Three chlamydial organisms are pathogenic to humans: Chlamydophilapneumoniae, Chlamydophila psittaci, and Chlamydia trachomatis. These are small, gram-negative, obligate intracellular organisms. All three species can cause pneumonia in humans.
C pneumoniae causes mild pneumonia or bronchitis in adolescents and young adults. Older adults may experience more severe disease and repeated infections.
C psittaci causes psittacosis or ornithosis after exposure to an infected bird. Ornithosis is the preferred term, because almost any bird can transmit the organism. The clinical spectrum of C psittaci infection ranges from an asymptomatic infection to a fulminant toxic syndrome. Patients with ornithosis most commonly present with pneumonia or fever of unknown origin.
C trachomatis is an important cause of sexually transmitted diseases, including trachoma, pelvic inflammatory disease, and cervicitis. C trachomatis can also cause pneumonia, primarily in infants and young children. Document cases of pneumonia due to C trachomatis have been reported in immunocompromised adults and laboratory workers.
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Chlamydiae have a unique biphasic reproductive cycle. They attach to the outer membrane of susceptible host cells and enter throughout endocytosis. Once inside, they produce cytoplasmic inclusions known as reticulate body. These replicate into multiple colonies of the infectious form, known as elementary body, which are then released during cell lysis to start the cycle again. 
The mode of transmission is different among the three species (C pneumoniae, C psittaci, and C trachomatis), but all can cause systemic disease by hematogenous spread. Respiratory secretions transmit C pneumoniae from human to human, whereas infected birds transmit C psittaci to humans via a respiratory route through direct contact or aerosolization.  Birds known to cause ornithosis include cockatiels, parrots, parakeets, macaws, chickens, ducks, turkeys, pigeons, and sparrows, among others.
When a pregnant woman have a C trachomatis infection of the cervix, the organism is transmitted when the infant passes through the infected birth canal. C trachomatis infection may cause neonatal conjunctivitis, nasopharyngitis, otitis media, and pneumonitis. The tendency to chronic inflammation is typical, and chronic persistent infection may occur if a neonatal infection remains untreated.
Immunity to chlamydial organisms is usually not persistent, leading to repeated and chronic infections, particularly in the ocular and urogenital systems.
The incidence and prevalence of the chlamydial pneumonias vary with the causative organism.
C pneumoniae pneumonia
Accurate epidemiologic data on C pneumoniae is limited due to multiple factors. Successful isolation of a causative organism in cases of community-acquired pneumonia in the US is achieved in only one third of the cases.  In addition, data also vary based on the population studied, the clinical setting, and the diagnostic test used.
The estimated number of cases of C pneumoniae pneumonia per year in the United States is 300,000, and the pathogen is estimated to cause 1-20% of community-acquired pneumonia (CAP) cases among adults. [4, 5, 6, 3, 7] In contrast, the incidence of C pneumoniae pneumonia may be as high as 50% in children with CAP.  Globally, an analysis using two comprehensive international databases showed that the incidence of CAP due to C pneumoniae from 4,337 patients was 8% in North America, 7% in Europe, 6% in Latin America, and 5% in Asia. 
Although C pneumoniae pneumonias occur every year, epidemiologic studies suggest a 4-year cycle. This disease is more common in males (60-90%) than in females, a difference possibly due to cigarette smoking. The incidence of C pneumoniae pneumonia is highest among the elderly. This organism has also been linked to outbreaks of pneumonia among young adults in close-quarter environments. 
C pneumoniae pneumonia is often a primary infection in persons aged 7-40 years. Reinfection pneumonia is more common in the elderly. Approximately 50% of young adults and 75% of elderly persons have serologic evidence of a previous infection. 
C psittaci pneumonia
Psittacosis was first reported in Europe in 1879. Anyone exposed to an infected bird is at risk for infection with C psittaci. This disease is found worldwide and year-round, with most cases being sporadic.
Cases of ornithosis in the United States declined after the introduction of antibiotic-laced bird feed and a quarantine period of 30 days for imported birds. From 1988-1998, 813 cases of psittacosis in humans were reported to the US Centers for Disease Control and Prevention (CDC).  The Council of State and Territorial Epidemiologists revised the case definition for psittacosis in June 2009 to include more stringent laboratory criteria for confirmed and probable cases. As a result, only 4 cases of psittacosis were reported in 2010, as compared with an average of 16 (range: 9–25) cases reported from 2000-2009.  Additional information about case reporting of psittacosis can be found through the National Association of State Public Health Veterinarians.
Approximately 70% of the psittacosis cases with a known source of infection result from exposure to a pet bird. The diagnosis of psittacosis can be difficult, and many more cases may be undiagnosed or unreported.
C trachomatis pneumonia
In infants, an estimated 12,000 cases of pneumonia due to C trachomatis occur each year, and approximately 5-22% of pregnant women are thought to have C trachomatis infection of the cervix; 30-50% of neonates born to infected mothers show culture evidence of infection. Of infected neonates, 15-25% present with clinical conjunctivitis and/or nasopharyngitis which can develop into neonatal pneumonitis in some cases, and approximately 11-20% of infants born to infected mothers develop symptomatic pneumonia before 8 weeks of age.  Adult cases have been reported in immunocompromised hosts. 
The evaluation of suspected cases of chlamydial pneumonias is discussed below.
C pneumoniae pneumonia
Most patients infected with C pneumoniae remain asymptomatic. The incubation period is approximately 3-4 weeks. Symptoms develop in a biphasic pattern characterized by an initial period of upper respiratory tract symptoms (eg, rhinitis, laryngitis, pharyngitis, sinusitis), followed by symptoms of pneumonia after 1-4 weeks.
Fever is present in the first several days, less often after 1 week. Cough is prominent, with scant sputum production and may persist for weeks to months despite therapy, along with malaise. 
Hoarseness is more common in C pneumoniae pneumonia than in mycoplasma or other pneumonias. Headache occurs in as many as 60% of cases and may be important as a nonclassic pneumonia finding. 
Pharyngeal erythema without exudate occurs in various atypical pneumonias; however, sinus percussion tenderness is more common with C pneumoniae pneumonia than with other pneumonias.
Rhonchi and rales are often present even in mild disease.
C psittaci pneumonia
Exposure to birds, especially sick ones, is a clue to the diagnosis of C psittaci pneumonia. However, as many as 25-50% of cases with ornithosis deny contact with a bird.  Pet shop employees and poultry industry workers are also at risk. It is important to obtain an occupational and avocational history in all patients with CAP.
The incubation period of C psittaci pneumonia is 5-14 days or longer. Disease severity ranges from mild to severe with associated systemic illness. Mortality occurs in less than 5% of cases. Abrupt onset of constitutional symptoms is a common presentation in symptomatic patients. Fever is the most common symptom and may reach 103-105°F (39.4-40.5°C). Some patients may present with culture-negative endocarditis or fever of unknown origin. Defervescence is usually slow. Nonproductive cough has been observed in 50-80% of cases; however, this symptom is often absent initially. Chest pain is common, but pleuritic pain is rare. Auscultatory findings may be sparse and may underestimate the extent of pneumonia.
Photophobia, epistaxis, tinnitus, deafness, gastrointestinal symptoms, and arthralgia have been reported in less than half of patients.
Physical findings that suggest ornithosis include a pulse-temperature dissociation (fever without elevated pulse), somnolence, and splenomegaly. The pulse-temperature dissociation is also seen in Q fever, typhoid fever, and Legionnaires disease. 
Signs of meningitis or encephalitis, including a focal neurologic deficit and seizures, may develop. In addition, hepatitis, hemolytic anemia, disseminated intravascular coagulation, meningoencephalitis, or reactive arthritis may be observed, as well as cutaneous manifestations, including Horder spots (erythematous, blanching, maculopapular rash), splinter hemorrhages, superficial venous thromboses, acrocyanosis, and erythema nodosum. Horder spots resemble rose spots which are observed in patients with typhoid fever.
C trachomatis pneumonia
Nasal obstruction/discharge, cough, and tachypnea are common symptoms in C trachomatis infection. Infants are usually symptomatic for 3 weeks or longer before presentation.
Most patients are afebrile and only moderately ill. Scattered crackles with good breath sounds are characteristic. Wheezing is usually absent. Conjunctivitis and middle ear abnormality are present in half of C trachomatis pneumonia cases.
The differential diagnoses of chlamydial pneumonias include the following conditions:
Other disorders to consider include the following:
C trachomatis infant pneumonia
Respiratory syncytial virus infection
Bordetella pertussis infection
Infection with other respiratory viruses
Tests in Chlamydial Pneumonias
Laboratory studies for diagnosis of chlamydial pneumonias vary with the causative organism.
C pneumoniae pneumonia
The Infectious Diseases Society of America and American Society of Microbiology currently recommend serologic testing or polymerase chain reaction (PCR) for the diagnosis of C pneumoniae. Despite evident drawbacks, serology is still considered the gold standard, but this is likely to change. 
Culture for C pneumoniae is technically complex and time consuming. When compared to serology and PCR, it also has low sensitivity and is mainly used in research labs. 
The preferred serologic test is microimmunofluorescence (MIF). This is more sensitive and specific than complement fixation (CF), although cross reactivity with other chlamydiae species may still occur. 
Criteria for infection include a single IgM titer ≥1:16 or a 4-fold increase in IgG titer. The absence of detectable titers a few weeks after symptom onset does not exclude the diagnosis because antibodies may take several weeks to appear (2-3 weeks for IgM and 6-8 weeks for IgG). In reinfections, IgM may be absent or low, and IgG may appear within 2 weeks.  A single elevation in IgG titer may not be reliable, because elderly patients can have persistently elevated IgG titers due to repeated infections. [22, 20]
Enzyme-linked immunosorbent assay is another serologic test available but has not been validated due to cross reactivity and variations in specificity depending on the antigen used. 
Real-time PCR assays of pharyngeal swab, bronchoalveolar lavage, sputum or tissue can be used to detect C pneumoniae-specific DNA. Because of the complexity of these tests, widespread implementation had been limited until recent years. [26, 27]
The FilmArray Respiratory Panel is a multiplex PCR which detects common respiratory pathogens in nasopharyngeal specimens. In 2012, the US Food and Drug Administration (FDA) approved the addition of 2 corona viruses and 3 bacteria to the Panel, including C pneumoniae, Bordetella pertussis, and Mycoplasma pneumonia.  The FilmArray Panel can now detect 17 viruses and 3 bacteria from a single sample.  Reported sensitivity and specificity were both 100% for C pneumoniae but the sample size was small and fewer than 10 samples were positive in the study. 
Studies comparing PCR to MIF IgM during outbreaks of C pneumoniae have shown comparable sensitivity (68-71% vs. 60-79%) and higher specificity (93-97% vs 77-86%). Overall data suggests molecular testing may be a more useful diagnostic tool in this setting. [31, 20]
Widespread use of molecular testing in the future may increase reliable data on presentation and epidemiology of C pneumoniae pneumonia. 
The white blood cell count is usually not elevated in C pneumoniae infection. Alkaline phosphate levels may be elevated.
C psittaci pneumonia
A single serum titer is insensitive and nonspecific. Confirmation with paired acute and convalescent sera is advised. Serologic tests are preferred, because culture is difficult and hazardous.
According to case definitions from the CDC, a confirmed case involves one of the following criteria: 
Isolation of the organism by culture
Compatible clinical illness with a 4-fold rise (to a reciprocal titer of 32 or greater by paired sera collected at least 2 weeks apart) in CF or MIF antibodies against C psittaci
Detection of an IgM titer of 16 or greater against C psittaci by MIF
The CDC defines a probable case as a compatible clinical illness that is epidemiologically linked to a confirmed case or that has a single antibody titer of 32 or greater by MIF or CF after the onset of symptoms. Above definitions were originally developed for epidemiologic purposes and should not be used as the sole criteria for establishing clinical diagnoses.
A CF test can cross-react with C pneumoniae and C trachomatis. MIF and PCR assays can be used to distinguish C psittaci infection from other chlamydial infections. PCR methods for the detection of C. psittaci are not standardized and currently under investigation.
CDC, Atlanta, GA (404) 639-3563: MIF, CF, PCR, culture
Microbiology Research Labs, Cypress, CA (800) 445-4032: immunofluorescence (IFA), PCR, culture
Lab Corp of America, Burlington, NC: (800) 334-5161: Culture, polyclonal antibody
Specialty Labs, Santa Monica, CA (800) 421-4449: MIF
Antibiotic treatment may delay or diminish the antibody response; therefore, a third sample may be necessary. All serologic tests should be performed simultaneously at the same laboratory.
C trachomatis pneumonia
Clinical findings suggest the diagnosis of C trachomatis pneumonia (see Presentation of Chlamydial Pneumonias); the presence of chlamydial inclusions or elementary bodies on Giemsa-stained smears of the conjunctivae or nasopharynx confirms the diagnosis.
Antichlamydial IgM titer may be elevated in infected infants. Peripheral eosinophilia and elevated serum immunoglobulin levels are characteristic. It is important to screen parents for chlamydia and other sexually transmitted diseases.
Chest radiographs of patients with C pneumoniae pneumonia most commonly show a single subsegmental infiltrate that is mainly located in the lower lobes. Extensive consolidation is rare, although acute respiratory distress syndrome (ARDS) has been reported. No radiographic findings are characteristic. Residual changes can be observed even after 3 months. Pleural effusion occurs in 20-25% of cases.
In C psittaci pneumonia, consolidation in a single lower lobe is the most common finding. However, various findings have been observed, including patchy reticular infiltrates radiating from the hilum, a diffuse ground-glass appearance, and a miliary pattern. Pleural effusions are evident in as many as 50% of cases; however, the effusions are usually small and do not cause symptoms.
In cases of C trachomatis pneumonia, a chest radiograph typically shows bilateral interstitial infiltrates with hyperinflation. 
Intra-alveolar inflammation with a milder degree of interstitial reaction is a characteristic pathologic finding in patients with chlamydial pneumonias. Alveolar-lining cells contain intracytoplasmic inclusions.
Antimicrobials in Chlamydial Pneumonias
The goals of pharmacotherapy are to eradicate infection, reduce morbidity, and prevent complications.
Tetracyclines and macrolides are the drugs of choice for chlamydial pneumonias.  Tetracyclines are bacteriostatic in nature; they work by inhibiting protein synthesis. As a class, tetracyclines have similar antimicrobial profiles, and cross-resistance is likely. Macrolides inhibit bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, thus causing cessation of RNA-dependent protein synthesis.
AZD0914 (AstraZeneca) is a novel DNA-gyrase inhibitor, which has in-vitro activity against C trachomatis and C pneumoniae comparable to commonly used antimicrobials such as levofloxacin, azithromycin, and doxycycline. 
Two new fluoroquinolones have received Fast Track designation by the FDA for different indications. Nemonoxacin was comparable to levofloxacin for the treatment of CAP in a phase II trial. [35, 36] Phase III trials are currently ongoing (NCT02205112).
Management of C pneumoniae Pneumonia
Administer empiric treatment when mixed infections with other organisms are present (eg, pneumococci, mycoplasma, legionella). The frequency of mixed infection can be as high as 60%. Clinicians must treat empirically, because rapid testing for atypical pathogens is not readily available, and antibiotic therapy is usually completed before the results of serology testing become available.
Severely ill hypoxemic patients may require ventilatory support in an intensive care unit.
Drug of choice
Macrolides are the first-line antibiotics for the treatment of C pneumoniae pneumonia. [25, 6] Newer macrolides such as azithromycin (500 mg PO/IV once daily) and clarithromycin (1 g PO once daily [clarithromycin XL] or 500 mg PO twice daily) are better tolerated than erythromycin (250-500mg PO 4 times a day).
Treatment should be continued for at least 10-14 days after defervescence. If symptoms persist, a second course with a different class of antibiotics is usually effective.
Doxycycline (100 mg PO twice daily for 10-14 days) was once the treatment of choice. It is still a favored agent but should be avoided in children younger than 9 years and in pregnant women. Tetracycline hydrochloride (500 mg PO 4 time a day) is also active in vitro.
Fluoroquinolones, including levofloxacin (500 mg PO/IV once daily for 10-14 days or 750 mg PO/IV once daily for 5 days) and moxifloxacin (400 mg PO/IV once daily for 10-14 days) are also alternative options.  Studies investigating the efficacy of erythromycin, clarithromycin, azithromycin, levofloxacin, and moxifloxacin have shown similar results (70-86%) for the eradication of the organism from the nasopharynx. [38, 39]
Telithromycin is the first ketolide antibiotic approved for the treatment of C pneumoniae by US FDA in 2007. This agent is more expensive than doxycycline. Telithromycin is a potent inhibitor of CYP3A4 and can cause potentially dangerous increases in serum concentrations of simvastatin, lovastatin, atorvastatin, midazolam, and other drugs. If this agent is used, statins should be withheld for the duration of therapy. Hepatotoxicity (some fatal cases) has been reported in about 1/1,000,000. Telithromycin is contraindicated in patients with myasthenia gravis.
Patient education and consultations
Educate patients about the possible need for retreatment in case of a protracted course or recurrence.
Consultations with an infectious disease and/or a pulmonary specialist may be required if a patient requires hospitalization or does not respond to therapy.
Complications of C pneumoniae infection include otitis, erythema nodosum, exacerbations of asthma, endocarditis, Guillain-Barré syndrome, reactive arthritis, and encephalitis. 
Although some studies associate C pneumoniae organisms with atheromatous plaques,  multiple sclerosis, macular degeneration, Alzheimer's disease, chronic fatigue syndrome, asthma,  or sarcoidosis, the role of C pneumoniae in the pathogenesis of these diseases remains to be established.  Clinical studies are not supportive of antibiotic use for the prevention of coronary artery disease. [43, 44]
Management of C psittaci Pneumonia
Tetracycline (500 mg PO four times a day) or doxycycline (100 mg PO or IV twice daily) is the treatment of choice for the treatment of C psittaci pneumonia. Severely ill patients should receive doxycycline intravenously (4.4 mg/kg divided in two doses). The optimal duration of therapy is 10 days, followed by an additional 10-14 days after defervescence. A longer course to prevent relapse is controversial.
Azithromycin (250-500 mg PO once daily) is probably effective based on in vitro data and in vivo animal data and considered as second-line treatment.
Erythromycin is an alternative option, but this drug is clearly inferior to tetracyclines and azithromycin and likely to be less efficacious in severe cases.
Patient education and consultations
Educate patients about possible transmission of the disease. Suspected birds should be isolated until a veterinarian examines them.
Patients may require a consultation with an infectious disease and/or a pulmonary disease specialist. In most states, physicians are required to report cases of ornithosis to the appropriate health care authority.
Complications of psittacosis include endocarditis, thrombophlebitis, myocarditis, thyroiditis, pancreatitis, hepatitis, renal failure, disseminated intravascular coagulation, and fetal death. Aortic valve replacement and a prolonged course of antibiotic therapy may be necessary for patients with endocarditis. Severely ill hypoxemic patients may require ventilatory support in an intensive care unit.
Aortic valve replacement may be required for patients with endocarditis.
The incidence of C pneumoniae infection among military recruits during basic training is high, and weekly azithromycin prophylaxis was effective in 58% of the population in this setting.
Past infection with C psittaci does not confer immunity to the disease. Individuals should avoid dust from bird feathers and cage contents as well as handling sick birds for the prevention of C psittaci infection. Furthermore, imported psittacine birds must be treated for 45 days with a balanced feed containing chlortetracycline with 0.7% calcium. Refer infected or potentially infected birds to a veterinarian. Standard infection-control measures and droplet precautions are indicated for patients diagnosed with C psittaci infection. Isolation procedures such as a private room, negative pressure air flow, or masks are not necessary. 
Evaluate mothers of children infected with C trachomatis and their sexual partners, and treat them appropriately. Repeated parental screening may be warranted in a high-risk population.
Outcomes of patients with a chlamydial pneumonia depend on the causative organism and the severity of disease.
C pneumoniae pneumonia
Most cases of infection with C pneumoniae are mild and usually respond to treatment in an outpatient setting. Patients with underlying disease or with concurrent infection (eg, pneumococcal bacteremia) can develop severe illness.
Treatment failure in C pneumoniae pneumonia may occur more often with erythromycin.  Retreatment is often successful, especially with tetracyclines. Complete recovery is slow: cough and malaise may persist for weeks to months despite appropriate treatment.
The mortality rate from C pneumoniae infection was 9.8% in one meta-analysis.  Secondary infection, such as pneumococcal bacteremia, or the presence of severe underlying disease is associated with increased mortality.  A Canadian study reported a mortality rate of 4.9% with C pneumoniae pneumonia, which is comparable to the rate for bacteremic pneumococcal pneumonia (5.4%) and the overall cohort of community-acquired pneumonia (9.4%). 
C psittaci pneumonia
C psittaci infection is usually curable with early diagnosis and appropriate treatment. A full recovery from C psittaci pneumonia usually takes 6-8 weeks, and relapse may occur.
The mortality rate from infection with C psittaci was 20% in the era before the advent of antibiotics. The mortality rate is 5% with antibiotic treatment; it is less than 1% with early diagnosis and appropriate treatment.
C trachomatis pneumonia
Most infants with C trachomatis pneumonia are only moderately ill and respond to appropriate antibiotics; if the infection is not treated, the clinical course may be protracted, and respiratory failure and prolonged spells of apnea may occur.
A higher-than-normal incidence of obstructive airway disease or asthma occurs in children who had chlamydial pneumonia before age 6 months.
Avoid tetracyclines in pregnant women as well as in children younger than 9 years of age.
C pneumoniae or C psittaci pneumonia can be fatal, especially in elderly patients with an underlying disease.
It is important to not only consider C pneumoniae or other atypical pathogens in patients with bronchitis or CAP but also to treat with an appropriate antibiotic.
It is important to consider C psittaci infection in patients who are exposed to a bird or with fever of unknown origin. C psittaci pneumonia must be reported to an appropriate health care authority, and a consultation with a veterinarian should be made for the evaluation and treatment of potentially infected birds which may have transmitted the disease to the patient.
In cases of infants with C trachomatis infection, mothers and their sexual partners must be evaluated and treated appropriately. In younger children, C trachomatis infection can also occur through sexual abuse. An appropriate action should be taken in case of sexual abuse.
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