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Nonsevere Community-Acquired Pneumonia
Correlation Between Cause and Severity or Comorbidity
Miquel Falguera, MD;
Oscar Sacristán, MD;
Antoni Nogués, MD;
Agustín Ruiz-González, MD;
Mercè García, MD;
Anton Manonelles, MD;
Manuel Rubio-Caballero, MD
Arch Intern Med. 2001;161:1866-1872.
ABSTRACT
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Background Community-acquired pneumonia frequently constitutes a nonsevere infection
manageable at home. However, for these low-risk episodes, the epidemiological
features have not been carefully analyzed.
Objectives To determine the cause of nonsevere community-acquired pneumonia and
to investigate if a correlation exists between cause and severity or comorbidity.
Methods During a 3-year period, all patients with nonsevere community-acquired
pneumonia, according to the Pneumonia Patient Outcome Research Team prognostic
classification (patients in groups 1-3), were included in the study. Causes
were investigated through the following procedures: cultures of blood, sputum,
and pleural fluid; serologic tests; and polymerase chain reaction methods
to detect Streptococcus pneumoniae DNA in whole blood
or Mycoplasma pneumoniae and Chlamydia
pneumoniae DNA in throat swab specimens.
Results Of 317 initially included patients, 247 were eligible for the study.
A microbial diagnosis was obtained in 162 patients (66%), and the main pathogens
detected were S pneumoniae (69 patients [28%]), M pneumoniae (40 patients [16%]), and C pneumoniae (28 patients [11%]). For the 58 patients in prognostic
group 1, M pneumoniae was the most prevalent cause,
and atypical microorganisms constituted 40 (69%) of the isolated agents. In
contrast, for patients in prognostic groups 2 and 3, S pneumoniae was the leading agent, and a significant reduction of M pneumoniae cases and a greater presence of other more uncommon pathogens
were observed. The existence of comorbid conditions was not a determining
factor for particular causes.
Conclusions Among low-risk patients with community-acquired pneumonia, there was
a certain correlation between severity and cause. In contrast, the existence
of a comorbidity did not have a predictive causative value.
INTRODUCTION
IT IS USUAL to state that community-acquired pneumonia (CAP) is responsible
for considerable morbidity and mortality; however, many patients with this
infection certainly have a nonsevere illness. Several studies have sought
risk factors for the severity of pneumonia, and, actually, low-risk patients
with CAP can be reasonably well identified. Fine et al1
recently developed and validated one of the most interesting risk classification
systems, the Pneumonia Patient Outcome Research Team (Pneumonia PORT) prediction
rule, to detect patients with nonsevere infection, based on age, sex, physical
findings at hospital admission, the presence of selected coexisting illnesses,
and some laboratory and radiographic results. Accordingly, patients are stratified
into 5 categories with respect to the risk of death within 30 days, and those
classified into groups 1 to 3 (a score of  90) constitute the low-risk
group, a relatively homogeneous subset of patients because they have an overall
good prognosis and can be managed at home, immediately or after a short hospitalization.
This prognostic prediction rule has been widely accepted and has become a
valuable tool for clinicians.2-4
Simultaneously, during the past decade, several guidelines5-7
for the diagnostic and therapeutic management of patients with CAP have been
published. These guidelines also stratify patients according to age, severity
of the clinical picture, and existence of a comorbidity. Therefore, a distinction
between ambulatory and hospitalized populations is suggested and, in the absence
of a causative diagnosis, specific empirical recommendations for outpatients
are usually established. Furthermore, the presense or absence of comorbid
conditions frequently constitutes an additional criterion to separate patients
into 2 differentiated therapeutic subsets.
Obviously, empirical therapeutic recommendations should be based on
the knowledge of the most prevalent causes for each category of patients,
but, surprisingly, little information is available about pathogens causing
these nonsevere infections in previously healthy subjects and in patients
with underlying disease.
This study determines, by means of a full diagnostic workup, the more
prevalent causative agents for patients with nonsevere CAP and investigates
if a relationship exists between the spectrum of causative pathogens and the
severity of disease, according to the Pneumonia PORT prognostic classification,
or the existence of a comorbidity.
PATIENTS AND METHODS
On March 1, 1997, the Pneumonia PORT prognostic rule was incorporated
into the management of CAP at our institution (a 500-bed university hospital
in Catalonia, Spain). Simultaneously, we designed a prospective study to determine
the cause of infection in those patients with low-risk infection.
STUDY POPULATION
During a 3-year period, demographic and clinical data at presentation
from all adult patients (aged  18 years) admitted to the emergency department
with a clinical and radiological image suggestive of CAP were analyzed, and
the score, according to the prognostic rule, was calculated. For patients
assigned to risk categories 2 to 5, laboratory tests were also performed.
Finally, those patients assigned to categories 1 to 3 constituted the study
group, and they were microbiologically studied through the further described
methods. Informed consent was obtained from the patients, and the study was
approved by the ethical and the scientific committees of our institution.
The presence of the following comorbid conditions was also determined
by patient report and medical record review: chronic pulmonary diseases (chronic
obstructive pulmonary disease, interstitial lung disease, or bronchiectasis),
cardiovascular diseases (congestive heart failure or advanced ischemic heart
disease), chronic hepatitis and hepatocellular diseases, recent or active
neoplastic diseases, chronic renal insufficiency, diabetes mellitus, and cerebrovascular
diseases with significant neurologic residual effects. In fact, many of these
comorbidities were already identified as influencing factors in the Pneumonia
PORT prognostic classification. According to the criteria used by Fine et
al,1 patients with severe immunosuppression,
patients who had been hospitalized in the previous 15 days, and patients known
to have the human immunodeficiency virus infection were excluded.
COLLECTION OF MICROBIOLOGICAL SPECIMENS
The following battery of samples was obtained from patients:
- Two blood specimens, for aerobic and anaerobic
conventional cultures.
- A considerable effort was made to obtain a good
sputum sample. This was microscopically assessed to confirm its quality and,
if alright, it was examined according to conventional methods. Sputum was
also stained and cultured for Mycobacterium species
or opportunistic pathogens only when it was indicated.
- When present, pleural fluid was biochemically examined
and processed for aerobic and anaerobic cultures.
- An additional blood sample was obtained for Streptococcus pneumoniae DNA detection by polymerase chain
reaction (PCR).
- Since January 1, 1999, a throat swab sample was
also collected and processed for Mycoplasma pneumoniae
and Chlamydia pneumoniae genome detection by PCR.
- Based on clinical suspicion, a urine sample for Legionella pneumophila antigen detection was processed.
- Finally, a serum sample for serologic investigations
was obtained, stored at -70°C, and reserved. Within 4 to 6 weeks
of follow-up, a second serum sample was collected and processed with the first
one to detect M pneumoniae (immunofluorescence test), C pneumoniae and Chlamydia psittaci
(microimmunofluorescence test), Coxiella burnetii
(complement fixation test), and L pneumophila (immunofluorescence
test) antibodies.
PCR METHODS
The PCR technique was used to detect the S pneumoniae genome in whole blood and M pneumoniae and C pneumoniae in throat swab samples.
For the extraction of S pneumoniae DNA, 200
µL of whole blood samples was processed by using a kit (QIAamp Blood
Kit; QIAgen, Hilden, Germany). We used the nested PCR method by a selection
of 2 primer pairs based on the published pneumolysin gene sequence.8 The outer primers, Ia (5'-ATTTCTGTAACAGCTACCAACGA-3')
and Ib (5'-GAATTCCCTGTCTTTTCAAAGTC-3'), amplified a 348–base
pair (bp) region; and the inner primers, IIa (5'-CCCACTTCTTCTTGCGGTTGA-3')
and IIb (5'-TGAGCCGTTATTTTTTCATACTG-3'), amplified a 208-bp region
of the pneumolysin gene. The technical characteristics of the method for DNA
amplification were recently described.9
For M pneumoniae and C pneumoniae, DNA extraction was carried out as described for pneumococcal DNA,
on 200 µL of sample. In both cases, a single amplification was performed.
We selected the MP5-1 (5'-GAAGCTTATGGTACAGGTTGG-3') and MP5-2
(5'-ATTACCATCCTTGTTGTAAGG-3') pair of primers, described by Bernet
et al,10 which resulted in an amplification
product of 144 bp, to detect M pneumoniae; and the
HL1 (5'-GTTGTTCATGAAGGCCTACT-3') and HR1 (5'-TGGATAACCTACGGTGTGTT-3')
pair of primers, described by Campbell et al,11
which amplified a 438-bp C pneumoniae target sequence
of unknown function but proved species specificity, to detect C pneumoniae. The thermal cycles included, for both microorganisms,
were as follows: 1 cycle of 4 minutes at 94°C, 35 cycles of 1 minute at
94°C, 1 cycle of 1 minute at 55°C, 1 cycle of 1 minute at 72°C,
and 1 final cycle of 10 minutes at 72°C.
The amplified products were analyzed by 2% agarose gel electrophoresis
and ethidium bromide staining, and examined by UV transillumination. Identification
of the size of the bands was performed by comparison with standard molecular
weights (100-bp DNA ladder; GIBCO BRL, Rockville, Md) and the bands obtained
from positive controls. For confirmation, a nonradioactive DNA hybridization
technique (Gen-Eti-K DEIA; Sorin Biomédica, Saluggia, Italy) was performed
using the following biotin-labeled probes: 5'-TTGGAGAAAGCTATCGCTACTTGC-3'
for S pneumoniae, MP5-4 (5'-CGTAAGCTATCAGCTACATGGAGG-3')
for M pneumoniae, and HM-1 (5'-GTGTCATTCGCCAAGGTTAA-3')
for C pneumoniae.
To prevent contamination, a strict spatial separation of different PCR
steps was maintained during the process, and the recommendations of Kwok and
Higuchi12 were followed. In addition, one positive
control, constituted by a suspension of the microorganism in distilled water,
a second positive control to detect the presence of Taq polymerase inhibitors in the sample, and a negative control for each
studied sample, with target-free distilled water, were included in the procedure.
CAUSATIVE CLASSIFICATION OF PATIENTS
According to microbial results, the causative diagnosis was established
according to the following criteria: (a) Patients
had a definite diagnosis of bacterial pneumonia when the pathogen was isolated
from an uncontaminated sample (blood or pleural fluid) or, for S pneumoniae, when the genome was detected in whole blood by PCR. In
contrast, a diagnosis was considered only probable when a respiratory pathogen
was isolated from a good-quality sputum specimen. (b)
For atypical microorganisms, a 4-fold or greater increase in serologic titers,
the identification of specific DNA for M pneumoniae
or C pneumoniae in throat swab samples, and the detection
of the L pneumophila antigen in urine made a definite
causative diagnosis. In contrast, only high serologic titers (1/256 for
immunofluorescence tests or 1/10 for complement fixation tests) were indicative
of a probable microbial diagnosis. (c) Pneumonia of unknown cause was defined as those cases with negative
results using conventional microbial methods and genomic detection tests.
STATISTICAL ANALYSIS
Prevalences of microorganisms were expressed in percentages. Qualitative
variables were compared with  2 or Fisher exact tests and continuous
variables with t or Mann-Whitney tests. The level
of significance was set at P<.05.
RESULTS
PATIENT CHARACTERISTICS
From a total of 317 patients with potential nonsevere CAP eligible for
the study, 70 were excluded for several reasons: misdiagnosis at hospital
admission (n = 38), diagnosis of human immunodeficiency virus infection (n
= 16), error in the Pneumonia PORT rule application (n = 13), or absence of
informed consent (n = 3). Thus, 247 patients constituted the final study group.
The Pneumonia PORT prognostic score stratified patients as follows: 80 (32%)
were included in class 1, 75 (30%) in class 2 (mean of score value, 56), and
92 (37%) in class 3 (mean of score value, 78) (percentages do not total 100
because of rounding).
The main epidemiological characteristics at hospital admission, for
the overall population and for each prognostic subset, are shown in Table 1. The mean age of the patients was
50 years; patients in group 1 were clearly younger. Underlying diseases were
present in 64 (26%) patients, also summarized in Table 1; the incidence of a comorbidity was significantly lower
for patients in group 1. Differences were also noted for other analyzed characteristics,
such as sex distribution and smoking habit, logically derived from criteria
for patient classification used.
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Table 1. Baseline Characteristics of the Patients*
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DIAGNOSTIC YIELD OF DIFFERENT TECHNIQUES
Blood samples for culture were obtained from 238 (96%) patients and
gave positive results in 13 (5%), yielding S pneumoniae in 11, Streptococcus viridans in 1, and Staphylococcus aureus in 1. Bacteremia rates were 1% (1
of 78 patients), 7% (5 of 72 patients), and 8% (7 of 88 patients) for those
in groups 1, 2, and 3, respectively. A blood sample for pneumococcal DNA detection
by PCR was collected from 193 (78%) of 247 patients, and it was positive for S pneumoniae in 56. Pleural fluid, recovered from 22 (9%)
of 238 patients, showed the presence of a respiratory pathogen by culture
in 15 (S pneumoniae, 9; Haemophilus
influenzae, 3; S viridans, 1; Enterococcus faecium, 1; and Mycobacterium tuberculosis, 1). Finally, a sputum sample for gram stain and culture was collected
from 83 (35%) patients, of whom 66 provided a valid sample, and a significant
microorganism was isolated in 14 (S pneumoniae, 6; H influenzae, 3; M tuberculosis,
3; and Pseudomonas aeruginosa, 2).
The first serologic sample was taken from 211 (85%) patients, and the
second from 166 (67%), and the diagnosis by serologic analysis was made in
90 (M pneumoniae, 40; C pneumoniae, 26; C burnetii, 17; L
pneumophila, 5; and C psittaci, 3 [1 patient
had >1 infection]). A throat swab sample for PCR analysis was obtained from
66 (27%) patients, allowing the detection of M pneumoniae DNA in 1 patient and C pneumoniae DNA in
4 patients. Finally, 86 (35%) urine samples were analyzed for Legionella antigen detection, and the test result was positive in 6.
For patients with pneumococcal pneumonia, there was a good correlation
between positive culture results and PCR results, as can be seen in Table 2. Thus, we detected S pneumoniae DNA in the blood of 8 of 10 patients with bacteremia,
6 of 9 with positive pleural fluid culture results, and 2 of 5 with positive
sputum culture results. Conversely, many patients with sterile culture results
showed a positive PCR test result in blood. In contrast, for M pneumoniae and C pneumoniae, throat swab
assays had, compared with serologic tests, reduced sensitivities (Table 3). Thus, only 1 throat swab specimen
from 6 patients with M pneumoniae infection, serologically
diagnosed, and 2 from 4 patients with C pneumoniae
infection, with positive serologic test results, were positive by PCR; in
addition, 2 cases of C pneumoniae infection positive
by PCR and negative by serologic test result were found.
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Table 2. Comparison Between PCR Results in Blood and Culture Results
for Patients With Pneumococcal Pneumonia*
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Table 3. Comparison Between PCR Results in Throat Swab Samples and
Serologic Test Results for Patients With Pneumonia Caused by Mycoplasma pneumoniae and Chlamydia pneumoniae*
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In summary, a microbial diagnosis was made in 162 (66%) of the 247 patients:
138 had a definite diagnosis, while 24 had only a probable diagnosis. As Table 4 shows, S pneumoniae (n = 69), M pneumoniae (n = 40), and C pneumoniae (n = 28) were the most prevalent microorganisms.
A mixed infection was detected in 17 (7%) patients.
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Table 4. Pneumonia Cause in the Overall Group of Patients*
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DISTRIBUTION OF PATHOGENS BY PROGNOSTIC GROUPS
Among the 80 patients included in prognostic group 1, a causative diagnosis
was established in 56 (70%). As Table 5 shows, M pneumoniae was the most frequent
microorganism, identified as the causative agent in 23 patients; in addition,
other atypical pathogens (C pneumoniae, C burnetii, and C psittaci) also constituted
relatively frequent causes. Therefore, excluding tuberculosis, some atypical
agent was detected in 69% of the causatively diagnosed patients. Among conventional
bacteria, only S pneumoniae was detected with a significant
frequency, and it was isolated in 16 patients. All patients who had tuberculosis
were included in this prognostic category.
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Table 5. Distribution of Detected Causative Agents According to Prognostic
Groups of Patients*
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The microbial study of patients in prognostic groups 2 and 3 showed,
in relation to group 1, a different pattern. A causative diagnosis was achieved
in 55% (41/75) of the patients in group 2 and in 71% (65/92) of the patients
in group 3. For both groups, the importance of S pneumoniae notably increased, and it became the most frequently isolated microorganism,
responsible for 21 and 32 cases among patients from groups 2 and 3, respectively.
In contrast, the incidence of pneumonia caused by M pneumoniae was reduced to 7 and 10 cases, respectively. We also observed in these
groups (Table 5) an increasing
presence of cases due to other atypical (L pneumophila)
or conventional (P aeruginosa or several gram-positive
cocci) bacteria. In general, the causative distribution of pathogens in groups
2 and 3 does not appear to be differential.
IMPACT OF COMORBIDITY ON MICROBIAL CAUSE
The existence of a comorbidity was not a useful discriminant variable
for patients, as can be seen in Table 6. Thus, for both groups, either conventional or atypical bacteria
constituted about 50% of the determined causative agents. Special mention
merits the 7 cases of pneumonia caused by L pneumophila: all these patients did not have underlying disease and were younger
than 50 years (mean age, 34 years; age range, 18-46 years); however, all were
included into groups 2 (n = 4) and 3 (n = 3) because of the presence of clinical
signs of severity.
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Table 6. Influence of Comorbidity on the Cause*
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COMMENT
In the present study, we examined many patients with nonsevere CAP,
and the cause of pneumonia could be established in about 66% of the episodes. Mycoplasma pneumoniae and other atypical bacteria were
the predominant microorganisms for patients with milder episodes, while S pneumoniae was the most prevalent pathogen among patients
with a more severe infection, although atypical agents played an important
role too. We also found that the presence of comorbid conditions did not influence
the causative pattern.
Despite the fact that nonsevere episodes of CAP represent more than
50% of overall cases, they had previously received little attention from investigators
and the epidemiological features remained not well recognized. So, therapeutic
recommendations for empirical antibiotic therapy of these episodes mainly
derived from epidemiological data obtained from hospitalized patients. Macfarlane13 found, in a retrospective review published in 1994,
only 12 studies performed on ambulatory patients with CAP and, more recently,
the experience in this field has not significantly increased.14
Moreover, populations analyzed in these reports were not homogeneous, because
included together were ambulatory and hospitalized patients, in some reports,
or patients with CAP and patients with other infections of the lower respiratory
tract, in other reports. Also, the methods used to diagnose infection were
frequently incomplete and, in many studies, only serologic tests were used;
therefore, they undoubtedly underestimated the relative importance of bacterial
infections. We can conclude that more well-designed studies on low-risk patients
with CAP, with emphasis on bacterial and atypical causes, are needed.
Substantial progress, related to the prognostic classification and the
microbiological testing of patients with CAP, has been achieved over recent
years, supporting the development of better-performed studies. Thus, with
the publication of the Pneumonia PORT prognostic rule, specifically addressed
to detect low-risk patients, episodes of nonsevere CAP have been clearly defined;
therefore, uniform subsets of patients for study can be established.1 On the other hand, the availability of novel and more
sensitive microbiological tests, such as genome or antigen detection methods,
allows the identification of the responsible pathogen in more patients.
We know that serologic tests are sufficiently sensitive to detect infections
caused by atypical pathogens. In fact, serologic tests have been shown to
be more sensitive than cultures. In addition, novel diagnostic methods provide
earlier results, but the sensitivity does not appear to be increased. However,
to diagnose bacterial pneumonias, particularly those due to S pneumoniae, available conventional testing is imperfect. Blood and
pleural fluid cultures provide only a reduced rate of positive results, and
the utility of sputum gram stain and culture, when available, remains controversial
because of the influence of sample quality on results.15
Studies16 have demonstrated that these classical
diagnostic methods are even more poorly contributive to diagnosis in patients
with milder infection.
Therefore, we used, in association with traditional techniques, PCR
tests in determining the causative diagnosis. Our experience supports results
derived from a previous report,9 in which the
nested PCR technique, applied to whole blood samples and compared with an
extensive battery of alternative diagnostic methods, had a good sensitivity
and a high specificity for diagnosing pneumococcal pneumonia. Similarly, favorable
results of the method have also been reported by others.17-19
On the other hand, promising results have been reported with the application
of PCR analysis in throat swab samples for the detection of M pneumoniae or C pneumoniae infection, becoming,
for both microorganisms, a useful diagnostic method with clinical application.20-22 However, in our study,
PCR analysis for M pneumoniae and C pneumoniae appeared to be insensitive, and the method was mildly
contributive to the diagnosis. We believe that a possible explanation for
this discrepancy could be based on technical characteristics; certainly, the
nested PCR test has shown to be more sensitive than the single-step PCR, the
method that we used for these 2 agents. Alternatively, we also could speculate
about the relative nonspecificity of some serologic data; however, our limited
experience does not allow us to evaluate this possibility.
We hope that our results provide valuable and practical implications
in the management of low-risk patients with CAP, and, undoubtedly, the understanding
of the pathogens most frequently involved is a key consideration in the choice
of empirical antibiotic therapy. Thus, we found, among patients in group 1,
a clear predominance of atypical pathogens, causing about 70% of the cases; M pneumoniae was the most prevalent microorganism. This
finding is consistent with the results of previous articles; in fact, M pneumoniae has traditionally been associated with a young
and previously healthy population with CAP.23
Conversely, S pneumoniae, which appears as the most
frequent causative pathogen for outpatients in significant guidelines, had
a proportionally more reduced relevance.
For patients in prognostic groups 2 and 3, the microbial spectrum of
CAP was more diverse, and we found epidemiological features similar to those
found in present studies of hospital-based populations. Certainly, S pneumoniae was the most prevalent individual cause; however, the
atypical group of microorganisms was encountered in almost 50% of the cases.
In addition, other more uncommon agents appeared also as potential causative
pathogens; thus, we detected some cases of L pneumophila pneumonia or episodes caused by other conventional bacteria (S aureus, S viridans, or even
gram-negative bacilli). Interestingly, boths groups showed a similar causative
pattern. On the other hand, among patients included in these prognostic groups,
we also found, in relation to patients in group 1, higher levels of bacteremia,
although the difference did not reach statistical significance, probably due
to the reduced number of bacteremic episodes. Finally, the existence of underlying
diseases was not associated with any discernible microbial cause.
The present study has several limitations. First, it was developed using
patients who had been seen at the hospital. Certainly, the application of
a classification rule would theoretically have to provide homogeneous groups;
however, particularly among group 1 patients, we cannot exclude that many
of those with mild episodes did not reach the hospital. Therefore, they may
be underrepresented in our study. This potential bias exists, but, in Spain,
many patients seek medical care directly from the emergency service of the
hospital rather than after a visit to a primary care physician.24
In addition, as done by Fine et al,1 human
immunodeficiency virus–infected patients were explicitly excluded in
our study; we know from previous reports25-26
that this population shows a distinct causative pattern, with a predominance
for bacterial pathogens, even among those with less severe manifestations
of disease.
On the other hand, we were not uniformly aggressive in conducting the
causative investigations, with a proportionally reduced use of diagnostic
methods to detect some more improbable causative agents, such as H influenzae or gram-negative bacilli, and a limitation to conventional
tests. Thus, we cannot exclude that these microorganisms may have been underestimated
in the present study; however, we have evidence that the relevance of these
more unusual pathogens, particularly among nonsevere cases of pneumonia, is
truly low. In addition, microbiological studies to detect viral infections
were not routinely performed. Certainly, the pathogenic role of respiratory
viruses in adult patients with CAP is a controversial field and, frequently,
they are detected in patients with mixed infections, coexisting with another
bacterial cause.24, 27 However,
it is also possible that a proportion of these patients with an unknown cause
had definite viral pneumonia.
In summary, CAP constitutes, for Pneumonia PORT prognostic group 1 patients,
an infection commonly caused by atypical microorganisms. In contrast, for
patients in Pneumonia PORT groups 2 and 3, the microbial spectrum is more
varied, including, in a similar proportion, either bacterial or atypical agents.
Furthermore, we were unable to establish associations between particular pathogens
and the existence of underlying diseases.
AUTHOR INFORMATION
Accepted for publication January 18, 2001.
Corresponding author and reprints: Miquel Falguera, MD, Department
of Internal Medicine, Hospital Universitari Arnau de Vilanova, Rovira Roure
80, 25006 Lleida, Spain (e-mail: mfalguera{at}comll.es).
From the Departments of Internal Medicine (Drs Falguera, Sacristán,
and Rubio-Caballero), Microbiology (Drs Nogués, García, and
Manonelles), and Emergencies (Dr Ruiz-González), Hospital Universitari
Arnau de Vilanova, Lleida, Spain.
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ABSTRACT
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