Acute Proctitis
Men who practice receptive anal intercourse may develop acute proctitis from C. trachomatis strains of serovars D through K or, rarely, L1 through L3.36 Since 1998, chlamydial proctitis has been resurgent in homosexual and bisexual men in the United States.37 These infections occasionally develop in heterosexual women. The severity of disease ranges from asymptomatic (which generally occurs in patients infected with serovars D through K) to severe (generally, serovars L1 through L3).
Diagnosis Patients with severe infection typically present with rectal pain, a rectal mucosal discharge, tenesmus, and rectal bleeding. Characteristically, a rectal Gram stain shows one or more PMNs per 1000x oil-immersion field and anoscopy demonstrates a mucopurulent discharge and easily induced mu-cosal bleeding.36 The specific diagnosis can be made by rectal culture for Chlamydia or by a chlamydial DFA. The sensitivity and specificity of the newer nucleic acid amplification tests for rectal specimens has not been extensively studied, and these tests are not approved for this purpose.
Treatment Treatment regimens for chlamydial proctitis have not been extensively studied. Nevertheless, a 7-day regimen of doxycycline (100 mg b.i.d.) is recommended for cases caused by serovars D through K, and a 21-day course is recommended for cases caused by serovars L1 through L3 [see Table 2].
Reiter Syndrome
An unusual complication of chlamydial urethritis, Reiter syndrome (more recently termed reactive arthritis) consists of conjunctivitis, urethritis (or cervicitis in women), oligoarthritis, and characteristic lesions of the skin and mucous membranes [see 15:III Seronegative Spondyloarthropathies]. Although the pathogen-esis of Reiter syndrome is obscure, more than 80% of affected patients have the HLA B27 haplotype, so a genetic predisposition is clearly involved.38 Recent studies have found chlamydial antigens and genes in the involved joints, suggesting that viable Chlamydia organisms migrate from the urethra to the synovial tissue in these cases.
Lymphogranuloma Venereum
Lymphogranuloma venereum (LGV) is a sexually transmitted infection caused by C. trachomatis strains of the L1, L2, and L3 serovars. Typically, the disease begins with a transient primary genital lesion, followed by multilocular suppurative regional lymphadenopathy and, sometimes, hemorrhagic procti-tis with associated regional lymphadenitis.39 The acute phase of the disease is generally associated with fever, leukocytosis, and in some cases proctitis. Possible late complications include genital elephantiasis, rectal strictures, and fistulas of the penis, urethra, and rectum.
Epidemiology LGV occurs primarily in the second and third decades of life and is approximately four times more common in men than in women. Worldwide, the incidence is declining, but the disease is still endemic in parts of Asia, Africa, South America, and the Caribbean. The disease is rare in the United States, with only 186 cases reported in 1995. In the United States, many cases involve travelers or military personnel returning from endemic areas; most microbiologically confirmed cases have been in homosexual or bisexual men.
Clinical manifestations The initial lesion of LGV in heterosexual persons is often a papule, vesicle, or ulcer on the penis or, in women, on the labia. This lesion typically heals without scarring. LGV strains of C. trachomatis have occasionally been recovered from these genital ulcers, as well as from the urethra of men or the endocervix of women who present with inguinal adenopathy. It is thus not entirely clear whether the most important primary site of infection is the skin lesion, the urethra, or the endocervix. Alternatively, primary anal or rectal infection may develop in men or women after receptive rectal intercourse.41 Initial inoculation of the oral mucosa can also occur, leading to primary oral or pharyngeal lesions that may go unnoticed until adenopathy develops.
From the initial site of primary infection (urogenital, anal, rectal, or oral), the organism spreads to adjacent regional lymphatics. Typically, penile, vulvar, or anal infections spread to the inguinal and femoral lymph nodes. Rectal infection produces hypogastric and deep iliac lymphadenitis, whereas upper vaginal or cervical infection may result in obturator and iliac lymphadenitis. Heterosexual men with urogenital infection commonly display the so-called inguinal syndrome, which consists of painful inguinal lymphadenopathy developing approximately 2 to 6 weeks after the presumed exposure. Adenopathy generally is unilateral, with palpable enlargement of the iliac and femoral nodes on the same side as the enlarged inguinal nodes. Although the nodes may be discrete at first, they increasingly become matted, fluctuant, and suppurative. The overlying skin becomes fixed and inflamed and eventually develops multiple draining fistulas. Enlargement of lymph nodes both above and below the inguinal ligament may produce the so-called sign of the groove. On biopsy, the infected nodes have small abscesses surrounded by histiocytes. Spontaneous healing may occur after several months, but scarring and granulomatous masses often persist.
In the United States, LGV proctitis has increasingly been recognized in homosexual men. These patients present with rectal pain and mucopurulent bloody rectal discharge.42 They often complain of tenesmus and such systemic signs and symptoms as fever, malaise, and weakness. Sigmoidoscopy reveals ulcerative proctocolitis with a purulent exudate and mucosal bleeding.
During the active development of regional lymphadenopa-thy, many patients experience extensive constitutional symptoms, including fever, chills, headache, meningismus, myalgia, and arthralgias. Complications may include arthritis, aseptic meningitis, encephalitis, hepatitis, and arthritis. If left untreated, rectal infections may eventually progress to perirectal abscesses, anal fistula, and fistulas involving the rectum, the vagina, the bladder, and the pelvic musculature. Rectal strictures are a late complication, as is elephantiasis due to associated lymphatic obstruction.26
Laboratory tests LGV is most readily diagnosed serological-ly. Both the LGV complement fixation test and the microim-munofluorescence test become strongly positive soon after the onset of lymphadenopathy. Alternatively, demonstration of C. trachomatis by culture or nucleic acid amplification tests from urethral or cervical specimens or from pus aspirated from buboes can confirm the diagnosis.
Differential diagnosis LGV must be differentiated from other sexually transmitted conditions that produce genital ulcers and associated adenopathy. These include genital herpes simplex virus (HSV) infection, syphilis, chancroid, and granuloma inguinale. The clinical presentation, epidemiologic circumstances, and specific laboratory testing can usually differentiate these conditions unambiguously.
Treatment Doxycycline, 100 mg orally twice daily for 21 days, is generally recommended for treatment of LGV, despite the absence of trials demonstrating its efficacy. Alternative agents include erythromycin and sulfonamides.
Perinatal infections
Depending on the population tested, 5% to 25% of pregnant women have C. trachomatis infection of the cervix. A high proportion of infants born to these infected women will acquire C. trachomatis infection during passage through the birth canal.35 If not identified and treated, the infection may persist for months or years.43
Clinically apparent neonatal inclusion conjunctivitis develops in approximately 50% to 60% of infants with perinatally acquired C. trachomatis infection.44 In addition, C. trachomatis can often be isolated from the rectum, vagina, and nasopharynx of these infants.45 Approximately 10% of perinatally infected infants experience a distinctive afebrile pneumonitis-like syndrome.
Neonatal chlamydial conjunctivitis typically develops 5 to 14 days after birth and generally presents as a mucopurulent ocular discharge. Other causes of neonatal conjunctivitis—such as N. gonorrhoeae, Haemophilus influenzae, Streptococcus pneumoniae, and HSV—should also be considered. The diagnosis can be readily confirmed by DFA of a conjunctival smear or by PCR or LCR testing of the discharge. Because infants tend to be infected at multiple sites, systemic therapy is indicated, generally with erythromycin, 50 mg/kg/day orally in four divided doses for 10 to 14 days.
To prevent neonatal infection, all pregnant women should be screened for C. trachomatis infection in the third trimester, preferably with a nucleic acid amplification test. Those women found to be infected should be treated with a single 1 g oral dose of azithromycin; amoxicillin, 500 mg orally three times a day for 7 days; or erythromycin base, 500 mg orally four times a day for 7 days.
Adult inclusion conjunctivitis
Inclusion conjunctivitis caused by C. trachomatis is occasionally seen in adults.
Diagnosis
Adult chlamydial conjunctivitis usually arises from inadvertent inoculation of the conjunctiva in patients with sexually acquired chlamydial infection. These patients typically present with an acute unilateral follicular conjunctivitis. Associated preauricular adenopathy may be evident. Such cases must be distinguished from acute conjunctivitis due to other organisms, such as adenovirus, HSV, or bacterial pathogens. If not treated, the disease may persist for weeks to months, but it typically resolves without scarring or visual impairment. Approaches to diagnosis are the same as those used for neonatal conjunctivitis (see above).
Treatment
Systemic treatment is indicated to cure both the ocular and the genital infection. Treatment regimens are the same as for genital infection (see above). Sexual partners should be evaluated and treated to prevent reinfection.
Trachoma
C. trachomatis—specifically, serovars A, B, Ba, and C—is the source of trachoma, the major preventable cause of blindness throughout the world.
Epidemiology
Trachoma remains prevalent in arid portions of the developing world, especially North Africa and the Middle East. Trachoma was formerly endemic in Native Americans of the southwestern United States, but it has largely been eliminated from that population. Transmission of C. trachomatis in endemic areas is believed to occur via eye to hand to eye contact, as well as via contaminated towels and other fomites.48 Flies and other insects also may play a role in transmission. Most infections take place in early childhood, particularly in areas marked by crowding, poor standards of cleanliness, and the lack of clean water. The overall incidence of trachoma, as well as its severity, has been reduced dramatically over the past 35 years, primarily because of improved sanitary conditions and greater availability of clean water.
Pathogenesis
Severe, chronic, blinding trachoma is generally associated with repeated reinfection or persistent infection by trachoma-causing strains of C. trachomatis.49 The immune response to the C. trachomatis 60 kd heat shock protein appears to be strongly linked to the conjunctival scarring and pannus formation that causes blindness in trachoma. Host genetic factors are likely also to be important, because specific HLA types are more commonly found in persons with progressive trachoma.
Diagnosis
Clinical manifestations Initially, trachoma presents as a conjunctivitis characterized by multiple lymphoid follicles. Infection generally begins in children between 1 and 4 years of age. Reinfection is common, as is asymptomatic infection.51 With repeated episodes, the cornea becomes involved, with inflammatory infiltrates and pannus formation (superficial vasculariza-tion). Conjunctival scarring eventually develops and causes the eyelids to turn inward and abrade the eyeball.52 Eventually, corneal epithelial ulceration occurs. Destruction of the lacrimal glands and ducts produces a dry eye.
Laboratory tests Trachoma can be diagnosed on clinical grounds in a patient from an endemic area with follicular conjunctivitis. The diagnosis can be confirmed with culture, DFA, or nucleic acid amplification testing of secretions.
Treatment
Antimicrobial treatment should be provided in the early phases of trachoma, when its impact is potentially greatest. Oral tetracycline (in older children and adults) or erythromycin for 4 to 8 weeks has been recommended. Azithromycin (20 mg/kg orally in a single dose) can be used but may be prohibitively expensive in the developing world. Topical antimicrobials can be used, but their effectiveness is uncertain.
Public health measures to control endemic trachoma have focused on improving hygienic conditions and making clean water available. More recently, mass treatment of villages with single- dose azithromycin or topical antimicrobials has been utilized. Personal cleanliness and a reduction in flies in a village may also be important.
Disease Due to C. psittaci psittacosis
C. psittaci infects a wide variety of avian species, including parrots, parakeets, pigeons, finches, chickens, pheasants, and turkeys. Humans become infected through exposure to infected birds. Human infection is subacute, characterized by pneumoni-tis and a variety of systemic manifestations.53
Epidemiology
Parrots, parakeets, and budgerigars (so-called psittacine birds) are the most common sources of human psittacosis. However, human cases have also been attributed to pigeons, ducks, turkeys, chickens, and a variety of other bird species. Psittacosis is an occupational disease of pet-shop employees, pigeon fanciers, taxidermists, veterinarians, poultry workers, and others who work around birds. The actual incidence is unknown: 50 to 100 cases are reported each year in the United States,54 but it is likely that many cases, especially milder ones, go undiagnosed and thus unreported.
Pathogenesis
C. psittaci can be isolated from the nasal secretions, excreta, tissues, and feathers of infected birds. The birds may be ill, but many show only minor evidence of infection; complete absence of symptoms is uncommon, however.
C. psittaci enters humans via the upper respiratory tract and spreads throughout the body via the bloodstream, localizing primarily in pulmonary alveolar macrophages and the endo-thelial cells of the liver and spleen.55 A lymphocytic inflammatory response ensues in the lungs and at other sites of infection. Little is known of the pathogenesis of psittacosis at the cellular or molecular level.
Diagnosis
Clinical manifestations Psittacosis may vary in severity from a mild flulike illness to a fatal disease.56 The incubation period is typically 7 to 14 days. Often, the illness begins abruptly, with shaking chills and fever. In other cases, onset is more gradual. Among the most common symptoms are a severe headache and a nonproductive cough. Systemic illness characterized by fever, malaise, myalgias, and chills is also common. Features that may help differentiate psittacosis from other pneumonic processes include the absence of signs of consolidation, absence of a pleural effusion, a relative bradycardia, absence of neu-trophilia, splenomegaly, abnormal liver function tests, and a rash resembling the rose spots of typhoid fever (Horder spots). The course may be relatively benign and short-lived or severe and prolonged, with complications such as myocarditis, pericarditis, meningitis, or encephalitis.57
A history of a recent exposure to birds is most helpful. Other diseases that must be considered include influenza, other viral pneumonias, M. pneumoniae, Q fever, Legionnaires disease, and other bacterial or fungal pneumonias. With patients in whom pneumonia is not prominent, other systemic febrile illnesses such as brucellosis, leptospirosis, mononucleosis, hepatitis, or typhoid fever must be considered.
Laboratory tests In psittacosis, the white blood cell count is most commonly normal or decreased and the erythrocyte sedimentation rate is not elevated. Liver function tests may be abnormal. Changes on chest x-ray are typically nonspecific, with patchy infiltrates that may be lobar, wedge shaped, segmental, or nodular. The diagnosis of psittacosis is best confirmed by serologic studies, because C. psittaci is difficult to isolate from blood or infected secretions. In addition, the organism is hazardous to work with in the laboratory, and most clinical laboratories do not offer culture diagnosis. A fourfold rise in titer of complement-fixing antibody in acute and convalescent sera from a patient with a compatible clinical syndrome confirms the diagnosis.
Treatment
Tetracycline generally produces a rapid and dramatic response when initiated during the early phase of psittacosis.58 Generally, 2 g daily given in four divided doses is sufficient. Treatment should be continued for at least 14 days after defervescence to prevent relapse of infection. An alternative to tetracycline is erythromycin. Although as many as 20% of patients died in the preantibiotic era, fewer than 5% of patients do not respond to therapy currently.
Diseases Due to C. pneumoniae
C. pneumoniae is a recently described species that, as its name indicates, is associated primarily with respiratory tract infections. Initially, C. pneumoniae strains were thought to be variants of C. psittaci, but subsequent studies have demonstrated that C. pneumoniae is a distinct species, on the basis of differences in small subunit ribosomal RNA sequence, morphology, and anti-genic properties.59 The organisms are fastidious and cannot be easily isolated from respiratory or other clinical specimens. C. pneumoniae from clinical specimens grows most effectively in HL cells and Hep 2 cells.60
Epidemiology
Because of the difficulty in isolating the organism, most epi-demiologic studies have depended on microimmunofluores-cence serologic studies. Such studies have indicated that C. pneumoniae infection is extremely prevalent, with approximately 40% to 50% of adults demonstrating seropositivity in almost all countries examined worldwide. Infections are uncommon until late childhood; the peak period of incidence appears to be between 10 and 20 years of age.61 New infections or reinfections are acquired throughout life, however, with the seroprevalence continuing to increase throughout adult life. Serologic studies suggest that infections are more common in men than in women. Transmission is thought to occur from person to person via the respiratory route, much like Mycoplasma or respiratory viral infections. Most transmission occurs in schools or households. Well-described outbreaks of C. pneumoniae infection have also occurred in settings such as military barracks or school dormitories.62
Pathogenesis
Little is yet known about the molecular pathogenesis of C. pneumoniae infection. However, the organism is thought to initially infect the upper respiratory tract epithelium. In many individuals, long-lived, asymptomatic infection persists at these sites. Recent studies have demonstrated that after infection of respiratory tract epithelial cells and inflammatory cells, C. pneumoniae is likely transmitted throughout the body via macrophages in the bloodstream.63 There is clear evidence that replication of the organism occurs in vascular endothelium and synovial membranes. As with C. trachomatis, the outer membrane protein of C. pneumoniae may induce host immune responses that cross-react with human proteins, resulting in autoimmune inflammatory damage to tissues.
Diagnosis
Clinical Manifestations
C. pneumoniae, like other chlamydial species, can produce asymptomatic infection of the respiratory tract and endovascular tissues. C. pneumoniae was originally discovered as a cause of upper and lower respiratory tract infection, and the organism may produce a pneumonic illness somewhat like that produced by Mycoplasma, although few studies have utilized culture to confirm the presence of C. pneumoniae in infected tissues. Characteristically, patients with C. pneumoniae pneumonia have prominent antecedent upper respiratory infections and a mild illness with fever, nonproductive cough, and small segmental infiltrates on chest x-ray. Pleuritis and pleural effusion are uncommon. It is likely that C. pneumoniae also causes other respiratory infections, including bronchitis, pharyngitis, sinusitis, and otitis media, but this is less extensively studied.
In addition to respiratory diseases, C. pneumoniae has recently been associated in serologic studies with a wide range of other conditions, including myocarditis, pericarditis, aseptic meningitis, erythema nodosum, sarcoidosis, asthma, chronic fatigue syndrome, multiple sclerosis, and Alzheimer disease. At present, the validity of these associations remains uncertain; their significance must be demonstrated in further studies.
There is more convincing evidence linking C. pneumoniae infection with atherosclerotic vascular disease. More than 30 epi-demiologic studies have clearly demonstrated a strong association between serologic evidence for C. pneumoniae infection and atherosclerotic disease of the coronary and other arteries.64 These associations remain after adjustment for potential confounding variables. In addition, C. pneumoniae has been identified in atherosclerotic plaques by a variety of techniques, including electron microscopy, DNA hybridization, immunocytochemistry, and PCR.65 The organism has also been cultured from atherosclerotic plaques, demonstrating the presence of viable C. pneumoni-ae in the vessel wall.66 Studies in cell-culture systems and in animal models support the hypothesis that C. pneumoniae can infect vascular endothelial cells, including smooth muscle cells and macrophages. Animal models also support the contention that C. pneumoniae infection of the upper respiratory tract is followed by widespread dissemination of the organism to atheromatous lesions in vessels.67 In animals, antimicrobial treatment appears to slow the progression of atherosclerotic lesions associated with C. pneumoniae infection. Human trials are now ongoing to ascertain whether treatment with antimicrobials can reduce the risk of atherosclerotic heart disease and other vascular diseases associated with C. pneumoniae infection.
Laboratory Tests
Confirmation of C. pneumoniae respiratory infection is difficult because cell culture techniques are not widely available and in any case are not very sensitive. PCR and DNA probes have been utilized in research laboratories but are not available through most clinical laboratories. Microimmunofluorescence studies showing an increase in antibody to C. pneumoniae between acute and convalescent sera provide a specific diagnosis, but this technique is available in only a small number of laboratories. Complement-fixing antibody can also be measured, but that does not distinguish C. pneumoniae infection from C. psittaci or C. tra-chomatis infection. Accurate diagnosis of C. pneumoniae infection likely will await development and implementation of a more accurate and convenient PCR technology.
Treatment
There have been no controlled trials to ascertain the best antimicrobial regimen for C. pneumoniae respiratory infections. In vitro, C. pneumoniae is inhibited by erythromycin, tetracycline, doxycycline, azithromycin, clarithromycin, and some fluoroquino-lones, such as levofloxacin. Most experts recommend tetracy-cline (2 g daily in four divided doses) or doxycycline (100 mg b.i.d.) as initial therapy. Treatment should be given for at least 2 to 3 weeks. Many cases can be managed in the outpatient setting, although severe disease (especially in the elderly) may occasionally require hospitalization and ventilatory support.
The impact of antimicrobial therapy on either treatment or prevention of atherosclerotic cardiovascular disease is unknown. Antibiotics are not currently recommended for this indication.
