Etiology of community-acquired pneumonia in a population-based study: Link between etiology and patients characteristics, process-of-care, clinical evolution and outcomes

Community-acquired pneumonia (CAP) is a common clinical disorder with an estimated incidence range from 1.6/1,000 to 16/1,000 per year [1‐4]. The majority of pneumonia-related morbidity, mortality, and health care expenditures occur among persons who are hospitalized, however, 50 percent to 80 percent of adult patients with CAP are treated on an ambulatory basis [1, 2, 5, 6].

Initial antibiotic selection for treatment of CAP is empirical, though a thorough understanding of the likely pathogens raises important questions regarding the current care of patients with CAP. Although the microbiology of CAP has probably remained relatively stable over the last decade, indeed could have changed over time due to the success of vaccinations and a population which is getting older, and sicker. Until now the majority of pneumonia etiologic studies are based on selected series of hospitalized patients, and there have been no recent, comprehensive population-based studies including hospitalized patients and outpatients treated by family physicians.

Streptococcus pneumoniae is the most common etiologic agent in hospitalized patients with CAP, particularly those with severe disease [7]. Some studies have found atypical bacteria to be the predominant microorganism for cases of ambulatory CAP [6] and for patients hospitalized with milder episodes of pneumonia [8]. However, population-based studies [1, 9] have showed that S. pneumoniae was also the organism most frequently isolated in outpatients, and for each age group, the etiologic profile could be similar among inpatients and outpatients [9]. A better understanding of pathogens causer of CAP could lead to effective efforts to define their natural history and optimize the therapy.

The aim of the present study was to provide an assessment of the etiology of CAP that occurred in the adult population of a defined geographical area. Our second objective was to evaluate the relation that may exist between the different pathogens of CAP to patient characteristics, process-of-care, clinical evolution and outcomes.

A total of 700 patients with etiologic evaluation were included in our study: 276 hospitalized and 424 ambulatory patients. We were able to define the etiology of pneumonia in 390/700, 55.7% (310/390, 79.5% definitive diagnosis; 80/390, 20.5% presumptive diagnosis) (Table 1). The most frequently isolated organism was S. pneumoniae (170/390, 43.6%), followed by C. burnetti (72/390, 18.5%), M. pneumoniae (62/390, 15.9%), virus as a group (56/390, 14.4%), Chlamydia species (39/390, 106%), and L. pneumophila (17/390, 4.4%). Evidence of bacterial infection was present in 179 (179/360, 45.9%) episodes and atypical infection in 190 (190/390, 51.4%). Mixed infections were demonstrated in 9% (35/390). Results of sputum cultures were available for 12 cases. Pneumococcal infection was significantly more frequent among inpatients (64.8% vs. 22.2%; P < 0.0001). In contrast, atypical pathogens as a group were significantly more frequent among outpatients (67% vs. 30.6%; P < 0.0001). Among inpatients, the global incidence of S. pneumoniae was 64.8% (127/196) and that of atypical agent was 30.6% (60/196).

Microbial etiology by age group is shown in Table 2. A trend toward a higher proportion at older ages was found for Pneumococcal infection (trend P < 0.0001). In contrast, for atypical infection a trend toward a low proportion at older ages was found (trend P < 0.0001). Virus infection as a group was significantly more frequent among patients aged ≥65 years than among patients aged <65 years (22.2% vs. 7%; P < 0.0001).

Characteristics of patients according to etiologic categories are provided in Table 3. In contrast with patients infected by atypical agents, those infected by conventional bacteria were elderly, had more comorbidities, or had a higher severity of CAP at diagnostic. The rate of patients immunized against pneumococcal infection was very low for all groups.

Process-of-care is shown in Table 4. First-line antibiotic therapy was a monotherapy in 92.8% patients. Antibiotics initially prescribed were overcoat quinolones (60%) for all etiologic categories. Almost a quarter of CAP by atypical agents were treated with betalactam antibiotics.

Clinical evolution and outcomes are provided in Table 5. In contrast with patients infected by atypical agents, those infected by conventional bacteria had a higher hospitalization rate, showed worse evolution and higher length of hospital stay . However, among patients infected by atypical agents 25.8% needed hospitalization with an inhospital mortality rate of 5.1%. There was no difference according to etiologic categories for inhospital mortality, readmission within 30 days, and the mean duration of return to daily activity. No deaths were found for patients with mixed, virus or L. pneumophila infections, and none of them were admitted to an ICU. After adjusting by sex, age, and comorbidities, the previous analyses yielded similar results (Table 6).

All the patients who passed away, both in hospital as well as at 30-days had a definitive etiologic diagnostic. Out of all patients admitted at the ICU [15], for 14 (Table 5) the diagnostic was definitive, while 1 patient was not diagnosed etiologically: blood culture, negative; urinary antigen, negative; sputum culture, negative; serologic test 1° and 2°, negative. Out of all patients with septic shock [10], for 9 (Table 5) the diagnostic was definitive, while 1 patient was not diagnosed etiologically: blood culture, negative; urinary antigen, negative; sputum culture, negative; serologic test 1° and 2°, negative. Out of all patients with severe sepsis (131), for 105 (Table 5) the diagnostic was definitive, while 26 patients were not diagnosed etiologically: blood culture, negative for 17 (9 were not done); urinary antigen, negative for all; sputum culture, negative for 5 (21 not done); serologic test 2nd sample, negative for all, serologic test 1st sample, negative in 16 (10 not done).

In our population-based study we assessed the etiology for CAP, in search of evidence and insight into the different roles and pathlines concerning diverse pathogens. Our results confirm many already well documented features, i.e. – S. pneumoniae was the most common pathogen, causing a greater degree of severity. We bring to light as a new finding the fact that, viruses, mixed and L. pneumophila infections do not imply greater severity. What is more, atypical pathogens and the S. pneumoniae are found in a wide spectrum of severity and age levels. Our findings emphasize the part that atypical organisms play.

In agreement with other studies S. pneumoniae is still the predominant infection [1‐3, 18, 19]. It was the most common agent in hospitalized patients and the second most common cause of illness in outpatients. C. burnetti had unusual frequencies in our study due to regional epidemiological factors which are markedly different from those in other areas of the western world [20, 21]. In our region the sheep are the usual reservoir and the infection source for other domestic and wildlife species and the human population [22]. M. pneumoniae was the third most common pathogen isolated, although it was less common than in some earlier studies [23, 24] probably due to cyclicity of Mycoplasma epidemics. Consistent with previous studies [1, 19, 25], the frequency of L. pneumophila infection was very low (<2%) and was not implicated in greater severity. The mixed pneumonia group is a heterogeneous group in which proportions varied among studies [9, 26]. We found mixed infections in 9% of patients, and, like others [19], nearly all of our cases were non-severe CAP, contrary to the view that mixed infections can be severe [27, 28]. Viral infections were attributable to old age patients with chronic obstructive pulmonary disease. In contrast with previous studies [29], viral etiology was associated with low severity of illness, possibly related to the high rate of influenza immunization in this group. In previous population-based studies about CAP in adult population [1‐3]H. influenzae infection has been diagnosed in 1%-10%. The widely varying results are more likely to reflect differences in the bacteriologic methods than true differences in the etiology. In the present study the bacteriological examination of sputum was not compulsory. This approach implicated a failure to detect the true incidence of H. influenza, S. aureus, and P. aeruginosa. Moreover, the infection by S. aureus is always very infrequent in CAP, especially among outpatients.

According to etiologic categories the profile of patients is similar to the combined information from previous studies of CAP [1‐4, 8]: infections by atypical agents were characterized by milder episodes, while more severe infections were caused by conventional bacteria. In fact, patients with conventional bacteria have higher hospitalization rate, higher CURB65 scores at admission, more bilateral radiographic involvement and more adverse clinical evolution and outcomes such as severe sepsis, septic shock, ICU admission and longer length of stay. However, our findings confirm that atypical pathogens and the S. pneumoniae are present in pneumonias of a wide spectrum of severity and age, as had been stated in a previous study [30, 31]. Almost 26% of patients infected with any atypical agents needed to be hospitalized and, like others [32], atypical pathogens were present in a considerable proportion of inpatients with CAP (30.6%). Conversely, among patients with conventional bacteria almost 25% were treated at home with excellent evolution. In the present study the mortality can be compared between conventional bacteria and those atypicals who require a convalescent serum, because all the patients who passed away, both in hospital as well as at 30-days, has a definitive etiologic diagnostic. Therefore, the assessment of this outcome is not biased towards a better outcome for atypical organisms.

In our study antibiotic treatment was consistent with the Spanish guideline strategy [13], which recommends targeting pneumococcal and atypical infection for inpatients and outpatients. Likewise, the IDSA/ATS [14] guideline strategy recommends empirical antibiotic treatment to cover typical and atypical pathogens. Our data show that S. pneumoniae as well as atypical agents were causing pneumonia in hospitalized and ambulatory patients of all ages, questioning the empirical use of an antibiotic to cover atypical and not atypical agents in ambulatory pneumonia. There is concern about this question because evidence is lacking that clinical outcomes are improved by using antibiotics against atypical pathogens in all-cause non-severe CAP [33], and a greater dependence on quinolones as initial therapy raises concerns regarding the potential for the development of antibiotic resistance.

Our study has some limitations. We made a great effort to identify all patients with CAP in the catchment area: all local health care centers and the referral hospital participated in the reporting of patients; all primary health care centers were closely supervised by a local FP, and all information was coordinated by a member of the research team. However, full participation of all 150 FP was not obtained and, therefore, we must assume as a limitation the fact that not all real cases have been included. As in most pneumonia studies [1, 6, 25, 29, 34], specific etiologic diagnoses could not be assigned for 44.3% of the patients enrolled in the study. It is difficult to collect quality sputum samples from outpatients. Likewise, it is difficult to obtain blood cultures from outpatients. The absence of sputum cultures in the strategy of bacteriologic diagnosis and the lack of molecular testing for both conventional and atypical organisms are other limitations of the study.

Our study updates the information concerning the epidemiology and management of CAP. S. pneumoniae remains the most important pathogen, and almost 50% of the patients were infected with C. burnetti, M. pneumoniae, Chlamydia sp, or L. pneumophila. Although all identified agents infect patients of a wide spectrum of severity and age, infection by conventional bacteria showed higher severity, and there is a high incidence of S. pneumoniae in elderly patients.