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Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain
ORIGINAL ARTICLE
VIROLOGY
Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain D. Viasus1, J. R. Pan˜o-Pardo2, J. Pacho´n3, A. Campins4, F. Lo´pez-Medrano5, A. Villoslada6, M. C. Farin˜as7, A. Moreno8, J. Rodrı´guez-Ban˜o9, J. A. Oteo10, J. Martı´nez-Montauti11, J. Torre-Cisneros12, F. Segura13, F. Gudiol1 and J. Carratala`1, for the Novel Influenza A (H1N1) Study Group* of the Spanish Network for Research in Infectious Diseases (REIPI) 1) Hospital Universitari de Bellvitge—IDIBELL, University of Barcelona, Barcelona, 2) Hospital Universitario La Paz—IDIPAZ, Madrid, 3) Hospital Universitario Virgen del Rocı´o, Sevilla, 4) Hospital Universitario Son Dureta, Palma de Mallorca, 5) Hospital Universitario 12 de Octubre, Madrid, 6) Hospital Son Lla`tzer, Palma de Mallorca, 7) Hospital Universitario Marque´s de Valdecilla, Santander, 8) Hospital Universitario Clinic, Barcelona, 9) Hospital Universitario Virgen Macarena, Sevilla, 10) Hospital San Pedro—CIBIR, Logron˜o, 11) SCIAS—Hospital de Barcelona, Barcelona, 12) Hospital Universitario Reina Sofı´a—IMIBIC, University of Co´rdoba, Co´rdoba and 13) Hospital Parc Tauli, Sabadell, Spain
Abstract The risk factors for complications in patients with influenza A (H1N1)v virus infection have not been fully elucidated. We performed an observational analysis of a prospective cohort of hospitalized adults with confirmed pandemic influenza A (H1N1)v virus infection at 13 hospitals in Spain, between June 12 and November 10, 2009, to identify factors associated with severe disease. Severe disease was defined as the composite outcome of intensive-care unit (ICU) admission or in-hospital mortality. During the study period, 585 adult patients (median age 40 years) required hospitalization because of pandemic (H1N1) 2009. At least one comorbid condition was present in 318 (54.4%) patients. Pneumonia was diagnosed in 234 (43.2%) patients and bacterial co-infection in 45 (7.6%). Severe disease occurred in 75 (12.8%) patients, of whom 71 required ICU admission and 13 (2.2%) died. Independent factors for severe disease were age <50 years (OR, 2.39; 95% CI, 1.05–5.47), chronic comorbid conditions (OR, 2.93; 95% CI, 1.41–6.09), morbid obesity (OR, 6.7; 95% CI, 2.25–20.19), concomitant and secondary bacterial co-infection (OR, 2.78; 95% CI, 1.11–7) and early oseltamivir therapy (OR, 0.32; 95% CI 0.16–0.63). In conclusion, although adults hospitalized for pandemic (H1N1) 2009 suffer from significant morbidity, mortality is lower than that reported in the earliest studies. Younger age, chronic comorbid conditions, morbid obesity and bacterial co-infection are independent risk factors for severe disease, whereas early oseltamivir therapy is a protective factor. Keywords: Epidemiology, influenza A (H1N1) 2009, intensive-care unit, mortality, risk factors Original Submission: 1 July 2010; Revised Submission: 23 July 2010; Accepted: 19 August 2010 Editor: D. Raoult Article published online: 3 September 2010 Clin Microbiol Infect 2011; 17: 738–746 10.1111/j.1469-0691.2010.03362.x
Corresponding author: J. Carratala`, Department of Infectious Diseases, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain E-mail: [email protected] *Other members of the Novel Influenza A(H1N1) Study Group are: J. Niubo1, A. Martı´n-Quiro´s2, M. Romero-Go´mez2, G. Ruı´zCarrascoso2, J. C. Figueira2, M. C. Prados2, E. Cordero3, E. Garcı´aCabrera3, M. Riera4, J. M. Aguado5, J. Vila5, A. Payeras6, M. Garcı´aGasalla6, J. L. Gonza´lez-Ferna´ndez7, M. Gutie´rrez-Cuadra7, M. V. Sanjuan7, J. A. Parra7, L. Linares8, I. Hoyo8, M. A´. Marcos8, T. Pumarola8, M. de Cueto9, M. A. Muniain9, M. D. del Toro9, L. Pe´rez-Martı´nez10, J. R. Blanco10, M. Sanz10, L. Metola10, V. Ibarra10, L. Ortega11, R. Lara12, M. Causse12, E. M. Gonza´lez13.
Introduction Influenza pandemics have been associated with increased morbidity and mortality. Each pandemic is different and there are always a series of unknowns when an influenza virus emerges and becomes pandemic [1,2]. In April 2009, a novel influenza virus, now known as influenza A (H1N1)v virus, caused an outbreak of respiratory disease in Mexico [3] and spread rapidly throughout the world. Spain was the first country in Europe to report a laboratory-confirmed case of new influenza A (H1N1)v virus infection [4]. The number of
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Viasus et al.
hospitalizations and deaths caused by pandemic (H1N1) 2009 increased continuously until December 2009. The studies published indicate that there are differences between pandemic (H1N1) 2009 and seasonal influenza. Among adult patients, pandemic (H1N1) 2009 affects mainly those under the age of 60 years with chronic underlying diseases, pregnant women, and obese patients [5–7]. The overall mortality of this infection is similar to that presented by seasonal influenza and lower than previous pandemics [8– 10], although mortality varies considerably between countries [8]. There is also concern that subsequent waves of influenza pandemic could be more lethal than the first [2]. Little information is currently available on factors associated with severe disease in adults hospitalized for the pandemic influenza (H1N1)v virus. Moreover, the few studies published to date have been limited by small sample size [5,11–13], retrospective design [13,14], analysis based merely on database surveillance reports [15,16], or inclusion of only critically ill patients [11,17]. To identify risk factors for severe disease, and hence to determine the optimal case management and prevention, more clinical and treatment data of the pandemic (H1N1) 2009 are needed. The aim of the present multicentre study was to ascertain factors associated with severe disease among adults hospitalized for pandemic (H1N1) 2009 in Spain.
Materials and Methods Setting, patients and study design
This prospective cohort study was conducted at 13 tertiary hospitals belonging to the Spanish Network for Research in Infectious Diseases (REIPI). All adult patients admitted to the hospital for at least 24 h with confirmed influenza A (H1N1) virus infection from June 12 to November 10, 2009, were prospectively recruited and followed up. Following the recommendations of the Spanish Ministry of Health, specific laboratory tests for influenza A (H1N1)v virus (see below) were performed on all patients with community-onset pneumonia or influenza-like symptoms in any of the following circumstances: pregnancy, underlying chronic conditions, morbid obesity, and in the presence of complications [18]. If the first test was negative, a new sample was recommended whenever the clinical syndrome had not clearly improved. The results were typically available in <24 h (frequently <12 h). Cases were detected on a daily basis by reviewing the microbiological reports. A confirmed case was defined as a person with an influenza-like illness with laboratoryconfirmed pandemic influenza A (H1N1) virus infection using
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real-time polymerase chain reaction or viral culture [19]. Pandemic influenza A (H1N1)v virus testing was performed at each institution. For the purposes of this study patients were divided into two groups: severe disease and no severe disease. Severe disease was defined as the composite outcome of intensive-care unit (ICU) admission or in-hospital mortality. The study was approved by the Ethics Committee of the coordinating centre, the Hospital Universitari de Bellvitge, and informed consent was obtained from patients. Clinical assessment and follow-up
Microbiological studies, hospital and ICU admission criteria, and treatment decisions were not standardized and were made by attending physicians at each study centre. 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, comorbid conditions, body mass index (BMI, the weight in kilograms divided by the square of the height in metres), clinical signs and symptoms, biochemical analysis, chest radiograph findings, antiviral and antibacterial therapy, concomitant and secondary bacterial co-infection, and outcomes, including mortality. A long-term follow-up visit was scheduled 1 month after discharge. For time calculations, the day of admission was considered to be hospital day 0, except for time to antiviral administration in which the day of symptoms onset was considered day 0. Completed protocols were sent to the coordinating centre and all data were carefully reviewed by two clinical investigators (DV and JC) before the final validation. Definitions
Comorbidities were assessed using the Charlson Comorbidity Index definitions [20]. Other comorbidities, such as immunosuppression, neuromuscular disorders and sickle-cell disease, were also recorded. Obesity was defined as a BMI ‡30–39.9 and morbid obesity as a BMI ‡ 40 or a subjective assessment by the physician if weight and height were not available. Tobacco abuse was recorded when a patient had smoked more than ten cigarettes per day for at least 1 year preceding the study. Alcohol abuse was considered if alcohol intake was more than three standard drinks per day. Vaccination status was assessed from interviews with the patients or their relatives and from reviews of hospital and personal health records (vaccination card). Patients were considered to be pneumococcus-vaccinated if 23-valent polysaccharide pneumococcal vaccine had been administered in the 5 years before admission, and influenza-vaccinated if seasonal influenza vaccine had been administered during the year before
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or not. The relative risks were expressed as OR and 95% CI. Statistical significance was established at a 0.05. All reported p values are two-tailed.
admission. Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature ‡38.0C) and respiratory symptoms. Concomitant and secondary bacterial co-infection were diagnosed in patients with one or more positive cultures obtained from blood, normally sterile fluids, or sputum and a positive Streptococcus pneumoniae urinary antigen. Complications were defined as any untoward circumstances occurring during hospitalization. Mortality was defined as death from any cause during hospitalization.
Results Patient characteristics
During the study period, 585 consecutive hospitalized patients with influenza A (H1N1)v virus infection were included. The demographic and clinical characteristics of patients are detailed in Tables 1 and 2. Most patients were under the age of 50 years. Nearly half of the patients had at least one comorbid condition, with chronic respiratory disease, immunosuppression and diabetes mellitus being the most common. Twenty-eight (4.8%) patients were morbidly obese. Obese and morbidly obese patients had a high prevalence of underlying disease (59.3% and 67.9%, respectively). Ninety-eight patients (16.8%) were pregnant. The median time from onset of symptoms to hospitalization was 3 days. The most frequent symptoms and signs on hospital admission were fever, cough, shortness of breath, muscle aches and tachycardia. Conversely, altered mental status and hypotension at presentation were infrequent.
Statistical analysis
The results were analysed using a commercially available statistical software package (SPSS, version 15.0; SPSS Inc, Chicago, IL, USA). Descriptive statistics were performed for all study variables. 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 U-test for continuous variables, when appropriate. The multivariate logistic regression analysis of factors potentially associated with severe disease included the variables that were significant in the univariate analysis and clinically important variables, whether they were significant
TABLE 1. Demographic characterAll patients (n = 585) Demographic data Age, median (range), years Age groups, % 16–49 years 50–64 years ‡65 years Male sex Pregnancy Current smoker Alcohol abuse Influenza vaccine (season) Pneumococcal vaccine, 5 years Comorbid conditions Any one condition Chronic pulmonary disease Asthma COPD OSAS Chronic heart disease Chronic renal failure Chronic liver failure Diabetes mellitus Immunosuppressed HIV/AIDS Transplant recipients Cancer Obesity (BMI ‡ 30–39.9)a Morbid obesity (BMI ‡ 40 and subjective assessment)
39 (16–87)
Patients without severe disease (n = 510)
38 (16–87)
Patients with severe disease (n = 75)
39 (17–80)
istics of patients with pandemic p
0.26 96
424 111 50 300 98 184 33 62 23
(72.5) (19) (8.5) (51.3) (16.8) (31.7) (5.7) (12.5) (4.7)
370 96 44 260 96 152 24 54 21
(72.5) (18.8) (8.6) (51) (18.8) (30.1) (4.8) (12.4) (4.8)
54 15 6 40 2 32 9 8 2
(72) (20) (8) (53.3) (2.7) (42.7) (12) (13.8) (3.5)
0.70 <0.001 0.02 0.01 0.75 0.65
318 169 104 49 17 40 25 29 59 81 26 22 41 59 28
(54.4) (28.9) (17.8) (8.4) (2.9) (6.8) (4.3) (5) (10.1) (13.8) (4.4) (3.8) (7) (23.2) (4.8)
262 135 90 34 11 30 19 24 49 71 23 21 36 50 17
(51.4) (26.5) (17.6) (6.7) (2.2) (5.9) (3.7) (4.7) (9.8) (13.9) (4.5) (4.1) (7.1) (21.9) (3.3)
56 34 14 15 6 10 6 5 10 10 3 1 5 9 11
(74.1) (45.3) (18.7) (20) (8) (13.3) (8) (6.7) (13.3) (13.3) (4) (1.3) (6.7) (36) (14.7)
<0.001 0.001 0.82 <0.001 0.005 0.01 0.11 0.40 0.31 0.89 1 0.34 0.90 0.114 <0.001
BMI, body-mass index; COPD, chronic obstructive pulmonary disease; HIV/AIDS, human immunodeficiency virus/ acquired immunodeficiency syndrome; OSAS, obstructive sleep apnoea syndrome. Values given are n (%) unless otherwise stated. a Two hundred and fifty-three patients with height and weight available.
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TABLE 2. Clinical characteristics of Patients without Patients with All patients severe disease severe disease (n = 585) (n = 510) (n = 75) p
patients with pandemic (H1N1) 2009 Clinical features Reported symptoms Time from symptoms onset to hospitalization median (range), days Cough, % Shortness of breath Muscle aches Sore throat Headache Rhinorrhoea Diarrhoea Vomiting Pleuritic chest pain Physical findings Temperature at admission, median (range), C Fever (‡38.0C) Systolic blood pressure median (range), mmHg Hypotension (SBP £90 mmHg) Cardiac frequency median (range), beats/min Tachycardia (‡90 beats/min) Respiratory frequency median (range), breaths/min Tachypnoea (‡24 breaths/min) Impaired consciousness Wheezing
3 (0–21)
3 (0–21)
525 274 339 163 187 119 61 80 97
(89.9) (46.8) (58.1) (27.9) (32) (20.3) (10.4) (13.7) (16.6)
461 218 305 147 174 111 51 71 86
(90.6) (42.7) (60) (28.8) (34.2) (21.8) (10) (13.9) (16.9)
38 306 120 16 97 337 20 149 15 169
(35–41) (54.6) (65–280) (2.9) (46–160) (65.9) (8–50) (40.1) (2.6) (29.4)
38 270 120 10 96 280 19 112 4 139
(35–40) (55) (70–220) (2.1) (46–160) (63.2) (8–45) (34.6) (0.8) (27.7)
3 (1–10) 64 56 34 16 13 8 10 9 11 38 36 120 6 109 57 28 37 11 30
0.11
(85.3) (74.7) (45.3) (21.3) (17.3) (10.7) (13.3) (12) (14.7)
0.16 <0.001 0.01 0.17 0.003 0.02 0.37 0.65 0.63
(35–41) (52.2) (65–280) (8.7) (71–160) (83.8) (10–50) (77.1) (14.7) (41.1)
0.77 0.66 0.51 0.002 <0.001 0.001 <0.001 <0.001 <0.001 0.01
Values given are n (%) unless otherwise stated.
Diagnostic findings
The laboratory and radiographic findings are shown in Table 3. On admission, most patients had lymphopenia and elevated C-reactive protein and nearly half had elevated lactate dehydrogenase. Findings consistent with pneumonia on chest radiography were found in 234 (43.2%) patients. Fortyfive (7.6%) patients had bacterial co-infection. Overall, Streptococcus pneumoniae (28 cases) was the most frequent causative bacteria followed by methicillin-susceptible Staphylococcus aureus (four cases), Pseudomonas aeruginosa (four cases) and Haemophilus influenzae (three cases). Other organisms isolated were Haemophilus parainfluenzae, Moraxella catharralis, Streptococcus pyogenes, Escherichia coli, Acinetobacter baumannii and Streptococcus sanguis. Treatment and clinical outcomes
The treatment and clinical outcomes are summarized in Table 4. Oseltamivir was administered to 93.3% of patients. The treatment was initiated at a median of 3 days after onset of symptoms. Oseltamivir was given at a dose of 75 mg twice daily in all but 33 patients, who received 150 mg twice daily. Antibacterial therapy was administered in 416 (71.7%) patients. The most commonly used antibiotics were levofloxacin (237 cases), ceftriaxone (97 cases) and amoxicillin/clavulanate (86 cases). In-hospital complications developed in 88 (15%) patients. Severe disease occurred in 75 (12.8%), of whom 71 required admission to ICU and 13 died. Among the 71 patients requiring ICU admission, 53 had pneumonia and 52 under-
went mechanical ventilation. Fifty-two (73.2%) of the 71 ICU patients had chronic comorbid conditions, mainly chronic pulmonary disease (33 patients), chronic heart disease (ten patients), diabetes mellitus (ten patients) and immunosuppression (seven patients). Only two of 98 pregnant women required ICU admission. Other in-hospital complications included viral hepatitis (two cases), catheter-related thrombosis of the internal jugular vein (two cases), preterm delivery (two cases), meningitis/encephalitis (one case), acute renal failure requiring haemodialysis (one case), diabetic ketoacidosis (one case), and oseltamivir-related visual disturbances (one case). The in-hospital mortality was 2.2% (13 of 585 patients) and the median time from hospital admission to death was 9 days (range, 1–33). Among the 13 patients who died, nine were under 50 years of age, eight were women, 12 had comorbid conditions, two were morbidly obese, 11 had multilobar pneumonia, and five had bacterial co-infection (Table 5). Causes of death were respiratory failure/acute respiratory distress syndrome (three of 13 patients), shock/ multi-organ failure (four patients), decompensated comorbid condition (four patients) and nosocomial infection (four patients). Factors associated with severe disease
Patients with severe disease were more frequently current smokers and heavy alcohol drinkers and had more comorbidities and morbid obesity than patients without severe disease. Among comorbid conditions, chronic obstructive
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TABLE 3. Diagnostic findings of patients with pandemic (H1N1) 2009
Laboratory findings Leucocyte count median (range), per mm3 Leukopenia (<4000 per mm3), % Leukocytosis (‡12000 per mm3) Lymphopenia (lymphocytes <1500 cells per mm3) Hematocrit median (range), % Anaemia (Hcto <36%) Platelet count, median (range), per mm3 Thrombocytopenia (<150,000 per mm3) Alanine aminotransferase, median (range), IU/L Elevated alanine aminotransferase (>40 IU/L) Aspartate aminotransferase median (range), IU/L Elevated aspartate aminotransferase (>40 IU/L) Creatine phosphokinase, median (range), IU/L Elevated creatine kinase (>240 IU/L) Lactate dehydrogenase, median (range), IU/L Elevated lactate dehydrogenase (>350 IU/L) C-reactive protein, median (range), mg/L Elevated C-reactive protein (>20 mg/L) PaO2/FiO2, median (range) Respiratory failure (PaO2/FiO2 < 300 or oxygen saturation <90%) Concomitant/secondary bacterial co-infectiona Radiographic findings Infiltrates on chest radiography Multilobar infiltratesb
All patients (n = 585)
Patients without severe disease (n = 510)
Patients with severe disease (n = 75)
p
7230 84 76 468 40.1 146 187 000 153 28 119 29 105 94 34 335 131 43.7 264 295.6 172 45
7100 74 55 401 40 130 188 000 127 27 89 27.5 78 87 26 325 105 40 222 304.8 112 31
8870 10 21 67 41 16 167 500 26 53 30 45.2 27 110 8 427 26 75 42 233.3 60 14
0.003 0.76 <0.001 0.06 0.15 0.39 0.27 0.08 <0.001 <0.001 <0.001 <0.001 0.15 0.14 0.004 0.003 <0.001 0.02 <0.001 <0.001 <0.001
(240–41400) (14.5) (13.1) (81.5) (17–57) (25.3) (7000–467 000) (26.7) (6–840) (31.7) (9–429) (28.9) (9–6096) (20.1) (31–3545) (46.3) (1–506) (75.9) (47–519) (33.2) (7.6)
234 (43.2) 135 (57.7)
(300–41400) (14.7) (10.9) (80.4) (17–57) (25.9) (7000–467 000) (25.5) (6–840) (27.5) (9–400) (24.8) (9–6096) (18.2) (31–1519) (42.9) (1–398) (73.8) (83.5–519) (25.2) (6.3)
178 (38) 89 (50)
(240–23380) (13.3) (28) (89.3) (27–56) (21.3) (67 000–381 000) (35.1) (11–350) (58.8) (16.8–429) (55.1) (18–640) (30.8) (32–3545) (68.4) (4.1–506) (89.4) (47–342) (82.2) (18.9)
56 (75.7) 46 (82.1)
<0.001 <0.001
PaO2/FiO2, partial pressure arterial oxygen/fraction of inspired oxygen. Values given are n (%) unless otherwise stated. Six patients had more than one microorganism. b Percentages from patients with pneumonia. a
TABLE 4. Treatment and clinical
Treatment Antiviral treatment, % Time from symptoms onset to antiviral therapy, median (range), days Early treatment (£72 h after symptoms onset) Antibacterial treatment Corticosteroids Clinical outcomes Length of hospital stay, median (range), days In-hospital complications Shock Nosocomial infections Heart complications ICU admission Mechanical ventilation ARDS In-hospital mortality
All patients (n = 585)
Patients without severe disease (n = 510)
Patients with severe disease (n = 75)
545 (93.3) 3 (1–21)
473 (92.9) 3 (1–21)
72 (96) 4 (1–21)
0.32 0.004
297 (57) 416 (71.7) 160 (28)
272 (59.6) 342 (67.6) 118 (23.6)
25 (38.5) 74 (100) 42 (58.3)
0.001 <0.001 <0.001
5 (1–98)
5 (1–28)
11 (1–98)
<0.001
1 (0.2) 4 (0.8) 2 (0.4) – – – –
25 (33.8) 12 (16) 10 (13.3) – – – –
<0.001 <0.001 <0.001
26 16 12 71 52 23 13
(4.5) (2.7) (2.1) (12.1) (8.9) (3.9) (2.2)
outcomes of patients with panp
demic (H1N1) 2009
ARDS, acute respiratory distress syndrome; ICU, intensive-care unit. Values given are n (%) unless otherwise stated.
pulmonary disease, obstructive sleep apnoea syndrome and chronic heart disease were more frequent in patients with severe pandemic A(H1N1) 2009. No differences were found in pneumococcal vaccination and seasonal influenza vaccination rates between groups. No patient was vaccinated against pandemic influenza A(H1N1)v virus. As regards clinical features, shortness of breath, hypotension, impaired consciousness and tachypnoea were also more common in patients with severe disease. Moreover, these patients were more likely to present lymphopenia and
thrombocytopenia and they had significantly higher liver enzyme, lactate dehydrogenase and C-reactive protein levels. Among radiological and microbiological findings, they also had a higher prevalence of pneumonia and bacterial co-infection. The mean time from onset of symptoms to oseltamivir administration was significantly longer in patients with severe disease (95% CI of mean difference 0.3–2.1 days). Mean length of hospital stay was also significantly longer in these patients (95% CI of mean difference 7.7–15 days).
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21
28
29
32
33
34
39
46
47
50
51 72
77
1
2
3
4
5
6
7
8
9
10
11 12
13
F
M F
M
F
M
F
F
M
F
M
F
F
Sex
Metastatic cancer Diabetes mellitus/Chronic heart and liver disease/connective tissue disease Chronic renal disease
COPD/Chronic liver disease
Metastatic cancer
COPD/Diabetes mellitus/Intravenous drug addiction/Morbid obesity Asthma/Metastatic cancer
Intravenous drug addiction
Mental retardation
None
Metastatic cancer
Toxic liver failure/Intravenous drug addiction Morbid obesity
Underlying medical conditions
Unilobar
Multilobar Multilobar
a
No
No No
Acinetobacter baumanii/ Candida albicans/ Candida glabrata Haemophilus influenzae
Multilobar
Escherichia coli
Multilobara
Streptococcus pneumoniae No
No
No
No
No
Staphylococcus aureus
Bacterial co-infection
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Infiltrates in chest radiography
No
No No
No
No
No
Si
No
No
No
No
No
No
Early antiviral therapy
Amoxicilline/clavulanate
Piperaciline/tazobactam Piperaciline/tazobactam
Imipenem
Meropenem Fluconazol
Meropenem linezolid Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Cefotaxime Levofloxacin Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Meropenem
Empiric antibacterial therapy
Mechanical ventilation/Shock/Nosocomial infection
Mechanical ventilation/ARDS/Nosocomial infection/hemodialysis Decompensate comorbid condition Mechanical ventilation/ARDS
Nosocomial infection/Decompensate comorbid condition Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Nosocomial infection/Shock Mechanical ventilation/ARDS/Nosocomial infection/Shock Nosocomial infection
Complications
33
9 1
21
25
4
5
3
3
4
32
14
14
Length of hospital stay
Viasus et al.
ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease. Clinical diagnosis of bilateral pneumonia.
Age (years)
Case
TABLE 5. Demographic and clinical characteristics of patients with pandemic (H1N1) 2009 who died
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TABLE 6. Factors associated with severe pandemic (H1N1) 2009: multivariate analysis
Age (16–49 years) Male sex Current smoker Alcohol abuse Comorbid condition Morbidly obese Influenza vaccine (season) Early antiviral treatment (£72 h) Concomitant and/or secondary bacterial co-infection
Odds ratio
95% confidence interval
p
2.39 0.74 1.08 2.20 2.93 6.74 0.94 0.32 2.78
1.05–5.47 0.38–1.45 0.53–2.22 0.64–7.52 1.41–6.09 2.25–20.19 0.36–2.44 0.16–0.63 1.11–7.00
0.03 0.39 0.82 0.20 0.004 0.001 0.90 0.001 0.02
The results of multivariate logistic regression analysis for factors potentially associated with severe disease are shown in Table 6. Independent factors associated with severe disease were age <50 years (OR, 2.39; 95% CI, 1.05–5.47), comorbid conditions (OR, 2.93; 95% CI, 1.41–6.09), morbid obesity (OR, 6.74; 95% CI, 2.25–20.19), concomitant and/or secondary bacterial co-infection (OR, 2.78; 95% CI, 1.11–7) and early oseltamivir therapy (£72 h) (OR, 0.32; 95% CI 0.16–0.63).
Discussion In this prospective, multicentre study of a large number of adults hospitalized for pandemic influenza (H1N1)v virus infection in Spain, independent factors associated with severe disease were younger age, chronic comorbid conditions, morbid obesity and bacterial co-infection. Conversely, early oseltamivir therapy was a protective factor. Characteristics and clinical outcomes of our study patients were similar to those described elsewhere [5,11,21–23]. Although our mortality rate was lower than that reported in the earliest studies of hospitalized patients [5,14,23], our findings concur with those of more recent reports [24–26]. Previous studies found that current [5,11,22,27] and past pandemics [28] affected mainly younger patients. Similarly, adult patients younger than 50 years had a higher risk of death during the 1918 Spanish influenza pandemic [28] and during the recent H5N1 avian influenza [29]. Nevertheless, studies involving patients with pandemic (H1N1) 2009 found that although older patients had the lowest estimated incidence rate, they also had the highest case fatality rate [9,15,23]. In the present study, we found that among hospitalized adults, younger patients had a higher risk of severe disease, in agreement with the finding of earlier studies of critically ill patients [11,21]. Only 8.5% patients of our cohort were over 65 years old. The low prevalence of older
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patients in pandemic (H1N1) 2009 has been attributed to residual immunity against influenza A (H1N1) strains in people born before 1950 [30,31]. Other independent factors associated with severe disease identified in our study, such as chronic morbid conditions and morbid obesity, have previously been associated with ICU admission or mortality [5,11,15,16]. Regarding comorbidities, chronic obstructive pulmonary disease, obstructive sleep apnoea syndrome and chronic cardiac disease were more common in patients with severe disease than in the others. In our study, although asthma was the most frequent underlying condition, no difference was found in its prevalence between patients with and without severe disease. Conversely, O’Riordan et al. [32] and Libster et al. [33] reported that asthma was a significant risk factor for ICU admission and mortality among children admitted to hospital. Similarly, during previous influenza pandemics and interpandemic periods, patients with impaired cardiopulmonary function have presented a higher risk of complications [34]. We found that patients with morbid obesity had a higher risk of severe disease. Morbidly obese patients also had frequent comorbidities, especially obstructive sleep apnoea syndrome and diabetes mellitus. Interestingly, a recent study demonstrated that obese mice infected with influenza virus have diminished cell cytotoxicity, delayed pro-inflammatory cytokine expression, and higher mortality than lean mice controls [35]. Future investigations are needed to clarify the pathophysiology underlying the association of morbid obesity and severe influenza infection. There is evidence that influenza virus alters the host inflammatory response and predisposes to adherence, invasion, and induction of disease by bacterial microorganisms. It has long been recognized that bacterial co-infection complicates the course of illness for many patients with influenza infection. In fact, during the influenza pandemics of the twentieth century, secondary bacterial pneumonia was an important cause of illness and death and S. pneumoniae was reported to be the most common aetiology. In the present study, S. pneumoniae was by far the most frequently isolated microorganism. Although prevalence of bacterial co-infection in our study was relatively low, it was an independent factor for severe disease. The synergistic interaction between bacteria and influenza virus has been shown to contribute to the severity of the resulting infection in animal models [36]. Moreover, Palacios et al. [37] recently reported that identification of S. pneumoniae in nasopharyngeal swab samples from patients with pandemic (H1N1) 2009 was also a factor related to severe disease. Other investigators have found a high frequency of bacterial co-infection in lung tissue specimens from fatal cases of influenza (H1N1)v virus infection
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[38,39] and the 1918–1919 influenza pandemic [40]. In this regard, pneumococcal vaccination has been recommended as a key element in influenza preparedness plans [41]. No randomized controlled trials of neuraminidase inhibitors in patients admitted to hospital with influenza virus infection have been carried out to date. Therefore, determining the effect of antiviral treatment on complications in hospitalized patients during the current pandemic is a critical issue. In previous studies [13,23], early administration of antiviral treatment was associated with favourable outcome and with lower development of respiratory failure in patients with influenza A (H1N1)v 2009 virus infection. We found that patients who received early oseltamivir treatment tended to have more comorbidities, but had less evidence of pneumonia and bacterial co-infection (data not shown). These patients also had a significantly lower risk of severe disease. Although no solid conclusions can be established based on observational studies alone, these findings suggest that giving early antiviral treatment to hospitalized patients with pandemic (H1N1) 2009 might prevent complications. The present study was conducted in geographically diverse settings all across Spain during the first wave of the pandemic, before the introduction of the vaccination campaign against the influenza A(H1N1)v virus. Strengths of the study are its prospective and multicentre design, the large number of patients included and the comprehensive clinical data collection. These characteristics improve the external validity of the results. However, our study has some limitations that should be acknowledged. First, physicians did not use a uniform strategy for determining admission, and so factors other than disease severity may have contributed to site-ofcare decisions. In this regard, it should be noted that pregnant women did not have a higher risk of severe disease in the present study. It is possible that some pregnant women were hospitalized in spite of having mild disease and received early antiviral treatment more frequently. Second, bacterial co-infection may have been underestimated because microbiological studies were not performed routinely in all patients. In addition, these tests have some limitations in identifying the causative organisms of pneumonia. However, it is important to note that two or more bacterial microbiological studies were performed in about 78% of patients with pneumonia in this study. In conclusion, although hospitalized adults with pandemic (H1N1) 2009 suffer from significant morbidity, mortality is lower than that reported in the earliest studies. Younger age, comorbidities, morbid obesity and bacterial co-infection are independent risk factors for severe disease, whereas early oseltamivir therapy is a protective factor.
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Transparency Declaration This study was supported by the Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III, Programa de Investigacio´n sobre gripe A/H1N1 (Grant: GR09/0014), and Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III—co-financed by European Development Regional Fund ‘‘A way to achieve Europe’’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008). D. Viasus is the recipient of a research grant from the Institut d’Investigacio´ Biome`dica de Bellvitge (IDIBELL). The authors declare that no dual/conflicting interest exists.
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14. Echevarrı´a-Zuno S, Mejı´a-Arangure´ JM, Mar-Obeso AJ et al. Infection and death from influenza A H1N1 virus in Mexico: a retrospective analysis. Lancet 2009; 374: 2072–2079. 15. Campbell A, Rodin R, Kropp R et al. Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza. CMAJ 2010; 182: 349–355. 16. Fuhrman C, Bonmarin I, Paty AC et al. Severe hospitalised 2009 pandemic influenza A(H1N1) cases in France, 1 July–15 November 2009. Euro Surveill 2010;15. pii : 19463. 17. Domı´nguez-Cherit G, Lapinsky SE, Macias AE et al. Critically ill patients with 2009 influenza A(H1N1) in Mexico. JAMA 2009; 302: 1880–1887. 18. Eiros-Bouza JM, Garcı´a-Bermejo I, Pe´rez-Sa´ez JL et al. Use of Diagnostic Tests for the Diagnosis of the Novel Influenza A [Protocolo Uso de Pruebas Diago´sticas para la Nueva Gripe A]. Madrid: Spanish Ministry of Health, 2009. Available at: http://www.msc.es/profesionales/saludPublica/ gripeA/guiasProtocolosInf/profSanit.htm. Accessed September 2009. 19. Centers for Disease Control and Prevention (CDC). Interim guidance on case definitions to be used for investigations of novel influenza A (H1N1) cases, 2009. Available at: http://www.cdc.gov/h1n1flu/ casedef.htm. Accessed June 2009. 20. 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; 40: 373–383. 21. Rello J, Rodrı´guez A, Iban˜ez P et al. Intensive care adult patients with severe respiratory failure caused by influenza A (H1N1)v in Spain. Crit Care 2009; 13: R148. 22. Centers for Disease Control and Prevention (CDC). Patients hospitalized with 2009 pandemic influenza A (H1N1)—New York City, May 2009. MMWR Morb Mortal Wkly Rep 2010; 58: 1436– 1440. 23. Louie JK, Acosta M, Winter K et al. Factors associated with death or hospitalization due to pandemic 2009 influenza A(H1N1) infection in California. JAMA 2009; 302: 1896–1902. 24. Nougairede A, Ninove L, Zandotti C et al. Interim report on A/ H1N1 Influenza Virus pandemic in Marseille, France, April–November 2009. Clin Microbiol Infect 2010; 16: 322–325. 25. Verrall A, Norton K, Rooker S et al. Hospitalizations for pandemic (H1N1) 2009 among Maori and Pacific Islanders, New Zealand. Emerg Infect Dis 2010; 16: 100–102. 26. Cullen G, Martin J, O’Donnell J et al. Surveillance of the first 205 confirmed hospitalised cases of pandemic H1N1 influenza in Ireland, 28 April to 3 October 2009. Euro Surveill 2009;14. pii : 19389.
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27. Gill JR, Sheng ZM, Ely SF et al. Pulmonary pathologic findings of fatal 2009 pandemic influenza A/H1N1 viral infections. Arch Pathol Lab Med 2010; 134: 235–243. 28. Erkoreka A. The Spanish influenza pandemic in occidental Europe (1918–1920) and victim age. Influenza Other Resp Viruses 2010; 4: 81– 89. 29. Abdel-Ghafar AN, Chotpitayasunondh T, Gao Z et al. Update on avian influenza A (H5N1) virus infection in humans. N Engl J Med 2008; 358: 261–273. 30. Pe´rez-Trallero E, Pin˜eiro L, Vicente D, Montes M, Cilla G. Residual immunity in older people against the influenza A(H1N1)—recent experience in northern Spain. Euro Surveill 2009;14. pii : 19344. 31. Ikonen N, Strengell M, Kinnunen L et al. High frequency of crossreacting antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly in Finland. Euro Surveill 2010;15. pii : 19478. 32. O’Riordan S, Barton M, Yau Y, Read SE, Allen U, Tran D. Risk factors and outcomes among children admitted to hospital with pandemic H1N1 influenza. CMAJ 2010; 182: 39–44. 33. Libster R, Bugna J, Coviello S et al. Pediatric hospitalizations associated with 2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med 2010; 362: 45–55. 34. Cunha BA. Swine influenza (H1N1) pneumonia: clinical considerations. Infect Dis Clin North Am 2010; 24: 203–228. 35. Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr 2007; 137: 1236–1243. 36. McCullers JA. Insights into the interaction between influenza virus and pneumococcus. Clin Microbiol Rev 2006; 19: 571–582. 37. Palacios G, Hornig M, Cisterna D et al. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS ONE 2009; 4: e8540. 38. Mauad T, Hajjar LA, Callegari GD et al. Lung pathology in fatal novel human influenza A (H1N1) infection. Am J Respir Crit Care Med 2010; 181: 72–79. 39. Centers for Disease Control and Prevention (CDC). Bacterial coinfections in lung tissue specimens from fatal cases of 2009 pandemic influenza A (H1N1)—United States, May–August 2009. MMWR Morb Mortal Wkly Rep 2009; 58: 1071–1074. 40. Morens DM, Taubenberger JK, Fauci AS. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J Infect Dis 2008; 198: 962–970. 41. Klugman KP, Chien YW, Madhi SA. Pneumococcal pneumonia and influenza: a deadly combination. Vaccine 2009; 27 (Suppl. 3): C9–C14.
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Factors associated with severe disease in hospitalized adults with pandemic (H1N1) 2009 in Spain D. Viasus1, J. R. Pan˜o-Pardo2, J. Pacho´n3, A. Campins4, F. Lo´pez-Medrano5, A. Villoslada6, M. C. Farin˜as7, A. Moreno8, J. Rodrı´guez-Ban˜o9, J. A. Oteo10, J. Martı´nez-Montauti11, J. Torre-Cisneros12, F. Segura13, F. Gudiol1 and J. Carratala`1, for the Novel Influenza A (H1N1) Study Group* of the Spanish Network for Research in Infectious Diseases (REIPI) 1) Hospital Universitari de Bellvitge—IDIBELL, University of Barcelona, Barcelona, 2) Hospital Universitario La Paz—IDIPAZ, Madrid, 3) Hospital Universitario Virgen del Rocı´o, Sevilla, 4) Hospital Universitario Son Dureta, Palma de Mallorca, 5) Hospital Universitario 12 de Octubre, Madrid, 6) Hospital Son Lla`tzer, Palma de Mallorca, 7) Hospital Universitario Marque´s de Valdecilla, Santander, 8) Hospital Universitario Clinic, Barcelona, 9) Hospital Universitario Virgen Macarena, Sevilla, 10) Hospital San Pedro—CIBIR, Logron˜o, 11) SCIAS—Hospital de Barcelona, Barcelona, 12) Hospital Universitario Reina Sofı´a—IMIBIC, University of Co´rdoba, Co´rdoba and 13) Hospital Parc Tauli, Sabadell, Spain
Abstract The risk factors for complications in patients with influenza A (H1N1)v virus infection have not been fully elucidated. We performed an observational analysis of a prospective cohort of hospitalized adults with confirmed pandemic influenza A (H1N1)v virus infection at 13 hospitals in Spain, between June 12 and November 10, 2009, to identify factors associated with severe disease. Severe disease was defined as the composite outcome of intensive-care unit (ICU) admission or in-hospital mortality. During the study period, 585 adult patients (median age 40 years) required hospitalization because of pandemic (H1N1) 2009. At least one comorbid condition was present in 318 (54.4%) patients. Pneumonia was diagnosed in 234 (43.2%) patients and bacterial co-infection in 45 (7.6%). Severe disease occurred in 75 (12.8%) patients, of whom 71 required ICU admission and 13 (2.2%) died. Independent factors for severe disease were age <50 years (OR, 2.39; 95% CI, 1.05–5.47), chronic comorbid conditions (OR, 2.93; 95% CI, 1.41–6.09), morbid obesity (OR, 6.7; 95% CI, 2.25–20.19), concomitant and secondary bacterial co-infection (OR, 2.78; 95% CI, 1.11–7) and early oseltamivir therapy (OR, 0.32; 95% CI 0.16–0.63). In conclusion, although adults hospitalized for pandemic (H1N1) 2009 suffer from significant morbidity, mortality is lower than that reported in the earliest studies. Younger age, chronic comorbid conditions, morbid obesity and bacterial co-infection are independent risk factors for severe disease, whereas early oseltamivir therapy is a protective factor. Keywords: Epidemiology, influenza A (H1N1) 2009, intensive-care unit, mortality, risk factors Original Submission: 1 July 2010; Revised Submission: 23 July 2010; Accepted: 19 August 2010 Editor: D. Raoult Article published online: 3 September 2010 Clin Microbiol Infect 2011; 17: 738–746 10.1111/j.1469-0691.2010.03362.x
Corresponding author: J. Carratala`, Department of Infectious Diseases, Hospital Universitari de Bellvitge, Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain E-mail: [email protected] *Other members of the Novel Influenza A(H1N1) Study Group are: J. Niubo1, A. Martı´n-Quiro´s2, M. Romero-Go´mez2, G. Ruı´zCarrascoso2, J. C. Figueira2, M. C. Prados2, E. Cordero3, E. Garcı´aCabrera3, M. Riera4, J. M. Aguado5, J. Vila5, A. Payeras6, M. Garcı´aGasalla6, J. L. Gonza´lez-Ferna´ndez7, M. Gutie´rrez-Cuadra7, M. V. Sanjuan7, J. A. Parra7, L. Linares8, I. Hoyo8, M. A´. Marcos8, T. Pumarola8, M. de Cueto9, M. A. Muniain9, M. D. del Toro9, L. Pe´rez-Martı´nez10, J. R. Blanco10, M. Sanz10, L. Metola10, V. Ibarra10, L. Ortega11, R. Lara12, M. Causse12, E. M. Gonza´lez13.
Introduction Influenza pandemics have been associated with increased morbidity and mortality. Each pandemic is different and there are always a series of unknowns when an influenza virus emerges and becomes pandemic [1,2]. In April 2009, a novel influenza virus, now known as influenza A (H1N1)v virus, caused an outbreak of respiratory disease in Mexico [3] and spread rapidly throughout the world. Spain was the first country in Europe to report a laboratory-confirmed case of new influenza A (H1N1)v virus infection [4]. The number of
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hospitalizations and deaths caused by pandemic (H1N1) 2009 increased continuously until December 2009. The studies published indicate that there are differences between pandemic (H1N1) 2009 and seasonal influenza. Among adult patients, pandemic (H1N1) 2009 affects mainly those under the age of 60 years with chronic underlying diseases, pregnant women, and obese patients [5–7]. The overall mortality of this infection is similar to that presented by seasonal influenza and lower than previous pandemics [8– 10], although mortality varies considerably between countries [8]. There is also concern that subsequent waves of influenza pandemic could be more lethal than the first [2]. Little information is currently available on factors associated with severe disease in adults hospitalized for the pandemic influenza (H1N1)v virus. Moreover, the few studies published to date have been limited by small sample size [5,11–13], retrospective design [13,14], analysis based merely on database surveillance reports [15,16], or inclusion of only critically ill patients [11,17]. To identify risk factors for severe disease, and hence to determine the optimal case management and prevention, more clinical and treatment data of the pandemic (H1N1) 2009 are needed. The aim of the present multicentre study was to ascertain factors associated with severe disease among adults hospitalized for pandemic (H1N1) 2009 in Spain.
Materials and Methods Setting, patients and study design
This prospective cohort study was conducted at 13 tertiary hospitals belonging to the Spanish Network for Research in Infectious Diseases (REIPI). All adult patients admitted to the hospital for at least 24 h with confirmed influenza A (H1N1) virus infection from June 12 to November 10, 2009, were prospectively recruited and followed up. Following the recommendations of the Spanish Ministry of Health, specific laboratory tests for influenza A (H1N1)v virus (see below) were performed on all patients with community-onset pneumonia or influenza-like symptoms in any of the following circumstances: pregnancy, underlying chronic conditions, morbid obesity, and in the presence of complications [18]. If the first test was negative, a new sample was recommended whenever the clinical syndrome had not clearly improved. The results were typically available in <24 h (frequently <12 h). Cases were detected on a daily basis by reviewing the microbiological reports. A confirmed case was defined as a person with an influenza-like illness with laboratoryconfirmed pandemic influenza A (H1N1) virus infection using
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real-time polymerase chain reaction or viral culture [19]. Pandemic influenza A (H1N1)v virus testing was performed at each institution. For the purposes of this study patients were divided into two groups: severe disease and no severe disease. Severe disease was defined as the composite outcome of intensive-care unit (ICU) admission or in-hospital mortality. The study was approved by the Ethics Committee of the coordinating centre, the Hospital Universitari de Bellvitge, and informed consent was obtained from patients. Clinical assessment and follow-up
Microbiological studies, hospital and ICU admission criteria, and treatment decisions were not standardized and were made by attending physicians at each study centre. 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, comorbid conditions, body mass index (BMI, the weight in kilograms divided by the square of the height in metres), clinical signs and symptoms, biochemical analysis, chest radiograph findings, antiviral and antibacterial therapy, concomitant and secondary bacterial co-infection, and outcomes, including mortality. A long-term follow-up visit was scheduled 1 month after discharge. For time calculations, the day of admission was considered to be hospital day 0, except for time to antiviral administration in which the day of symptoms onset was considered day 0. Completed protocols were sent to the coordinating centre and all data were carefully reviewed by two clinical investigators (DV and JC) before the final validation. Definitions
Comorbidities were assessed using the Charlson Comorbidity Index definitions [20]. Other comorbidities, such as immunosuppression, neuromuscular disorders and sickle-cell disease, were also recorded. Obesity was defined as a BMI ‡30–39.9 and morbid obesity as a BMI ‡ 40 or a subjective assessment by the physician if weight and height were not available. Tobacco abuse was recorded when a patient had smoked more than ten cigarettes per day for at least 1 year preceding the study. Alcohol abuse was considered if alcohol intake was more than three standard drinks per day. Vaccination status was assessed from interviews with the patients or their relatives and from reviews of hospital and personal health records (vaccination card). Patients were considered to be pneumococcus-vaccinated if 23-valent polysaccharide pneumococcal vaccine had been administered in the 5 years before admission, and influenza-vaccinated if seasonal influenza vaccine had been administered during the year before
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or not. The relative risks were expressed as OR and 95% CI. Statistical significance was established at a 0.05. All reported p values are two-tailed.
admission. Pneumonia was defined as the presence of a new infiltrate on a chest radiograph plus fever (temperature ‡38.0C) and respiratory symptoms. Concomitant and secondary bacterial co-infection were diagnosed in patients with one or more positive cultures obtained from blood, normally sterile fluids, or sputum and a positive Streptococcus pneumoniae urinary antigen. Complications were defined as any untoward circumstances occurring during hospitalization. Mortality was defined as death from any cause during hospitalization.
Results Patient characteristics
During the study period, 585 consecutive hospitalized patients with influenza A (H1N1)v virus infection were included. The demographic and clinical characteristics of patients are detailed in Tables 1 and 2. Most patients were under the age of 50 years. Nearly half of the patients had at least one comorbid condition, with chronic respiratory disease, immunosuppression and diabetes mellitus being the most common. Twenty-eight (4.8%) patients were morbidly obese. Obese and morbidly obese patients had a high prevalence of underlying disease (59.3% and 67.9%, respectively). Ninety-eight patients (16.8%) were pregnant. The median time from onset of symptoms to hospitalization was 3 days. The most frequent symptoms and signs on hospital admission were fever, cough, shortness of breath, muscle aches and tachycardia. Conversely, altered mental status and hypotension at presentation were infrequent.
Statistical analysis
The results were analysed using a commercially available statistical software package (SPSS, version 15.0; SPSS Inc, Chicago, IL, USA). Descriptive statistics were performed for all study variables. 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 U-test for continuous variables, when appropriate. The multivariate logistic regression analysis of factors potentially associated with severe disease included the variables that were significant in the univariate analysis and clinically important variables, whether they were significant
TABLE 1. Demographic characterAll patients (n = 585) Demographic data Age, median (range), years Age groups, % 16–49 years 50–64 years ‡65 years Male sex Pregnancy Current smoker Alcohol abuse Influenza vaccine (season) Pneumococcal vaccine, 5 years Comorbid conditions Any one condition Chronic pulmonary disease Asthma COPD OSAS Chronic heart disease Chronic renal failure Chronic liver failure Diabetes mellitus Immunosuppressed HIV/AIDS Transplant recipients Cancer Obesity (BMI ‡ 30–39.9)a Morbid obesity (BMI ‡ 40 and subjective assessment)
39 (16–87)
Patients without severe disease (n = 510)
38 (16–87)
Patients with severe disease (n = 75)
39 (17–80)
istics of patients with pandemic p
0.26 96
424 111 50 300 98 184 33 62 23
(72.5) (19) (8.5) (51.3) (16.8) (31.7) (5.7) (12.5) (4.7)
370 96 44 260 96 152 24 54 21
(72.5) (18.8) (8.6) (51) (18.8) (30.1) (4.8) (12.4) (4.8)
54 15 6 40 2 32 9 8 2
(72) (20) (8) (53.3) (2.7) (42.7) (12) (13.8) (3.5)
0.70 <0.001 0.02 0.01 0.75 0.65
318 169 104 49 17 40 25 29 59 81 26 22 41 59 28
(54.4) (28.9) (17.8) (8.4) (2.9) (6.8) (4.3) (5) (10.1) (13.8) (4.4) (3.8) (7) (23.2) (4.8)
262 135 90 34 11 30 19 24 49 71 23 21 36 50 17
(51.4) (26.5) (17.6) (6.7) (2.2) (5.9) (3.7) (4.7) (9.8) (13.9) (4.5) (4.1) (7.1) (21.9) (3.3)
56 34 14 15 6 10 6 5 10 10 3 1 5 9 11
(74.1) (45.3) (18.7) (20) (8) (13.3) (8) (6.7) (13.3) (13.3) (4) (1.3) (6.7) (36) (14.7)
<0.001 0.001 0.82 <0.001 0.005 0.01 0.11 0.40 0.31 0.89 1 0.34 0.90 0.114 <0.001
BMI, body-mass index; COPD, chronic obstructive pulmonary disease; HIV/AIDS, human immunodeficiency virus/ acquired immunodeficiency syndrome; OSAS, obstructive sleep apnoea syndrome. Values given are n (%) unless otherwise stated. a Two hundred and fifty-three patients with height and weight available.
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TABLE 2. Clinical characteristics of Patients without Patients with All patients severe disease severe disease (n = 585) (n = 510) (n = 75) p
patients with pandemic (H1N1) 2009 Clinical features Reported symptoms Time from symptoms onset to hospitalization median (range), days Cough, % Shortness of breath Muscle aches Sore throat Headache Rhinorrhoea Diarrhoea Vomiting Pleuritic chest pain Physical findings Temperature at admission, median (range), C Fever (‡38.0C) Systolic blood pressure median (range), mmHg Hypotension (SBP £90 mmHg) Cardiac frequency median (range), beats/min Tachycardia (‡90 beats/min) Respiratory frequency median (range), breaths/min Tachypnoea (‡24 breaths/min) Impaired consciousness Wheezing
3 (0–21)
3 (0–21)
525 274 339 163 187 119 61 80 97
(89.9) (46.8) (58.1) (27.9) (32) (20.3) (10.4) (13.7) (16.6)
461 218 305 147 174 111 51 71 86
(90.6) (42.7) (60) (28.8) (34.2) (21.8) (10) (13.9) (16.9)
38 306 120 16 97 337 20 149 15 169
(35–41) (54.6) (65–280) (2.9) (46–160) (65.9) (8–50) (40.1) (2.6) (29.4)
38 270 120 10 96 280 19 112 4 139
(35–40) (55) (70–220) (2.1) (46–160) (63.2) (8–45) (34.6) (0.8) (27.7)
3 (1–10) 64 56 34 16 13 8 10 9 11 38 36 120 6 109 57 28 37 11 30
0.11
(85.3) (74.7) (45.3) (21.3) (17.3) (10.7) (13.3) (12) (14.7)
0.16 <0.001 0.01 0.17 0.003 0.02 0.37 0.65 0.63
(35–41) (52.2) (65–280) (8.7) (71–160) (83.8) (10–50) (77.1) (14.7) (41.1)
0.77 0.66 0.51 0.002 <0.001 0.001 <0.001 <0.001 <0.001 0.01
Values given are n (%) unless otherwise stated.
Diagnostic findings
The laboratory and radiographic findings are shown in Table 3. On admission, most patients had lymphopenia and elevated C-reactive protein and nearly half had elevated lactate dehydrogenase. Findings consistent with pneumonia on chest radiography were found in 234 (43.2%) patients. Fortyfive (7.6%) patients had bacterial co-infection. Overall, Streptococcus pneumoniae (28 cases) was the most frequent causative bacteria followed by methicillin-susceptible Staphylococcus aureus (four cases), Pseudomonas aeruginosa (four cases) and Haemophilus influenzae (three cases). Other organisms isolated were Haemophilus parainfluenzae, Moraxella catharralis, Streptococcus pyogenes, Escherichia coli, Acinetobacter baumannii and Streptococcus sanguis. Treatment and clinical outcomes
The treatment and clinical outcomes are summarized in Table 4. Oseltamivir was administered to 93.3% of patients. The treatment was initiated at a median of 3 days after onset of symptoms. Oseltamivir was given at a dose of 75 mg twice daily in all but 33 patients, who received 150 mg twice daily. Antibacterial therapy was administered in 416 (71.7%) patients. The most commonly used antibiotics were levofloxacin (237 cases), ceftriaxone (97 cases) and amoxicillin/clavulanate (86 cases). In-hospital complications developed in 88 (15%) patients. Severe disease occurred in 75 (12.8%), of whom 71 required admission to ICU and 13 died. Among the 71 patients requiring ICU admission, 53 had pneumonia and 52 under-
went mechanical ventilation. Fifty-two (73.2%) of the 71 ICU patients had chronic comorbid conditions, mainly chronic pulmonary disease (33 patients), chronic heart disease (ten patients), diabetes mellitus (ten patients) and immunosuppression (seven patients). Only two of 98 pregnant women required ICU admission. Other in-hospital complications included viral hepatitis (two cases), catheter-related thrombosis of the internal jugular vein (two cases), preterm delivery (two cases), meningitis/encephalitis (one case), acute renal failure requiring haemodialysis (one case), diabetic ketoacidosis (one case), and oseltamivir-related visual disturbances (one case). The in-hospital mortality was 2.2% (13 of 585 patients) and the median time from hospital admission to death was 9 days (range, 1–33). Among the 13 patients who died, nine were under 50 years of age, eight were women, 12 had comorbid conditions, two were morbidly obese, 11 had multilobar pneumonia, and five had bacterial co-infection (Table 5). Causes of death were respiratory failure/acute respiratory distress syndrome (three of 13 patients), shock/ multi-organ failure (four patients), decompensated comorbid condition (four patients) and nosocomial infection (four patients). Factors associated with severe disease
Patients with severe disease were more frequently current smokers and heavy alcohol drinkers and had more comorbidities and morbid obesity than patients without severe disease. Among comorbid conditions, chronic obstructive
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TABLE 3. Diagnostic findings of patients with pandemic (H1N1) 2009
Laboratory findings Leucocyte count median (range), per mm3 Leukopenia (<4000 per mm3), % Leukocytosis (‡12000 per mm3) Lymphopenia (lymphocytes <1500 cells per mm3) Hematocrit median (range), % Anaemia (Hcto <36%) Platelet count, median (range), per mm3 Thrombocytopenia (<150,000 per mm3) Alanine aminotransferase, median (range), IU/L Elevated alanine aminotransferase (>40 IU/L) Aspartate aminotransferase median (range), IU/L Elevated aspartate aminotransferase (>40 IU/L) Creatine phosphokinase, median (range), IU/L Elevated creatine kinase (>240 IU/L) Lactate dehydrogenase, median (range), IU/L Elevated lactate dehydrogenase (>350 IU/L) C-reactive protein, median (range), mg/L Elevated C-reactive protein (>20 mg/L) PaO2/FiO2, median (range) Respiratory failure (PaO2/FiO2 < 300 or oxygen saturation <90%) Concomitant/secondary bacterial co-infectiona Radiographic findings Infiltrates on chest radiography Multilobar infiltratesb
All patients (n = 585)
Patients without severe disease (n = 510)
Patients with severe disease (n = 75)
p
7230 84 76 468 40.1 146 187 000 153 28 119 29 105 94 34 335 131 43.7 264 295.6 172 45
7100 74 55 401 40 130 188 000 127 27 89 27.5 78 87 26 325 105 40 222 304.8 112 31
8870 10 21 67 41 16 167 500 26 53 30 45.2 27 110 8 427 26 75 42 233.3 60 14
0.003 0.76 <0.001 0.06 0.15 0.39 0.27 0.08 <0.001 <0.001 <0.001 <0.001 0.15 0.14 0.004 0.003 <0.001 0.02 <0.001 <0.001 <0.001
(240–41400) (14.5) (13.1) (81.5) (17–57) (25.3) (7000–467 000) (26.7) (6–840) (31.7) (9–429) (28.9) (9–6096) (20.1) (31–3545) (46.3) (1–506) (75.9) (47–519) (33.2) (7.6)
234 (43.2) 135 (57.7)
(300–41400) (14.7) (10.9) (80.4) (17–57) (25.9) (7000–467 000) (25.5) (6–840) (27.5) (9–400) (24.8) (9–6096) (18.2) (31–1519) (42.9) (1–398) (73.8) (83.5–519) (25.2) (6.3)
178 (38) 89 (50)
(240–23380) (13.3) (28) (89.3) (27–56) (21.3) (67 000–381 000) (35.1) (11–350) (58.8) (16.8–429) (55.1) (18–640) (30.8) (32–3545) (68.4) (4.1–506) (89.4) (47–342) (82.2) (18.9)
56 (75.7) 46 (82.1)
<0.001 <0.001
PaO2/FiO2, partial pressure arterial oxygen/fraction of inspired oxygen. Values given are n (%) unless otherwise stated. Six patients had more than one microorganism. b Percentages from patients with pneumonia. a
TABLE 4. Treatment and clinical
Treatment Antiviral treatment, % Time from symptoms onset to antiviral therapy, median (range), days Early treatment (£72 h after symptoms onset) Antibacterial treatment Corticosteroids Clinical outcomes Length of hospital stay, median (range), days In-hospital complications Shock Nosocomial infections Heart complications ICU admission Mechanical ventilation ARDS In-hospital mortality
All patients (n = 585)
Patients without severe disease (n = 510)
Patients with severe disease (n = 75)
545 (93.3) 3 (1–21)
473 (92.9) 3 (1–21)
72 (96) 4 (1–21)
0.32 0.004
297 (57) 416 (71.7) 160 (28)
272 (59.6) 342 (67.6) 118 (23.6)
25 (38.5) 74 (100) 42 (58.3)
0.001 <0.001 <0.001
5 (1–98)
5 (1–28)
11 (1–98)
<0.001
1 (0.2) 4 (0.8) 2 (0.4) – – – –
25 (33.8) 12 (16) 10 (13.3) – – – –
<0.001 <0.001 <0.001
26 16 12 71 52 23 13
(4.5) (2.7) (2.1) (12.1) (8.9) (3.9) (2.2)
outcomes of patients with panp
demic (H1N1) 2009
ARDS, acute respiratory distress syndrome; ICU, intensive-care unit. Values given are n (%) unless otherwise stated.
pulmonary disease, obstructive sleep apnoea syndrome and chronic heart disease were more frequent in patients with severe pandemic A(H1N1) 2009. No differences were found in pneumococcal vaccination and seasonal influenza vaccination rates between groups. No patient was vaccinated against pandemic influenza A(H1N1)v virus. As regards clinical features, shortness of breath, hypotension, impaired consciousness and tachypnoea were also more common in patients with severe disease. Moreover, these patients were more likely to present lymphopenia and
thrombocytopenia and they had significantly higher liver enzyme, lactate dehydrogenase and C-reactive protein levels. Among radiological and microbiological findings, they also had a higher prevalence of pneumonia and bacterial co-infection. The mean time from onset of symptoms to oseltamivir administration was significantly longer in patients with severe disease (95% CI of mean difference 0.3–2.1 days). Mean length of hospital stay was also significantly longer in these patients (95% CI of mean difference 7.7–15 days).
ª2010 The Authors Clinical Microbiology and Infection ª2010 European Society of Clinical Microbiology and Infectious Diseases, CMI, 17, 738–746
21
28
29
32
33
34
39
46
47
50
51 72
77
1
2
3
4
5
6
7
8
9
10
11 12
13
F
M F
M
F
M
F
F
M
F
M
F
F
Sex
Metastatic cancer Diabetes mellitus/Chronic heart and liver disease/connective tissue disease Chronic renal disease
COPD/Chronic liver disease
Metastatic cancer
COPD/Diabetes mellitus/Intravenous drug addiction/Morbid obesity Asthma/Metastatic cancer
Intravenous drug addiction
Mental retardation
None
Metastatic cancer
Toxic liver failure/Intravenous drug addiction Morbid obesity
Underlying medical conditions
Unilobar
Multilobar Multilobar
a
No
No No
Acinetobacter baumanii/ Candida albicans/ Candida glabrata Haemophilus influenzae
Multilobar
Escherichia coli
Multilobara
Streptococcus pneumoniae No
No
No
No
No
Staphylococcus aureus
Bacterial co-infection
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Multilobar
Infiltrates in chest radiography
No
No No
No
No
No
Si
No
No
No
No
No
No
Early antiviral therapy
Amoxicilline/clavulanate
Piperaciline/tazobactam Piperaciline/tazobactam
Imipenem
Meropenem Fluconazol
Meropenem linezolid Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Cefotaxime Levofloxacin Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Ceftriaxone Levofloxacin Meropenem
Empiric antibacterial therapy
Mechanical ventilation/Shock/Nosocomial infection
Mechanical ventilation/ARDS/Nosocomial infection/hemodialysis Decompensate comorbid condition Mechanical ventilation/ARDS
Nosocomial infection/Decompensate comorbid condition Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Shock
Mechanical ventilation/ARDS/Nosocomial infection/Shock Mechanical ventilation/ARDS/Nosocomial infection/Shock Nosocomial infection
Complications
33
9 1
21
25
4
5
3
3
4
32
14
14
Length of hospital stay
Viasus et al.
ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease. Clinical diagnosis of bilateral pneumonia.
Age (years)
Case
TABLE 5. Demographic and clinical characteristics of patients with pandemic (H1N1) 2009 who died
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TABLE 6. Factors associated with severe pandemic (H1N1) 2009: multivariate analysis
Age (16–49 years) Male sex Current smoker Alcohol abuse Comorbid condition Morbidly obese Influenza vaccine (season) Early antiviral treatment (£72 h) Concomitant and/or secondary bacterial co-infection
Odds ratio
95% confidence interval
p
2.39 0.74 1.08 2.20 2.93 6.74 0.94 0.32 2.78
1.05–5.47 0.38–1.45 0.53–2.22 0.64–7.52 1.41–6.09 2.25–20.19 0.36–2.44 0.16–0.63 1.11–7.00
0.03 0.39 0.82 0.20 0.004 0.001 0.90 0.001 0.02
The results of multivariate logistic regression analysis for factors potentially associated with severe disease are shown in Table 6. Independent factors associated with severe disease were age <50 years (OR, 2.39; 95% CI, 1.05–5.47), comorbid conditions (OR, 2.93; 95% CI, 1.41–6.09), morbid obesity (OR, 6.74; 95% CI, 2.25–20.19), concomitant and/or secondary bacterial co-infection (OR, 2.78; 95% CI, 1.11–7) and early oseltamivir therapy (£72 h) (OR, 0.32; 95% CI 0.16–0.63).
Discussion In this prospective, multicentre study of a large number of adults hospitalized for pandemic influenza (H1N1)v virus infection in Spain, independent factors associated with severe disease were younger age, chronic comorbid conditions, morbid obesity and bacterial co-infection. Conversely, early oseltamivir therapy was a protective factor. Characteristics and clinical outcomes of our study patients were similar to those described elsewhere [5,11,21–23]. Although our mortality rate was lower than that reported in the earliest studies of hospitalized patients [5,14,23], our findings concur with those of more recent reports [24–26]. Previous studies found that current [5,11,22,27] and past pandemics [28] affected mainly younger patients. Similarly, adult patients younger than 50 years had a higher risk of death during the 1918 Spanish influenza pandemic [28] and during the recent H5N1 avian influenza [29]. Nevertheless, studies involving patients with pandemic (H1N1) 2009 found that although older patients had the lowest estimated incidence rate, they also had the highest case fatality rate [9,15,23]. In the present study, we found that among hospitalized adults, younger patients had a higher risk of severe disease, in agreement with the finding of earlier studies of critically ill patients [11,21]. Only 8.5% patients of our cohort were over 65 years old. The low prevalence of older
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patients in pandemic (H1N1) 2009 has been attributed to residual immunity against influenza A (H1N1) strains in people born before 1950 [30,31]. Other independent factors associated with severe disease identified in our study, such as chronic morbid conditions and morbid obesity, have previously been associated with ICU admission or mortality [5,11,15,16]. Regarding comorbidities, chronic obstructive pulmonary disease, obstructive sleep apnoea syndrome and chronic cardiac disease were more common in patients with severe disease than in the others. In our study, although asthma was the most frequent underlying condition, no difference was found in its prevalence between patients with and without severe disease. Conversely, O’Riordan et al. [32] and Libster et al. [33] reported that asthma was a significant risk factor for ICU admission and mortality among children admitted to hospital. Similarly, during previous influenza pandemics and interpandemic periods, patients with impaired cardiopulmonary function have presented a higher risk of complications [34]. We found that patients with morbid obesity had a higher risk of severe disease. Morbidly obese patients also had frequent comorbidities, especially obstructive sleep apnoea syndrome and diabetes mellitus. Interestingly, a recent study demonstrated that obese mice infected with influenza virus have diminished cell cytotoxicity, delayed pro-inflammatory cytokine expression, and higher mortality than lean mice controls [35]. Future investigations are needed to clarify the pathophysiology underlying the association of morbid obesity and severe influenza infection. There is evidence that influenza virus alters the host inflammatory response and predisposes to adherence, invasion, and induction of disease by bacterial microorganisms. It has long been recognized that bacterial co-infection complicates the course of illness for many patients with influenza infection. In fact, during the influenza pandemics of the twentieth century, secondary bacterial pneumonia was an important cause of illness and death and S. pneumoniae was reported to be the most common aetiology. In the present study, S. pneumoniae was by far the most frequently isolated microorganism. Although prevalence of bacterial co-infection in our study was relatively low, it was an independent factor for severe disease. The synergistic interaction between bacteria and influenza virus has been shown to contribute to the severity of the resulting infection in animal models [36]. Moreover, Palacios et al. [37] recently reported that identification of S. pneumoniae in nasopharyngeal swab samples from patients with pandemic (H1N1) 2009 was also a factor related to severe disease. Other investigators have found a high frequency of bacterial co-infection in lung tissue specimens from fatal cases of influenza (H1N1)v virus infection
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Viasus et al.
[38,39] and the 1918–1919 influenza pandemic [40]. In this regard, pneumococcal vaccination has been recommended as a key element in influenza preparedness plans [41]. No randomized controlled trials of neuraminidase inhibitors in patients admitted to hospital with influenza virus infection have been carried out to date. Therefore, determining the effect of antiviral treatment on complications in hospitalized patients during the current pandemic is a critical issue. In previous studies [13,23], early administration of antiviral treatment was associated with favourable outcome and with lower development of respiratory failure in patients with influenza A (H1N1)v 2009 virus infection. We found that patients who received early oseltamivir treatment tended to have more comorbidities, but had less evidence of pneumonia and bacterial co-infection (data not shown). These patients also had a significantly lower risk of severe disease. Although no solid conclusions can be established based on observational studies alone, these findings suggest that giving early antiviral treatment to hospitalized patients with pandemic (H1N1) 2009 might prevent complications. The present study was conducted in geographically diverse settings all across Spain during the first wave of the pandemic, before the introduction of the vaccination campaign against the influenza A(H1N1)v virus. Strengths of the study are its prospective and multicentre design, the large number of patients included and the comprehensive clinical data collection. These characteristics improve the external validity of the results. However, our study has some limitations that should be acknowledged. First, physicians did not use a uniform strategy for determining admission, and so factors other than disease severity may have contributed to site-ofcare decisions. In this regard, it should be noted that pregnant women did not have a higher risk of severe disease in the present study. It is possible that some pregnant women were hospitalized in spite of having mild disease and received early antiviral treatment more frequently. Second, bacterial co-infection may have been underestimated because microbiological studies were not performed routinely in all patients. In addition, these tests have some limitations in identifying the causative organisms of pneumonia. However, it is important to note that two or more bacterial microbiological studies were performed in about 78% of patients with pneumonia in this study. In conclusion, although hospitalized adults with pandemic (H1N1) 2009 suffer from significant morbidity, mortality is lower than that reported in the earliest studies. Younger age, comorbidities, morbid obesity and bacterial co-infection are independent risk factors for severe disease, whereas early oseltamivir therapy is a protective factor.
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Transparency Declaration This study was supported by the Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III, Programa de Investigacio´n sobre gripe A/H1N1 (Grant: GR09/0014), and Ministerio de Ciencia e Innovacio´n, Instituto de Salud Carlos III—co-financed by European Development Regional Fund ‘‘A way to achieve Europe’’ ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008). D. Viasus is the recipient of a research grant from the Institut d’Investigacio´ Biome`dica de Bellvitge (IDIBELL). The authors declare that no dual/conflicting interest exists.
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