Pneumonia caused by Chlamydia pneumoniae in adults

INTRODUCTION — Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory tract infections including pharyngitis, bronchitis, and pneumonia. Pneumonia caused by C. pneumoniae is typically community acquired and mild.

Pneumonia caused by C. pneumoniae in adults will be discussed here. Pneumonia caused by C. psittaci, a zoonotic Chlamydia species that can also cause respiratory infections in humans, is discussed separately (see "Psittacosis" and "Pneumonia caused by Chlamydia pneumoniae in children"). Pneumonia due to Chlamydia trachomatis, which is limited to infants, is discussed separately. (See "Chlamydia trachomatis infections in the newborn".)

The epidemiology, clinical features, diagnosis, and management of community-acquired pneumonia are discussed separately:

●(See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)

●(See "Clinical evaluation and diagnostic testing for community-acquired pneumonia in adults".)

●(See "Treatment of community-acquired pneumonia in adults in the outpatient setting".)

●(See "Morbidity and mortality associated with community-acquired pneumonia in adults".)

●(See "Community-acquired pneumonia in children: Clinical features and diagnosis".)

●(See "Community-acquired pneumonia in children: Outpatient treatment".)

DEFINITIONS — The term "atypical pneumonia" is often used to describe pneumonia caused by C. pneumoniae.

Atypical pneumonia refers to pneumonia caused by C. pneumoniae and other bacteria including Mycoplasma pneumoniae, Legionella pneumophila and Legionella species, C. psittaci, and Coxiella burnetii. The origin of the term "atypical" is a matter of debate. The term may refer to the fact that these organisms are not "typical" bacteria that cannot be identified by standard microbiologic techniques. Others suggest that atypical refers to the mild nature of the pneumonia caused by some of these organisms compared with pneumonia caused by Streptococcus pneumoniae [1].

EPIDEMIOLOGY — Rates of C. pneumoniae infection in adults with community-acquired pneumonia (CAP) vary widely among studies, ranging from <1 to 20 percent of cases in which a pathogen was identified [2-13]. The wide range in reported prevalence is likely due to variability in diagnostic methods used and potential cyclic patterns of illness or clustering of cases. Without a reliable reference standard for diagnosis, prevalence cannot be precisely or accurately determined. Rates of infection appear to be higher in patients with mild infection seen in the ambulatory setting and decline in patients with increasing disease severity, including hospitalized patients and those admitted to the intensive care unit (ICU) [5,6,9].

The overall seroprevalence of C. pneumoniae is about 50 to 85 percent across continents, suggesting that infection is often asymptomatic and that C. pneumoniae is a ubiquitous organism found worldwide [14-18]. Seroprevalence appears to increase with age, with antibodies detectable in <10 percent of children under 10 years old, 30 to 40 percent of teenagers, and 50 percent of middle-aged adults [15]. Seroprevalence may be overestimated because the serologic assays used for the detection of C. pneumoniae can cross-react with other Chlamydia species [19]. Many patients with culture-documented C. pneumoniae pneumonia, especially children, do not develop antibody responses that are detectable with currently available methods [20,21]. The rate of C. pneumoniae infection in children as determined by culture and polymerase chain reaction is similar to that found in adults [21].

C. pneumoniae is transmitted from person to person, likely via respiratory droplets, small particle aerosolization, and fomites [20,22]. Outbreaks of C. pneumoniae infections have been reported in persons living in close quarters, including residents of long-term care facilities, prisoners, and military personnel [23-31]. Attack rates reported in the literature range from about 10 to 68 percent, with a median of 34 percent [26,32].

MICROBIOLOGY

Taxonomy — C. pneumoniae belongs to the Chlamydiaceae family and Chlamydia genus [33]. The Chlamydia genus contains a total of 11 species [34], 3 of which are pathogenic in humans: C. pneumoniae, C. trachomatis, and C. psittaci [19].

In 1999, there was a proposal to divide the Chlamydia genus into two genera, Chlamydia and Chlamydophila, based on genetic analysis [35]. Upon further analysis, reclassification was not deemed necessary by the scientific community, and it was agreed that the Chlamydiaceae family contains a single genus, Chlamydia [36,37].

Pathogen — C. pneumoniae is an obligate intracellular organism. It is one of the smallest prokaryotes, with a genome size of about 1.2 million nucleotides [38,39].

Chlamydia species share several structural and metabolic features that differentiate them from other bacteria. The cell wall of Chlamydia spp contains an inner and outer membrane as well as lipopolysaccharide (LPS), similar to all gram-negative bacteria. However, the chlamydial LPS variant is less endotoxic than in many gram-negative bacteria [40]. Chlamydia spp have very little peptidoglycan between the inner and outer membranes and thus have limited susceptibility to penicillins [19,41].

Metabolically, Chlamydia species rely on the host cell for host adenosine triphosphate (ATP) for protein synthesis, making replication outside the host cell nonsustainable [19,40]. Among Chlamydia species, C. pneumoniae specifically lacks a tryptophan recovery or biosynthesis pathway, rendering the organism vulnerable to host interferon-gamma-mediated immune control [42] as well as intrinsically resistant to sulfonamides and trimethoprim [43].

One of the most unique features of Chlamydia species is that bacterial growth requires a biphasic developmental cycle, with two morphologically distinct infectious and reproductive forms [19,40,43]:

●Elementary body (EB) – The extracellular, metabolically inactive, spore-like infectious form, which is able to survive outside the host cell

●Reticulate body (RB) – The intracellular, metabolically active but noninfectious form, which is able to rely on the host cell for replication

Aberrant bodies, variants of RBs that are less metabolically active and less infectious than RBs, have been observed in in vitro systems designed to induce persistent infection [19]. The extent to which they are operative in human infection is uncertain.

PATHOGENESIS — The biphasic life cycle of C. pneumoniae plays an important role in pathogenesis. Outside the host, the organism exists as a small, dense elementary body (EB). The EB has a rigid wall, resulting from disulfide cross-linking of envelope proteins, allowing it to survive outside the host for a short amount of time [40].

Upon infection, the EB attaches to respiratory mucosal epithelial cells and enters the cell through receptor-mediated endocytosis. Following endocytosis, the EB persists within the phagosome and differentiates into a metabolically active reticulate body (RB). The RB replicates within the host cell forming microcolonies, or intracytoplasmic inclusions composed of hundreds of bacteria, within 36 to 72 hours. The RBs reorganize into the smaller, denser EBs, which are released either via cell lysis or exocytosis. The EBs can then go on to infect new cells [19,40].

During replication, chlamydial antigens are released onto the host cell surface, inducing the host immune response [40]. One critical feature of Chlamydia organisms is that immunity to infection is not long lived. As a result, reinfection is possible [19,40]. In vitro data suggest that Chlamydiae can also cause persistent infection. While persistent infection has not been definitively demonstrated in humans, it is hypothesized to play a role in multiple chronic illnesses [19,43]. (See 'Prognosis' below.)

CLINICAL FEATURES — Pneumonia caused by C. pneumoniae is similar to other forms of community-acquired pneumonia (CAP) and is characterized by fever, cough, and shortness of breath. Pneumonia due to C. pneumoniae is typically mild; however, severe cases, cases complicated by pleural effusion and empyema [44], intensive care unit admission, and death have been reported [6,30,45].

Although there are no clinical features that clearly distinguish pneumonia caused by C. pneumoniae from pneumonia due to other causes, small case series suggest that upper respiratory involvement such as pharyngitis, laryngitis, and sinusitis may occur more frequently with C. pneumoniae and that a gradual onset of illness is common [30,45-47]. These features are also frequent in patients with pneumonia due to M. pneumoniae.

White blood cell counts are typically normal or mildly elevated [11,48]. Chest radiograph findings are usually nonspecific. The most commonly reported findings are unilateral alveolar opacities [49,50]; lobar opacification is reported to be less common than with S. pneumoniae [49].

The overall spectrum of illness associated with C. pneumoniae is wide, ranging from asymptomatic infection to life-threatening disease. The majority of infections are asymptomatic [14,17]. Other reported manifestations include pharyngitis, laryngitis, otitis media, and bronchitis [30,51]. Reports of acute infections outside the respiratory tract are rare but exist, including meningoencephalitis [52-54], Guillain-Barré syndrome [55], myocarditis [56-60], and endocarditis [61]. In some of these cases, diagnosis was made by serology alone, and a causal role for C. pneumoniae in these infections is not definitively established. Studies from China and Italy have found that patients with severe acute respiratory syndrome coronavirus 2 can be coinfected with other respiratory pathogens, including C. pneumoniae and M. pneumoniae, which may be associated with a more severe presentation [62,63].

DIAGNOSIS

Approach to diagnosis — The clinical presentation of pneumonia caused by C. pneumoniae is nonspecific, and there is no defined population for whom testing can be recommended. Thus, we typically individualize our approach to testing based on the patient’s severity of illness, the likelihood that results would change management, and the availability of a polymerase chain reaction (PCR)-based assay.

When a PCR-based assay is available onsite, we favor testing for most patients as results are typically available within a few hours of testing. A positive test result (in the absence of clinical suspicion for coinfection) is considered diagnostic and can help rapidly direct antibiotic therapy (see 'Directed therapy' below). When PCR-based testing is not available onsite, we make the decision to test on a case-by-case basis.

Microbiologic testing

●PCR-based assays – When microbiologic diagnosis is pursued, we use a PCR-based assay. PCR-based assays can be performed on most specimen types, including nasopharyngeal swabs, sputum, and bronchoalveolar lavage fluid [64].

There are three US Food and Drug Administration (FDA)-cleared multiplexed PCR respiratory panels that include C. pneumoniae (eg, BioFire FilmArray, GenMark ePlex, Luminex NxTAG Respiratory Pathogen Panel, and QIAstat-Dx Respiratory) [65-69]. Each includes respiratory viruses and M. pneumoniae. The BioFire FilmArray and QIAstat-Dx also includes Bordetella pertussis and B. parapertussis. Studies using these panels have found the performance in adults and children with respiratory illness to be generally equivalent. Identification of C. pneumoniae has been low, <1 percent, which is consistent with epidemiologic studies over the past 10 years [65-68,70]. If the assays are run onsite, the turnaround time is usually one to two hours.

●Cell culture – Cell culture can have diagnostic yields as high as PCR in some settings [71] and allows for antimicrobial susceptibility testing [19]. However, this method is rarely used as most clinical laboratories are not equipped to culture Chlamydia spp. Culture requires specialized techniques and can take up to a week [72].

●Serology – We do not use serology for diagnosing acute infection due to its poor predictive value. Serologic testing is not FDA approved and requires collection of both acute and convalescent serum spaced four to six weeks apart, which is clinically impractical [19]. Serology is most often used for retrospective diagnosis.

TREATMENT

Empiric therapy — For most patients with community-acquired pneumonia (CAP), the etiology is not known at the time of diagnosis, and empiric treatment is appropriate. In the United States, most recommended empiric regimens include an agent that targets both “typical” pathogens (eg, S. pneumoniae, Staphylococcus aureus) as well as atypical pathogens, such as C. pneumoniae [73].

●For outpatients, most empiric regimens generally include a macrolide (eg, azithromycin), doxycycline, or a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin) (algorithm 1).

●For hospitalized patients not requiring intensive care unit (ICU) admission, treatment with a either a respiratory fluoroquinolone (such as levofloxacin or moxifloxacin) or treatment with a beta-lactam (such as ceftriaxone or cefotaxime) plus a macrolide (such as azithromycin) are first-line options (algorithm 2).

Precise recommendations differ for patients requiring admission to the ICU and may require modification based on severity of illness, patient comorbidities and drug intolerances, local epidemiology, and risk factors for multidrug-resistant organisms. Recommendations for antibiotic selection and duration of therapy vary with treatment setting and are discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

Directed therapy — Chlamydia spp. are susceptible to antibiotics that target protein and DNA synthesis, with a spectrum similar to M. pneumoniae.

●When a microbiologic diagnosis of C. pneumoniae infection has been made in a patient with pneumonia, we suggest azithromycin as first-line therapy (table 1).

●Fluoroquinolones, other macrolides, and tetracyclines that have high intracellular penetration are also reasonable options.

Our recommendations are derived from the in vitro susceptibility patterns of C. pneumoniae, antibiotic side effect profiles, and limited data from clinical trials. In vitro, C. pneumoniae is susceptible to tetracyclines, fluoroquinolones, and rifampin. Acquired resistance to these agents does not appear to occur, including when isolates are tested following therapy [74]. Penicillins have limited activity against Chlamydia spp; cephalosporins have no meaningful activity. C. pneumoniae is intrinsically resistant to aminoglycosides, glycopeptides (eg, vancomycin), trimethoprim, and sulfamethoxazole [74].

No clinical trial has directly evaluated the efficacy of these antibiotics on clinical outcomes in adults with pneumonia caused by C. pneumoniae, although several studies have evaluated microbiologic efficacy. In evaluation of all-comers with CAP, several large systemic reviews and randomized trials found no difference in mortality when comparing empiric regimens that contain antibiotics that target atypical organisms with those overall [75-78]. However, reduced rates of clinical failure have been detected in a meta-analysis of randomized trials [78] as well as several subgroup analyses of patients with CAP caused by atypical organisms [75-77].

Subgroup analyses of patients with culture-confirmed C. pneumoniae pneumonia from several clinical trials have demonstrated approximately 80 percent efficacy for microbiologic eradication of the organism from the nasopharynx with 5-day courses of azithromycin [79,80] and 70 to 100 percent efficacy with 10-day courses of clarithromycin, erythromycin, or moxifloxacin [81,82] and 7- to 10-day courses of levofloxacin [83]. Whether microbiologic eradication is necessary for clinical cure is not known.

PROGNOSIS — Pneumonia caused by C. pneumoniae is typically mild, and most patients recover without complications. The associated cough can be prolonged, with a median duration of 21 days and range of 1 to 64 days [26,45]. Mortality is most often reported for atypical pneumonia in aggregate and ranges from about 0 to 4 percent [9,84]. C. pneumoniae has also been associated with asthma [51,85-87] and reactive arthritis [88-90].

INFECTION CONTROL — C. pneumoniae can be transmitted from person to person, although the precise mode of transmission is not known. The United States Centers for Disease Control and Prevention (CDC) recommend standard precautions for patients in health care facilities with pneumonia caused by C. pneumoniae, as well as for patients with community-acquired pneumonia in whom the cause is not known. We also use standard precautions for isolated cases of pneumonia caused by C. pneumoniae, but enhanced infection control measures include droplet precautions during outbreaks or when there is evidence of intra-facility transmission.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Community-acquired pneumonia in adults".)

SUMMARY AND RECOMMENDATIONS

●Microbiology – Chlamydia pneumoniae is an obligate intracellular bacterium that causes respiratory tract infections including pharyngitis, bronchitis, and pneumonia. Pneumonia caused by C. pneumoniae is typically community acquired and mild. (See 'Microbiology' above.)

●Epidemiology – Rates of C. pneumoniae in adults with community-acquired pneumonia (CAP) vary among studies, ranging from <1 to 20 percent of cases in which a pathogen was identified. The incidence appears to be higher in patients with mild infection seen in the ambulatory setting and declines in patients with increasing disease severity, including hospitalized patients and those admitted to intensive care units. (See 'Epidemiology' above.)

●Clinical features – Pneumonia caused by C. pneumoniae presents similarly to other forms of CAP and is characterized by fever, cough, and shortness of breath. No clinical features clearly distinguish pneumonia caused by C. pneumoniae from pneumonia due to other causes. (See 'Clinical features' above.)

●Approach to diagnosis – We typically individualize our approach to testing based on the patient's severity of illness, the likelihood that results would change management, and the availability of a polymerase chain reaction (PCR)-based assay. When a PCR-based assay is available onsite, we favor testing for most patients as results are typically available within a few hours of testing. A positive test result (in the absence of clinical suspicion for coinfection) is considered diagnostic and can help rapidly direct antibiotic therapy. (See 'Approach to diagnosis' above and 'Directed therapy' above.)

●Test of choice (PCR) – When microbiologic diagnosis is pursued, we use a PCR-based assay. PCR-based assays can be performed on most specimen types, including nasopharyngeal swabs, sputum, and bronchoalveolar lavage (BAL) fluid. (See 'Microbiologic testing' above.)

●Empiric treatment – For most patients with CAP, the etiology is not known at the time of diagnosis, and empiric treatment for CAP is appropriate (algorithm 1 and algorithm 2). (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Initial empiric therapy'.)

●Directed therapy – For patients with microbiologically confirmed C. pneumoniae pneumonia, we suggest azithromycin as first-line therapy (Grade 2C). We use 500 mg of azithromycin orally on day 1 followed by 250 mg orally once daily on days 2 to 5. Fluoroquinolones, other macrolides, and tetracyclines are also reasonable options. Refer to the table for drug dosing and duration of therapy (table 1). (See 'Directed therapy' above.)

●Prognosis – Most patients with pneumonia caused by C. pneumoniae recover without complications, although cough can be prolonged, with a median duration of 21 days. (See 'Prognosis' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Dori F Zaleznik, MD, who contributed to an earlier version of this topic review.

UpToDate also gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.