Key words: chronic heart failure; community-acquired pneumonia; respiratory viral infection; risk factor

Viral Community-Acquired Pneumonia in Nonimmunocompromised Adults* Andrés de Roux, MD; Maria A. Marcos, MD; Elisa Garcia, MD; Jose Mensa, MD; Santiago Ewig, MD, PhD; Hartmut Lode, MD, PhD; and Antoni Torres, MD, PhD, FCCP Introduction: Viral community-acquired pneumonia (CAP) has been poorly studied and clinically characterized. Using strict criteria for inclusion, we studied this type of infection in a large series of hospitalized adults with CAP. Materials and methods: All nonimmunocompromised adult patients with a diagnosis of CAP having paired serology for respiratory viruses (RVs) [338 patients] were prospectively included in the study from 1996 to 2001 at our 1,000-bed university teaching hospital, and subsequently were followed up. We compared patients with pure viral (PV), mixed viral (RV bacteria), and pneumococcal CAP. RVs (ie, influenza, parainfluenza, respiratory syncytial virus, and adenovirus) were diagnosed by means of paired serology. Results: Sixty-one of 338 patients (18%) with paired serology had an RV detected, and in 31 cases (9%) it was the only pathogen identified. Influenza was the most frequent virus detected (39 patients; 64%). Patients with chronic heart failure (CHF) had an increased risk of acquiring PV CAP (8 of 26 patients; 31%) when compared to a mixed viral/bacterial etiology (2 of 26 patients; 8%; p 0.035) or CAP caused by Streptococcus pneumoniae (1 of 44 patients; 2%; p 0.001). Multivariate analysis revealed that CHF (odds ratio [OR], 15.3; 95% confidence interval [CI], 1.4 to 163; p 0.024) and the absence of expectoration (OR, 0.14; 95% CI, 0.04 to 0.6; p 0.006) were associated with PV pneumonia compared to pneumococcal CAP. Conclusion: RVs are frequent etiologies of CAP (single or in combination with bacteria). Patients with CHF have an increased risk of acquiring a viral CAP. (CHEST 2004; 125:1343 1351) Key words: chronic heart failure; community-acquired pneumonia; respiratory viral infection; risk factor Abbreviations: CAP community-acquired pneumonia; CHF chronic heart failure; MP mixed viral; PSI pneumonia severity index; PV pure viral; RSV respiratory syncytial virus; RV respiratory virus; SP Streptococcus pneumoniae; TBAS tracheobronchial aspirates Community-acquired pneumonia (CAP) remains a serious illness with an important impact on health expenses. It is estimated that in Spain between 1.62 and 3.79 cases per 1,000 population occur each year, 1,2 and in 1 to 30 cases per 1,000 population worldwide, depending on immune status, age, and comorbidities, among other factors. 3 7 It is well-known that the principal etiologic agents are bacteria, with Streptococcus pneumoniae (SP) being *From the Servei de Pneumologia (Dr. de Roux and Torres), Institut Clínic de Pneumologia i Cirurgia Toràcica, and the Servei de Microbiologia (Dr. Marcos) and Servei de Malaties Infeccioses (Drs. Garcia and Mensa), Institut Clínic D Immunologia i Infeccions, Institut d Investigacions Biomèdiques August Pi i Sunyer Hospital Clínic, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain; Pneumologische Klinik (Dr. Ewig), Augusta Kranken Anstalt, Bochum, Germany; and the Department Lungenklinik Heckeshorn I (Dr. Lode), Zentralklinik Emil von Behring, Berlin, Germany. Dr. de Roux was supported by a research fellowship grant from the European Respiratory Society (2001). This research was supported by Commisionat per a Universitats i Reserca de la the most frequently occurring pathogen. 8 10 The percentage of viruses causing CAP ranges between 5% and 34%, the most frequent being Influenza spp. In a Spanish series of CAP, 1 25% of all episodes were caused by a respiratory virus (RV). However, studies focusing on viral pathogens causing CAP in nonimmunocompromised adults are rare. Some guidelines 3 describe their incidence but no recommendations regarding the assessment of risk groups and antiviral treatment are made. Generalitat de Catalunya 1999 228, Fondo de Investigaciones Sanitarias grant 00/0505, Red Grupo Insuficiencia Respiratoria Aguda, and Red RESPIRA. Manuscript received March 7, 2003; revision accepted November 10, 2003. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org). Correspondence to: Antoni Torres, MD, PhD, FCCP, Respiratory Intensive Care Unit, Institut Clinic de Pneumologia i Cirurgia Toracica, escalera 2, planta 3, Hospital Clinic, Villarroel 170, Barcelona, 08036, Spain; e-mail: atorres@medicina. ub.es www.chestjournal.org CHEST / 125 / 4/ APRIL, 2004 1343

The aim of the study was to investigate the epidemiology and to detect the clinical characteristics of viral CAP. For that purpose, we conducted a retrospective analysis of three different cohorts of CAP patients, as follows: patients with viral CAP; patients with mixed viral CAP (virus bacteria); and patients with pneumococcal CAP. Data were obtained from a prospective investigation on CAP initiated in 1996 at the Hospital Clínic of Barcelona. We were particularly interested in identifying characteristics of patients with viral CAP when compared to those with mixed viral/bacterial as well as pneumococcal etiology. Patients and Methods From October 1996 to February 2001, consecutive adults ( 18 years of age) in whom CAP had been diagnosed and who had been admitted to Hospital Clinic, Institut d Investigations Biomèdiques August Pi i Sunyer (Universitat de Barcelona, Barcelona, Spain) were prospectively studied. The protocol has been described in detail elsewhere. 10,11 In short, CAP was defined by the presence of a new infiltrate seen on a chest radiograph together with clinical symptoms suggestive of a lower respiratory tract infection and no alternative diagnosis during follow-up. Only patients without immunosuppression (ie, HIV patients and subjects receiving immunosuppressive therapy other than prednisolone, 15 mg/d) were included in the database. Regular sampling for a microbiological diagnosis included sputum, blood culture, paired serology (at hospital admission, and within the third and sixth weeks thereafter for Mycoplasma pneumoniae, Chlamydia pneumoniae, Coxiella burnetii, Legionella pneumophila, and RVs), pleural puncture when appropriate, and urine samples for the detection of L pneumophila antigen (serogroup 1) [Biotest Legionella urine antigen enzymelinked immunoassay; Biotest; Frankfurt am Main, Germany]. Invasive diagnostic methods were applied according to clinical judgment. The RVs that were investigated were influenza virus A and B, parainfluenza virus 1, 2 and 3, respiratory syncytial virus (RSV), and adenovirus. For the diagnosis of all mentioned viral etiologies, two commercially available type-specific complement fixation kits were used (for the diagnosis of parainfluenza 3, and influenza A and B: BIO; Whittaker; Walkersville, MD; for the diagnosis of the RSV, parainfluenza 1 and 2, and adenovirus: Virion/Serion; Serion Immundiagnostica GmbH; Würzburg, Germany). A diagnosis of definite viral infection was made if seroconversion (ie, a fourfold rise in IgG titers) was measured. The minimum IgG titers that were considered to be diagnostic were as follows: influenza virus (A and B), 1:32; and adenovirus, parainfluenza virus (1, 2, and 3), and RSV, 1:8. A diagnosis of a viral infection was made after obtaining the second serum sample. Patients with no second serum sample were not included in the analysis. 12 Inclusion Criteria Patients were included in this study if the following criteria were met: a complete microbial investigation including sputum or tracheobronchial aspirates (TBAS) [valid samples], blood cultures, and paired serology for viruses, as well as for atypical pathogens, as described above, and L pneumophila serogroup 1; and the absence of antimicrobial treatment before sampling collection. Definitions For retrospective cohort comparisons, we identified all patients with CAP caused by a RV, a mixed viral/bacterial infection, and an infection caused by SP using the following definitions: 1. The pure viral pneumonia (PV) group was defined as follows: evidence for a viral etiology according to serologic criteria; and the absence of other etiologies in serologies, urinary antigen detection, or cultures. 2. The mixed viral pneumonia (MP) group was defined as follows: the presence of a RV diagnosed by paired serology, and the presence of one or more additional microorganisms in serologies, urinary antigen detection, or cultures. 3. The SP group was defined as follows: isolation of SP from a good quality sputum sample, quantitative TBAS (colony counts 10 5 cfu/ml) or blood culture; and the absence of a mixed infection as detected by serologies or cultures. A mixed infection of PV or pneumococcal CAP (ie, the SP group) was ruled out in the absence of evidence for another pathogen in sputum, quantitative TBAS (if available), blood culture, quantitative cultures of protected specimen brush/bal (if available), pleural fluid (if available), urinary antigen detection (if available), and complete paired serology. Data Recorded The clinical, radiographic, and laboratory data evaluated included 6,11,13 the following: (1) baseline characteristics such as age and gender; (2) clinical symptoms such as mean temperature, chills, cough, expectoration, chest pain, dyspnea, and crackles on chest examination; (3) radiographic patterns defined as the type of condensation (alveolar or interstitial) or pleural effusion at hospital admission; (4) the presence and number of comorbid illnesses, history of chronic heart failure (CHF), present or prior pulmonary disease (COPD in particular), hepatic, renal, or neurologic disease, and diabetes mellitus; (5) toxic habits like alcohol abuse (defined as the daily consumption of 80 g alcohol) and tobacco abuse (defined as a current smoking habit of 10 cigarettes per day and/or a smoking history 10 packyears; (6) factors related to severity such as mental confusion, hypotension (systolic BP, 90 mm Hg) at hospital admission, respiratory rate of 30 breaths/min, bilateral radiologic infil- Table 1 Distribution of RVs Detected in 338 CAP Cases With Valid Paired Viral Serologies Virus Any RV Detected (n 61) Only RVs Detected (n 31) Influenza A 27 16 Influenza B 10 7 Parainfluenza (1, 2, or 3) 11 2 RSV 5 4 Adenovirus 5 2 More than one virus* 3 Excluded for cohort analysis because of missing data 9 5 *Influenza B parainfluenza, influenza A parainfluenza, or parainfluenza RSV. 1344 Clinical Investigations

trates, renal insufficiency (creatinine level, 1.5 mg/dl), admission to the ICU, or the development of septic shock; (7) the presence of prior ambulatory antimicrobial treatment (defined as any oral antimicrobial treatment administered during the evolution of symptoms that were attributable to the current pneumonia episode); and (8) pneumonia severity index (PSI) classification, 14 with patients subdivided into classes I and II (PSI, 70 points), class III (PSI, 70 to 90 points), and classes IV and V (PSI, 91 to 130 points). Statistical Analysis Results are expressed as the means SD. Categoric variables were compared using the 2 test or Fisher exact test, when appropriate. Continuous variables were compared using the unpaired Student t test or the Mann-Whitney nonparametric test, when appropriate. Multiple comparisons were performed by analysis of variance with Bonferroni post hoc correction. Multivariate analysis was performed using logistic regression models. Variables with a p value 0.1 in univariate analysis were entered in the multivariate analysis. The level of significance was set at 0.05. We performed the following two multivariate model analyses including viral pneumonia as the dependent variable and entering the following variables according the univariate analyses: (1) comparison of viral pneumonia to mixed pneumonia included the following variables: gender (male 1; female 0), CHF, the presence of expectoration at hospital admission, and the development of shock; and (2) comparing viral pneumonia and SP. The following variables were included in this analysis: the presence of CHF at hospital admission; and the presence of cough and/or expectoration at hospital admission. Figure 1. Origin of the different cohorts for analysis. A total of 518 of 1,356 patients (38%) had received an etiologic diagnosis. The flow sheet shows the cases left after application of the diagnostic criteria. A total of 79 of 338 patients (nonviral, 70 patients; viral, 9 patients) were excluded from cohort analysis because of missing paired serologies for atypical microorganisms, previous antibiotic treatment, or lack of a valid respiratory sample and/or blood culture. www.chestjournal.org CHEST / 125 / 4/ APRIL, 2004 1345

Table 2 Distribution of the Microorganisms Responsible for MP Infections Included in the Analysis (n 26)* Influenza (A, B) Parainfluenza (1, 2, 3) RSV Adenovirus SP (5) SP (2) SP (2) C pneumoniae (1) C pneumoniae (4) C pneumoniae (1) C pneumoniae (1) H influenzae (2) L pneumophila (1) M pneumoniae (1) M pneumoniae (1) Staphylococcus aureus (1) C pneumoniae C burnetii (1) SP H influenzae (1) SP C burnetii (1) SP C pneumoniae (1) *Values in parentheses are No. of patients. Results Study Population Of 1,356 patients (893 men and 463 women; mean age, 68 18 years) with CAP who were admitted at our hospital during the study period, a microbial etiology could be established in 518 patients (38%). Overall, the most commonly identified pathogens were SP (41%), Haemophilus influenzae (14.5%), Pseudomonas aeruginosa (12%), and L pneumophila (10%). Cohort Analyses We initially included in the study the 338 patients who had valid paired viral serology findings for viruses. In sixty-one patients (18%), at least one RV was detected by serology. Of those patients, the virus was the only identified microorganism in 31 (9%). The distribution of the different viruses is shown in Table 1. The largest number of infections was caused by viruses from the influenza group (ie, influenza A and B), followed by parainfluenza, RSV, and adenovirus infections. For cohort analyses and comparative purposes, patients with previous ambulatory antimicrobial treatment (that could have altered bacterial growth in blood or respiratory samples) were excluded from the study, and those with no valid serology findings for atypical microorganisms and Legionella were Figure 2. Monthly distribution of viral infections of 338 CAP events with valid paired viral serologies. Black bars show the CAP events that were only attributed to a RV (PV group, 26 patients). MP was ruled out, as described in the Methods section. White bars show all CAP events (including PV) in which a RV was detected (61 patients). 1346 Clinical Investigations

available for the study. From the group of patients with no valid respiratory sample or blood specimen for bacterial culture, 259 patients remained for further analysis. Of these patients, 26 had pneumonia caused by PV infection (10%), 26 had pneumonia caused by a MP infection (10%), and 44 patients had pneumonia caused by SP (17%). The origin of the cohorts is depicted in Figure 1. Of the 26 cases in the MP group, the most frequent copathogen was SP (12 patients) followed by C pneumoniae (9 patients). The most frequent combinations were mixed infections of SP and either influenza virus (five patients) or parainfluenza virus (five patients), and influenza virus with C pneumoniae (five patients) [Table 2]. The monthly distribution of CAP viral infections is shown in Figure 2. We found no marked seasonal distribution of infections included in the PV group. However, when taking into account all viral infections (61 patients), we observed an increased incidence in January and February compared to the rest of the year. Baseline Characteristics We did not find any differences in age, incidence of alcohol abuse, and smoking status when comparing the three groups (ie, PV, MP, and SP group; differences not significant). There were significantly more male patients with CAP in the MP group (22 of 26 patients; 84%; p 0.04) compared to the PV group (54% men and 46% women). In the SP group, 66% of the patients were men (30 of 44 patients; differences with the other groups were not significant). Overall, a high percentage of patients had a history of pulmonary comorbidities (PV group, 54%; MP group, 55%; SP group, 34%; differences not significant), with COPD being the most prevalent. Patients from the viral group were significantly more likely to have a history of CHF (PV group [8 of 26 patients; 31%] vs MP group [2 of 26 patients; 8%], p 0.035; PV group vs SP group [1 of 44 patients; 2%], p 0.001) [Table 3]. In all groups, prognostic score index classes IV and V were the most frequent, including around 50% of all patients (PV group, 58%; MP group, 46%; SP group, 54%). However, PSI classes I and II were more prevalent in patients with PV infections, thus making the differences not significant (PV group, 27%; MP group, 8%; SP group, 18%) [Table 3]. Clinical Presentation Expectoration was significantly less frequent in the PV group when compared to the other groups (PV group [8 of 26 patients; 31%] vs MP group [17 of 26 patients; 65%], p 0.012; PV group vs SP group [32 of 44 patients; 73%], p 0.019). In addition, patients in the SP group presented more frequently with cough (SP group [40 of 44 patients; 91%] vs PV group [17 of 65 patients; 65%], p 0.012). In 66% of all patients from the PV group, radiologic infiltrates were classified as alveolar. This was not significantly different compared to the other groups (SP Table 3 Baseline Characteristics* Characteristics PV Group (n 26) MP Group (n 26) SP Group (n 44) p Value Age, yr 64 22 63 17 67 17 NS Sex Female 12 4 14 0.004 Male 14 22 30 Any comorbidity present 17 (65) 20 (80) 31 (40) NS Type of comorbidity CHF 8 (31) 2 (8) 1 (2) 0.05 Renal 2 (8) 3 (12) 2 (4.5) NS Hepatic cirrhosis 0 2 (8) 4 (9) NS Diabetes mellitus 3 (12) 0 10 (23) NS CNS 3 (12) 0 10 (23) NS Neoplastic disease 2 (8) 2 (8) 4 (9) NS Pulmonary 14 (54) 15 (57) 23 (43) NS COPD 9 (35) 7 (27) 15 (34) NS Alcohol use 80 g/d 2 (8) 6 (23) 4 (9) NS Current smoker 7 (27) 9 (34) 14 (32) NS PSI classes I II 7 (27) 2 (8) 8 (18) NS III 4 (15) 7 (27) 12 (27) NS IV V 15 (58) 12 (46) 24 (54) NS *Values given as mean SD or No. (%), unless otherwise indicated. NS not significant. Significantly differing parameters. PV vs MP group, p 0.0035; PV vs SP group, p 0.001. www.chestjournal.org CHEST / 125 / 4/ APRIL, 2004 1347

group, 98%; MP group, 69%; difference not significant). The percentage of radiologic infiltrates showing an interstitial pattern was close to 10% in all groups. We found no significant differences in regard to other clinical symptoms, such as chills, chest pain, and dyspnea, and paraclinical parameters, such as leukocyte count, C-reactive protein level, Po 2, hematocrit, and creatinine level (Table 4). Patient temperature was recorded at hospital admission and was compared among the different groups. The mean temperature at hospital admission did not differ significantly among the following groups: SP group, 37.96 1.2 C; MP group, 37.9 1.29 C; PV group, 37.86 1.1 C. In the studied cohort, the mean temperature at hospital admission is often biased because patients frequently take prescription free antipyretic drugs. Therefore, we decided to show the parameters fever before admission (defined as an episode of measured temperature of 38 C for 48 h before hospital admission) and presence of chills (ie, a sensation of shivering, cold, and sweating) in the study. Therefore, neither the temperature at hospital admission nor vaccination status was included in the multivariate model. Severity Assessment and Outcome Significantly more patients with a viral pneumonia had a higher respiratory rate than 30 breaths/min compared to those in the MP group (PV group [13 of 26 patients; 50%] vs MP group [4 of 26 patients; 15%], p 0.008). No patient in the PV group, but four patients in the MP group and two patients in the SP group, developed septic shock (PV group [0%] vs MP group [4 of 26 patients; 15%], p 0.037; PV group vs SP group [2 of 44 patients; 5%], difference not significant). Other parameters reflecting severity did not differ significantly. Only one patient died from pneumonia (in the SP group) [Table 5]. Multivariate Analysis of Risk Factors for Viral CAP The presence of CHF (odds ratio, 15.4; 95% confidence interval, 1.4 to 163; p 0.024) and the absence of expectoration (odds ratio, 0.14; 95% confidence interval, 0.04 to 0.6; p 0.006) were independently associated with the presence of viral CAP as opposed to SP. There were no independent significant risk factors when PV CAP was compared to MP CAP. Discussion The main findings of our study are the following: (1) a viral etiology was detected in 18% of the patients with CAP who had undergone a complete diagnostic evaluation, with half of them having a mixed infection; (2) CHF was an independent risk factor for viral pneumonia compared to patients with SP; and (3) the absence of expectoration was independently associated with a PV CAP. Viruses are a frequent etiologic finding in patients with CAP. In the present study, RVs were implicated in 18% of all subjects in whom a valid viral serology finding was available. Furthermore, in 9% of patients a RV was the only detected microorganism. In different series of CAP (in Finland, Switzerland, and Wales), 9,15,16 it has been shown that viral pathogens Table 4 Clinical Presentation at Hospital Admission* Variables PV Group (n 26) MP Group (n 26) SP Group (n 44) p Value Chills 12 (46) 14 (53) 26 (59) NS Cough 17 (65) 20 (77) 40 (90) 0.012 Expectoration 8 (31) 17 (65) 32 (73) 0.05 Chest pain 12 (28) 11 (42) 23 (52) NS Dysnea 19 (73) 13 (50) 31 (70) NS Crackles 22 (85) 18 (69) 31 (70) NS Radiographic patterns Alveolar pattern 17 (65) 18 (69) 36 (98) NS Pleural effusion 2 (8) 4 (15) 9 (20) NS Interstitial infiltrates 3 (12) 2 (8) 4 (9) NS Laboratory values Leukocytes, 1,000 cells/ L 13.1 ( 6.6) 14.7 ( 7.3) 16 ( 6.6) NS CRP, mg/dl 16 ( 12) 19 ( 9) 20 ( 16) NS Po 2,mmHg 61 ( 14) 60 ( 13) 58 ( 11) NS Creatinine, mg/dl 1.1 ( 0.6) 1.3 ( 0.8) 1.1 ( 0.5) NS Hematocrit, % 38 ( 5.8) 41 ( 7) 40 ( 6.5) NS *Values given as No. (%) or mean SD, unless otherwise indicated. CRP C-reactive protein. See Table 3 for abbreviation not used in the text. Significantly differing parameters. PV vs MP, p 0.012; PV vs SP, p 0.019. 1348 Clinical Investigations

Table 5 Clinical Evolution, Severity, and Outcome* Variables PV Group (n 26) MP Group (n 26) SP Group (n 44) p Value Mental confusion 4 (15) 4 (15) 8 (18) NS Hypotension 5 (19) 4 (15) 9 (20) NS Respiratory rate 30 breaths/min 13 (50) 4 (15) 18 (41) 0.008 Bilateral infiltrates 1 (4) 5 (19) 3 (7) NS Creatinine 1.5 mg/dl 4 (15) 4 (15) 6 (13) NS Admission to ICU 2 (8) 5 (20) 5 (11) NS Mechanical ventilation 0 2 (8) 3 (7) NS Renal failure 1 (4) 4 (17) 4 (9) NS Shock 0 4 (15) 2 (5) 0.037 Any complication 3 (12) 7 (27) 7 (16) NS Death 0 0 1 (2) NS *Values given as No. (%), unless otherwise indicated. See Table 3 for abbreviation not used in the text. All parameters compared to those of PV group. Systolic BP 90 mm Hg. Significantly differing parameters. are responsible for 10%, 5.5%, and 11% of patients with CAP, respectively. When mixed infections with RVs are included, the incidence increases to around 20%. 9,15,16 These figures fit with those found in a large Spanish study 17 from Valencia in which CAP was caused by a RV in 20% of all patients. However, the current figures on viral CAP are probably underestimated, since for most of the studies, and for the present one, only one serologic study has been used. In our study, we found that influenza A and B, and parainfluenza viruses were the most frequent viral causes. Other viruses less frequently found were RSV and adenovirus. Most of the studies dealing with viruses and CAP have shown that the main viruses responsible for CAP are influenza virus A and B, parainfluenza virus, and RSV. In a single study in Finland, 16 the main viral pathogen was the parainfluenza virus. For future studies, increasing the spectrum of RVs investigated will probably show us that there are other viruses related to CAP. Another interesting finding of this study is that viruses formed part of mixed infections, including mainly C pneumoniae and SP. The controversy about mixed infections is still alive in the literature, and it is important to clarify it for treatment purposes and outcome knowledge. 18,19 One striking finding of the present work is the increased risk of patients with CHF for acquiring PV pneumonia, and we do not have a clear explanation for that. This finding may fit with that of a previous report that found cardiovascular disease to be increased by fourfold in patients with viral CAP compared to pyogenic CAP. 15 In addition, it is known that influenza causes a seasonal excess mortality in patients with underlying cardiac illness. 20 One study 21 shows that influenza vaccination protects against the development of a myocardial infarction in patients with coronary heart disease. Influenza vaccination could be of potential benefit in patients with CHF. It would be important for clinicians to know what the specific clinical manifestations of viral CAP could be. In our study, we found that cough and expectoration were less frequent in patients with viral CAP compared to patients with mixed infections and pneumococcal CAP. Other clinical symptoms, radiologic presentation, or laboratory parameters were not useful in differentiating viral infections from pneumococcal or mixed viral infections. Dowell et al 22 studied the incidence and clinical characteristics of CAP caused by RSV in nonimmunocompromised adult patients. CAP caused by RSV was compared to typical and atypical pathogens. Apart from a marked seasonal variability, the presence of wheezing and rhonchi on physical examination were more frequent in the RSV group. Although it is interesting to know the specific features of viral CAP (ie, less cough and expectoration), we believe that we cannot rely on clinical manifestations to adjust empirical antibiotic treatments. This opinion is in accordance with previous studies that clearly have demonstrated that clinical signs and symptoms cannot be relied on to predict the etiology in the individual patient. Specifically, in a study published by our group, 10 it was clearly shown that neither clinical features, such as fever, chills, pleuritic pain, and expectoration, nor radiographic features were sensitive or specific enough to differentiate among pneumococcal, viral and atypical CAP. However, there were the following differences between the two studies: (1) purulence expectoration was investigated in the former study instead of the absence or presence of expectoration alone; and (2) viral and atypical pneumonias were pooled together for the analysis of the diagnos- www.chestjournal.org CHEST / 125 / 4/ APRIL, 2004 1349

tic value of clinical manifestations. Consequently, comparisons with the present study have to be made carefully. One important feature of the present study is that we applied very strict criteria to the definition of the different cohorts compared. Thus, this reinforces the validity of the study in regard to potential missing etiologies. Specifically, the serologic detection of viruses by type-specific complement fixation remains a well-established, sensitive, and specific test. 23 25 In addition, and of particular importance, was the exclusion of patients with prior antibiotic treatment, a fact that could have led to the underdiagnosis of classic bacterial etiologies. We recognized two limitations in our study. First, and since we relied on serologic criteria for determining the presence of viral pneumonia, only patients with a paired serology were included. This implied that only patients surviving for at least 2 to 3 weeks were investigated. Since we selected this population and did not apply other methods for viral detection (eg, molecular biology methods or viral cultures), the presence of viral infections could have been underestimated. Probably, the incidence of viral CAP is higher than commonly believed. However, the sensitivity by serologic testing is approximately 80%, suggesting that most of the 277 patients with paired serology and no seroconversion are true negatives. 23 25 Other methods such as culture or molecular biology techniques may be useful for the routine diagnosis of CAP. 15,26 The second limitation of the study refers to the severity of illness and outcome of patients. Although there were no apparent major differences in severity presentation and outcome among patients in the three groups, the criteria of inclusion (paired serology) limits our conclusions to the population studied (ie, those with paired serology). It is interesting to point out that none of the patients with viral pneumonia received an antiviral treatment. Despite this, and despite the fact that 58% of patients with viral pneumonia were classified as being in PSI classes IV and V, only 8% of those in the PV group had to be admitted to the ICU, and no patients died. Our observations in selected patients surviving viral pneumonia indicate that viral pneumonia may cure itself without specific antiviral treatment. In the future, it could be important to detect patients with viral pneumonia who are at risk for an adverse outcome early, especially because today effective antiviral therapy (eg, with neuraminidase inhibitors) is available. As long as these data are not available, we cannot make specific recommendations for antiviral treatment in the initial antimicrobial treatment strategies for CAP. However, during an epidemic situation (eg, a confirmed influenza outbreak) the position of empiric neuraminidase inhibitors in the initial empiric therapy should be considered. 27 In conclusion, viral pathogens play an important role in the etiology of CAP, and influenza virus is the leading viral pathogen. Nonimmunocompromised adults with CHF have an increased risk of acquiring a viral infection, and an influenza vaccination could be of potential benefit. Clinical characteristics are not useful (except the absence of expectoration) in predicting infection with viral pneumonia. Our data do not suggest the need for the inclusion of antiviral coverage in antimicrobial treatment strategies of CAP. However, future studies should be aimed at defining risk factors for severe viral CAP and the potential role of antiviral treatment. ACKNOWLEDGMENT: The authors thank Joaquim Angrill, for his help with statistical analysis. Furthermore, we appreciate the critical comments and collaboration of Mauricio Ruiz, Ana Rañó, and Carlos Agustí. References 1 Almirall J, Bolíbar I, Balanzó X, et al. Risk factors for community-acquired pneumonia in adults: a populationbased case-control study. Eur Respir J 1999; 13:349 355 2 Subdirección General de Prestaciones y Evaluación de Tecnologías Sanitarias, Ministro de Sanidad y Consumo. Informe sobre la vacuna neumocócica. Med Clin (Barc) 1994; 102: 383 386 3 American Thoracic Society. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, initial antimicrobial therapy and prevention. Am J Respir Crit Care Med 2001; 163:1730 1754 4 Ewig S. Community-acquired pneumonia: epidemiology, risk and prognosis. In: Torres A, Woodhead M, eds. Pneumonia. Sheffield, UK: European Respiratory Society Journals Ltd, 1997; 13 35 5 Rello J, Rodriguez R, Jubert P, et al. Severe communityacquired pneumonia in the elderly: epidemiology and prognosis; Study Group for Severe Community-Acquired Pneumonia. Clin Infect Dis 1996; 23:723 728 6 Ruiz M, Ewig S, Torres A, et al. Severe community-acquired pneumonia: risk factors and follow-up epidemiology. Am J Respir Crit Care Med 1999; 160:923 929 7 Schaberg T, Dalhoff K, Ewig S, et al. Recommendations for therapy of community-acquired pneumonia: German Society of Pneumology. Pneumologie 1998; 52:450 462 8 Lim WS, Maclarfane JT, Boswell TCJ, et al. Study of community-acquired pneumonia aetiology (SCAPA) in adults admitted to hospital: implications for management guidelines. Thorax 2001; 56:296 301 9 Macfarlane J, Holmes W, Gard P, et al. Prospective study of the incidence, etiology and outcome of adult lower respiratory tract illness in the community. Thorax 2000; 154:109 114 10 Ruiz M, Ewig S, Marcos MA, et al. Etiology of communityacquired pneumonia in hospitalized patients: impact of age, comorbidity and severity. Am J Respir Crit Care Med 1999; 160:397 405 11 Ewig S, Ruiz M, Mensa J, et al. Severe community-acquired pneumonia: assessment of severity criteria. Am J Respir Crit Care Med 1998; 158:1102 1108 1350 Clinical Investigations

12 Harmon MW, Kendal AP. Influenza viruses. In: Schmidt NJ, Emmons RW, eds. Diagnostic procedures for viral, rickettsial and chlamydial infections. 6th ed. Washington, DC: American Public Health Association, 1989; 631 668 13 Ewig S, Ruiz M, Marco F, et al. Pneumonia acquired in the community trough drug-resistant Streptococcus pneumoniae. Am J Respir Crit Care Med 1999; 159:1835 1842 14 Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243 250 15 Bochud PI, Moser F, Erad P, et al. Community-acquired pneumonia: a prospective outpatient study. Medicine 2001; 80:75 87 16 Jokinen C, Heiskanen L, Juvonen H, et al. Communityacquired pneumonia in Finland. Clin Infect Dis 2001; 32: 1141 1154 17 Nauffal D, Menéndez R, Morales P. Neumonia comunitaria por virus en la población adulta: estudio prospectivo multicéntrico de 62 casos. Rev Clin Esp 1990; 187:229 232 18 Brown RB, Sands M, Ryczak M. Community-acquired pneumonia caused by mixed aerobic bacteria. Chest 1986; 90:810 814 19 Lieberman D, Schlaeffer F, Boldur I, et al. Multiple pathogens in adult patients admitted with community-acquired pneumonia: a one year prospective study of 346 consecutive patients. Thorax 1996; 51:179 184 20 Neuzil KM, Reed GW, Mitchel EF, et al. Influenza-associated morbidity and mortality in young and middle-aged woman. JAMA 1999; 281:901 907 21 Naghavi M, Barlas Z, Siadaty S, et al. Association of influenza vaccination and reduced risk of recurrent myocardial infarction. Circulation 2000; 102:3039 3045 22 Dowell SF, Anderson LJ, Gary HE, et al. Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults. J Infect Dis 1996; 174:456 462 23 Greenberg SB, Krilov LR. Laboratory diagnosis of viral respiratory disease. In: Drew WL, Rubin SJ, eds. Cumitech 21. Washington DC: American Society for Microbiology, 1986 24 Friedmann HM, Forrer CB. Diagnosis of viral infections in the 1980s. Clin Lab Med 1982; 2:383 391 25 Zambon M, Hays J, Webster A, et al. Diagnosis of influenza in the community. Arch Intern Med 2001; 161:2116 2122 26 Liolios L, Jenney A, Spelman D, et al. Comparison of a multiplex reverse transcription-pcr-enzyme hybridization assay with conventional viral culture and immunofluorescence techniques for the detection of seven viral respiratory pathogens. J Clin Microbiol 2001; 39:2779 2783 27 Hayden FG, Gubareva LV, Monto AS, et al. Inhaled zanamivir for the prevention of influenza in families: Zanamivir Family Study Group. N Engl J Med 2000; 343:1282 1289 www.chestjournal.org CHEST / 125 / 4/ APRIL, 2004 1351