Changes in epidemiology, clinical features and severity of influenza A (H1N1) 2009 pneumonia in the first post-pandemic influenza season

Authors


Corresponding author: Dr J. Carratalà, Department of Infectious Diseases, Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L’Hospitalet de Llobregat, Barcelona, Spain
E-mail: jcarratala@ub.edu

Abstract

Clin Microbiol Infect 2012; 18: E55–E62

Abstract

Although the influenza A (H1N1) 2009 virus is expected to circulate as a seasonal virus for some years after the pandemic period, its behaviour cannot be predicted. We analysed a prospective cohort study of hospitalized adults with influenza A (H1N1) 2009 pneumonia at 14 teaching hospitals in Spain to compare the epidemiology, clinical features and outcomes of influenza A (H1N1) 2009 pneumonia between the pandemic period and the first post-pandemic influenza season. A total of 348 patients were included: 234 during the pandemic period and 114 during the first post-pandemic influenza season. Patients during the post-pandemic period were older and more likely to have chronic obstructive pulmonary disease, chronic kidney disease and cancer than the others. Septic shock, altered mental status and respiratory failure on arrival at hospital were significantly more common during the post-pandemic period. Time from illness onset to receipt of antiviral therapy was also longer during this period. Early antiviral therapy was less frequently administered to patients during the post-pandemic period (22.9% versus 10.9%; p 0.009). In addition, length of stay was longer, and need for mechanical ventilation and intensive-care unit admission were significantly higher during the post-pandemic period. In-hospital mortality (5.1% versus 21.2%; p <0.001) was also greater during this period. In conclusion, significant epidemiological changes and an increased severity of influenza A (H1N1) 2009 pneumonia were found in the first post-pandemic influenza season. Physicians should consider influenza A (H1N1) 2009 when selecting microbiological testing and treatment in patients with pneumonia in the upcoming influenza season.

Introduction

Pandemic influenza A (H1N1) virus emerged in Mexico during the spring of 2009 and spread rapidly worldwide [1], resulting in the first influenza pandemic of the twenty-first century. The epidemiological features, clinical spectrum of illness and risk factors for severe disease of pandemic influenza were broadly consistent across all countries [2–4]. Cases of infection occurred mostly in children and young adults. The majority of patients had self-limited mild-to-moderate uncomplicated disease. However, some patients developed severe illness and some died; most of these were adults between the ages of 20 and 50 years, with or without underlying medical conditions [2–6]. Importantly, most patients requiring intensive-care unit (ICU) admission had respiratory failure due mainly to primary influenza pneumonia [5,7,8]. Bacterial co-infection, although relatively infrequent, has also been associated with poor prognosis [5,9]. These patterns differed significantly from those seen during epidemics of seasonal influenza. In addition, in experimentally infected animals, the level of pulmonary replication of the influenza A (H1N1) 2009 virus was higher than that of seasonal influenza viruses [10].

In August 2010, the WHO declared the pandemic (H1N1) 2009 to be over. However, the pandemic influenza A (H1N1) 2009 virus is expected to remain in circulation as a seasonal virus for some years after the pandemic period, and its behaviour cannot be predicted [11]. The 1918–19 pandemic occurred in three waves: a mild first wave in spring and summer 1918, an extremely lethal second wave in autumn 1918, followed by a less severe third wave in winter 1919 [12,13]. Furthermore, the pattern of successive waves of varying severity also occurred in the 1957 and 1968 pandemics [12]. It is not clear, however, whether past pandemics are an appropriate register for evaluating the current influenza pandemic evolution. In addition, no study has specifically analysed influenza A (H1N1) 2009 pneumonia during the 2010–11 influenza season [14].

The aim of this study was to ascertain whether there have been changes in the epidemiology, clinical features and outcomes of influenza A (H1N1) 2009 infection. To this end, we compared hospitalized adults with confirmed influenza A (H1N1) 2009 pneumonia during the pandemic period with those hospitalized during the first post-pandemic influenza season.

Materials and Methods

Study design and study population

This is a prospective cohort study of adults hospitalized for at least 24 h with laboratory-confirmed pandemic influenza A (H1N1) 2009 virus pneumonia at 14 Spanish teaching hospitals during the pandemic period before the introduction of the vaccination campaign against the influenza A (H1N1) 2009 virus (12 June to 10 November 2009) and the first post-pandemic influenza season (1 December 2010 to 31 March 2011). Confirmed infection was defined as detection of pandemic influenza A (H1N1) 2009 virus by real-time RT-PCR in a respiratory sample (nasopharyngeal aspirate or nasal plus pharyngeal swab, and samples from the lower respiratory tract in selected patients). Cases were identified at the emergency department by attending physicians or investigators or by the daily review of the positive microbiology results of the RT-PCR. Pandemic influenza A (H1N1) 2009 virus testing was performed at each institution. The study was approved by the Institutional Review Board of the coordinating centre, Hospital Universitari de Bellvitge, and informed consent was obtained from patients.

For the purpose of this study, patients were divided into two groups: those hospitalized during the pandemic period and those hospitalized during the first post-pandemic influenza season. Epidemiological and clinical features and outcomes of hospitalized patients with influenza A (H1N1) 2009 pneumonia during these periods were compared.

Clinical assessment and follow up

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, body mass index (BMI, the weight in kilograms divided by the square of the height in metres), clinical signs and symptoms, biochemical analysis, chest X-ray findings, antiviral and antibacterial therapy, bacterial co-infection, time to reach clinical stability [15], complications and in-hospital mortality. For time from onset of symptoms or hospital arrival until antiviral administration, the day of onset of symptoms or hospital arrival was considered as day 0, respectively.

Study variables and definitions

Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature ≥38.0°C) and/or respiratory symptoms. Primary viral pneumonia was diagnosed in patients presenting pneumonia with negative respiratory and blood bacterial cultures and negative urine antigen tests. Bacterial co-infection was diagnosed in patients with one or more positive cultures obtained from blood, normally sterile fluids, or sputum and/or a positive urinary antigen test. Sputum Gram staining was performed on a purulent portion of each sample. Samples were considered to be of good quality when >25 polymorphonuclear cells and <10 squamous cells were observed under low-power magnification. Good-quality specimens were then screened for a predominant bacterial morphotype by oil immersion microscopy.

To stratify patients according to risk, we used community-acquired pneumonia scores: pneumonia severity index (PSI) and CURB-65 (confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older) [16,17].

Underlying medical conditions were assessed according to the Charlson Comorbidity Index [18]. Other comorbidities such as immunosuppression, neuromuscular disorders and sickle-cell disease were also recorded. A vaccinated patient was any individual who had received a pneumococcal vaccine in the previous 5 years or a pandemic influenza A (H1N1) 2009 vaccine in the previous year. Obesity was defined as BMI ≥ 30. The diagnosis of septic shock was based on the definition of the 1992 ACCP/SCCM Consensus Conference Committee [19]. Altered mental status was defined as disorientation with respect to person, place or time that was not known to be chronic, stupor or coma. Severe disease was defined as the composite outcome of ICU admission or death. The diagnosis of acute respiratory distress syndrome was established by the attending physicians, based on the usual practice guidelines [20].

Because hospital admission criteria were not standardized, we cannot rule out the possibility that factors other than disease severity may have contributed to site-of-care decisions. Therefore, to control for possible confounding because of differences in the criteria governing admission to hospital, we defined patients as having complicated pneumonia when any of the following were observed at presentation: intercostal retractions, tachypnoea (respiratory rate ≥30 per min), Pao2/Fio2 <300 or arterial saturation below 90%), altered mental status, hypotension (systolic blood pressure ≤90 mmHg), pleural effusion, multilobar infiltrates in chest X-rays or bacterial co-infection based on laboratory testing.

Statistical analyses

All proportions were calculated as percentages of the patients with available data. To detect significant differences between groups, we used the chi-square test or Fisher exact test for categorical variables and the t test or Mann–Whitney test for continuous variables, when appropriate. A subgroup analysis was performed in patients with complicated pneumonia at hospital admission to control for factors other than disease severity that may have contributed to site-of-care decisions. The results were analysed using SPSS (version 15.0; SPSS Inc., Chicago, IL, USA). A p value of <0.05 was considered to indicate a significant difference. All reported p values are two-sided.

Results

Three hundred and forty-eight patients with laboratory confirmed influenza A (H1N1) 2009 pneumonia required hospitalization: 234 during the pandemic period (June to November 2010) and 114 during the first post-pandemic influenza season period (December 2010 to March 2011).

The epidemiological characteristics of hospitalized patients during the pandemic and post-pandemic periods are compared in Table 1. Hospitalized patients during the post-pandemic influenza season were older (95% CI of mean difference 8.1–14.4 years). Regarding age groups, the number of patients below the age of 30 years was lower in the post-pandemic period, but the number of patients above 50 years was higher. Moreover, hospitalized patients during the post-pandemic influenza season had a higher Charlson score and were more likely to present comorbid conditions, such as chronic obstructive pulmonary disease, chronic kidney disease and cancer. Conversely, asthma was more likely to be present during the pandemic period. No significant differences were found regarding pregnancy, obesity, smoking and alcohol drinking between groups. Patients hospitalized during the post-pandemic influenza season had more frequently received a previous pandemic influenza (H1N1) 2009 and pneumococcal vaccine. Nearly 50% of influenza-vaccinated patients were older (>60 years).

Table 1.   Epidemiology of influenza A (H1N1) 2009 pneumonia by study periods
 All patients (n = 348)Pandemic period (n = 234)Post-pandemic season (n = 114)p
  1. Data are given as numbers (percentages) except where otherwise indicated. BMI, body mass index; COPD, chronic obstructive pulmonary disease; HIV/AIDS, human immunodeficiency virus/acquired immunodeficiency syndrome; IQR, interquartile range.

  2. aIncludes patients with mild (creatinine >1.5 mg/dL), and moderate and severe chronic renal disease according to Charlson Comorbidity Index.

  3. bIncludes patients with mild, moderate and severe chronic liver disease according to Charlson Comorbidity Index.

  4. cData available for 189 patients.

Demographic data
 Age, median (IQR), years44 (33–55)40 (30–50)53 (43–60)<0.001
 Age groups
  16–29 years60 (17.2)56 (23.9)4 (3.5)<0.001
  30–39 years78 (22.4)58 (24.8)20 (17.5)0.12
  40–49 years81 (23.3)57 (24.4)24 (21.4)0.49
  50–64 years96 (27.6)49 (20.9)47 (41.2)<0.001
  ≥65 years33 (9.5)14 (6)19 (16.7)0.001
 Male sex196 (56.3)129 (55.1)67 (58.8)0.52
 Pregnancy12 (3.4)10 (4.3)2 (1.8)0.22
 Current smoker126 (36.4)89 (38.2)37 (32.7)0.32
 Alcohol abuse35 (10.2)22 (9.5)13 (11.5)0.56
 Pandemic influenza vaccine15 (4.8)0 (0)15 (15.3)<0.001
 Pneumococcal vaccine, 5 years16 (5.5)7 (3.6)9 (9.4)0.04
Comorbid conditions
 Charlson score, median (IQR)0 (0–1)0 (0–1)1 (0–2)0.01
 Chronic pulmonary disease80 (23)53 (22.6)27 (23.7)0.83
  Asthma28 (8)24 (10.3)4 (3.5)0.03
  COPD37 (10.6)17 (7.3)20 (17.5)0.004
 Chronic heart disease30 (8.6)16 (6.8)14 (12.3)0.09
 Chronic kidney diseasea21 (6)9 (3.8)12 (10.5)0.01
 Chronic liver diseaseb23 (6.6)14 (6)9 (7.9)0.50
 Diabetes mellitus41 (11.8)25 (10.7)16 (14)0.36
 Immunosuppressed49 (14.1)29 (12.4)20 (17.5)0.19
  HIV/AIDS18 (5.2)13 (5.6)5 (4.4)0.64
  Transplant recipients12 (3.4)6 (2.6)6 (5.3)0.19
 Cancer31 (8.9)15 (6.4)16 (14)0.01
 Obesity (BMI ≥ 30)c55 (29)33 (30.8)22 (26.8)0.54

Clinical features and laboratory findings of both groups are detailed in Table 2. Time from symptoms onset to hospital admission was significantly longer in patients hospitalized during the post-pandemic influenza season (95% CI of mean difference 0.3–1.6 days). Regarding symptoms, significant increases in proportions of patients reporting rhinorrhoea, chills and dyspnoea during the post-pandemic influenza season were noted. As for clinical signs and laboratory findings, altered mental status, septic shock, tachypnoea, hyponatraemia, respiratory failure and multilobar pneumonia at hospital presentation were significantly more common in patients hospitalized during the post-pandemic period. The frequency of bacterial co-infection was similar in the two groups. Streptococcus pneumoniae was the most frequently identified pathogen (26 of 36 cases during the pandemic period and 12 of 16 cases during the post-pandemic period; p 0.83). No significant difference was found in the frequency of pneumococcal bacteraemia between the two periods (two and three cases, respectively; p 0.19).

Table 2.   Clinical features, laboratory findings, and prognostic scores of influenza A (H1N1) 2009 pneumonia by study periods
 All patients (n = 348)Pandemic period (n = 234)Post-pandemic season (n = 114)p
  1. Data are given as numbers (percentages) except where otherwise indicated. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CURB-65, confusion, urea nitrogen, respiratory rate, blood pressure, 65 years of age and older; PSI, pneumonia severity index.

  2. aPao2/Fio2 <300 or oxygen saturation <90%.

  3. bPatients were stratified into the following risk classes according to the PSI score: low risk (≤90 points, classes I, II, and III) and high risk (>90 points, classes IV and V).

Clinical features
 Reported symptoms
  Days of symptoms, median (range)4 (2–7)4 (2–6)5 (3–7)0.007
  Cough317 (91.6)213 (91.4)104 (92)0.84
  Shortness of breath229 (66)138 (59)91 (80.5)<0.001
  Muscle aches196 (56.5)141 (60.3)55 (48.7)0.04
  Sore throat76 (22.1)60 (25.6)16 (14.5)0.02
  Headache81 (23.3)58 (24.8)23 (20.4)0.36
  Rhinorrhoea63 (18.3)34 (14.5)29 (26.4)0.008
  Diarrhoea50 (14.4)32 (13.7)18 (15.9)0.57
  Vomiting52 (15)39 (16.7)13 (11.5)0.20
 Physical findings at presentation
  Fever (≥38°C)169 (51.1)123 (55.7)46 (41.8)0.01
  Septic shock14 (4)4 (1.7)10 (8.8)0.002
  Tachycardia (≥100 beats/min)148 (46.7)85 (41.5)63 (56.3)0.01
  Tachypnoea (≥30 breaths/min)78 (32.2)38 (26.2)40 (41.2)0.01
  Altered mental status23 (6.6)10 (4.3)13 (11.4)0.01
  Wheezing128 (37.2)69 (30)59 (51.8)<0.001
Laboratory findings
 Leukopenia (<4000 per mm3)73 (21.1)51 (21.8)22 (19.6)0.64
 Leukocytosis (≥12 000 per mm3)65 (18.8)37 (15.8)28 (25)0.04
 Lymphopenia (<1500 per mm3)184 (83)189 (81.8)95 (85.6)0.38
 Anaemia (Haematocrit <30%)23 (6.6)11 (4.7)12 (10.5)0.04
 Thrombocytopenia (<100 000 per mm3)31 (8.9)13 (5.6)18 (15.8)0.002
 Elevated ALT (>40 IU/L)104 (43.7)68 (42.8)36 (45.6)0.68
 Elevated AST (>40 IU/L)114 (44.7)75 (45.5)39 (43.3)0.74
 Hyponatraemia44 (12.7)21 (9.1)23 (20.2)0.004
 Respiratory failurea181 (56.2)107 (50.7)74 (66.7)0.006
 Bacterial co-infection52 (14.9)36 (15.4)16 (14)0.74
Radiographic findings
 Multilobar infiltrates203 (58.5)125 (53.4)78 (69)0.006
 Pleural effusion35 (10.1)21 (9)14 (12.4)0.32
Prognostic scores
 High-risk PSI classes (IV-V)b71 (20.6)27 (11.7)44 (38.6)<0.001
 High-risk CURB-65 score (≥2)65 (19)31 (13.6)34 (29.8)<0.001

Patients hospitalized during the post-pandemic influenza season period were more frequently classified into high-risk classes of the PSI and CURB-65 score. In addition, PSI and CURB-65 properly identified more cases of severe disease during the post-pandemic influenza season period (29.1% versus 51.9% and 30.9% versus 42.3%, respectively).

Treatment and clinical outcomes are detailed in Table 3. Time from illness onset to receipt of antiviral therapy (95% CI of mean difference 0.4–1.9 days) was longer during the post-pandemic influenza season period. Also, early antiviral therapy (≤48 h) was less frequently administered to patients during this period. Time to reach clinical stability and hospital stay (95% CI of mean difference 0.9–6.2 days) were longer among hospitalized patients during the post-pandemic period. ICU admission, acute respiratory distress syndrome, and need for mechanical ventilation were also higher in these patients.

Table 3.   Treatment and clinical outcomes of influenza A (H1N1) 2009 pneumonia by study periods
 All patients (n = 348)Pandemic period (n = 234)Post-pandemic season (n = 114)p
  1. Data are given as numbers (percentages) except where otherwise indicated.

  2. ARDS, acute respiratory distress syndrome; ICU, intensive-care unit, IQR, interquartile range.

  3. aIncludes acute coronary syndromes, new onset arrhythmias and decompensated heart failure.

Treatment
 Antiviral treatment341 (98)229 (97.9)112 (98.2)0.81
 Time from symptoms onset to antiviral therapy, median (IQR), days5 (3–7)5 (3–7)5.5 (4–7)0.002
  Early therapy (≤48 h after symptoms onset)62 (18.9)50 (22.9)12 (10.9)0.009
  Initiation of therapy the day of hospital arrival106 (31.5)61 (27.1)45 (40.5)0.01
 Antibacterial treatment341 (98)228 (97.4)113 (99.1)0.29
Clinical outcomes
 Length of hospital stay, median (IQR), days7 (5–12)7 (5–11)9 (6–16)0.005
 In-hospital complications
  Nosocomial infections27 (7.8)14 (6)13 (11.4)0.07
  Acute cardiac complicationsa22 (6.3)10 (4.3)12 (10.5)0.02
  ICU admission101 (29)53 (22.6)48 (42.1)<0.001
  Mechanical ventilation65 (18.7)30 (12.8)35 (30.7)<0.001
  ARDS51 (14.7)21 (9)30 (26.3)<0.001
  In-hospital mortality36 (10.3)12 (5.1)24 (21.2)<0.001

Severe disease occurred in 56/234 (23.9%) during the pandemic period and in 52/114 (45.6%) during the post-pandemic period (p <0.001). Patients with severe disease during the post-pandemic influenza season were older (median 42 and 53.5 years, respectively; 95% CI of mean difference 3–13.6 years). Septic shock was more frequent in hospitalized patients with severe disease during post-pandemic period. By contrast, early antiviral therapy was more commonly administered to hospitalized patients during the pandemic period. No significant differences were found in the other characteristics.

In-hospital mortality (5.1% versus 21.2%; p <0.001) was higher in patients during the post-pandemic influenza season. Causes of death were respiratory failure/acute respiratory distress syndrome (three of 13 patients in the pandemic period and eight of 24 patients in the post-pandemic period), shock/multiorgan failure (four of 13 patients and nine of 24 patients, respectively), decompensated comorbid condition (four of 13 patients and two of 24 patients, respectively) and nosocomial infection (two of 13 patients and five of 24 patients, respectively).

Table 4 shows epidemiology, clinical features and outcomes of influenza A (H1N1) 2009 pneumonia by study periods according to age. ICU admission and mortality were higher during the post-pandemic period in younger patients. In addition, early antiviral therapy was administered less frequently during the post-pandemic period, mainly in younger patients.

Table 4.   Epidemiology, clinical features and outcomes of influenza A (H1N1) 2009 pneumonia by study periods according to age
 Pandemic periodPost-pandemic period
16–29 years30–49 years50–64 years>64 years16–29 years30–49 years50–64 years>64 years
  1. Data are given as numbers (percentages) except where otherwise indicated.

  2. ICU, intensive care unit.

  3. ap value <0.05.

Male sex27 (48.2)66 (57.4)30 (61.2)6 (42.9)1 (25)24 (54.5)32 (68.1)10 (52.6)
Comorbidities17 (30.4)52 (45.2)37 (75.5)12 (85.7)1 (25)17 (38.6)32 (68.1)18 (94.7)
Septic shock1 (1.8)1 (0.9)a2 (4.1)0 (0)1 (25)4 (9.1)a3 (6.4)2 (10.5)
Altered mental status2 (3.6)4 (3.5)3 (6.1)1 (7.1)1 (25)2 (4.5)7 (14.9)3 (15.8)
Bacterial co-infection9 (16.1)20 (17.4)6 (12.2)1 (7.1)0 (0)5 (11.4)8 (17)3 (15.8)
Early antiviral therapy (≤48 h)14 (25.5)23 (21.3)a9 (21.4)4 (30.8)0 (0)1 (2.3)a9 (20)2 (10.5)
ICU admission11 (19.6)25 (21.7)a11 (22.4)a6 (42.9)1 (25)20 (45.5)a22 (46.8)a5 (26.3)
Mortality3 (5.4)a5 (4.3)a2 (4.1)a2 (14.3)2 (50)a8 (18.6)a11 (23.4)a4 (21.1)

Patients with complicated pneumonia

We performed a subgroup analysis of patients with complicated pneumonia at hospital admission. Of the 234 patients hospitalized during the pandemic period and the 114 during the first post-pandemic influenza season period, 140 (59.8%) and 91 (79.8%), respectively, had at least one criterion of complicated pneumonia. The differences regarding epidemiology, clinical characteristics and severity found in the subgroup of patients with complicated pneumonia at hospital admission were similar to those encountered in the entire population (data not shown).

Discussion

This prospective study shows that there were significant changes in the epidemiology and an increased severity of influenza A (H1N1) 2009 pneumonia during the first post-pandemic influenza season. Hospitalized adults with influenza A (H1N1) 2009 pneumonia during the recent first post-pandemic influenza season were older and were more likely to have comorbid conditions than those in the pandemic period. They also had a longer time to antiviral administration and had more severe disease at hospital presentation, as evidenced by the higher percentages of septic shock, altered mental status, respiratory failure and values of PSI and CURB-65 scores. Admission to ICU and need for mechanical ventilation were also more frequent. Importantly, in-hospital mortality was four-fold higher in the post-pandemic period than during the pandemic.

Although pregnancy, obesity and bacterial co-infection have been associated with poor prognosis during the pandemic (H1N1) 2009 [5,21–23], we did not find significant differences in the prevalence of these factors between the two study periods. Moreover, we performed a subgroup analysis of patients with complicated pneumonia to control for reasons other than disease severity that might have contributed to site-of-care decisions. Differences found between periods in this subgroup of patients with severe pneumonia were similar to those encountered in the entire population. On the other hand, it has recently been reported that the pandemic influenza A (H1N1) 2009 virus has remained genetically stable, with no increase in virulence since its origin [24,25]. Consequently, other factors may have been involved in the striking changes documented in the present study.

A recent study [12] has shown that immune protection naturally acquired during the first wave of the 1918 influenza pandemic provided mortality and morbidity protection during the successive pandemic wave. Several investigations have evaluated the frequency of the pre-existing cross-reactive antibodies and the acquisition of immunity in the pre-pandemic and post-pandemic (H1N1) 2009 periods [26–29]. These studies have found higher seropositivity in older patients (those born before 1957) and negligible or minimal seropositivity in younger patients in the pre-pandemic period. By contrast, after the pandemic period, higher seropositivity against pandemic (H1N1) virus was found among the school-aged population and young adult patients (<30 years old). Seropositivity rates were similar to those in the pre-pandemic period in the elderly population, indicating low infection rates. These data show that patients aged >30 years developed lower immune protection capable of neutralizing pandemic influenza A (H1N1) 2009 virus. Our findings of an older age in hospitalized patients during the post-pandemic influenza season are therefore consistent with the seroprevalence studies mentioned above.

Moreover, other studies have reported that the implementation of vaccination against the influenza A (H1N1) 2009 virus has been suboptimal [30–32]. In the present study, although 61% of the hospitalized patients with pneumonia during the post-pandemic period had one or more criteria for influenza A (H1N1) 2009 vaccination according to current guideline recommendations, only 17% of them had been vaccinated. These data reinforce the importance of vaccination in vulnerable subjects after the pandemic period. However, it should be noted that some studies have reported a vaccine effectiveness of 60–93% [33].

The WHO strongly recommends administration of antiviral treatment as soon as possible to all hospitalized patients during the post-pandemic influenza season [34]. In the present study, however, time from illness onset to receipt of antiviral therapy was significantly longer in patients hospitalized in the post-pandemic period than during the pandemic. Importantly, a large proportion of patients did not receive antiviral therapy on the day of arrival at the hospital, in spite of previous results from observational studies of hospitalized patients with pandemic (H1N1) 2009 showing that early antiviral treatment was associated with a decrease in viral load, disease severity and mortality [35–39]. Therefore, it can be hypothesized that the delay in the administration of antiviral treatment during the first post-pandemic influenza season may explain at least in part the differences in severity and outcomes found between the study periods. It is important that physicians should be aware that patients presenting with pneumonia in the emergency department during the upcoming influenza seasons may have influenza A (H1N1) 2009 and may require a targeted diagnostic and therapeutic approach.

Moreover, the baseline differences of greater age and the higher number of co-morbid illnesses between the two study periods may be also a possible explanation for the higher morbidity and mortality documented during the post-pandemic influenza season. In this respect, studies involving patients with pandemic (H1N1) 2009 found that older patients had the highest case fatality rate. Additionally, several comorbidities have been associated with complications, ICU admission and mortality during pandemics [2–6].

Strengths of the present study are its prospective and multicentre design, the large number of consecutive hospitalized patients with pneumonia included in both periods, and the comprehensive clinical data collection. In addition, this study was conducted in geographically diverse settings across Spain, a feature that improves the external validity of the results. However, our study has several limitations that should be acknowledged. We only examined hospitalized patients with influenza A (H1N1) 2009 pneumonia and cannot make assertions about other populations. Hospital criteria decisions were not standardized and we did not have information regarding the percentage of patients tested by PCR for H1N1 influenza virus in each study period. Moreover, we have no data regarding the percentage of patients with influenza A (H1N1) 2009 pneumonia treated by primary-care physicians. Likewise, we could not calculate incidence rates and the differences between study periods. However, according to data provided by the Spanish Influenza Surveillance System (http://vgripe.isciii.es/gripe/inicio.do), the highest incidence of influenza cases during the pandemic period (2009) were in weeks 43–47 (372 cases/100 000 inhabitants) and during post-pandemic influenza season period (2011) were in weeks 2–3 (230 cases/100 000 inhabitants). Finally, serum samples to determine antibodies against influenza A (H1N1) 2009 virus were not obtained and we did not perform testing to identify emerging new antigenic virus.

In conclusion, significant epidemiological changes and an increased severity of influenza A (H1N1) 2009 pneumonia were found in the first post-pandemic influenza season. Physicians dealing with patients with pneumonia in the upcoming influenza seasons should carefully consider influenza A (H1N1) 2009 as a possible causative agent when ordering microbiological tests and selecting treatment. Early diagnosis and antiviral therapy of influenza A (H1N1) 2009 pneumonia would help to improve patient outcomes.

Acknowledgements

Other members of the Novel Influenza A(H1N1) Study Group are: Carolina Garcia-Vidal, Jordi Niubó, Francesc Gudiol (Hospital Universitari de Bellvitge—IDIBELL, Barcelona); Jerónimo Pachón, Guiovana Osorio, Antonio Gutiérrez (Hospital Universitario Virgen del Rocío, Sevilla); Felipe Fernández-Cuencia, Juan Gálvez (Hospital Universitario Virgen Macarena, Sevilla); Lara García-Álvarez (Hospital San Pedro—CIBIR, Logroño); Joaquín Martínez-Montauti (SCIAS—Hospital de Barcelona, Barcelona); Julián Torre-Cisneros, Manuel Casal, Manuel Causse, Juan Gutiérrez-Aroca, Rosario Lara, Antonio Rivero (Hospital Universitario Reina Sofía—IMIBIC, University of Córdoba, Córdoba); Manuel Gutiérrez-Cuadra, María Victoria Sanjuan, José Luis González-Fernández (Hospital Universitario Marqués de Valdecilla, Santander); Adria Ramírez, Carmen Marinescu, Melchor Riera (Hospital Universitario Son Espases, Palma de Mallorca); Adriana González-Micheloud (Hospital Son Llàtzer, Palma de Mallorca); Sarah Caro-Bragado, María Romero-Gómez (Hospital Universitario La Paz—IDIPAZ, Madrid); Francisca Portero-Azorín, Antonio Ramos-Martínez, Rosa María Malo de Molina-Ruiz, María Agud (Hospital Universitario Puerta de Hierro, Madrid); Ferrán Segura (Hospital Parc Tauli, Sabadell), Francisco López-Medrano (Hospital Universitario 12 de Octubre, Madrid), and Asunción Moreno, María Ángeles Marcos, Tomás Pumarola, Laura Linares (Hospital Universitario Clinic, Barcelona).

Transparency Declaration

This work was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, Programa de Investigación sobre gripe A/H1N1 [GR09/0014] and Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III—co-financed by European Regional Development Fund ‘A way to achieve Europe’ ERDF, Spanish Network for Research in Infectious Diseases [REIPI RD06/0008]. D.V. is the recipient of a research grant from the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). All authors declare that they have no conflicting interests that are relevant to this article.

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