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(Chest. 2002;121:1776-1781.)
© 2002 American College of Chest Physicians

Clinical Presentation of Community-Acquired Chlamydia pneumoniae Pneumonia in Adults*

Naoyuki Miyashita, MD, PhD; Hiroshi Fukano, MD; Niro Okimoto, MD, PhD, FCCP; Hiroki Hara, MD, PhD, FCCP; Koichiro Yoshida, MD, PhD; Yoshihito Niki, MD, PhD, FCCP and Toshiharu Matsushima, MD, PhD, FCCP

* From the Division of Respiratory Diseases (Drs. Miyashita, Fukano, Yoshida, Niki, and Matsushima), Department of Medicine, Kawasaki Medical School; Kawasaki Medical School Kawasaki Hospital (Dr. Okimoto); and Kurashiki Daiichi Hospital (Dr. Hara), Okayama, Japan.

Correspondence to: Naoyuki Miyashita, MD, PhD, Division of Respiratory Diseases, Department of Internal Medicine, 577 Matsushima, Kurashiki City, Okayama 701-0192, Japan; e-mail: nao{at}med.kawasaki-m.ac.jp


    Abstract
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To investigate the clinical presentation of community-acquired Chlamydia pneumoniae pneumonia in adults.

Design: Prospective study.

Setting: Kawasaki Medical School Hospital, Kawasaki Medical School Kawasaki Hospital, and Kurashiki Daiichi Hospital in Japan.

Participants: Forty patients with community-acquired pneumonia with C pneumoniae as the only pathogen identified admitted to three hospitals between April 1996 and March 2001 and their clinical presentations were compared to patients with Streptococcus pneumoniae and Mycoplasma pneumoniae pneumonia.

Measurements: The diagnosis of C pneumoniae infection was based on isolation and serologic testing of antibodies by the microimmunofluorescence test.

Results: The clinical presentations, except for shortness of breath, were similar for the three major etiologic agents. The mean temperature of C pneumoniae patients on hospital admission was 37.9°C, which was lower than that of patients with S pneumoniae and M pneumoniae. The mean WBC count on hospital admission was lower in the patients with C pneumoniae (mean, 9,100/µL) than in those with S pneumoniae pneumonia but higher than in those with M pneumoniae pneumonia. No patients required respiratory support or admission to an ICU, and no deaths occurred among the C pneumoniae pneumonia patients.

Conclusions: Our results indicate that C pneumoniae pneumonia as a single etiologic agent is mild and that the underlying conditions and clinical symptoms closely resemble those of S pneumoniae pneumonia. However, the physical examinations, laboratory findings, and prognostic factors of the C pneumoniae patients resembled those of patients with M pneumoniae pneumonia.

Key Words: Chlamydia pneumoniae • clinical picture • community-acquired pneumonia • Mycoplasma pneumoniae • Streptococcus pneumoniae


    Introduction
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Community -acquired pneumonia (CAP) continues to be a major medical problem. Since CAP also is a potentially fatal disease, even in previously healthy persons, early appropriate antibiotic treatment is vital. In Japan, pneumonia is the fourth leading cause of death, and from 57 to 70 persons of 100,000/yr died of this disease during the last decade.1 Because of this high morbidity, guidelines for CAP management have been created in Japan.2 However, prospective studies on the etiology of CAP among the Japanese population have been very limited, and the clinical presentations of some etiologic agents including Chlamydia pneumoniae have not been evaluated.

C pneumoniae has been established as an important cause of both lower and upper acute respiratory illnesses, including pneumonia, bronchitis, pharyngitis, and sinusitis.3 4 Studies4 5 6 have suggested a possible association of C pneumoniae infection and acute exacerbations of asthma and COPD. Since seroepidemiologic studies3 4 have demonstrated that 50 to 70% of adults have antibody to C pneumoniae, it is estimated that the majority of the population acquires at least one C pneumoniae infection during their lifetime. Approximately 10% of cases of CAP are associated with C pneumoniae worldwide.4 In Japan, this organism is the third or fourth leading pathogen in patients with CAP requiring hospital treatment,7 8 but its incidence (about 7%) is lower than that in Western countries. The most common pathogens in Japan were Streptococcus pneumoniae, accounting for up to 20% of cases, followed by Mycoplasma pneumoniae (9.5%).8 Because of this high incidence, knowledge of the specific clinical presentation of C pneumoniae pneumonia might be useful in guiding the choice of antibiotic therapy. However, there are no data regarding the clinical presentation of C pneumoniae pneumonia in Japanese adults. Furthermore, previous reports9 10 11 12 13 14 15 have not been entirely in agreement regarding the clinical presentation of C pneumoniae pneumonia.

The purposes of this study were to clarify the clinical presentation of C pneumoniae pneumonia in Japan, and to evaluate the newly created Japanese CAP guidelines. We prospectively investigated C pneumoniae pneumonia in hospitalized Japanese adults and compared the results with those of CAP caused by other major pathogens, S pneumoniae and M pneumoniae. These, along with C pneumoniae pneumonia, are the top three etiologies of CAP in Japan.


    Materials and Methods
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study Population
All adult patients with CAP who were admitted to Kawasaki Medical School Hospital, Kawasaki Medical School Kawasaki Hospital, and Kurashiki Daiichi Hospital, Okayama, Japan, from April 1996 to March 2001 were enrolled in this study. None of our patients were immunocompromised; that is, patients with HIV infection, patients with neutropenia secondary to chemotherapy or patients receiving immunosuppressants, patients from nursing homes, or patients with recent (< 30 days) hospital admission. The diagnosis was based on clinical signs and symptoms (cough, fever, productive sputum, dyspnea, chest pain, or abnormal breath sounds), and radiographic pulmonary abnormalities that were at least segmental and were due to preexisting or other known causes. All cases of pneumonia occurring > 3 days after hospitalization were considered nosocomial and were excluded.

Microbiological Laboratory Tests
Blood cultures and nasopharyngeal swab specimens were obtained from all patients at hospital admission and, if pleural fluid and sputum were available, a Gram stain test and a quantitative culture were obtained. Sputum data were only evaluated when the Gram stain test revealed numerous leukocytes (> 25 in a 100 x microscopic field) and few squamous epithelial cells (< 10 in a 100 x microscopic field). Certain invasive methods such as bronchoscopic examination were employed to obtain specimens in some patients after full explanation of the procedures. These specimens were also used for culturing of M pneumoniae and Legionella species on pleuropneumonia-like organism agar (70% Mycoplasma agar base [Becton Dickinson Microbiology Systems; Cockeysville, MD] 20% horse serum, 10% fresh yeast extract, thallium acetate [final concentration 0.5 mg/mL] and sterile penicillin G [final concentration 1,000 U/mL]) and buffered charcoal-yeast extract agar, respectively. Cultures for C pneumoniae and Chlamydia psittaci were performed in cycloheximide-treated HEp-2 cells grown in a 24-well cell culture plate.5 16 All specimens were passed twice. Culture confirmation was done by fluorescent-antibody staining with C pneumoniae and C psittaci species-specific and genus-specific monoclonal antibodies.5 16

Paired serum samples were collected at intervals of at least 4 weeks (range, 4 to 12 weeks; average, 6 weeks) after onset. Complement fixation tests were done in all patients for antibodies to influenza A and B viruses, adenovirus, respiratory syncytial virus, cytomegalovirus, parainfluenza virus types 1, 2 and 3, and M pneumoniae. Antibody to Legionella species was measured by the microagglutination test (detection of Legionella pneumophila serogroups 1 to 6, Legionella bozoemanii, Legionella dumoffii, Legionella gormanii, and Legionella micdadei) and Coxiella burnetii was measured by the indirect immunoflorescence test. The microimmunofluorescence test was used for titration of IgG and IgM antibodies against Chlamydial species,3 using formalinized elementary bodies of C pneumoniae KK-pn15, Chlamydia trachomatis L2/434/Bu and C psittaci 6BC strains as antigens. Rheumatoid factors were absorbed with Gullsorb (Gull Laboratories; Salt Lake City, UT) before IgM titrations. In addition to serology and culturing, the urinary antigen test (Biotest; Dreieich, Germany) was used for detection of L pneumophila.

Criteria for Determination of Microbial Etiology
The microbial etiology was classified as "definitive," "presumptive," or "unknown" according to definitions established previously by Fang and colleagues.10 Bacteria were considered to be definitive causative agents when isolated from blood or pleural fluid cultures. We considered the results of sputum cultures in combination with Gram stain findings. An organism showing heavy (>= 107 cfu/mL) or moderate (106 cfu/mL) growth of a predominant bacterium on a sputum culture was considered to be a presumptive pathogen. Any microorganism isolated from BAL fluid was considered to be a presumptive pathogen when its concentration reached > 105 cfu/mL in quantitative culture. If M pneumoniae or Legionella species was isolated from a specimen, that specimen was considered to be a definitive pathogen even if the culture showed little growth. L pneumophila was considered to be a presumptive agent when the urinary antigen test result was positive. For serologic tests, a fourfold rise in the antibody titer level between paired sera was considered definitive.

Statistical Analysis
Statistical analysis for the incidence of symptoms and laboratory data were done by Fisher exact test and the {chi}2 test. A mean age comparison was done by the Student t test.


    Results
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Clinical Presentation of CAP With Only One Pathogen Identified
The patients who fulfilled the diagnostic criteria for pneumonia caused by C pneumoniae, S pneumoniae, or M pneumoniae without any evidence of other causative agents formed the groups for comparison of the clinical presentations. Among all CAP cases, there were 40 cases where C pneumoniae was the only pathogen identified by the panel of diagnostic tests used, 58 cases where S pneumoniae was identified, and 46 cases where M pneumoniae was identified. Of the 40 cases of C pneumoniae, 35 cases demonstrated fourfold or greater rises in IgG antibody titers, while 11 cases demonstrated fourfold or greater rises in IgM antibody titers (six cases met both criteria). All cases of M pneumoniae demonstrated fourfold antibody seroconversion (eight cases were culture positive).

Table 1 shows the underlying conditions of the patients with the three etiologic agents of CAP. There were no statistically significant differences in terms of gender, smoking history, or underlying clinical diseases between the patients with C pneumoniae and those with S pneumoniae pneumonia, but the frequencies of a smoking history and underlying diseases of the patients with M pneumoniae pneumonia were significantly lower than those of C pneumoniae and S pneumoniae pneumonia. The mean age of the patients with S pneumoniae pneumonia (63.8 years) was significantly higher than that of patients with C pneumoniae (54.4 years, p = 0.014) and M pneumoniae (35.3 years, p = 0.0001) pneumonia. The mean age of the patients with C pneumoniae pneumonia was also significantly higher than that of patients with M pneumoniae (p = 0.0001) pneumonia.


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Table 1. Underlying Conditions of the Patients With the Major Three Etiologic Agents of CAP*

 
Table 2 shows the major symptoms and physical findings at hospital admission. Among the respiratory symptoms, an important difference was observed between C pneumoniae and S pneumoniae pneumonia with regard to dyspnea. The prevalence of shortness of breath in patients with S pneumoniae pneumonia was significantly higher than that in those with C pneumoniae (p = 0.001) and M pneumoniae (p = 0.000) pneumonia. The prevalence of CNS and GI symptoms was almost the same for C pneumoniae and S pneumoniae pneumonia. The average of maximum temperature during the first 24 h after hospital admission of C pneumoniae patients was 37.9°C, which was lower than that of S pneumoniae (38.7°C, p = 0.0001) and M pneumoniae (39.0°C, p = 0.0001) patients. The frequency of hypotension in the patients with S pneumoniae pneumonia was significantly higher than that in those with C pneumoniae (p = 0.010) or M pneumoniae (p = 0.040) pneumonia.


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Table 2. Major Symptoms and Physical Findings at Hospital Admission of the Patients With the Major Three Etiologic Agents of CAP*

 
Table 3 shows laboratory findings on hospital admission and prognostic factors. Both the mean WBC count and C-reactive protein (CRP) value on hospital admission were significantly higher in the patients with S pneumoniae pneumonia than those in the patients with C pneumoniae or M pneumoniae pneumonia (both, p = 0.0001). The mean WBC count was higher in patients with C pneumoniae than that in patients with M pneumoniae pneumonia, but these data were not significant. In contrast, the mean serum level of glutamic pyruvic transaminase (GPT) was significantly higher in the patients with C pneumoniae and M pneumoniae pneumonia than in those with S pneumoniae pneumonia (vs C pneumoniae, p = 0.0353; vs M pneumoniae, p = 0.0008). No patients required respiratory support and/or admission to an ICU, and no patients died among those with C pneumoniae or M pneumoniae pneumonia. Therefore, the laboratory findings and prognostic factors were almost identical for C pneumoniae and M pneumoniae pneumonia.


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Table 3. Laboratory Findings on Hospital Admission and Prognostic Factors of the Patients With the Major Three Etiologic Agents of CAP*

 
Clinical Presentation of Mixed C pneumoniae Pneumonia With Other Microorganisms:
Among all of our CAP cases, C pneumoniae was identified as the etiologic agent in 62 cases. Of these, C pneumoniae was the only pathogen identified in 40 cases (64.5%), and one or more additional etiologic factors were found in 22 cases (35.5%). Of 22 cases of mixed C pneumoniae, 22 cases demonstrated fourfold or greater rises in IgG antibody titers, while three cases demonstrated fourfold or greater rises in IgM antibody titers. Table 4 shows the distribution of etiologies among the 22 cases of mixed C pneumoniae pneumonia. The most common additional pathogens were S pneumoniae (10 patients), followed by M pneumoniae (6 patients), and Haemophilus influenzae (6 patients). Among all the mixed C pneumoniae pneumonia cases, one additional agent was found in 15 cases and two additional agents were found in 7 cases.


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Table 4. Frequency Distribution of Additional Etiologies of CAP in 62 Patients Infected With C pneumoniae*

 
Table 5 shows the clinical presentations of the CAP patients with mixed C pneumoniae with other microorganisms and those of patients with C pneumoniae with only one pathogen identified. There were many differences between these two groups, and the clinical presentations of cases of mixed C pneumoniae pneumonia with other bacteria, but not M pneumoniae, resembled those of cases with S pneumoniae pneumonia.


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Table 5. Characteristics of the 62 Patients With C pneumoniae Pneumonia*

 

    Discussion
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
C pneumoniae was classified as a new Chlamydial species by Grayston and colleagues3 in 1989. The diagnostic criteria for pneumonia caused by C pneumoniae are based on a fourfold or greater increase in the titer for any Ig class of antibodies to C pneumoniae between paired serum samples or an IgG titer of >= 1:512, or the presence of IgM (>= 1:16) antibodies for any serum sample examined by the microimmunofluorescence test.3 4 The diagnosis of C pneumoniae pneumonia in previous reports9 10 11 12 13 14 15 was also based on these criteria. In addition, Kauppinen et al13 and Lieberman et al14 included a high IgA titer as one of the diagnostic criterion of acute C pneumoniae pneumonia. However, criteria using single serum antibodies, IgG >= 1:512 and IgM >= 1:16, are a controversial issue because a high incidence of IgG >= 1:512 or IgM >= 1:16 has been seen among healthy asymptomatic subjects,17 18 19 and we also made the same observation.20 Also, criteria for definition of IgA levels as indicative of acute infection have not been established. In this study, therefore, we excluded the IgG titer >= 1:512, IgM titer >= 1:16, and IgA titer from our diagnostic criteria.

Furthermore, C pneumoniae has been reported to cause pneumonia frequently in association with other respiratory pathogens, mainly S pneumoniae.8 9 12 13 14 15 21 In our study, about 35% of the C pneumoniae pneumonia case-patients had a concomitant infection with other microorganisms. It has been noted that the clinical presentations of CAP cases with multiple pathogens and cases where C pneumoniae was the only pathogen identified differ.13 We also confirmed this observation in the present study (Table 5) . In addition, it has been suggested that mixed cases of mild or asymptomatic upper respiratory tract infections are probably induced by C pneumoniae and are followed by secondary bacterial pneumonia due to another proven etiology. Therefore, we also excluded mixed C pneumoniae pneumonia in this study in order to analyze the clinical presentations of pneumonia cases with C pneumoniae as the only pathogen identified.

Among clinical symptoms, it has been reported that CNS symptoms including headache seem to be common in patients with C pneumoniae pneumonia.10 11 12 13 Blasi et al11 and Kauppinen et al13 reported that 43 to 46% of their case-patients experienced headache. Further, Fang et al10 and Sundelöf et al12 reported that 38 to 45% of their case-patients experienced changes in mental status. In our study, 25% of case-patients had headaches and 7% had confusion. Therefore, the frequency of CNS symptoms was lower than that in previous reports. The difference may be due to the demographic factors, particularly age (the mean age of the study population was older in previous studies than in our study). In addition, no significant differences were found in clinical symptoms, except for shortness of breath, among the patients with C pneumoniae, S pneumoniae, and M pneumoniae pneumonia.

Among laboratory findings, elevated WBC counts have been reported in association with C pneumoniae pneumonia.9 10 13 14 15 However, this finding was not evident in the study by Blasi et al11 or in our patients, although a high WBC count (mean 15,600/µL) was seen in patients with mixed C pneumoniae pneumonia with other bacteria (Table 5) . Elevated levels of alkaline phosphatase have also been documented in association with C pneumoniae pneumonia,12 but not in our study or other previous reports.9 10 11 13 14 The relatively slow pulse rate in relation to the fever reported in association with other intracellular infections such as legionellosis and psittacosis was not seen in our patients with C pneumoniae pneumonia, and this result was consistent with the data of Kauppinen et al.13

Analysis of the age distribution of CAP patients in our study showed that while CAP affects adults of all ages, the mean age of patients with C pneumoniae pneumonia is significantly higher than that of those with M pneumoniae pneumonia and lower than that of patients with S pneumoniae pneumonia. Our results also showed that the mean age of patients with single agent C pneumoniae pneumonia was significantly lower than that of those with mixed C pneumoniae pneumonia, with the exception of those with a concomitant infection with M pneumoniae (54.4 vs 69.5, p = 0.003). Therefore, the highest incidence of C pneumoniae pneumonia observed among the elderly people in previous reports9 10 12 may reflect concomitant infection with other microorganisms.

Recently, Lim et al22 reported that they found C pneumoniae to be more common in the winter than in the summer (p = 0.015). In this study, however, we could not detect any evidence of seasonality during a 5-year period. The difference may be due to the fact that the data in the study by Lim et al22 covered only one winter period.

In conclusion, our results indicate that C pneumoniae pneumonia as a single etiologic agent is mild and that the underlying conditions and clinical symptoms closely resemble those of S pneumoniae pneumonia. However, the results of physical examinations, laboratory findings, and the prognostic factors of C pneumoniae resemble those of M pneumoniae pneumonia.


    Footnotes
 
Abbreviations: CAP = community-acquired pneumonia; CRP = C-reactive protein; GPT = glutamic pyruvic transaminase

Received for publication May 30, 2001. Accepted for publication November 14, 2001.


    References
 TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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