INTRODUCTION

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Severe community-acquired pneumonia (CAP) is now generally recognized as an entity of its own requiring a specific management approach (1). However, whereas risk factors for CAP have been studied, no study has specifically addressed risk factors for severe CAP. Because severe CAP is associated with a mortality of around 30%, the identification of corresponding risk factors may help to define better strategies of prevention and early recognition of severe CAP.

With regard to the causes of severe CAP, Streptococcus pneumoniae was consistently found to represent the most frequent pathogen. On the other hand, considerable differences were evident with regard to the frequencies of the remaining pathogens. This is especially true for Legionella spp., Staphylococcus aureus, "atypical" bacterial pathogens, gram-negative enteric bacilli (GNEB), and Pseudomonas aeruginosa. Whereas part of these differences are likely to reflect different epidemiological settings, potential changes of microbial patterns over time in the same epidemiological setting have only rarely been determined (10). However, since the publication of our first study (3), the frequent use of macrolides in the initial antimicrobial treatment of CAP as well as the emergence of drug-resistant S. pneumoniae and the identification of Chlamydia pneumoniae may have significantly affected current microbial patterns of severe CAP.

We therefore carried out a study of risk factors and follow-up epidemiology of severe CAP in our respiratory intensive care unit (ICU). Risk factors were determined by a hospital-based case-control design. Current microbial patterns were compared with our previous study originating from 1984 to 1987 (3).

	METHODS

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Patient Population

During the period from October 1996 until September 1998, we prospectively studied all patients hospitalized with CAP at our 1,000-bed teaching hospital after they had been investigated by our general medical emergency department. The diagnosis of CAP was made in the presence of a new infiltrate on chest radiograph together with symptoms suggestive of a lower respiratory tract infection and no alternative diagnosis emerging during follow-up.

Overall, 91 patients were admitted to the ICU. These patients were defined as having severe CAP. To detect risk factors of severe CAP, each study patient was matched with a patient hospitalized (but not admitted at the ICU) because of CAP within ± 3 d. The decision about ICU admission was made according to clinical judgment by the physician in charge. Patients in whom eventual ICU admission was denied because of advanced age and/or end-stage disease were not considered as potential control patients. Matching according to age and comorbidity was not performed because these factors were considered potential independent risk factors. If more than one patient met the matching criterion of hospitalization within ± 3 d, the patient being admitted most closely to the case with severe CAP was selected. Only two patients (2%) with severe CAP could not be appropriately matched.

Patients with severe immunosuppression as defined by the presence of solid organ or bone marrow transplantation, human immunodeficiency virus (HIV) infection, neutropenia less than 1 × 10⁹/L, treatment with steroids more than 20 mg prednisolone-equivalent per day for more than at least 2 wk, and in any dose as part of an immunosuppressive combination regimen with azathioprine, cyclosporin, and/or cyclophosphamide were excluded.

Microbiologic Evaluation

The microbiologic evaluation included sputum, blood cultures, serological sampling (at admission and within the third and sixth week thereafter), and pleural puncture in case of large pleural effusions. Transthoracic needle punction, tracheobronchial aspirates (TBAs), and bronchoscopic sampling techniques (protected specimen brush [PSB] and bronchoalveolar lavage [BAL]) were applied according to clinical judgment.

Sputum was stained for Gram and Giemsa and only cultured if more than 25 granulocytes and less than 10 epithelial cells were present. PSB and BAL fluid (BALF) samples were cultured for aerobic and anaerobic bacterial pathogens, mycobacteria, and fungi. In addition, they were evaluated by direct fluorescence antibody (DFA) test for Legionella spp. Undiluted and serially diluted respiratory secretions were plated on blood-sheep agar, CDC agar, chocolate agar as well as Sabouraud's agar. All cultures (including blood and pleural effusion cultures) were incubated at 37° C in aerobic and anaerobic culture and in CO₂-enriched atmosphere. Identification of microorganisms was performed according to standard methods (11). Negative bacterial cultures were discarded after 5 d, and negative fungal cultures after 4 wk.

The cause of pneumonia was classified as presumptive if a valid sputum sample yielded one or more predominant bacterial strains. It was considered definite if one of the following criteria were met: (1) blood cultures yielding a bacterial or fungal pathogen (in the absence of an apparent extrapulmonary focus); (2) pleural fluid and transthoracic needle aspiration cultures yielding a bacterial pathogen; (3) seroconversion, i.e., a fourfold rise in IgG titers for C. pneumoniae (IgG  1:512), Chlamydia psittaci (IgG  64), Legionella pneumophila  1:128, Coxiella burnetii  1:80, and respiratory viruses, i.e., influenza virus A and B, parainfluenza virus 1-3, respiratory syncytical virus (RSV), adenovirus; (4) single elevated IgM titer for C. pneumoniae  1:32, C. burnetii  1:80, and Mycoplasma pneumoniae (any titer); (5) a single titer  1:128 or a positive urinary antigen for L. pneumophila; (6) bacterial growth in cultures of TBAs  10⁵ cfu/ml, in PSB  10³ cfu/ml, and in BAL fluid (BALF)  10⁴ cfu/ml. Growth of fungi in respiratory samples was only considered diagnostic in the presence of a concomitant positive blood culture with the same microorganism.

Independently of microbiological results, a diagnosis of probable aspiration was made in case of witnessed aspiration or in the presence of risk factors for aspiration (severely altered consciousness, abnormal gag reflex, or abnormal swallowing mechanism).

Analysis of Risk Factors for Severe CAP

In study patients and in control patients, the following parameters were protocolled and tested as possible risk factors for severe CAP: age ( 65/< 65 yr), male sex, residency in nursing home, smoking status (smokers defined as current cigarette smokers of  10 cigarettes/d during at least the last year), alcoholism (alcohol consumption  80 g/d during the last year), history of alcoholism (alcohol consumption of  80 g/d during at least one but not in the last year), presence and number of comorbid illnesses (cardiac, pulmonary, and chronic obstructive pulmonary disease [COPD] in particular, hepatic and liver cirrhosis in particular, renal, neurological, and dementia in particular, diabetes mellitus and insulin-dependent diabetes mellitus in particular; presence of  2/< 2 comorbid illnesses), treatment with oral corticosteroids  20 mg/d, previous hospitalizations within the last year (yes/no), presence of prior ambulatory antimicrobial treatment (as defined by any oral antimicrobial treatment administered during the evolution of symptoms attributable to the current pneumonia episode), origin of disease identified as S. pneumoniae, penicillin- or cephalosporin-resistant S. pneumoniae, Haemophilus influenzae, S. aureus, Legionella spp., GNEB and P. aeruginosa, "atypical" bacterial pathogens (M. pneumoniae, C. pneumoniae, C. burnetii), "atypical" viral pathogens (influenza virus, parainfluenza virus, RSV, Adenovirus), bacteremia, nondiagnostic initial microbiologic evaluation, and aspiration.

Statistics

Results are expressed as means ± SD. Continuous variables were compared using the Student's t test, categorial variables using the chi-square test or Fisher exact test, where appropriate. Analysis of risk factors was performed by uni- and multivariate analysis. Multivariate analysis was performed by logistic regression with stepwise forward selection. All reported p values are two-tailed. The level of significance was set at 5%.

	RESULTS

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Patient Descriptives

Mean age was 65 ± 14 yr (range 16 to 86) in patients with severe CAP, and 70 ± 15 yr (range 23 to 98) in control subjects (p = 0.03). Sixty-seven patients (75%) were male, and 22 (25%) female, as compared with 58 (65%) and 31 (35%), respectively (p = 0.19). Four and five patients, respectively, were admitted from nursing homes (p = 1.0).

Clinical symptoms and radiographic patterns as well as comorbid illnesses of patients and control subjects are summarized in Table 1. As expected, clinical symptoms known to be associated with adverse outcome (absence of chills, absence of chest pain, mental confusion, hypotension, and bilateral or multilobar infiltrates) were significantly more frequent in patients with severe CAP. Moreover, dyspnea was significantly more frequent in patients and cough and expectoration in control subjects. Both patients and control subjects had similar proportions of patients with comorbid illnesses (83% versus 80%), and in both populations pulmonary comorbid illnesses were the most frequent (54%).

According to the 10 severity criteria proposed by the American Thoracic Society (ATS) guidelines (12), eight criteria were present in two patients admitted to the ICU, seven in two patients, six in nine patients, five in 14 patients, four in 17 patients, three in 18 patients, two in 15 patients, one in 11 patients, and none in only one patient. The corresponding numbers in control patients were six criteria in one patient, four in one patient, three in eight patients, two in 23 patients, one in 21 patients, and none in 35 patients (p < 0.0001). The mean number of severity criteria was 3.6 ± 1.8 versus 1.1 ± 1.2 (p < 0.0001). Sixty-eight of 89 (76%) cases met the criteria of severe CAP, and 87 of 89 (98%) control subjects of nonsevere CAP according to a rule recently proposed by our group (13).

Antimicrobial Treatment

Forty-three patients received prior oral ambulatory antimicrobial treatment as defined previously. This included: benzylpenicillin (n = 1), aminopenicillin (n = 21), oral cephalosporin (n = 6), macrolides (n = 6), cotrimoxazole (n = 2), quinolone (n = 1), and rifampicin (n = 1). In five patients, the prior antimicrobial regimen could not be reliably assessed.

Initial empiric antimicrobial treatment after admission to the hospital in patients and control subjects comprised monotherapy (n = 26), dual combination (n = 129), triple combination (n = 19), and quadruple combination (n = 4) therapy. Monotherapy was significantly less often in patients with severe CAP (19 versus 7), whereas triple and quadruple combination therapy was more frequent in these patients (13 and 4 versus 6 and none) (Table 2).

Outcome

Patients with severe CAP were hospitalized significantly longer than control subjects (15 ± 10 versus 9 ± 6 d, p < 0.0001). Respiratory failure (ratio of arterial oxygen pressure to fraction of inspired oxygen [Pa_O2/FI_O2] < 250) was present in 55 (62%) patients with severe CAP compared with 29 (33%) control patients, and 51 (57%) required mechanical ventilation at any time compared with none in control patients. Septic shock occurred in 32 (36%) patients with severe CAP compared with none in control patients. Twenty-six patients (29%) with severe CAP died, whereas all control patients survived (p < 0.0001 for all comparisons).

Microbial Etiology

The microbial origin of disease could be determined in 47 of 89 (53%) patients with severe CAP and 43 of 89 (48%) control patients (p = 0.55). Overall, 65 pathogens were isolated in patients with severe CAP; 31 patients had one pathogen, 14 patients had two, and two patients had three pathogens. Correspondingly, 58 pathogens were isolated in control patients, with 29 patients disclosing one pathogen, 13 patients two, and one patient three pathogens.

Mixed infections in patients with severe CAP are listed in Table 3. Four double infections and two triple infections included combined "typical" and "atypical" bacterial pathogens (7%). Two additional double infections included P. aeruginosa (2%). Moreover, one double infection with typical pathogens included intermediately resistant strains and two further infections highly resistant strains of S. pneumoniae (3%). The corresponding numbers for control patients were four double infections and one triple infection including combined typical and atypical bacterial pathogens (6%) and one pseudomonal infection (1%) as well as one intermediately resistant and one highly resistant strain of S. pneumoniae involved in double infections with typical pathogens (2%).

S. pneumoniae was the most frequent pathogen in both groups (n = 21 versus n = 17). Resistance to penicillin was 43% in patients with severe CAP and 59% in control patients. With regard to cephalosporins and macrolides, the corresponding proportions were 14% and 41%, as well as 24% and 33%, respectively (p = not significant [NS] for all comparisons). Resistance rates to any drug were 48% and 65%, respectively. In severe pneumonia, the second and third most common pathogens were C. pneumoniae and C. burnetii (n = 6 each), and atypical bacterial pathogens summed up to n = 15. GNEB and P. aeruginosa accounted for n = 9 pathogens (n = 5 and n = 4 pathogens, respectively), and represented the third most common group of pathogens. Conversely, H. influenzae (n = 9) and influenza virus (n = 5) were the second and third most common pathogens in control patients. The GNEB and group of atypical bacterial pathogens (n = 9 pathogens), and P. aeruginosa (n = 5 pathogens; corresponding to n = 3 and n = 2 pathogens, respectively), were equally frequent. However, no pathogens or grouped pathogens were significantly more frequent in cases than in control patients (Table 4).

In nonsurvivors with cause of disease established, 11 of 15 patients (73%) died with typical bacterial pathogens (mainly S. pneumoniae [n = 4], S. aureus [n = 1], Escherichia coli [n = 3] and P. aeruginosa [n = 2]), and in patients with septic shock and cause of disease established, the corresponding proportion was 18 of 20 (90%) (mainly S. pneumoniae [n = 11], S. aureus [n = 1], E. coli [n = 1], and P. aeruginosa [n = 3]).

A microbial diagnosis in patients with severe CAP and control patients was based on the following media: sputum n = 9 versus 26 (p = 0.001), blood culture n = 13 versus 11 (p = 0.66), serology n = 22 versus 21 (p = 0.86), TBAs n = 20 versus 0 (p < 0.0001), transthoracic puncture n = 3 versus 0 (p = 0.25), and others (pleural fluid culture, PSB, and BALF n = 1 versus 0 each, and Legionella antigen n = 0 versus 1).

Comparison of Causes of Severe CAP to Our Previous Study

When comparing the causes of severe CAP to our previous study conducted between 1984 and 1987 (3), three significant changes were evident: a lower incidence of Legionella spp.; a higher incidence of C. burnetii; and a significant role for C. pneumoniae and atypical viral pathogens, both of which were not tested for in our previous study. Moreover, the incidence of H. influenzae was close to significantly higher (p = 0.06). S. pneumoniae, and, to a lesser extent, GNEB and P. aeru-ginosa continued to represent frequent pathogens (Table 5).

Risk Factors of Severe CAP

In univariate analysis, an alcohol ingestion of > 80 g/d was associated with severe CAP. The presence of prior ambulatory antimicrobial treatment was protective against severe CAP. The prior ambulatory antimicrobial regimen was appropriate in only one of four (25%) patients with definite cause established and severe CAP compared with four of 10 (40%) control patients (p = NS). Renal disease as well as prior treatment with corticosteroids were additional risk factors close to significance (p < 0.1). Neurological disease was more frequent in control patients. All other variables tested were not associated with severe CAP at a p level of < 0.1 (Table 6).

In multivariate analysis including alcohol ingestion of > 80 g/d and presence of prior ambulatory antimicrobial treatment, both factors remained independently associated with severe CAP (Table 7). The additional inclusion of renal disease, neurological disease, liver cirrhosis as well as prior treatment with corticosteroids did not change the results. This was also true when the model was adjusted for age.

	DISCUSSION

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This study provides two important insights: first, the presence of an alcohol ingestion of > 80 g/d was found to be an independent risk factor for severe CAP and prior ambulatory antimicrobial treatment to be protective; second, the causes of severe pneumonia revealed important differences when compared with our study originating from 1984 to 1987 (3). The most striking changes included a lower frequency of legionellosis and the importance of atypical bacterial as well as viral pathogens that were not tested for in our previous report. On the other hand, S. pneumoniae, and, to a lesser extent, GNEB and P. aeruginosa continued to be leading pathogens.

In this study on risk factors of severe CAP, we decided to rely on a hospital-based design. A methodological shortcoming of this design consists of potential biases originating from referral habits. This must be taken into account when interpreting our findings; for example, the fact that control patients were found to have an increased age and more frequently neurological comorbid illness compared with severe pneumonia patients is most probably due to the fact that younger patients with severe pneumonia were more readily referred to a tertiary care hospital. Moreover, the decision to hospitalize a patient implies at least moderate severity of pneumonia in the majority of cases, precluding the identification of highly prevalent potential risk factors such as COPD, chronic heart failure, or diabetes mellitus. On the other hand, the hospital physician may more confidently rely on risk factors identified in hospital-based designs because the patients studied are more likely to be similar to those he will have to treat.

In studies of severe CAP published so far, COPD, alcoholism, chronic heart disease, and diabetes mellitus were the most common comorbid illnesses (3, 4, 6, 9, 14). In addition, lung disease, bronchial asthma, and heart disease were found to be risk factors of pneumonia in the elderly (15). Therefore, these conditions were expected to be potential factors predisposing to severe CAP. Nevertheless, pulmonary comorbidity, chronic heart disease, liver disease, and diabetes mellitus were not found to be associated with severe CAP, even when specified for COPD, liver cirrhosis, and insulin-dependent diabetes mellitus. This may be a result of the hospital-based approach discussed previously as well as the relatively limited number of patients studied. The presence of renal disease as a risk factor was close to significance. Somewhat surprisingly, only few studies of severe CAP have reported patients with chronic renal failure as a comorbid condition (4, 14).

We found alcoholism (as defined by a daily alcohol intake of  80 g/d) to represent an important independent risk factor also for severe CAP. This finding is in line with a previous study from our hospital where high alcohol intake (> 100 g/d in men and > 80 g/d in women) was found to be the only independent risk factor of CAP and also to be significantly associated with death (16). In another study, alcoholism was also described as a risk factor of CAP in the elderly (15). Alcoholism has long been suggested to bear a potential role in the pathogenesis of CAP by reducing alertness and favoring aspiration and, possibly, also by an impairment of several local and systemic host immune mechanisms, especially of neutrophil and lymphocyte functions (17, 18). In the present study, a history of high alcohol intake was not associated with an increased risk of severe CAP. Accordingly, in our previous study, neither the total lifetime dose of alcohol nor a history of alcoholism were identified as risk factors, suggesting that acute effects of alcohol consumption are most important for the development of pneumonia.

There was a trend for treatment with corticosteroids  20 mg/d to be associated with severe CAP. This finding suggests that even a low dose of corticosteroids has immunosuppressive effects favoring severe pulmonary infection independent of the underlying disease. By the same token, it at least does not support the hypothesis that preexisting treatment with low doses of corticosteroids may modify favorably the inflammatory response.

S. pneumoniae, GNEB, P. aeruginosa as well as bacteremia failed to be significantly associated with severe CAP, all of which were found to bear adverse prognostic potential in several previous studies (3, 6, 8, 14, 19). This failure may be due to age distribution, the use of hospitalized patients as controls, and the limited number of patients studied. Nevertheless, there was a trend toward a higher incidence of GNEB and P. aeruginosa in severe CAP. Accordingly, typical pathogens (mainly S. pneumoniae, S. aureus, E. coli, and P. aeruginosa) were predominant in nonsurvivors as well as in patients presenting with septic shock.

Prior ambulatory antimicrobial treatment was protective against severe CAP also in multivariate analysis. Because of the limited number of pretreated patients with definite cause of disease, we were not able to establish a significant relation of inappropriate ambulatory treatment and severe CAP. Nevertheless, consistent with our finding, two studies examining prognostic factors of severe CAP have demonstrated the adverse prognostic potential of inappropriate or a delay in appropriate initial antimicrobial treatment (3, 7). Rapid empirical antimicrobial treatment seems to be of paramount importance for the course of CAP. Most probably, the potentially harmful inflammatory response to the underlying pathogens is most effectively limited by an early reduction of the bacterial load, whereas later on the inflammatory cascades may equally run relatively independently of the initial pathogens and, therefore, of antimicrobial treatment (20, 21). Because current antibiotics do effectively reduce the bacterial load within the first 24 h in the presence of a susceptible pathogen, the most important concern is to introduce them as early as possible.

The comparison of current microbial patterns of patients with severe CAP with previous findings from our group (3) must be interpreted with caution because several diagnostic techniques were not applied in the latter series. These include validated sputum cultures, and serology for C. pneumoniae and viruses. Accordingly, the significantly higher incidence of atypical bacterial pathogens is in part explained by the emergence of C. pneumoniae which was not considered during our previous study period. Although this pathogen is usually found in mild to moderate CAP, it has been also found to cause severe CAP (22). The frequency of M. pneumoniae was similar (3% versus 6%). There was, however, also an unexpected high incidence of C. burnetii, a pathogen not detected in our previous study. The reasons for this are unclear. A comparison of the incidence of viral pathogens is also not possible because these pathogens were not investigated in our previous study. Overall, our findings confirm an important role for atypical bacterial and viral pathogens in severe CAP.

Perhaps the most important change is the significantly lower incidence of severe legionellosis. Recent studies originating from Spain have provided some evidence for a generally decreasing incidence of legionellosis (9, 19, 23). In addition, a British follow-up epidemiological study conducted at the same ICU reported only half of cases of severe legionellosis compared with the previous study (16% versus 30%, p = 0.08) (1, 10). A possible explanation for this decreasing incidence of severe legionellosis may be a more widespread early use of macrolides.

As expected, S. pneumoniae continued to be the leading pathogen in severe CAP. However, the emergence of drug- resistant strains has been dramatic, leading to a high incidence in severe CAP as well as in control patients in our present study. The initiation of an appropriate antimicrobial treatment taking into account these changing susceptibility patterns is pivotal, because we recently could show that the outcome is not affected by drug resistance in the presence of an appropriate antimicrobial treatment (24). GNEB and P. aeruginosa continued to be frequent pathogens in the present study (6% and 5%, respectively). This finding is particularly important because there are considerable variations in the reported frequencies of these pathogens in different settings, ranging from 0-34% for GNEB (1, 6, 10) and 0-5% for P. aeruginosa (1, 6, 14).

An interesting finding was that nearly 10% of patients with severe CAP had mixed etiologies requiring a combination antimicrobial treatment covering additionally atypical bacterial pathogens (including Legionella spp.) or P. aeruginosa, and a further 3% of patients had mixed infections with typical pathogens including drug-resistant strains of S. pneumoniae. Both a broad-spectrum initial antimicrobial treatment and a comprehensive microbial investigation seem mandatory to cope with the problem of mixed infections in severe CAP.

This follow-up epidemiologic study provides evidence that obvious differences in microbial patterns comparing recent studies are only in part caused by differences in local settings. A considerable part of these discrepancies may additionally originate from the period under study, even in the same local setting. Because the recommended empirical approach in the ATS guidelines is based on microbial patterns derived from several epidemiologic surveys (12), it remains particularly important for the clinician to additionally consider current peculiarities of the local setting as well as global and regional trends of changing microbial and susceptibilty patterns.