due to the uncertainty surrounding disease progression and prognosis during the initial period of the pandemic. In fact, we found that ∼ 30% of patients did not have criteria for progressive, severe, or complicated illness at hospital admission. Similar beneficial results of timely oseltamivir administration were obtained in these patients with progressive, severe, or complicated illness at hospital admission.

In addition, in a further analysis, a delay (> 24 h) in the administration of oseltamivir after arrival to the hospital was also associated with higher morbidity and mortality independently of time from symptom onset to hospital admission. Further, although the specific reasons for delay of oseltamivir administration were not recorded, we found that RT-PCR results were more frequently available after the first day of hospitalization in these patients. Thus, laboratory confirmation of A(H1N1) virus infection should not delay the initiation of empirical treatment in hospitalized patients.

During the pandemic, it was recommended that antiviral treatment be administered to patients at a high risk for influenza complications, in need of hospitalization, and with severe or complicated influenza illness.2 However, most available data on the use of antiviral drugs come from several prospective studies in ambulatory healthy adult and pediatric patients with seasonal influenza treated within 48 h of symptom onset.1012 Significantly, few clinical data have been published on the clinical effectiveness of antiviral drugs in hospitalized patients with seasonal influenza1820 or A(H1N1).69,14 Therefore, little information is currently available to assess whether there is a benefit on prognosis in treating patients with severe illness, including those requiring hospital admission for influenza or its complications.12

The present data concur with those from previous observational studies of hospitalized patients with A(H1N1) virus infection, which suggests that early antiviral treatment (< 48-72 h) may reduce disease severity and mortality. However, to our knowledge, this study is the first to address the effect of each day of delay in the administration of oseltamivir after symptom onset and after arrival to the hospital on clinical outcomes in hospitalized adults. In a study in the United States carried out between April 2009 and June 2009, early antiviral treatment (≤ 2 days) was significantly associated with a decreased risk of ICU admission or mortality.6 Similarly, in a previous study, we reported that oseltamivir treatment within 72 h was independently associated with a lower risk of severe disease.9 In addition, among pregnant women, those who received antiviral treatment > 48 h after symptom onset were more likely to be admitted to an ICU,7 and Chien et al8 found that late oseltamivir treatment (> 48 h) was associated with a higher risk of developing respiratory failure among hospitalized patients with pneumonia. However, a recent multicenter, retrospective study in China14 found no association between early oseltamivir treatment and improvement outcome in hospitalized patients with pneumonia.

The present results are also consistent with data from studies that evaluated the role of neuraminidase inhibitors in patients with seasonal influenza requiring hospitalization. In a prospective cohort study, McGeer et al18 found that treatment with oseltamivir (independently of time between symptom onset to antiviral administration) was associated with a reduction in mortality. Similarly, in a retrospective study to examine factors associated with earlier hospital discharge of adult patients with severe influenza illness, Lee et al19 found that oseltamivir initiated within 2 days of onset and influenza vaccination within 6 months were independently associated with shorter LOS. In a further report,20 these researchers also found that oseltamivir initiated within 96 h after illness onset was independently associated with a decreased mortality.

Another important finding in the present study was that the patients appeared to benefit from oseltamivir therapy initiated > 48 h after symptom onset. In this regard, Lee et al21 and Leekha et al22 reported that patients hospitalized with severe influenza have more active and prolonged viral replication. Major comorbidities, immunosuppression, and systemic corticosteroid use for asthma or COPD exacerbations have been related to slower viral clearance. In addition, observational studies showed that the A(H1N1) virus can be shed for a longer period than seasonal influenza.23 Prolonged viral shedding in hospitalized patients suggests that late onset of antiviral therapy (> 48 h) may decrease morbidity. Thus, Adisasmito et al24 reported that patients with A(H5N1) virus infection presented a survival benefit when prescribed antiviral treatment, preferably within 2 days of symptom onset, although the benefit remained even with treatment initiation up to 5 to 6 days after onset. Moreover, oseltamivir treatment has been associated with an accelerated decrease in viral load.21,25,26 Similarly, viral RNA clearance has been related to a shorter hospital stay.21

Significantly, however, two recent meta-analyses10,11 reported that the effectiveness of antiviral treatment in preventing serious complications and mortality in patients with seasonal influenza is still unsatisfactory. Falagas et al10 reported that neuraminidase inhibitors are effective in reducing influenza complications, such as acute otitis media or pharyngitis but not pneumonia. In addition, Jefferson et al11 found that neuraminidase inhibitors are effective in reducing the symptoms of influenza, but there is little evidence at present that they have any effect on complications of the lower respiratory tract, antibiotic use, or admissions to the hospital. Nevertheless, most of the trials studied in these meta-analyses evaluated only healthy adult patients and did not include hospitalized patients. Notably, the only published randomized placebo-controlled study regarding the use of antivirals (zanamivir) in hospitalized patients with seasonal influenza was terminated early and included a small number of patients. Thus, the authors pointed out that further investigations are needed to assess the efficacy of antiviral drugs in this context.13

The strengths of the present study are its prospective and multicenter design, the large number of patients included, and the comprehensive clinical data collection. In addition, we adjusted for confounding factors to determine the relation between timing of oseltamivir administration and outcomes. However, our study has several limitations that should be acknowledged. It was not a randomized trial and, as is the case with any observational study, there is potential for residual confounding. However, a randomized trial that intentionally delays treatment would present significant ethical challenges. In addition, because of the small sample size of patients who died in the present study, our data for mortality should be interpreted with caution. Finally, we did not evaluate the response of viral shedding to oseltamivir treatment and its relation with outcomes.

The results of this study suggest that timely oseltamivir administration has a beneficial impact on duration of fever, LOS, need for mechanical ventilation, and mortality in hospitalized patients with A(H1N1) virus infection. Consequently, treatment with oseltamivir should be administered as soon as possible to improve the clinical outcomes, even in patients who seek medical advice at a relatively late stage in the course of the illness.

Author contributions: Drs Viasus and Carratalà had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Viasus: contributed to the protocol design, data collection and analysis, writing and final approval of the manuscript.

Dr Paño-Pardo: contributed to data collection and analysis and review and final approval of the manuscript.

Dr Pachón: contributed to obtaining funding, data collection, and review and final approval of the manuscript.

Dr Riera: contributed to data collection and analysis and review and final approval of the manuscript.

Dr López-Medrano: contributed to data collection and review and final approval of the manuscript.

Dr Payeras: contributed to data collection and analysis and review and final approval of the manuscript.

Dr Fariñas: contributed to data collection and review and final approval of the manuscript.

Dr Moreno: contributed to data collection and review and final approval of the manuscript.

Dr Rodríguez-Baño: contributed to data collection and analysis and review and final approval of the manuscript.

Dr Oteo: contributed to data collection and review and final approval of the manuscript.

Dr Ortega: contributed to data collection and review and final approval of the manuscript.

Dr Torre-Cisneros: contributed to data collection and review and final approval of the manuscript.

Dr Segura: contributed to data collection and review and final approval of the manuscript.

Dr Carratalà: contributed to obtaining funding, protocol design, analysis, writing and final approval of the manuscript, and study supervision.

Role of sponsors: The funding sources had no role in the study design, data collection, data analysis and interpretation, or writing of the manuscript.

Additional information: The e-Appendix can be found in the Online Supplement at http://chestjournal.chestpubs.org/content/140/4/1025/suppl/DC1.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

A(H1N1)

pandemic 2009 influenza A(H1N1)

IQR

interquartile range

LOS

length of stay

RT-PCR

reverse-transcription polymerase chain reaction

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Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009;339:b5106 http://www.bmj.com/content/339/bmj.b5106. Accessed January 15, 2010.
 
Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America Expert Panel of the Infectious Diseases Society of America Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;488:1003-1032 [CrossRef] [PubMed]
 
Ison MG, Gnann JW Jr, Nagy-Agren S, et al; NIAID Collaborative Antiviral Study Group NIAID Collaborative Antiviral Study Group Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther. 2003;83:183-190 [PubMed]
 
Cui W, Zhao H, Lu X, et al. Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China. BMC Infect Dis. 2010;10:145 http://www.biomedcentral.com/1471-2334/10/145. Accessed June 30, 2010.
 
Uyeki T. Antiviral treatment for patients hospitalized with 2009 pandemic influenza A (H1N1). N Engl J Med. 2009;36123:e110 [CrossRef] [PubMed]
 
World Health OrganizationWorld Health Organization Interim WHO guidance for the surveillance of human infection with swine influenza A(H1N1) virus, 27 April 2009. World Health Organization Web site. http://www.who.int/csr/disease/swineflu/WHO_case_definitions.pdf. Accessed June 1, 2009.
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;405:373-383 [CrossRef] [PubMed]
 
McGeer A, Green KA, Plevneshi A, et al; Toronto Invasive Bacterial Diseases Network Toronto Invasive Bacterial Diseases Network Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007;4512:1568-1575 [CrossRef] [PubMed]
 
Lee N, Chan PK, Choi KW, et al. Factors associated with early hospital discharge of adult influenza patients. Antivir Ther. 2007;124:501-508 [PubMed]
 
Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clin Infect Dis. 2008;468:1323-1324 [CrossRef] [PubMed]
 
Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009;2004:492-500 [CrossRef] [PubMed]
 
Leekha S, Zitterkopf NL, Espy MJ, Smith TF, Thompson RL, Sampathkumar P. Duration of influenza A virus shedding in hospitalized patients and implications for infection control. Infect Control Hosp Epidemiol. 2007;289:1071-1076 [CrossRef] [PubMed]
 
Yu H, Liao Q, Yuan Y, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. BMJ. 2010;341:c4779 http://www.bmj.com/content/341/bmj.c4779. Accessed October 10, 2010.
 
Adisasmito W, Chan PK, Lee N, et al. Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010;2028:1154-1160 [CrossRef] [PubMed]
 
Li IW, Hung IF, To KK, et al. The natural viral load profile of patients with pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment. Chest. 2010;1374:759-768 [CrossRef] [PubMed]
 
Cao B, Li XW, Mao Y, et al; National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N Engl J Med. 2009;36126:2507-2517 [CrossRef] [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1 —Crude Outcomes Stratified by Groups of Time From Onset of Symptoms to Oseltamivir Administration in All Hospitalized Patients With A(H1N1): Univariate Analysis

Data are presented as median (IQR) or No. (%). A(H1N1) = pandemic 2009 influenza A(H1N1); IQR = interquartile range; LOS = length of stay.

a 

χ2 test for trend P = .001.

b 

χ2 test for trend P ≤ .001.

c 

χ2 test for trend P = .008.

d 

χ2 test for trend P ≤ .001.

Table Graphic Jump Location
Table 2 —Factors Associated With Prolonged Duration of Fever (Above the Median of 2 d) in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 3 —Factors Associated With a Prolonged Length of Hospital Stay (Above the Median of 5 d) in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 4 —Factors Associated With Mortality in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 5 —Factors Associated With the Need for Mechanical Ventilation in Hospitalized Patients With A(H1N1): Multivariate Analysis

See Table 1 legend for expansion of abbreviation.

Table Graphic Jump Location
Table 6 —Crude Outcomes Stratified by Groups of Time >From Onset of Symptoms to Oseltamivir Administration in Hospitalized Patients With Progressive, Severe, or Complicated Illness: Univariate Analysis

Data are presented as median (IQR). See Table 1 legend for expansion of abbreviations.

a 

χ2 test for trend P = .003.

b 

χ2 test for trend P = .005.

c 

χ2 test for trend P = .07.

d 

χ2 test for trend P = .006.

Table Graphic Jump Location
Table 7 —Effect on Outcomes of Delay of Oseltamivir Administration After Arrival to the Hospital in All Hospitalized Patients With A(H1N1)

See Table 1 legend for expansion of abbreviations.

a 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, age (< 50 y), pleural effusion, pneumonia, and bacterial coinfection.

b 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, age (< 50 y), comorbidities, pleural effusion, pneumonia, bacterial coinfection, and ICU admission.

c 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, time from symptom onset to hospital admission, comorbidities, morbid obesity, pleural effusion, pneumonia, and bacterial coinfection.

d 

The multivariate logistic regression included timing of oseltamivir administration after arrival to the hospital, age (< 50 y), and comorbidities.

References

Dawood FS, Jain S, Finelli L, et al; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009;36025:2605-2615 [CrossRef] [PubMed]
 
Centers for Disease Control and PreventionCenters for Disease Control and Prevention Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the 2009-2010 season. Centers for Disease Control and Prevention Web site. http://www.cdc.gov/h1n1flu/recommendations.htm. Accessed October 5, 2010.
 
Morgan OW, Bramley A, Fowlkes A, et al. Morbid obesity as a risk factor for hospitalization and death due to 2009 pandemic influenza A(H1N1) disease. PLoS ONE. 2010;53:e9694 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009694. Accessed August 1, 2010.
 
La Ruche G, Tarantola A, Barboza P, Vaillant L, Gueguen J, Gastellu-Etchegorry M. Epidemic Intelligence Team at InVS Epidemic Intelligence Team at InVS The 2009 pandemic H1N1 influenza and indigenous populations of the Americas and the Pacific. Euro Surveill. 2009;1442:pii: 19366 http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19366. Accessed December 22, 2009.
 
Centers for Disease Control and Prevention (CDC)Centers for Disease Control and Prevention (CDC) Deaths related to 2009 pandemic influenza A (H1N1) among American Indian/Alaska Natives-12 states, 2009. MMWR Morb Mortal Wkly Rep. 2009;5848:1341-1344 [PubMed]
 
Jain S, Kamimoto L, Bramley AM, et al; 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team 2009 Pandemic Influenza A (H1N1) Virus Hospitalizations Investigation Team Hospitalized patients with 2009 H1N1 influenza in the United States, April-June 2009. N Engl J Med. 2009;36120:1935-1944 [CrossRef] [PubMed]
 
Louie JK, Acosta M, Jamieson DJ, Honein MA. California Pandemic (H1N1) Working Group California Pandemic (H1N1) Working Group Severe 2009 H1N1 influenza in pregnant and postpartum women in California. N Engl J Med. 2010;3621:27-35 [CrossRef] [PubMed]
 
Chien YS, Su CP, Tsai HT, et al. Predictors and outcomes of respiratory failure among hospitalized pneumonia patients with 2009 H1N1 influenza in Taiwan. J Infect. 2010;602:168-174 [CrossRef] [PubMed]
 
Viasus D, Paño-Pardo JR, Pachón J, et al. Factors associated with severe disease in hospitalised adults with pandemic (H1N1) 2009 in Spain. Clin Microbiol Infect. 2010;175:738-746 [CrossRef] [PubMed]
 
Falagas ME, Koletsi PK, Vouloumanou EK, Rafailidis PI, Kapaskelis AM, Rello J. Effectiveness and safety of neuraminidase inhibitors in reducing influenza complications: a meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010;657:1330-1346 [CrossRef] [PubMed]
 
Jefferson T, Jones M, Doshi P, Del Mar C. Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis. BMJ. 2009;339:b5106 http://www.bmj.com/content/339/bmj.b5106. Accessed January 15, 2010.
 
Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America Expert Panel of the Infectious Diseases Society of America Seasonal influenza in adults and children—diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;488:1003-1032 [CrossRef] [PubMed]
 
Ison MG, Gnann JW Jr, Nagy-Agren S, et al; NIAID Collaborative Antiviral Study Group NIAID Collaborative Antiviral Study Group Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza. Antivir Ther. 2003;83:183-190 [PubMed]
 
Cui W, Zhao H, Lu X, et al. Factors associated with death in hospitalized pneumonia patients with 2009 H1N1 influenza in Shenyang, China. BMC Infect Dis. 2010;10:145 http://www.biomedcentral.com/1471-2334/10/145. Accessed June 30, 2010.
 
Uyeki T. Antiviral treatment for patients hospitalized with 2009 pandemic influenza A (H1N1). N Engl J Med. 2009;36123:e110 [CrossRef] [PubMed]
 
World Health OrganizationWorld Health Organization Interim WHO guidance for the surveillance of human infection with swine influenza A(H1N1) virus, 27 April 2009. World Health Organization Web site. http://www.who.int/csr/disease/swineflu/WHO_case_definitions.pdf. Accessed June 1, 2009.
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;405:373-383 [CrossRef] [PubMed]
 
McGeer A, Green KA, Plevneshi A, et al; Toronto Invasive Bacterial Diseases Network Toronto Invasive Bacterial Diseases Network Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007;4512:1568-1575 [CrossRef] [PubMed]
 
Lee N, Chan PK, Choi KW, et al. Factors associated with early hospital discharge of adult influenza patients. Antivir Ther. 2007;124:501-508 [PubMed]
 
Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clin Infect Dis. 2008;468:1323-1324 [CrossRef] [PubMed]
 
Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult patients hospitalized with influenza. J Infect Dis. 2009;2004:492-500 [CrossRef] [PubMed]
 
Leekha S, Zitterkopf NL, Espy MJ, Smith TF, Thompson RL, Sampathkumar P. Duration of influenza A virus shedding in hospitalized patients and implications for infection control. Infect Control Hosp Epidemiol. 2007;289:1071-1076 [CrossRef] [PubMed]
 
Yu H, Liao Q, Yuan Y, et al. Effectiveness of oseltamivir on disease progression and viral RNA shedding in patients with mild pandemic 2009 influenza A H1N1: opportunistic retrospective study of medical charts in China. BMJ. 2010;341:c4779 http://www.bmj.com/content/341/bmj.c4779. Accessed October 10, 2010.
 
Adisasmito W, Chan PK, Lee N, et al. Effectiveness of antiviral treatment in human influenza A(H5N1) infections: analysis of a Global Patient Registry. J Infect Dis. 2010;2028:1154-1160 [CrossRef] [PubMed]
 
Li IW, Hung IF, To KK, et al. The natural viral load profile of patients with pandemic 2009 influenza A(H1N1) and the effect of oseltamivir treatment. Chest. 2010;1374:759-768 [CrossRef] [PubMed]
 
Cao B, Li XW, Mao Y, et al; National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China National Influenza A Pandemic (H1N1) 2009 Clinical Investigation Group of China Clinical features of the initial cases of 2009 pandemic influenza A (H1N1) virus infection in China. N Engl J Med. 2009;36126:2507-2517 [CrossRef] [PubMed]
 
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