Chlamydophila (Chlamydia) pneumoniae

The Pathogen

Chlamydiae are obligate intracellular pathogens, which former genus Chlamydia pneumoniae has been reclassified (somewhat controversially ) through genome sequencing and comparative analysis of the ribosomal operon to Chlamydophila pneumoniae, with three biovars—human (TWAR), koala, and equine. Still controversial, Chlamydophila pneumoniae is considered a homotypic synonym for Chlamydia pneumoniae . In this chapter, C. pneumoniae refers to the biovar TWAR, the agent causing infection in humans.

C. pneumoniae was first described as a human respiratory tract pathogen in the mid-1980s. ^, This obligate intracellular pathogen causes atypical pneumonia and upper respiratory tract disease and has been associated with several nonrespiratory conditions. Chlamydia spp. are classified as bacteria because of the ability to reproduce by binary division. Like Chlamydia trachomatis and Chlamydophila psittaci, C. pneumoniae has a biphasic developmental cycle of replication. The infectious bacterial form, known as the elementary body, enters the eukaryotic cell by endocytosis, resides within a cytoplasmic inclusion, and then transforms into a vegetative form (the reticulate body) to replicate by binary fission. As the inclusion fills with progeny, chlamydiae transform back into the metabolically inactive but infectious elementary body and are released through host cell rupture or fusion of the inclusion with the host cell plasma membrane.

Epidemiology

C. pneumoniae is a common infection worldwide. Variable quality of diagnostic assays and lack of standardization remain important challenges to a precise description of the epidemiology, but many retrospective serologic studies as well as prospective studies using culture and polymerase chain reaction (PCR) testing have identified the mode of transmission, incidence of disease, and clinical characteristics of infection. ^{, ,}

Infection occurs most commonly in late winter or early spring. ^, The age at which primary infection apparently occurs differs according to the testing tools used. Population-based serologic studies indicate that acquisition of specific antibody occurs most often in children 5–15 years of age; the seroprevalence in this age group is approximately 30%. New or repeat infections continue through adolescence and adulthood, culminating in 70%–80% seropositivity in the elderly. Acute infections (either primary infection or reinfection) are most common in school-aged children. In a prospective population-based study in Seattle, the incidence of acute infection by age groups per 100 person-years was as follows: 0–4 years (no cases); 5–9 (9.2); 10–14 years (6.2); 15–19 years (2.2); and ≥20 years (1.5). In contrast, a population-based study in Thailand identified rates of C. pneumoniae pneumonia of 2–20 per 100,000 population with the highest rates occurring in those <1 year and >65 years of age. If culture or PCR testing is used for such studies, colonization (or possibly infection) in younger children also is identified commonly in the absence of a detectable antibody response. ^{, , ,} It remains unresolved whether the absence of a serologic response in young children results from use of an insensitive test or from the absence of tissue invasion. C. pneumoniae has been isolated from the nasopharynx or throat of 1%–10% of healthy children and can be detected by PCR testing in 5%–25% of children who attend out-of-home childcare; those with respiratory tract symptoms and those from large families had the highest rates of recovery/detection of C. pneumoniae . ^{, , ,}

C. pneumoniae is shed from the respiratory tract during the acute clinical illness and for up to 1 year later. Subclinical infection with antibody response is also common. ^{, , ,} It is not known whether the presence of symptoms increases the likelihood of transmission. Animal experiments suggest that aerosolized particles are an inefficient means of spreading C. pneumoniae. The organism is most likely transmitted person-to-person by respiratory droplets. Although the organism remains viable only briefly on skin, it survives for 20–30 hours on environmental surfaces, suggesting that direct inoculation may also be an important mode of transmission in clinical settings.

Among military trainees in Finland, attack rates during a C. pneumoniae epidemic ranged from 60–84 per 1000 exposed men. Attack rates during an outbreak of C. pneumoniae respiratory infections among Air Force cadets ranged from 1.5%–3.4% and rates were highest among freshman military recruits, who tend to spend more time in close proximity to one another. The outbreak ended after 8 months, possibly related to the movement of cadets off base after senior graduation. Attack rates were higher during institutional outbreaks, ranging from 44%–68% among nursing home residents and 22%–34% among nursing home staff. ^,

The incubation period is 2–4 weeks as determined by the temporal clustering of cases during institutional and military outbreaks. Protracted epidemics of C. pneumoniae infection can occur in some settings. Epidemics among military trainees in Finland lasted approximately 6 months. Some evidence points to epidemic periods occurring every 6 months to 3 years superimposed on low levels of endemic C. pneumoniae infection. ^{, ,}

Clinical Manifestations

C. pneumoniae infects the upper respiratory tract epithelium of young children, where it occasionally causes or contributes to acute otitis media and sinusitis, as well as prolonged cough illness and community-acquired pneumonia. C. pneumoniae has been identified by culture and PCR testing in middle-ear fluid specimens from approximately 5% of children with acute otitis media. ^{, ,} Most often, another bacterial pathogen is found concurrently, and infection resolves in the absence of therapy directed at C. pneumoniae . The organism has not been detected in individuals with chronic middle-ear effusions. C. pneumoniae can cause prolonged cough illness. The organism has been detected in 5%–17% of individuals with prolonged cough, with clinical features resembling pertussis. ^{, ,} In patients with prolonged cough during outbreaks of pertussis-like illness, the mean duration of cough associated with C. pneumoniae infection has been 25–30 days, compared with 50 days for cough associated with Bordetella pertussis. ^{, ,} C. pneumoniae -associated fever and upper respiratory tract symptoms, including sore throat and hoarseness, can be self-limited or can progress to coughing and a lower respiratory tract illness. ^{, ,}

C. pneumoniae is an uncommon cause of severe pneumonia in children. Earlier studies implicated C. pneumoniae in 5%–14% of cases of pediatric community-acquired pneumonia. ^{, , , ,} However, C. pneumoniae was identified using a nasopharyngeal swab PCR test in only 0.5% of 2222 children who were hospitalized with chest radiograph-confirmed community-acquired pneumonia at 3 US hospitals in 2011–2012. In India, C. pneumoniae infection was identified by serologic testing in 1.1% of 2345 children <12 years of age who met the World Health Organization definition of pneumonia in 2011–2013. The illness tends to have a subacute onset, indistinguishable from that due to Mycoplasma pneumoniae or influenza. More than one half of infected patients have fever, cough, shortness of breath, chills, nausea, headache, and myalgia. ^, Crackles, wheezing, and rhonchi often are detected on physical examination. Chest auscultation and radiograph can indicate pneumonia even when respiratory tract symptoms are mild. Because of the prolonged and relatively mild nature of initial symptoms, the patient may seek medical attention >1 week after onset of illness, at which time fever and signs of systemic illness may have resolved. C. pneumoniae infections cannot be differentiated reliably from other causes of pneumonia in children. Among adults requiring hospitalization for community-acquired pneumonia, patients with a C. pneumoniae etiology were more likely than those with a bacterial etiology to have a duration of illness >7 days (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.3–9.4) and less likely to have a productive cough (OR, 0.3; 95% CI, 0.1–0.7).

C. pneumoniae has been associated with severe illness in sporadic case reports. C. pneumoniae was isolated from culture of the respiratory tract and pleural fluid of a previously healthy adolescent boy with severe pneumonia complicated by respiratory failure and parapneumonic effusions. A 13-year old girl developed pneumonia and hemorrhagic pericarditis; C. pneumoniae was detected in the pericardial fluid by PCR. Encephalitis has also been attributed to C. pneumoniae in pediatric reports. A 12-year-old girl developed concomitant lower respiratory tract infection and encephalitis; C. pneumoniae DNA was detected by multiplex PCR in endotracheal secretions and immunoglobulin M (IgM) and IgG antibodies were detected in serum, but not cerebrospinal fluid specimens.

Most studies that include appropriate control groups fail to demonstrate an association between asthma and acute or chronic C. pneumoniae infection. For example, C. pneumoniae was identified in 3.4% of children during an exacerbation of asthma, in 6% of children during an initial episode of wheezing, and in 2.5% with stable asthma or allergic rhinitis. However, Teig and colleagues detected C. pneumoniae in respiratory secretions by PCR from 24% of children with stable asthma but from none of healthy nonasthmatic children ; it is not clear why C. pneumoniae was detected less frequently in the control population in this study compared with previous studies.

Nonstandardized laboratory testing has resulted in widely varying and often unconfirmed reports of new clinical associations of C. pneumoniae, including with Alzheimer disease, atherosclerotic cardiovascular disease, multiple sclerosis, meningoencephalitis, pyoderma gangrenosum, and a variety of other conditions in children and adults ( Table 166.1 ). C. pneumoniae was identified by immunohistochemistry in cardiovascular tissue of sporadic cases of Kawasaki disease. However, this association was not confirmed in a case-control study.