Chlamydia pneumoniae Pneumonia

Thomas M. File, Jr., M.D. and James S. Tan, M.D.

[Sem Resp Crit Care Med 21(4):285-294, 2000. © 2000 Thieme Medical Publishers, Inc.]

Abstract

Chlamydia pneumoniae is a common cause of community-acquired pneumonia. At present there is no "gold" standard for diagnosis and there is no easily accessible means of rapid diagnosis available. The best indication of acute C. pneumoniae infection is a fourfold rise in antibody titer, accompanying a positive polymerase chain reaction or culture. C. pneumoniae is usually associated with nonsevere clinical manifestations but the features will vary depending upon the occurrence as primary or reinfection syndrome, the presence of co-pathogens, or the existence of co-morbid conditions. C. pneumoniae has been described as a cause of severe disease requiring intensive care unit admission. Recommendations for therapy of C. pneumoniae pneumonia include macrolides, tetracyclines, or the new fluoroquinolones.

Introduction

Association of Chlamydia pneumoniae with human disease was first identified by Grayston and colleagues [1] in 1983 when they described cases of pneumonia, bronchitis, and pharyngitis in a series of students in Washington. Today it is widely accepted that community-acquired pneumonia (CAP) is commonly attributed to C. pneumoniae infection. In the past decade there has been considerable information accumulated concerning the role of C. pneumoniae as a cause of pneumonia. Despite this, there still remains controversy concerning various issues. This review will present an update of the pathogenesis, prevalence, laboratory diagnosis, clinical manifestations, and therapy of C. pneumoniae pneumonia.

Microbiology and Pathophysiology

Like other common species of Chlamydiae (such as C. trachomatis and C. psittaci), C. pneumoniae is an obligate intracellular organism with a unique biphasic life-cycle.[2] This life-cycle has two distinct phases: a nonreplicating extracellular infectious phase and an obligate intracellular noninfectious replicating stage. The infectious form or elementary body (EB), attaches to the target cell membrane and enters the host cell via endocytosis. Following cell entry, the elementary body reorganizes into reticular bodies (RBs), which form inclusion bodies. RBs multiply in the cytoplasm of the cells and subsequently condense to form EBs, which are released from the cell to begin another infection cycle.

Humans are the only known reservoir, and transmission is from person to person via respiratory secretions; close contact is generally required. The incubation is several weeks.[2-4]

The exact pathophysiology of pneumonia due to C. pneumoniae remains unclear. Presently our understanding is that primary infection occurs early in life and that reinfection is common during adulthood. Autoimmune mechanisms may play a role in the pathogenesis of reinfections.[3] Although reinfection is generally thought to occur as a result of another exogenous infection, it is not well-appreciated how often reactivation of a latent infection occurs.

Animal models have been developed to the study the effect of intranasally inoculated organisms.[4-7] After a large inoculum (10 [7] inclusion-forming units), lung pathology in mice is initially characterized by an acute interstitial pneumonitis with polymorphonuclear leukocyte infiltration. In the late stage, or after a smaller inoculum (10 [5] ), a mild pneumonitis with predomination of peribronchular and perivascular infiltrates of lymphocytes and plasma cells is found. This inflammation persists for at least 2 months even in the absence of the organism. Yang et al [8] found that C. pneumoniae infects not only the epithelial cells of the respiratory tract, but also interstitial macrophages in the mouse model. The ability of the organisms to establish infection within the macrophages may provide a means for latent infection as well as systemic dissemination via infected mononuclear phagocytes. This is substantiated by the isolation of viable organisms from spleen tissue and from other extrapulmonary tissues in the model of pneumonitis.

C. pneumoniae may persist in vivo following acute infections.[7] Malinverni et al [9] showed that mice previously infected with C. pneumoniae reactivate infection when administered cortisone, suggesting that a persistent latent infection occurs. Other investigators have reisolated C. pneumoniae after reactivation of infection from a culture negative state providing evidence of a persistent infection.[7]

Most C. pneumoniae infections in adults are rein-fections.[10] Pneumonia due to reinfection can be either milder or more severe than with primary infection.[11] Previous infection with C. pneumoniae may lead to only partial immunity and symptoms may be due to hypersensitivity reaction.[11] When a reinfecting strain, although closely related to its predecessor, is sufficiently different to escape immunological defense mechanisms, the outcome may be more severe than the illness observed in primary infection. This may help to explain the observation that pneumonia may be more severe in the elderly (although the association of co-morbid conditions in the elderly undoubtedly plays a significant role). In the mouse model, it is observed that reinfection precipitates pronounced inflammation in the lungs, but organisms are much more difficult to isolate than in primary infection.[12] Immune-based host responses may be responsible for some chronic manifestations of C. pneumoniae infection such as reactive arthritis, vasculitis, or asthma.[13-15]

Prevalence

C. pneumoniae is a common infection and most humans will have at least one infection during their lifetime. By 20 years of age, approximately 50% of patients will have detectable levels of antibody to the organism and the seroprevalence continues to increase among older age groups and reaches approximately 75% in the elderly.[2] The incidence of pneumonia due to C. pneumoniae in this group, however, is more difficult to estimate. It is suspected that the majority of C. pneumoniae infections that occur during a lifetime are either subclinical or mild self-limiting respiratory illnesses. The relative occur-rence of pneumonia is derived from the results of numerous studies which have evaluated the etiologic agents of CAP. The relative proportion rates for these studies will vary depending upon the criteria for diagnosis, age group, location (endemic versus nonendemic area), and whether an epidemic is occurring at the time of evaluation. Several studies indicate that approximately 10% of all cases of CAP requiring hospitalization are associated with C. pneumoniae (Table 1). One study performed during an epidemic in Finland found that C. pneumoniae was the etiological agent in 43% of cases of CAP requiring hospitalization.[16] In another study of the cause of CAP requiring admission to a "semi-intensive care unit," Cosentini and colleagues [17] found C. pneumoniae was the cause in 10% of patients. For ambulatory-treated pneumonias (in adults), the relative proportion of cases due to C. pneumoniae is somewhat higher (approximately 15 to 20%), although there are only a limited number of studies for which this has been studied. C. pneumoniae has recently been identified as the source of outbreaks of respiratory infections in nursing homes.[18]

The specific incidence of C. pneumoniae pneumonia can be derived from studies that have identified cases from a well-defined population base. In an epidemiological study from two counties in Ohio in 1991, the incidence of C. pneumoniae pneumonia in adults requiring hospitalization was 16/100,000 population.[19] In a study of patients with CAP treated as outpatients in a defined region of Spain (Maesden region, Barcelona), [20] observed an incidence of 40/100,000 population during the year of the study.[20]

Diagnosis

A definitive etiological diagnosis of pneumonia due to C. pneumoniae remains problematic as well as controversial.[21,22] At present, there has been established no diagnostic "gold" standard for determination of infection or disease with C. pneumoniae and no easily accessible means of rapid diagnosis is available. The diagnosis of C. pneumoniae has been made by several diagnostic techniques: serologic antibody test, cell culture, antigen detection, and identification of specific DNA sequences by polymerase chain reaction (PCR) (Table 2).

To date the most common method for diagnosis of C. pneumoniae pneumonia has been by serology. While a complement fixation antibody test is available, there is too much cross reaction with other Chlamydia species (C. trachomatis and C. psittaci) to make this a reliable test. The most commonly used serologic assay presently available, which is specific and sensitive, is the microimmuno-fluorescent (MIF) test. Some have claimed that this test lacks sensitivity and specificity.[23] Other laboratories have found that when performed properly MIF is sensitive,[24,25] however, the skill required to evaluate appropriate fluorescence may be difficult to master. The reliability of serodiagnosis is children appears to be less than in adults.[26] Rheumatoid factor may cause false-positive IgM titers and it is recommended that sera be absorbed before testing.[27]

The MIF test allows differentiation of IgG and IgM antibodies, which allows interpretation as to primary or reinfection with C. pneumoniae. [2] In primary infection, an MIF IgM antibody appears approximately 3 weeks after the onset of illness and usually subsides within a couple months. However, Grayston et al [24] have found a small number of patients who have had IgM antibodies persisting for over a year. Antibody in the IgG fraction in primary infection may not appear until 6 to 8 weeks after onset and therefore a low IgG titer even 4 weeks after onset of infection in a primary infection does not "rule out" acute C. pneumoniae infection. Because of the relatively long period until development of serologic response in primary infection, the antibody response may be missed if convalescent sera are obtained too soon (i.e., prior to 4 weeks). In reinfection IgM anti-bodies may not appear or may appear only at low titers. The IgG antibody titers rise quickly often in 1 to 2 weeks and may reach a value of 512 or greater.

A set of criteria for serologic diagnosis using the MIF test has been previously proposed. For acute infection, the patient should have a fourfold rise in the IgG titer or a single IgM titer >/= 1:16 or a single IgG titer >/= 1:512.[2] However, while a fourfold rise in antibody titer is usually considered diagnostic, questions persist concerning other serologic criteria (single IgM or IgG titer) for diagnosis of acute infection. While the presence of an elevated IgM MIF titer is likely indicative of an acute infection, the high prevalence of IgG antibodies to C. pneumoniae in the general population (often 5 to 10% in asymptomatic controls) makes the criteria of a single high IgG titer very questionable. One study demonstrated that about 18 to 19% of healthy healthcare workers who were culture negative and/or PCR negative had elevated IgG ( >/= 1:512) antibody titers, when only a single serology was performed.[28] For definitive serodiagnosis, acute and convalescent sera are required -- a distinct disadvantage for "rapid" diagnosis. IgA antibodies can also be measured and when elevated add verification of C. pneumoniae infection (versus C. psittaci or C. trachomatis) and suggests chronic or reinfection rather than primary infection. The MIF test is also not well standardized and there can be significant interlaboratory differences of intrepretation.[29] Cross-reactions with Bartonella spp. may also occur.[29] Isolation of C. pneumoniae is relatively difficult and can be accurately performed in only a few laboratories. The organism can be isolated from NP and throat swabs, sputum, and pleural fluid of patients with pneumonia. The nasopharynx appears to be the optimal site for isolation, especially in children. The relative yield from sputum is not known Early studies suggested that C. pneumoniae was more difficult to culture than C. trachomatis; however, the same methods were used: Hela or McCoy cells. It is now recognized that C. pneumoniae grows more readily in other cell lines: Hep-2 and HL cells (derived from respiratory tissue). Culture with an initial inoculum and one passage should take 4 to 7 days.[29]

Direct antigen detection and use of PCR to identify specific DNA sequences in a specimen might allow for rapid diagnostic techniques. However, there are no standardized PCR or other nucleic acid amplification tests for the detection of C. pneumoniae. Fluorescent antibody staining of clinical specimens has been successfully used in the diagnosis of C. trachomatis infection but has shown to be relatively insensitive for C. pneumoniae in throat swab samples.[29] Previous studies have demonstrated that PCR can be used to detect C. pneumoniae and recent data suggest that this may be a promising technique to provide timely diagnostic.[30,31] A recent study by Gaydos et al [32] indicate that a PCR assay technique using gene primers with amplification detected by enzyme immunoassay (EIA) (PCR-EIA) is 77% sensitive and 99% specific and more reliable than single point serology for prompt diagnosis.

Recently a consensus panel of leading experts on C. pneumoniae emphasized a need for a standardized, rapid diagnostic test to optimize the diagnosis of and specific therapy for C. pneumoniae infections. The consensus was that the ideal indicator of acute C. pneumoniae infection is a fourfold rise in antibody titer, accompanying a positive PCR or culture.[22]

Clinical Manifestations

C. pneumoniae causes a wide variety of respiratory manifestations. The most frequently recognized illnesses associated with the C. pneumoniae are pneumonia[11,24,33-35] and bronchitis. Cases of isolated sinusitis, pharyngitis, and otitis have been reported.[2] It is likely that asymptomatic[28,36] or unrecognized mildly symptomatic respiratory illnesses are more common. The clinical manifestations of pneumonia secondary to C. pneumoniae remain unclear because of several factors: lack of Gold standard of diagnosis, confusion of primary infection versus reinfection (perhaps reactivation), and the compounding effect of co-pathogens.

The general perception is that C. pneumoniae causes a mild, "atypical" pneumonia that is often associated with a low degree of temperature, a sub-acute onset and frequently associated with pharyngitis and sometimes hoarseness. These characterizations are often based on studies using serology for diagnosis and have often included patients who have a single elevated IgG titer ( >/= 512) as the sole criterion of diagnosis. Inclusions of such patients may falsely include patients without acute C. pneumoniae infection. In addition, C. pneumoniae as a cause of pneumonia is often a co-pathogen (sequential or concurrent infection). The clinical characteristics of these infections may reflect manifestations associated with the other pathogen rather than manifestations of C. pneumoniae specifically.

In our experience, other pathogens are also identified in approximately 40% of pneumonias associated with C. pneumoniae. [37] A compilation of studies reviewed recently by Kauppinen and Saikku [11] included a total of 150 cases of C. pneumoniae pneumonia of which 70 (47%) represented pneumonia with mixed etiology. The most common other organism was Streptococcus pneumoniae. In such cases, upper or lower respiratory tract infection caused by C. pneumoniae may pave the way for invasion by other bacteria such as Streptococcus pneumoniae. The ciliostatic effect of C. pneumoniae may allow this invasion and thus render patients prone to other pathogens. In such cases, the clinical characteristics of these infections may reflect manifestations of the associated pathogen rather than the manifestations due to C. pneumoniae. Kauppinen et al [38] have reviewed clinical manifestations of C. pneumoniae as a sole pathogen versus C. pneumoniae as part of a mixed infection. Of note, pneumonia due to C. pneumoniae as a sole pathogen was associated with a younger age group and who had less number of preexisting co-morbidities, a greater likelihood of receiving antibiotics before arrival, a longer length of symptoms before therapy and were less likely to have productive sputum than patients with mixed infection associated with S. pneumoniae.

We have recently reported our experience with patients with C. pneumoniae pneumonia with a definite serologic diagnosis (fourfold rise in antibody titer; excluding cases that only had a single high antibody titer) for whom no other pathogen was recognized (Table 3).[37] All patients were hospitalized. Although no set of signs or symptoms appears to be unique for pneumonia due to C. pneumoniae, several comments may be made:

A subacute course is common with most patients having symptoms greater than 7 days before admission. Cough is common, but is often nonproductive. Fever is usually low grade. A mild leukocytosis was usually present in patients who required hospitalization. The presence of co-morbid illnesses and the requirement of supplemental oxygen therapy were the most common criteria for hospital admission. The findings from other studies that evaluated C. pneumoniae pneumonia as the apparent sole cause of infection are similar.[33,38,39]

Kuo et al [2] has indicated that symptoms of sinus infection are common and sore throat, sometimes with hoarseness, is often present early in the course of illness -- often prior to the onset of the pneumonia. We have found that Gram stain of sputum from patients who are able to expectorate appropriate specimens most often show polymorphonucleocytes without a predominance of an organism.[37] Radio-graphs most often demonstrate a localized infiltrate (often subsegmental). In one study from Ohio, which included radiograph analysis of 17 patients with serologic evidence of acute infection (12 with fourfold rise of IgG or IgM titer and 5 with IgM anti-body titers >/= 1:32), 12 (71%) had unilateral infiltrates of which 9 were lobar (most subsegmental) and 3 multilobar; 4 had bilateral infiltrates (2 with diffuse and 2 with multilobar infiltrates).[40] Pleural effusion was present in three patients.

Young patients with C. pneumoniae pneumonia are likely to have primary infection, whereas most infections in older adults are due to reinfection. The clinical characteristics associated with primary infection may be difficult to distinguish from those of reinfection because of the confounding effect of co-morbidities associated with age. However, one study conducted in Finland during an epidemic in military conscripts provided a comparison of the symptoms of primary infection and reinfection in young adults. Those with primary infection were more often hospitalized; more often had fever, an elevated sedimentation rate, rales, and chest pain.[41]

Mortality due to C. pneumoniae pneumonia is usually low and is most often associated with under-lying host factors or due to secondary infections (such as Pneumococcal bacteremia). Older adults appear to have, on the average, a more severe clinical course than do young patients (although this may be more associated with the increased prevalence of co-morbid conditions). Even in mild cases, however, resolution of symptoms despite appropriate antibiotic therapy may be prolonged lasting for many weeks.

C. Pneumoniae As a Cause of Serious Pneumonia and Opportunistic Infection

Although most cases of pneumonia are relatively mild, C. pneumoniae has been described to cause severe disease requiring intensive care unit admission.[2,17] Cosentini et al [17] describe 6 patients with severe pneumonia due to C. pneumoniae who required admission to a "semi-intensive" care unit (Table 4). All patients had significant underlying conditions and were hypoxemic (PaO2 < 60mmHg). The most common radiographic finding was subseg-mental involvement. All patients had received antimicrobial therapy prior to admission; all improved with hospital management (antimicrobial therapy included erythromycin in four patients and high-dose ciprofloxacin and teicoplanin plus gentamicin in one patient each).

The role of C. pneumoniae as an opportunistic pathogen is unclear. C. pneumoniae has been identified in bronchoalveolar lavage (BAL) specimens of patients with HIV infection.[2] It is unclear if this represents an acute infection or reactivation of a latent or chronic infection (perhaps somewhat similar to that seen with cytomegalovirus (CMV) in HIV-infected patients). Whether immunocompromised patients are at increased risk of infection with C. pneumoniae has not yet been determined.

Association with Copd and Asthma

C. pneumoniae may cause acute exacerbation of chronic obstructive pulmonary disease (COPD), but the findings of studies are divergent. Beatty et al [42] were unable to show an increased association of C. pneumoniae in patients with acute exacerbation versus controls whereas a study in Italy did appear to find a higher prevalence of C. pneumoniae antibody among persons with acute exacerbation of chronic obstructive lung disease. Available data suggest that there is a link between C. pneumoniae and asthma or reactive airways disease. Hammerschlag and colleagues have found a definite association of the isolation of C. pneumoniae pneumonia from respiratory secretions and symptomatic asthma in children but not in adults.[43,44] Hahn [15] has recently defined a "Chlamydia-asthma" hypothesis and feels that the production of C. pneumoniae specific IgE and cytokines may lead to inhibition of ciliary motion and a possible shedding of cells with an enhanced penetration of aeroallergens. C. pneumoniae could act as a long-term asthma promoter through T-cell immunological processes during reinfection or chronic infection. Finally, C. pneumoniae could infect vascular smooth muscle and thereby promote bronchial hyper-reactivity.[15]

Association with Coronary Artery Disease

C. pneumoniae and Athersclerosis. Numerous serologic surveys conducted in Finland, the United States, and elsewhere have demonstrated an epidemiological link between C. pneumoniae infection and atherosclerosis. C. pneumoniae has been identified within atherosclerotic plaques by immunochemistry, PCR, and by culture. However, the present state of knowledge does not clarify the exact role the organism plays in the pathogenesis of athersclerosis.[45] Recent therapeutic trials suggesting a positive effect of macrolide therapy (azithromycin and roxithromycin) in reducing subsequent coronary events are intriquing but require confirmation with controlled studies.[46,47] The hypothesis that C. pneumoniae may be causative of arterial disease remains plausible but unproven.[48] A causal relationship of C. pneumoniae infection with subsequent coronary artery disease, if demonstrated, will have a great impact on the management of C. pneumoniae infections.

Therapy

There are few reported controlled studies evaluating specific therapy for C. pneumoniae pneumonia. Because there is often ambiguity concerning the diagnosis (as well as confounding issues of mixed infection), it is often difficult to interpret results.

C. pneumoniae is susceptible in vitro to the macrolides, tetracyclines, and fluoroquinolones.[49] Because C. pneumoniae is an intracellular pathogen, it is important to note that all three of these antimicrobials classes achieve good to excellent intracellular activity.

Initial reports evaluating specific therapy for C. pneumoniae pneumonia have relied on serologic diagnosis; they all suggest a benefit of the tetracyclines, macrolides, or the newer fluoroquinolones. Blasi et al [50] have reported the clinical response of 14 cases diagnosed by serology (12 had fourfold rise) of which 7 were treated with a macrolide and 7 with a beta-lactam initial regimen. Of seven patients treated with a macrolide, six had good response, whereas all patients treated with a beta-lactam required alteration (to a macrolide or doxycycline) before a positive clinical response was observed.

Only a few studies have evaluated the microbiological eradication of C. pneumoniae in pneumonia in relationship to the clinical course. In a multicenter study comparing erythromycin and clarithromycin (each for 10 days) in children < 12, C. pneumoniae was eradicated from the nasopharynxes of 12 of 14 (86%) of the children who were treated with erythromycin and from 15 of 19 (79%) of the children who received clarithromycin.[51] However, all the children with persistent infection improved clinically with complete resolution of the chest X rays. In a study involving adults with C. pneumoniae pneumonia or acute bronchitis, 12 (75%) of 16 patients treated with azithromycin (1.5 g total oral dose over 5 days) had bacteriological eradication when evaluated 4 to 6 weeks after treatment.[52] However, all 4 patients with persistent infections had improved clinically, including two who were coinfected with Mycoplasma pneumoniae. In an additional study of CAP of children (through 16 years of age) treated with either azithromycin or an alternative agent (amoxicillin-clavulanate if < 5 years of age; erythromycin if > 5 years of age), C. pneumoniae was eradicated from 17 of 21 (81%) patients who received azithromycin and from all eleven who received the alternative agent.[53] Persistence of C. pneumoniae infection after treatment with clarithromycin or azithromycin in these preceding studies was not associated with development of antibiotic resistance.

The findings of the above mentioned studies evaluating microbiological eradication suggest that C. pneumoniae may not be eradicated with effective antimicrobial therapy even when a good clinical response occurs. Hammerschlag et al [54] also noted persistence of infection after treatment of 5 patients with tetracycline (5 to 31 days). Most of these patients were clinically improved despite failure to eradicate the organism. In this respect, C. pneumoniae may be similar to Mycoplasma pneumoniae in that treatment may significantly reduce morbidity of illness, but may not eradicate the organism in acute respiratory infections. Failure to eradicate and possible subsequent development of chronic infection may, however, have significant clinical consequences such as reactivation of respiratory infection, possible role in immunological phenomenon (asthma and reactive arthritis), and most concerning in association with coronary artery disease.

In the initial descriptions of C. pneumoniae infection, Grayston et al [1] noted that respiratory symptoms frequently recurred or persisted after short courses (5 to 10 days) of erythromycin or tetracycline. Others have confirmed this observation. Recommendations for therapy of C. pneumoniae pneumonia on the basis of the currently available data are listed in Table 5. For children, either erythromycin or clarithromycin suspension for 10 days to 2 weeks is recommended or azithromycin 10 mg/kg on Day 1 followed by 5 mg/kg q.d. on Days 2 through 5. Ofloxacin 400 mg twice a day for 10 to 14 days would appear to be another appropriate alternative. Newer fluoroquinolones, levofloxacin, spar-floxacin, trovafloxacin, gatifloxacin, and moxifloxacin have increased activity against C. pneumoniae and initial studies have shown good clinical efficacy.[55,56] The choice of regimen will depend upon patient compliance, tolerance, and cost. Hopefully future prospective studies will provide additional information concerning the best therapeutic regimen for treatment of respiratory infections caused by C. pneumoniae.

It must be acknowledged that most patients with C. pneumoniae are treated empirically. Certainly the absence of convenient, accessible means of rapid diagnosis precludes initiating specific therapy at the onset of management. Recently published guidelines for the therapy of CAP suggest that therapy should include antimicrobial agents effective against C. pneumoniae (as well as Mycoplasma and often Legionella) in addition to the standard "pyogenic" common causes (S. pneumoniae and Hemophilus influenzae). It is recognized that C. pneumoniae infection is often self-limited and some patients have apparently responded clinically to beta-lactam therapy. In reality, patients with C. pneumoniae infection who respond to beta-lactam therapy may conceivably be responding to an undiagnosed bacterial copathogen. Based on present data, therefore, the decision to use therapy which will be specific against C. pneumoniae in the management of patients with CAP will, to a great extent, depend upon clinical judgment as well as the recommendations of various guidelines. It is certainly hoped that in the future diagnostic tests may be available (such as PCR of respiratory secretions) that may be cost-effective and allow specification of therapy early in the course of management.

Table 1. Prevalence of Chlamydia pneumoniae as a Cause of Community-Acquired Pneumonia

Study
(refs)

Number
of Patients

Type
of Patients

Method
of Diagnosis

% Due to
C. pneumoniae

Grayston 1989 [39] 198 Hospitalized adults Serology 10
Marrie 1987 [34] 301 Hospitalized adults Serology 6
Fang 1990 [33] 359 Hospitalized adults Serology 6.1 (5)*
Chirgwin 1991 [35] 91 Hospitalized children;
adult outpatients 		Culture and serology 18.7
Mundy 1995 [57] 385* Hospitalized adults PCR 3.6 (3.6)
Consentini 1996 [17] 61 Hospitalized to critical-
care unit 		Culture and
serology 		10
Martson 1997 [19] 2775 Hospitalized adults Serology 8.8 (2.4)
Ishida 1998 [58] 318 Hospitalized adults Serology 3.7
Ruiz-Gonzalez 1999 [59] 109 Hospitalized adults PCR, serology 13
Cassell 1991 [60] 120 Adult outpatients Serology 17
Almirall 1993 [20] 105 Adult oupatients Serology 13
Block 1995 [51] 260 Pediatric outpatients Culture and serology 28 [13 by culture]
Hammerschlag 1996 [53] 456 Pediatric outpatients Culture 7.5

PCR = polymerase chain reaction.
*45% with HIV infection.
( ) Represents % of cases identified as "definite" diagnosis (for serology this represent fourfold rise of antibody. titer [see diagnostic tests section]).

Table 2. Diagnostic Tests for C. pneumoniae

Test

Specimen

Sensitivity (%)

Specificity (%)

Comments

Culture NP swab, sputum,
Bronchial washings,
pleural fluid 		50-90 ? Requires tissue
culture; not
widely available; requires
several days incubation
IgG 1:512
IgM 1:32
PCR Sputum, bronchial
washings, pleural
fluid, tissue, throat
or NP swab 		80-90 > 85 No FDA-approved kits;
available from reference and
research laboratories
Potential for rapid diagnosis
Serology Serum
microimmunofluorescence
(MIF); IgG and IgM 		50-90 Unknown Paired
Acute and convalescent
Preferred (therefore retrospective)
IgM may take up to 4-6 weeks to appear
Diagnostic criteria
Definite:
4-fold rise MIF Ab
Possible:

From ref. 61.

Table 3. Characteristics of 26 Patients with C. pneumoniae as Sole Pathogen of Community-Acquired Pneumonia Requiring Hospitalization

Demographics

 

Duration of Illness
Prior to Admission

 
Age, mean
(range) 		55 Median days 7
  (21-82)  


Range days 1-70
% Male 50    
+ % Smoker 40 Findings  
% Comorbid illness (heart disease,   Temperature (°C)  
COPD, diabetes, Cancer) 54 Mean38.1  
% Prior community-acquired
pneumonia 		50 % < 37.8 (100°F) 35


% > 38.9 (102°F) 35
Symptoms (%)   Respiratory rate 17


> 30/min (%)  
Viral prodrome 30 Pulse > 130/min (%) 8
Cough
(productive) 		88 Systolic BP < 90 mmHg
(%) 		0
  50    


Rhonchi (%) 30
Fever 80 Rales (%) 50
Shortness of breath 73 Wheezing (%) 15
Chills 73  
Nausea 73 Laboratory studies  
Headache 56 WBC  
Myalgia 50 Mean (range) 12,700/mm 3



(200-45,000)
Chest pain 46  
Rhinitis 46 > 10,000/mm 3 50
Diarrhea 42 Sodium < 135 mEg/L 42
Sore throat 42 Sodium < 130 mEg/L 15
Hoarseness 36 Elevated LDH (%) 33
Sinus pain 15 Purulent Sputum (%) 46*

*All but one showed PMNs without predominant organism on Gram stain.
From File et al, 1999. [37]

Table 4. Characteristics of 6 Patients with Severe Community-Acquired Pneumonia Due to C. pneumoniae

Demographics

Age, mean(range) 59(28-81)
Number male 6
Number with underlying disease 6*

Findings

Number with fever 6
Number with dyspnea 6
PaO2 mmHg, mean (range) (49-59)
Number with WBC > 10,000 4

Outcome

Cure 4 †
Improved 2 ‡

*Leukemia, thalassemia, coronary disease 2, peptic ulcer, COPD.
†All treated with erythromycin.
‡One treated with ciprofloxacin; one treated with teicoplanin plus tobramycin.
From ref. 17.

Table 5. Author's Recommendation for Antimicrobial Therapy of C. pneumoniae (Adult Doses*)

Antimicrobial Dose Duration
(days)
Erythromycin † 500 mg q.i.d. 14-21
Clarithromycin (Biaxin) 500 mg b.i.d. 10-14
Azithromycin (Zithromax) † 500 mg initially
then 250 mg q.d.
(alternative 500
mg q.d.) 		5


(3)
Dirithromycin (Dynabac) 500 mg q.d. 14
Tetracycline 500 mg q.i.d. 14-21
Doxycycline † 100 mg b.i.d. 10-14
Levofloxacin (Levaquin) † 500 mg q.d. 7-14
Gatifloxacin 400 mg q.d. 7-14
Moxifloxacin 400 mg q.d. 10
Sparfloxacin (Xagam) 400 mg initially, 7-14

200 mg q.d.

*Oral except where noted; other fluoroquinolones pending FDA approval include gatifloxacin and moxifloxacin.
† Also can be administered intravenously in equivalent dose.

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