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* 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 |
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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 |
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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 |
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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
2 test. A mean age comparison was done by the Student t test.
| Results |
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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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| Discussion |
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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 |
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Received for publication May 30, 2001. Accepted for publication November 14, 2001.
| References |
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This article has been cited by other articles:
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N. Miyashita, K. Ouchi, H. Shoji, Y. Obase, M. Fukuda, K. Yoshida, Y. Niki, and M. Oka Outbreak of Chlamydophila pneumoniae infection in long-term care facilities and an affiliated hospital J. Med. Microbiol., December 1, 2005; 54(12): 1243 - 1247. [Abstract] [Full Text] [PDF] |
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N. Miyashita, H. Fukano, K. Mouri, M. Fukuda, K. Yoshida, Y. Kobashi, Y. Niki, and M. Oka Community-acquired pneumonia in Japan: a prospective ambulatory and hospitalized patient study J. Med. Microbiol., April 1, 2005; 54(4): 395 - 400. [Abstract] [Full Text] [PDF] |
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