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Chlamydia Infections
In 1911, Lindner and colleagues identified typical intracytoplasmic inclusions in infants with a nongonococcal form of ophthalmia neonatorum called inclusion conjunctivitis of the newborn (ICN) or inclusion blennorrhea, leading to the elucidation of the epidemiology of sexually transmitted chlamydial infections. Mothers of affected infants were found to have inclusions in their cervical epithelial cells, and fathers of affected infants had inclusions in their urethral cells. For 50 years, cytologic demonstration of chlamydial inclusions in epithelial cells was the only diagnostic procedure available. When chlamydial isolation procedures were developed, first in the yolk sac of the embryonated hen’s egg and later in tissue culture, studies again showed Chlamydia trachomatis as the etiology of conjunctivitis in the index case and then confirmed the genital tract reservoir of the agent. Although ICN was studied for 60 years, an appreciation of the importance of chlamydial infection of the respiratory tract in infants did not evolve until the late 1970s, with the impetus of the report by Beem and Saxon.
C. trachomatis is now recognized as the most common sexually transmitted bacterial pathogen in Western industrialized society. Although most C. trachomatis infections in men and women are asymptomatic, infection can lead to severe reproductive complications in women. The infection can be transmitted from an infected mother to her newborn during delivery, producing conjunctivitis or pneumonia or both. C. trachomatis is likely the most common cause of conjunctivitis in infants younger than 1 month and is a common cause of afebrile pneumonia in infants younger than 3 months.
Epidemiology and Transmission
Reported chlamydial prevalence rates in the United States include 2% to 7% among female college students, 4% to 12% among women attending a family planning clinic, and 6% to 20% among men and women attending a clinic for sexually transmitted diseases or persons entering correctional facilities. Many men and most women infected with C. trachomatis are either asymptomatic or minimally symptomatic, and presentation for diagnosis is a result of screening or referral after a contact develops symptoms. Regional estimates are hampered by underdiagnosis and underreporting of cases. Because symptoms are absent or minimal in most women and many men, a large reservoir of asymptomatic infection is present that can sustain the pathogen within a community.
Young age (<20 years) is the sociodemographic factor most strongly associated with chlamydial infection (relative risk among women <25 years of age compared with older women is 2 to 3.5). Although the prevalence of chlamydial infection is increased in the black population and in socioeconomically disadvantaged individuals, there is broad socioeconomic and geographic distribution of infection. Other risk factors for cervical chlamydial infection in women are anatomic or hormonal (i.e., use of depot-medroxyprogesterone acetate injections or ectopy after use of oral contraceptives), and behavioral (i.e., number of sexual partners).
For purposes relevant to this chapter, the major method of transmission of C. trachomatis is sexual. Partner transmission rates are approximately 65% and appear to be similar for female-male and male-female transmission. The child-to-child and intrafamilial infecting patterns that predominate in trachoma endemic areas have not been proven to cause disease in newborns. Chlamydiae cause one third to one half of nongonococcal urethritis in men, and concomitant infections with gonococci are common in both men and women.
An infant born to a mother with a chlamydial infection of the cervix is at 60% to 70% risk of acquiring the infection during passage through the birth canal. Of exposed infants, 20% to 50% develop conjunctivitis, and 5% to 20% develop pneumonia. The rectum and vagina of infants exposed during delivery may also be infected, but a clear-cut relationship with disease in these sites has yet to be elucidated. In utero transmission is not known to occur. Infection after cesarean section is seen rarely, usually after premature rupture of the membranes. No evidence supports postnatal transmission from the mother or other family members.
Studies in the 1980s identified C. trachomatis in 14% to 46% of infants younger than 1 month with conjunctivitis. The prevalence of neonatal chlamydial inclusion conjunctivitis has decreased in areas where screening and treatment of chlamydial infection in pregnant women is a regular practice. In the Netherlands, prenatal screening for C. trachomatis is not routine. Evaluation of infants younger than 3 months referred to a Dutch children’s hospital or to an ophthalmologist for evaluation of persistent conjunctivitis from 1996 to 2002 revealed C. trachomatis infection in 63%.
There is no evidence to suggest that infants with chlamydial infections should be isolated. Transmission of the organism to other infants in nurseries or intensive care units has not been reported. Standard precautions consisting of hand hygiene between patient contacts are recommended. Use of protective gloves, masks or face shields, and nonsterile gowns is recommended when performing procedures likely to generate splashes of body fluids, secretions, or excretions.
Microbiology
Pathogen
Chlamydiae are obligate intracellular parasites that cause various diseases in animal species at virtually all phylogenetic levels. Traditionally, the order Chlamydiales has contained one genus with four recognized species: C. trachomatis, Chlamydia psittaci, Chlamydia pneumoniae, and Chlamydia pecorum. More recent taxonomic analysis involving the 16S and 23S ribosomal RNA genes has found that the order Chlamydiales contains at least four distinct groups at the family level and provides a potential rationale for splitting the genus Chlamydia into two genera, Chlamydia and Chlamydophila . The genus Chlamydophila would contain C. pneumoniae, C. pecorum, and C. psittaci. The scientific community has not to date accepted this split of the genus, and for the purposes of this chapter, these organisms are referred to as Chlamydia.
C. psittaci is responsible for psittacosis, a chlamydial infection contracted by humans from infected birds and characterized by interstitial pneumonitis. This infection should be suspected in any patient with atypical pneumonia who has contact with birds. C. pneumoniae causes pneumonia, pharyngitis, and bronchitis in humans and may accelerate atherosclerosis. Epidemiologic studies have revealed that C. pneumoniae is a common cause of infection in school-age children and young adults; along with Mycoplasma, it is probably the most common cause of community-acquired pneumonia in this age group. It is not known to cause disease in newborns and is not discussed further here. C. trachomatis is associated with a spectrum of diseases. The species C. trachomatis contains 18 serologically distinct variants known as serovars. Serovars A, B, Ba, and C cause ocular trachoma, a major cause of blindness in many developing countries, particularly in Africa, Asia, and the Middle East. Ocular trachoma is considered the most common cause of preventable blindness in the world. Three serovars, L 1 , L 2 , and L 3 , are associated with lymphogranuloma venereum, a sexually transmitted disease that is rare in the United States but is still quite prevalent in many developing countries and is more common among men who have sex with men. Perinatal transmission is rare with lymphogranuloma venereum. Serovars D through K produce infections of the genital tract—urethritis and epididymitis in men and cervicitis and salpingitis in women—the most prevalent chlamydial diseases. Major complications of female genital tract disease include acute pelvic inflammatory disease, ectopic pregnancy, infertility, and infant pneumonia and conjunctivitis.
Similar to gram-negative bacteria, chlamydiae have an outer membrane that contains lipopolysaccharide and membrane proteins, but their outer membrane contains no detectable peptidoglycan, despite the presence of genes encoding proteins for its synthesis. This genomic finding is the basis for the so-called chlamydial peptidoglycan paradox because it has been known for years that β-lactam antibiotics inhibit chlamydial development. Although chlamydiae contain DNA, RNA, and ribosomes, during growth and replication, they obtain high-energy phosphate compounds from the host cell. Consequently, they are considered energy parasites. The chlamydial genome size is only 660 kDa, which is smaller than that of any other prokaryote except Mycoplasma species. All chlamydiae encode an abundant protein, the major outer membrane protein (MOMP) that is surface exposed in C. trachomatis and is the primary determinant of serologic classification.
Chlamydial Developmental Cycle
The biphasic developmental cycle of chlamydiae is unique among microorganisms and involves two highly specialized morphologic forms, as shown in Figure 19-1 . The extracellular form or elementary body (EB) contains extensive disulfide cross-links within and between outer membrane proteins, giving it an almost sporelike structure that is stable outside of the cell. The small (350 nm in diameter) infectious EB is inactive metabolically. The developmental cycle is initiated when an EB attaches to a susceptible epithelial cell. Numerous candidate adhesins have been proposed, but their identity and that of associated epithelial cell receptors remain uncertain. One documented mechanism of entry into the epithelial cell is by receptor-mediated endocytosis via clathrin-coated pits, but evidence exists that chlamydiae may exploit multiple mechanisms of entry. The process of EB internalization is very efficient, suggesting that EBs trigger their own internalization by cells that are not considered professional phagocytes.
When inside the cell, surface antigens of the EB seem to prevent fusion of the endosome with lysosomes, protecting the pathogen from enzymatic destruction. Hiding from host attack by antibody or cell-mediated defenses, the EB reorganizes into the replicative form, the reticulate body (RB). RBs successfully parasitize the host cell and divide and multiply. As the RB divides by binary fission, it fills the endosome, now a cytoplasmic inclusion, with its progeny. After 48 to 72 hours, multiplication ceases, and nucleoid condensation occurs as the RBs transform to new infectious EBs. The EBs are released from the cell by cytolysis, by a process of exocytosis, or by extrusion of the whole inclusion, leaving the host cell intact. The last-mentioned process may explain the frequency of asymptomatic or subclinical chlamydial infections. Release of the infectious EBs allows infection of new host cells to occur.
Pathogenesis
Conjunctivitis
Chlamydiae replicate extensively in epithelial cells of the conjunctiva and cause considerable cell damage. The inflammatory reaction consists mostly of neutrophils. Conjunctivitis in most untreated patients resolves spontaneously during the first few months of life. On occasion, infants maintain persistent conjunctivitis, and pannus formation (neovascularization of the cornea) and scarring typical of trachoma have been reported. Loss of vision is rare. Micropannus and some scarring may occur in infants if they are not treated within the first 2 weeks of the disease. If treated early, no ocular sequelae develop.
Pneumonia
The nasopharynx is the most frequent site of perinatally acquired chlamydial infection, with approximately 70% of infected infants having positive cultures at that site. Most of these infections are asymptomatic and may persist for 29 months. Chlamydial pneumonia develops in only about 30% of infants with nasopharyngeal infection. Conjunctivitis is not a prerequisite for development of pneumonia.
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