Chapter 259. Chlamydia

The name chlamydiae is derived from the Greek word “chlamys” representing the cloak-like mantle worn by men in Ancient Greece.1 Upon initial discovery, chlamydiae were thought to be intracellular pathogens that cloaked the nucleus of an infected cell. Scientists have since discovered that chlamydiae are nonmotile, gram-negative, obligatory intracellular bacteria. These organisms cannot produce energy and thus survive by acting as a parasite using the energy mechanics of its infected host. The appearance of the cloak is now known to represent the host’s cytoplasmic vesicle with numerous individual chlamydia organisms inside.

The four recognized species within the genus of Chlamydia are C psittaci, C pneumoniae, and C trachomatis, all of which cause disease in humans (Table 259-1), and C pecorum which causes disease in pigs, sheep, and cattle, but not in humans.1Chlamydia psittaci is responsible for psittacosis (ornithosis). Chlamydia pneumoniae causes pneumonia, pharyngitis, and bronchitis. Chlamydia trachomatis has at least 15 different serotypes, known as serovars, that are associated with a spectrum of diseases. Serovars A to C are associated with trachoma, D to K with genital infections, and L1 to L3 with lymphogranuloma venereum. The most common infections of C trachomatis are those of the genital tract which present as urethritis and epididymitis in the male and cervicitis and salpingitis in the female. Neonates can present with conjunctivitis and pneumonia infection acquired by passage through an infected mother’s genital tract.

Chlamydiae all have biphasic cycles of replication.1 The elementary body that represents the “infectious” particle enters the host cell and lives within the host’s cytoplasmic inclusion particles. The organism then begins its secondary vegetative state known as the reticulate body and replicates by binary fission. Each inclusion body begins to form multiple progeny that will be extruded as new infectious elementary bodies to begin the cycle once again.

Chlamydia psittaci or the new proposed name Chlamydophila psittaci is an obligate intracellular, gram-negative bacterium.2 The pathogen causes psittacosis which is also referred to as ornithosis. Psittacosis is contracted by human beings from infected birds and their contaminated droppings All birds, including pet birds (parrots, parakeets, macaws, and cockatiels) and poultry (turkeys, ducks, chickens, and other fowl), are most frequently involved in transmission to humans; however, mammals such as sheep, cattle, goats, and cats have also been shown to transmit infection to humans.2-8 The birds show a spectrum of disease as they can have no evidence of disease or could appear ill and die. Birds transmit the disease to humans by the respiratory route from feces, fecal dust, or secretions of infected animals. The incidence among poultry workers, pet shop workers, and exotic bird importers can be high. In one study, during an outbreak of psittacosis on an Australian duck farm and processing plant, serological tests found that 76% of workers had antibody to C psittaci.8 From 1991 through 2006, the US Centers for Disease Control and Prevention reported 607 cases of psittacosis.9 This is likely an underestimate because C psittaci is difficult to diagnose and may not be considered in the differential diagnosis. Person-to-person transmission is also possible, and health care personnel can acquire the disease from patients. Children infrequently acquire the disease, probably because they are less likely to be exposed to infected animals.

Clinical Features

C psittaci should be included in the differential diagnosis for atypical pneumonia and is difficult to distinguish between C psittaci pneumonia and other causes of community-acquired pneumonia such as Legionella pneumophilia, Mycoplasma pneumoniae, or Coxiella burnetii. The onset of symptoms of psittacosis typically present 5 to 10 days after exposure.2 Clinically, two main forms of the infection occur. The more common form presents with symptoms of fever, chills, headache, and pneumonia; less commonly, the illness may present as a severe influenza-like illness or mild case of typhoid feve. The patient’s temperature rises steadily, and there may be complaints of headache, malaise, and nausea.3 Mental confusion may be observed. If pneumonia is present, as it is in most patients, the cough is prominent and the sputum may be blood-streaked. Delay in diagnosis and treatment can lead to septic shock, multiorgan failure, pancreatitis, and myocarditis, which are all severe complications of the disease. C psittaci can be associated with significant morbidity and mortality during pregnancy in mothers exposed to infected sheep.5-7 Radiologically, the appearance is that of an extensive interstitial pneumonia which can be confused with other atypical pneumonia etiologies. If the infection is left untreated, the disease can last several weeks and present as a nonremitting chronic cough.

Diagnostic Evaluation

A diagnosis of psittacosis can be confirmed by one of three confirmatory laboratory studies combined with a history of potential exposure and a clinical history suggestive of the illness.10 The first laboratory method is culture from respiratory secretions yielding positive growth of C psittaci. The second method is using complement fixation (CF) or microimmunofluorescence (MIF) techniques to demonstrate a 4-fold or greater increase between paired acute- and convalescent-phase serum specimens collected 2 weeks apart. The third method is detection of IgM antibody against C psittaci by MIF (to a reciprocal titer of greater than or equal to 16). Elevated CF titers also may result from C pneumoniae and C trachomatis infections; therefore, MIF assays should be used to distinguish C psittaci infection from infection with other Chlamydial species.

Treatment and Prevention

The treatment of choice for C psittaci infection is tetracycline 500 mg every 6 hours given orally for 10 to 14 days.2 Alternatively, tetracycline can be given parenterally if the oral medication cannot be given. Clinical improvement occurs in 48 to 72 hours, and treatment should continue for at least 10 to 14 days after the fever resolves to avoid relapse. Erythromycin is recommended for children less than 8 years of age and for pregnant women. Azithromycin, clarithromycin, and chloramphenicol are also effective.

The incidence of psitticosis has decreased since the implementation of importation controls of parrots and other exotic birds into the United States. Confirmed cases of psitticosis should be reported to the local or state health department.2 Standard precautions are appropriate for infection control.2,10

Chlamydia pneumoniae, or the proposed new name, Chlamydophila pneumoniae, is a common respiratory pathogen worldwide.11 In 1983, the first respiratory isolate of C pneumoniae was collected in Seattle during a study involving college students with pharyngitis.12 The first 2 isolates from these young adults were designated “TW-183,” which was a conjunctival isolate, and “AR-39,” which was a respiratory isolate; the organism was called “TWAR.” The organism is antigenically distinct from the other two Chlamydia species of Chlamydia trachomatis and Chlamydia psittaci and has been classified as a separate and third species under the name Chlamydia pneumoniae or Chlamydophilia pneumoniae.11

Over the past 2 decades with improvements in diagnostics and epidemiologic studies, C pneumoniae was found to be a common and important cause of community-acquired pneumonia in children and adults.11 It is transmitted by aerosolized respiratory secretions from person-to-person contact. The average incubation period is 21 days.11

In the United States, about 50% of adults have evidence of past infection with C pneumoniae by age 20.11Hospital-based studies have shown that C pneumoniae is responsible for 2% to 10% of community-acquired pneumonia in adults.13 In children, studies using the microimmunofluorescence method show increasing C pneumoniae antibody prevalence rates beginning in school-agechildren which reach 30% to 45% in adolescents.14 Small epidemics have also been described in colleges and among military recruits.13,15

Clinical Features

C pneumoniae can cause upper and lower respiratory tract infections; the most common clinical manifestations of C pneumoniae include pneumonia and bronchitis.16 In studies examining the etiology of pediatric community acquired pneumonia worldwide, C pneumoniae was found in 3% to 14% of cases.17-20 In addition to pneumonia, acute otitis media, rhinitis, sinusitis, and pharyngitis can also be seen.

The most common symptoms include cough, rhinitis, fever, and sore throat, followed by headache, dyspnea, and earache (eTable 259.1).15 Clinical findings may resemble influenza. The initial rhinitis and pharyngitis are followed by the development of a chronic cough with bronchitis or pneumonia that can last for several weeks. In addition to a prominent cough, the patient may have rales, rhonchi, or wheezing. A radiograph of the chest typically shows patchy infiltrates. The overall nature of this infection is typically nonspecific and resembles other etiologic agents of atypical pneumonia such as Legionella or Mycoplasma pneumoniae (see Chapters 264 and 273).

Diagnostic Evaluation

C pneumoniae may be identified by culture, polymerase chain reaction (PCR), antigen detection, and serologic testing; however, no reliable commercial diagnostic tests have been approved by the US Food and Drug Administration for clinical use.11 In the clinical setting, serology is the testing of choice. The microimmunofluorescence (MIF) antibody test is the most sensitive and specific serologic test for acute infection.11 IgM antibodies appear within 2 to 3 weeks after onset of illness followed by IgG antibodies, which peak 6 to 8 weeks after onset.11 A confirmatory test will show an IgM titer of 1:16 or greater or a 4-fold rise in IgG titer when comparing acute to convalescent titers.

Because C pneumoniae is a fastidious and slow-growing organism, culture is not useful clinically. PCR has been used to detect C pneumoniae in the nasopharynx, sputum, blood, or tissue,22 but it is mainly used in research settings and is not readily available clinically. A positive PCR may reflect asymptomatic shedding of C pneumoniae and may not actually identify the cause of the patient’s illness.

Treatment and Prevention

Macrolides (erythromycin, azithromycin, and clarithromycin) and tetracyclines are effective for treatment of C pneumoniae and are therefore recommended as first-line treatment options.11 One study showed a 79% eradication rate of C pneumoniae from the nasopharynx after a 10-day course of clarithromycin and an 86% eradication rate with a 10-day course of erythromycin.23 The newer fluoroquinolones such as levofloxacin and moxifloxacin which have been shown to be effective.24 A duration of 5 to 10 days may be effective, but given the tendency for prolonged symptoms and recurrence of symptoms, treatment of 14 to 21 days is suggested.11With regard to infection control, standard precautions are used.11

Complications

Certain chronic inflammatory diseases have been linked with C pneumoniae infection, including asthma and chronic obstructive pulmonary disease.25-26 For asthma, C pneumoniae has been studied as a risk factor for either the development or the exacerbation of asthma. C pneumoniae has also been linked to chronic obstructive pulmonary disease (COPD) exacerbations. Further study is needed to examine these relationships.

C pneumoniae has been associated with atherosclerosis and cardiovascular disease. C pneumoniae may exist within atherosclerotic plaques.27 It remains unclear whether C pneumoniae is a causal agent or whether its presence reflects prior infection.

Chlamydia trachomatis is the leading bacterial pathogen of sexually transmitted infections worldwide. Sexually transmitted infections are discussed in Chapter 233, including a detailed discussion of the diagnosis and management of nongonococcal urethritis, epididymitis, and endocervitis. In 1999, the World Health Organization (2001) estimated that 92 million new cases of C trachomatis infections occurred globally.28-30 In the United States in 2006, there were 1,030,911 chlamydia diagnoses reported to the CDC.29 However, it is estimated that there are as many as 2.8 million new cases of C trachomatis infection each year because the majority of cases go undiagnosed.29-30 Most infected men and women are asymptomatic and are diagnosed from either routine screening or as a result of a known infected partner. Men usually do not have long-term complications from infection but are important in continued transmission as carriers. Women are at greater risk for complications because most infections are initially asymptomatic and unrecognized. If the infection is not diagnosed and treated, severe complications including pelvic inflammatory disease (PID), ectopic pregnancy, and infertility can occur. Therefore, C trachomatis infections present an enormous public health problem throughout the world. Although the highest age-specific rates of chlamydia were in females 15 to 19 years of age (2862.7 cases per 100,000 females), followed by females 20 to 24 years of age (2797.0 cases per 100,000 females) these higher rates compared to men reflect increased detection from higher rates of screening in women.29 Given the high prevalence of Chlamydia in women 15 to 24 years of age, the CDC recommends annual chlamydia screening for all sexually active women who are younger than 26 years of age (eFig. 259.1).30

Clinical Features, Treatment, and Prevention by Site

Infections of the Genital Tract

Nongonococcal Urethritis

Nongonococcal urethritis in the male is a common sexually transmitted disease caused by C trachomatis in 15% to 55% of cases.30 The presumptive diagnosis is made by examining the urethral discharge and excluding gonorrhea by smear and culture; or by rapid tests using ligase or nucleic acid amplification technique (polymerase chain reaction) testing of urine for C trachomatis. The definitive diagnosis is made by culturing chlamydia from a urethral specimen.

The treatment of choice for chlamydial urethritis is azithromycin 1 g orally in a single dose or doxycycline 100 mg orally twice a day for 7 days.30 Erythromycin, ofloxacin, or levofloxacin are alternative drugs. Successful treatment requires that the sexual partners of the patient be treated as well.

Epididymitis

Epididymitis, an important complication of urethritis in young men, may be caused by Neisseria gonorrhea or Chlamydia trachomatis and is treated with a 10-day course of oral doxycycline twice daily for the chlamydia and ceftriaxone 250 mg IM in a single dose for gonorrhea. A 10-day course of ofloxacin or levofloxacin can also be used.30

Female Genital Tract Infections

In most women, chlamydial infections are asymptomatic, but women with C trachomatis can present with endocervical erosions, a mucopurulent cervical exudate, or urethritis.30 In addition, chlamydial infection is a common cause of PID in sexually active adolescents and women. Diagnosis depends on demonstration of C trachomatis in a cervical specimen either by culture or the rapid direct slide immunofluorescence method using monoclonal antibodies. Nucleic acid amplification tests (NAATs) can also be used and are able to detect small amounts of chlamydial nucleic acid by a urine sample, or a urethral or endocervical swab. Treatment for uncomplicated female genital tract infections includes doxycycline, 100 mg orally twice daily for 7 days or 1 gram of azithromycin given orally in a single dose (Table 233-2).30 Azithromycin, erythromycin, or amoxicillin is recommended for treatment in pregnant women (eTable 259.2).30 Sexual partners must also be treated to prevent reinfection.

Data from a randomized controlled trial of chlamydia screening in a managed care setting suggested that screening programs can lead to a reduction in the incidence of PID by as much as 60%.31 As with other inflammatory sexually transmitted infections, chlamydia infection can facilitate the transmission of HIV infection. In addition, pregnant women infected with chlamydia can pass the infection to their infants during delivery, potentially resulting in neonatal ophthalmia and pneumonia.

Lymphogranuloma Venereum

Lymphogranuloma venereum is a sexually transmitted chlamydial disease caused by serovars L1 to L3. The incidence of this disease has declined in the United States, but it is still quite prevalent in tropical and subtropical areas.32 Tender, unilateral inguinal or femoral lymphadenopathy is the most common clinical manifestation of LGV among heterosexual men.30,32 Women and homosexually active men may have proctocolitis or involvement of perirectal or perianal lymphatic tissues resulting in fistulas and strictures.32 The disease is rare in children and infrequently seen in adolescents.

LGV can manifest as acute or chronic disease because it is a disease of the lymphatic tissue.33First, there is a primary lesion, which is transient and clinically mild, usually appears as a papule or a shallow ulcer on the penis or vaginal wall, and generally heals without scar formation (eFig. 259.2). Systemic manifestations can include fever, chills, and anorexia. In the secondary stage, occurring 2 to 6 weeks after the primary lesion, there is pronounced lymphadenitis or lymphadenopathy in the inguinal area (Fig. 259-1). The nodes are large and often fluctuant, forming buboes. This stage of disease is found predominantly in males. In the tertiary stage, which is not necessarily preceded by lymphadenopathy, there is a chronic inflammatory response with fibrosis which can result as strictures in the anal, rectal, and vaginal areas. Once suspected, the diagnosis can be best confirmed by complement-fixation or microimmunofluorescence tests, using the specific antigens. The treatment of choice is doxycycline 100 mg orally twice a day for 21 days (eTable 259.3).30 For children less than 8 years of age, erythromycin base (2 grams per day in 4 divided doses for 21 days) is recommended.32Some experts recommend a 1 gram dose of azithromycin weekly for 3 weeks; however, there are minimal data using this regimen.32

Perinatally Transmitted Infections

C trachomatis can be transmitted to newborns and can cause purulent conjunctivitis and pneumonia. Notably, 50% to 75% of infants born to infected mothers become infected at one or more sites including the conjunctiva, nasopharynx, vagina, and rectum.33-35 The most frequent site of perinatally acquired chlamydia infection in neonates is the nasopharynx with rates as high as 70% in exposed infants. Furthermore, in those with nasopharyngeal infection, chlamydia pneumonia develops in 30% of infants.35

Newborn Inclusion Conjunctivitis

Acute purulent conjunctivitis in the newborn, also known as inclusion blenorrhea, has an incubation period from 5 to 12 days.32 There is a watery discharge from the eyes that becomes progressively more purulent, with swelling of the eyelids. Left untreated, lymphoid follicles and a membranous conjunctivitis can develop and persist for weeks or months. The conjunctivitis should be distinguished from other pyogenic bacterial infections (N gonorrhoeae and S aureus,) and from chemical conjunctivitis resulting from silver nitrate prophylaxis. N gonorrhoeae conjunctivitis typically occurs in the first 2 to 5 days after birth, whereas chlamydia conjunctivitis occurs later. It may be difficult to distinguish between the two clinically.

Conjunctival cultures on blood and chocolate agar media will identify bacterial pathogens. The most useful diagnostic method is examination of Giemsa-stained conjunctival scrapings for inclusion bodies. Because chlamydia are obligate intracellular agents, the conjunctivae must be scraped rather than swabbed to obtain an adequate specimen. The infection can also be diagnosed by culture, immunofluorescence, or enzyme-linked immunosorbent assay (ELISA).

Topical treatment of neonatal conjunctivitis is not recommended because local eye treatment does not prevent or clear nasopharyngeal carriage and, thus, the further risk of developing pneumonia or repeated episodes of conjunctivitis.35

Optimal management is oral erythromycin, 50 mg/kg per day in 4 divided doses daily for 14 days.30 Because treatment is not 100% effective, a second course may be needed.32

Attempts to provide prophylaxis through antibiotic regimens administered topically to the eyes shortly after delivery has not been 100% effective with either erythromycin or tetracycline because neither eliminates nasopharyngeal colonization and further risk for pneumonia. Prevention can be achieved only by identifying and treating pregnant women prior to delivery.

Chlamydial Pneumonia of Infancy

C trachomatis pneumonia usually occurs during an infant’s first 4 months of life. Chlamydial pneumonia is seen in 30% of infants with nasopharyngeal infection.34,35 The classic symptoms of chlamydial pneumonia of infancy include a staccato cough that worsens over time; nasal obstruction; and a respiratory exam showing tachypnea or rales, but no wheezing.36 Fever is usually not present (eTable 259.4).37 The infant may appear mildly to moderately ill. On chest radiological imaging, hyperinflation with bilateral interstitial infiltrates is the classic finding. The recommended treatment is azithromycin (20 mg/kg orally once daily for 3 days) or erythromycin base or ethylsuccinate(50 mg/kg per day in 4 divided doses) for 14 days.30,32 The diagnosis of chlamydial pneumonia (or conjunctivitis) in a neonate is clear evidence of maternal infection, and thus the mother and her partner should be treated.

Trachoma

Trachoma is responsible for about 3% of blindness worldwide along with cataracts, glaucoma, and diabetic retinopathy. Approximately 1.3 million people worldwide are blind from trachoma, and 84 million people have active trachoma infection.38,39 The global distribution is shown in eFigure 259.2. Trachoma is caused by Chlamydia trachomatis which spreads through contact with eye discharge from the infected person (on towels, handkerchiefs, fingers, etc.) and through transmission by eye-seeking flies. It is associated with poverty and unsanitary living conditions. In hyperendemic areas active disease is most common in pre-school children with prevalence rates as high as 60–90%.

Active trachoma starts as the presence of follicles on the tarsal conjunctiva.40 The follicles heal with necrosis and cause severe conjunctival scarring. This in turn produces lacrimal stenosis, lid distortion, and entropion and trichiasis. The chronic keratoconjunctivitis then progresses to severe scarring of the cornea and finally to blindness. The end result occurs after many years of active disease. The World Health Organization (WHO) developed a grading system including at least 2 of the following 4 criteria to diagnose trachoma: lymphoid follicles on the upper tarsal conjunctiva, typical conjunctival scarring, vascular pannus, and limbal follicles.39,40 (See: http://www.who.int/ncd/vision2020_actionplan/documents/Simplifiedgradingoftrachoma.PDF, accessed August 8, 2010.)

The diagnosis of trachoma is usually clinical but can be confirmed by examining conjunctival scrapings with a Giemsa stain or immunofluorescence demonstrating the infective particles. Chlamydia can also be cultured. Serologic tests are not very helpful, but they are important epidemiologic tools to assess prevalence.

The World Health Organization (WHO) has a goal of globalelimination of blindness attributable to trachoma by 2020 by utilizing 4 preventionand treatment methods: surgery for trichiasis, antibiotics, face washing, and environmental improvement(SAFE). Antibiotic treatment is prolonged either with topical antibiotics or oral agents.32 Mass antibiotic treatment with azithromycin once or twice ayear or topical tetracycline twice daily for 6 weeks areeffective in treating large populations in areas of high endemicity.41The treatment and control of trachoma are complex and involve important international health issues as outlined in the WHO trachoma control guide for program managers available at: http://www.who.int/blindness/publications/tcm%20who_pbd_get_06_1.pdf(accessed August 8, 2010).