Chlamydia Pneumoniae (Chlamydophila)

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Chlamydia pneumoniae — an intracellular organism with a cell membrane but no cell wall

In many series, it is the third or fourth most common cause of community-acquired pneumoniae (CAP). However, given the difficulties in making an accurate etiological diagnosis of infection by this micro-organism, there is still some controversy as to whether or not this is a major pathogen in CAP.

Co-infections with S. pneumoniae and M. pneumoniae occur frequently.

C. pnemoniae has been implicated in quite a number of chronic illnesses, such as atherosclerosis, asthma, arthritis, multiple sclerosis, and many others. However, the evidence for causation in most of these is not strong.

Most of the empiric antibiotic treatments used for CAP will treat C. pneumoniae.

Chlamydiae are obligate intracellular bacterial pathogens. Recent taxonomic analysis of the genus Chlamydia has found that there are two genera – Chlamydia and Chlamydophila. Chlamydophila has the following species:C. pecorum, which causes infection in cattle, sheep, and koalas; C. pneumoniae and C. psittaci; C. abortus, which causes ovine and bovine abortion; C. cavieae, which causes guinea pig conjunctivitis; and C.felis, which causes keratoconjunctivitis in cats.

C. pneumoniae has a gram-negative cell wall and a unique development cycle with elementary (the infectious particle) and reticulate (the intracellular replicative particle) bodies. After infection, elementary bodies (200-400 nm in diameter) attach to the host cell by electrostatic binding and enter the cell by endocytosis. Elementary bodies (EB) differentiate into reticulate bodies (RB) that undergo binary fission. After about 36 hours, the reticulate bodies (RBs) differentiate back into elementary bodies (EBs). A large number of EBs accumulate in the cell (approximately 500-1000), yet host cell function is not affected. These large accumulations, or microcolonies, are referred to as intracytoplasmic inclusions. During this process, chlamydial antigens are released onto the host cell surface, inducing a host immune response. Release of EBs occurs by several processes, including extrusion of the inclusion. It is also likely that C. pneumoniae enters a persistent state wherein it is metabolically inactive and, at this stage, unaffected by antibiotic therapy. Gamma interferon, antibiotics, and nutrient deprivation are probable drivers for C. pneumoniae persistence.

C. pneumoniae was discovered during studies on trachoma in the 1960s by Dr. T. Grayston and colleagues. Initially, these investigators named the newly discovered organism TWAR after their first two isolates TW-183 (TW for Twain) and AR-39 (AR for acute respiratory). There is only one serotype of C. pneumonia, and all isolates from humans to date have a high percent (>98%) of relatedness.

C. pneumoniae is the only species to have a udk gene encoding uridine kinase. Sequencing of the koala strain of C.pneumoniae suggests that humans have acquired this infection zoonotically.

What is the best treatment?

• The preferred antimicrobial agents include Doxycycline 100 bid for 14-21 days; azithromycin 1.5 gm orally over 5 days; clarithromycin 500 mg bid for 10 days; levofloxacin 500 mg po or IV od for 7-14 days.

• Data on treatment are limited. Studies that have used culture have found that macrolides (erythromycin, clarithromycin, azithromycin) and quinolones (levofloxacin and moxifloxacin) have eradicated the microorganism 70-86% of the time. Clinical improvement usually occurs despite persistence of the organism.

• In vitro resistance to quinolones is associated with a point mutation in the GyrA gene.

How do patients contract this infection, and how do I prevent spread to other patients?

• Epidemiology

  C. pneumoniae is a common respiratory pathogen. Infection frequently occurs during childhood and adolescence, and, by adulthood, about 80% of the population has been infected. Asymptomatic respiratory infections occur in 2-5% of adults and children. The role of such infection is unclear. There is no seasonal variation, although there is a suggestion of a 4 year cycle in the incidence of C. pneumoniae pneumonia. Pneumonia due to this organism occurs worldwide. In one study it accounted for 8% of cases in North America, 7% in Europe, 6% in Latin America and 5% in Asia/Africa. Rates are highest among those younger than 1 year of age and those older than 70 years of age.

  Co-infections with S. pneumoniae and M. pneumoniae occur frequently.

  Adults seropositive for C. pneumoniae were more likely to have a higher body mass index, be a current smoker, and have chronic obstructive pulmonary disease and a higher systolic blood pressure than seronegative subjects.

  Acquisition via droplet infection occurred during a laboratory accident. C. pneumoniae can survive on countertops for up to 30 hours. Spread within families, military recruits, and nursing homes has been described. Interestingly, in at least one outbreak in a nursing home, those who had a higher level of physical activity were more likely to be infected. Contact with infected nursing home residents was a risk factor for infection in staff.

  There are no seasonal differences in the incidence of C. pneumonia, and the incidence appears stable.

• Infection control issues

  In everyday practice, there are no infection control issues in that it is rare that one knows that the infection is due to this micro-organism. However, in the event of an outbreak due to C. pneumoniae or if you know that a respiratory infection is caused by this organism, then respiratory precautions should be used.

  Currently, there is no vaccine, and anti-infective prophylaxis is not recommended.

What are the clinical manifestations of infection with this organism?

The most common manifestations are respiratory tract infections manifested as pneumonia or pharyngitis.

• The incubation period is 21 days. The duration of symptoms prior to admission was 4.6 days for C. pneumoniae versus 12.9 days for those with other causes of pneumonia. The illness ranges in severity from mild to very severe. Most cases are of mild to moderate severity. The symptoms are non-specific. Hoarseness is more commonly associated with C. pneumoniae pneumonia than with other respiratory pathogens. Fever may be accompanied by myalgia and chills and then cough. Cough is probably the most prominent feature of the illness. Cough and malaise may persist for several months despite antibiotic therapy. It can cause pneumonia in the immunocompromised host.

• In a comparison of the symptoms and signs of 18 patients serologically diagnosed as C. pneumoniae with 282 patients with community acquired pneumonia who were C. pneumoniae antibody negative, there were no differences in the symptoms or clinical manifestations. In this study, 61% of the C. pneumoniae patients had a white blood cell count greater than 10,000 per microliter. In many of the descriptions of C. pneumoniae pneumonia, the white blood cell count is said to be normal. The length of hospital stay for patients with C. pneumoniae alone was longer at 9 plus or minus 7.3 days compared with 7.58 plus or minus 3.49 days for those with C. pneumoniae and a co-pathogen. The mortality rate for the C. pneumoniae cases was 4.9%, not significantly different from the rest of the cases of pneumonia.

• In one study, patients with C. pneumoniae pneumonia were more likely to have congestive heart failure than those with pneumococcal pneumonia. This may be a reflection of older age since the mean ages were 67 and 55 years of age for the C. pneumoniae and S.pneumoniae patients, respectively.

• The radiographic manifestations of C. pneumoniae are much as shown above and are not specific for this illness. In a review of the computed tomographic features of 40 patients with C. pneumoniae pneumonia compared with 42 patients with Mycoplasma pneumoniae pneumonia the following features emerged:

  Ground glass attenuation (n = 38) and acinar patterns (n = 28) were the main CT findings in C. pneumoniae pneumonia.

  Acinar patterns and pleural effusions were more frequently observed in patients with M. pneumoniae pneumonia.

  Centrilobular nodules and bronchial wall thickening were seen less frequently than in M. pneumoniae pneumonia.

C. pneumoniae and chronic disease

• Asthma

  Chronic persistent infection with C. pneumoniae has been associated with asthma, arthritis, and atherosclerosis.

  In the early 1990s, workers in the United States reported an association between serologic evidence of acute C. pneumoniae infection and asthma. Since then, a number of studies have been done in different countries to determine if this is a true association. Intranasal inoculation of mice with C. pneumoniae results in sustained airway hyper-responsiveness and airway inflammation. A recent systematic review concludes that C. pneumoniae seems to be involved more with asthma persistence than acute exacerbations. A Cochrane review of marcolide treatment in chronic asthma revealed an overall positive effect on symptoms and eosinophilic markers of inflammation.

• Atherosclerosis

  Inflammation is an important but poorly understood factor in the development of atherosclerosis. The traditional risk factors of hypertension, dyslipidemia, tobacco smoking, obesity, and family history do not fully explain how inflammation contributes to the progression of atherosclerosis. Thus, attention has turned to the possibility that microbial infections and immunological mechanisms play a role in the pathogenesis of atherosclerosis. A case control study from Finland in 1988 found that patients with coronary artery disease were more likely to have antibodies to C. pneumoniae than control subjects. Since then, there have been many studies trying to establish that C. pneumoniae does indeed play a role in atherosclerosis. Using serological and isolation studies, there has not been good evidence of causality. In large part, this is due to the interlaboratory variation in the various methods used. For example, contamination is common with nested polymerase chain reaction (PCR) but less so with real time PCR. A more recent approach has used a quantitative assay for chlamydial lipopolysaccharide. Using this approach there was a correlation between serum levels of cLPS and C-reactive protein levels in acute myocardial infarction and unstable angina.

  Another approach is to use antibiotic therapy to influence the outcome in coronary artery disease. A meta-analysis of 11 randomized trials that had enrolled 19,217 patients that used a variety of antibiotics and different duration of follow-up found no effect for the antibiotics, indeed five of the larger studies favor placebo.

  Investigators are now using a proteomics approach to this problem. Eight (RpoA, MOMP, YscC, Pmp10, PorB, Pmp21-m, GroEL, and Cpaf-c) of 31 C. pneumoniae antigens showed higher reactivity with sera from PCR positive donors using a two-dimensional gel-immunoblotting technique. Furthermore, the antibody response of C. pneumonia DNA positive subjects showed reactivity toward antigens selectively upregulated during C. pneumoniae persistence.

• C. pneumoniae and multiple sclerosis

  Chlamydia pneumoniae is one in a long list (more than 20) of viruses and bacteria that have been implicated in the etiology of multiple sclerosis over the past 50 years. Indeed, the most recent controversy in this area is that dilatation and stenting of stenosed cervical veins leads to marked improved in the symptoms of multiple sclerosis (MS). The hypothesis is that C. pneumoniae acts as a cofactor to potentiate the already established inflammatory and demyelinating process in MS. To date, there is no proof for a role of C. pneumoniae in multiple sclerosis.

• C. pneumoniae and Alzheimer’s disease

  In one study, a high proportion of brain samples from patients with Alzheimer’s disease were PCR positive for C. pneumonia, whereas those from age/sex matched non-Alzheimer’s disease control subjects were not. In one study, a 3-month course of doxycycline was administered to AD patients, and at 6 months the treated group had less cognitive decline than the control group.

• C. pneumoniae and reactive arthritis

  In 1916, inflammatory arthritis following an episode of dysentery was noted. Since then, several bacterial species, including C. pneumonia, have been implicated in reactive arthritis (Reiter’s syndrome). Thirteen percent of 200 patients with various arthritis and synovial biopsies were positive for C. pneumoniae using PCR. As with other chronic disease states, the role of C. pneumoniae in reactive arthritis is far from clear.

• Other associations

  There is no association between pre-eclampsia and C. pneumoniae infection.

What common complications are associated with infection with this pathogen?

• The available data suggest that asthma persistence is a complication that can follow infection with this pathogen. Reactive arthritis can also follow infection with C. pneumoniae.

How should I identify the organism?

• C. pneumoniae has a unique development cycle with elementary (the infectious particle) and reticulate (the intracellular replicative particle) bodies. After infection elementary bodies (200-400 nm in diameter) attach to the host cell by electrostatic binding and enter the cell by endocytosis. Elementary bodies differentiate into reticulate bodies, which undergo binary fission. After about 36 hours, the RBs differentiate back into EBs. A large number of EBs accumulate in the cell (about 500-1000), yet host cell function is not affected. These large accumulations or microcolonies are referred to as intracytoplasmic inclusions. During this process, chlamydial antigens are released onto the host cell surface, inducing a host immune response. Release of EBs occurs by several processes, including extrusion of the inclusion. It is also likely that C. pneumoniae enters a persistent state wherein it is metabolically inactive and, at this stage, unaffected by antibiotic therapy. Gamma interferon, antibiotics, and nutrient deprivation are probable drivers for C. pneumoniae persistence.

• C. pneumoniae can be isolated in tissue culture using HEp-2 cells. Nasopharyngeal or pharyngeal swab specimens collected using aluminum or plastic shafted Dacron tip swabs is essential, because calcium alginate or cotton tips and wooden shafts may inhibit the growth of the organism in tissue culture and may be toxic to cells. After 72 hours of incubation, growth can be detected using an immunofluorescence stain. More than one passage may be necessary to detect growth.

  PCR is still a research test.

  The microimmunofluorescence (MIF) test is probably best. An enzyme-linked immunosorbent assay (ELISA) is easier to perform. Since C. pneumoniae is an intracellular organism, it is not surprising that there is a poor correlation between direct detection of the organism using isolation or PCR and serology. The difficulties with using serology to make an etiological diagnosis of C. pneumoniae infection are exemplified by two pneumonia studies in which 7-13% of the patients have positive cultures for C. pneumoniae and 7-18% had positive MIF serology. The only problem is that they were not the same patients.

  The accurate laboratory diagnosis of C. pneumoniae infection is dependent on a high degree of skill among the laboratory workers and access to tissue culture facilities.

How does this organism cause disease?

• For the most part, the mechanisms of how C. pneumoniae causes tissue damage are unknown. However, a considerable amount is known about how C. trachomatis causes tissue damage, and many of the same mechanisms may be operative for C. pneumoniae. The chlamydial heat shock protein 60 (hsp 60) elicits antibody responses associated with damage in the eye and genital tract when C. trachomatis infects these areas. There is a suggestion that continued synthesis of hsp 60 during latency of C. pneumoniae in the respiratory tract may be associated with asthma persistence.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Hammerschlag, MR. “Advances in the mangement of infections”. Expert Rev Anti-Infect Ther. vol. 1. 2003. pp. 493-504. (This source summarizes the data from multicenter studies that used culture to diagnose C. pneumoniae. Treatment with erythromycin, clarithromycin, azithromycin, levofloxacin, and moxifloxacin were about 70-80% effective in eradicating C. pneumoniae from the nasopharynx of children and adults with community-acquired pneumonia.)

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