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Chlamydial Infections

Chlamydial Infections

Walter E. Stamm

The genus Chlamydia contains three species that infect humans: Chlamydia psittaci, C. trachomatis, and C. pneumoniae (formerly the TWAR agent). C. psittaci is widely distributed in nature, producing genital, conjunctival, intestinal, or respiratory infections in many mammalian and avian species. Genital infections with C. psittaci have been well characterized in several species and cause abortion and infertility. Although mammalian strains of C. psittaci are not known to infect humans, avian strains occasionally do so, causing pneumonia and the systemic illness known as psittacosis.

C. pneumoniae is a fastidious chlamydial species that appears to be a common cause of upper respiratory tract infection and pneumonia, primarily in children and young adults, and is a cause of recurrent respiratory infections in older adults. Studies have also linked C. pneumoniae infection to atherosclerotic cardiovascular disease and perhaps to asthma and sarcoidosis. No animal reservoir has been identified for C. pneumoniae; it appears to be an exclusively human pathogen spread via the respiratory route through close personal contact. To date, all strains of C. pneumoniae studied have been serologically homologous.

C. trachomatis is also an exclusively human pathogen and was identified as the cause of trachoma in the 1940s. Since then, C. trachomatis has been recognized as a major cause of sexually transmitted and perinatal infection.

Chlamydiae are obligate intracellular bacteria that are classified in their own order (Chlamydiales). They possess both DNA and RNA, have a cell wall and ribosomes similar to those of gram-negative bacteria, and are inhibited by antibiotics such as tetracycline.

A unique feature of all chlamydiae is their complex reproductive cycle. Two forms of the microorganism—the extracellular elementary body and the intracellular reticulate body—participate in this cycle. The elementary body is adapted for extracellular survival and is the infective form transmitted from one person to another. Elementary bodies attach to susceptible target cells (usually columnar or transitional epithelial cells) and enter the cells inside a phagosome. Within 8 h of cell entry, the elementary bodies reorganize into reticulate bodies, which are adapted to intracellular survival and multiplication. They undergo binary fission, eventually producing numerous replicates contained within the intracellular membrane-bound “inclusion body,” which occupies much of the infected host cell. Chlamydial inclusions resist lysosomal fusion until late in the developmental cycle. After 24 h, the reticulate bodies condense and form elementary bodies still contained within the inclusion. The inclusion then ruptures, releasing elementary bodies from the cell to initiate infection of adjacent cells or transmission to another person.

Studies with monoclonal antibodies to and nucleotide sequencing of the major outer-membrane protein have delineated at least 20 serotypes of C. trachomatis. According to the classification of Wang and Grayston, strains associated with trachoma have generally been those of the A, B, Ba, and C serovars, while serovars D through K have largely been associated with sexually transmitted and perinatally acquired infections. Serovars L₁, L₂, and L₃ produce lymphogranuloma venereum (LGV) and hemorrhagic proctocolitis. The LGV strains demonstrate unique biologic behavior in that they are more invasive than the other serovars, produce disease in lymphatic tissue, grow readily in cell culture systems and macrophages, and are lethal when inoculated intracerebrally into mice and monkeys. Non-LGV strains of C. trachomatis characteristically produce infections involving the superficial columnar epithelium of the eye, genitalia, and respiratory tract.

C. trachomatis has been reported as an infrequent cause of endocarditis, peritonitis, pleuritis, and possibly periappendicitis and may occasionally cause respiratory infections in older children and adults. Some immunosuppressed patients with pneumonia have had either serologic or cultural evidence of C. trachomatis infection, but more data are necessary to define a pathogenic role for Chlamydia in these patients.

C. TRACHOMATIS INFECTIONS

C. TRACHOMATIS GENITAL INFECTIONS

Genital infections caused by C. trachomatis represent the most common bacterial sexually transmitted diseases (STDs) in the United States. An estimated 4 million cases occur each year. In adults, the clinical spectrum of sexually transmitted C. trachomatis infections parallels that of gonococcal infections. Both infections have been associated with urethritis, proctitis, and conjunctivitis in both sexes; with epididymitis in men; and with mucopurulent cervicitis (MPC), acute salpingitis, bartholinitis, and the Fitz-Hugh–Curtis syndrome (perihepatitis) in women. Moreover, both types of infection can be associated with septic arthritis. In general, however, chlamydial infections produce fewer symptoms and signs than corresponding gonococcal infections at the same anatomic site; in fact, chlamydial infections are often totally asymptomatic. Increasing evidence suggests that many chlamydial infections of the genital tract, especially in women, persist for months without producing symptoms. Simultaneous infection with C. trachomatis often occurs in women with cervical gonococcal infection and in heterosexual men with gonococcal urethritis.

Epidemiology

Infections due to C. trachomatis have been reportable in the United States since 1985, and national incidence data show steadily rising numbers of reported infections, undoubtedly reflecting both increased testing and increased reporting. Most testing to date has focused upon women, and thus the reported incidence is severalfold greater among women than among men; this difference likely represents a surveillance artifact.

The age of peak incidence of genital C. trachomatis infections, as of other sexually transmitted infections, is the late teens and early twenties. The prevalence of chlamydial urethral infection among young men is at least 3 to 5% for those seen in general medical settings or in urban high schools, >10% for asymptomatic soldiers undergoing routine physical examination, and 15 to 20% for heterosexual men seen in STD clinics. In areas where chlamydial control programs have been implemented, prevalence may be markedly reduced. In short, prevalence varies widely with the population group studied and with the geographic locale. With the newer, more sensitive nucleic acid amplification tests such as polymerase chain reaction (PCR) and ligase chain reaction (LCR), prevalences in most populations have been 10 to 30% higher than those measured with older, less sensitive tests.

The prevalence of cervical infection among women is ~5% for asymptomatic college students and prenatal patients in the United States, >10% for women seen in family planning clinics, and >20% for women seen in STD clinics. As in men, prevalence varies substantially by geographic locale, with the highest rates in the southeast. However, substantial prevalences (~8%) of asymptomatic chlamydial infection have been demonstrated among young female military recruits from all parts of the United States. In this country, the prevalence of C. trachomatis in the cervix of pregnant women is 5 to 10 times higher than that of Neisseria gonorrhoeae. The prevalence of genital infection with either agent is highest among individuals who are between the ages of 18 and 24, single, and non-Caucasian (e.g., African American or Latino). Recurrent chlamydial infections occur frequently in these same risk groups, often acquired from untreated sexual partners. Oral contraceptive pill use and the presence of cervical ectopy also confer an increased risk of chlamydial infection. The proportion of infections that are asymptomatic appears to be higher for C. trachomatis than for N. gonorrhoeae, and symptomatic C. trachomatis infections are clinically less severe. Mild or asymptomatic chlamydial infections of the fallopian tubes nonetheless cause ongoing tubal damage and infertility. Furthermore, because the total number of C. trachomatis infections exceeds the total number of N. gonorrhoeae infections in industrialized countries, the total morbidity caused by C. trachomatis genital infections in these countries equals or exceeds that caused by N. gonorrhoeae. The prevalence of C. trachomatis is higher than that of N. gonorrhoeae in industrialized countries, in part because measures such as treatment of sex partners and routine cultures for case detection in asymptomatic individuals have been applied much longer and more effectively to the control of gonorrhea than to the control of C. trachomatis infection.

Pathogenesis

C. trachomatis preferentially infects the columnar epithelium of the eye and the respiratory and genital tracts. The infection induces an immune response but often persists for months or years in the absence of antimicrobial therapy. Serious sequelae often occur in association with repeated or persistent infections. The precise mechanism through which repeated infection elicits an inflammatory response that leads to tubal scarring and damage in the female upper genital tract is not yet clear. One antigen, the chlamydial 60-kDa heat-shock protein, may be involved in inducing the pathologic immune response or may elicit antibodies that cross-react with human heat-shock proteins. The recent sequencing of the chlamydial genome may soon offer further insights into the pathogenic mechanisms of C. trachomatis.

Clinical Manifestations

NONGONOCOCCAL AND POSTGONOCOCCAL URETHRITIS

Nongonococcal urethritis (NGU) is a diagnosis of exclusion that is applied to men with symptoms and/or signs of urethritis who do not have gonorrhea. Postgonococcal urethritis (PGU) refers to nongonococcal urethritis developing in men 2 to 3 weeks after treatment of gonococcal urethritis with single doses of agents such as amoxicillin or cephalosporins that lack antimicrobial activity against chlamydiae. Since current treatment regimens for gonorrhea also include tetracycline, doxycycline, or azithromycin for possible concomitant chlamydial infection, both the incidence of PGU and the causative role of chlamydiae in this syndrome have declined. C. trachomatis causes 20 to 40% of cases of NGU in heterosexual men but is less commonly isolated from homosexual men with this syndrome. The cause of most of the remaining cases is uncertain; considerable evidence suggests that Ureaplasma urealyticum and Mycoplasma genitalium cause many cases of NGU, while Trichomonas vaginalis and herpes simplex virus (HSV) cause some cases.

NGU is diagnosed by documentation of a leukocytic urethral exudate and by exclusion of gonorrhea by Gram's staining or culture. C. trachomatis urethritis is generally less severe than gonococcal urethritis, although in an individual patient these two forms of urethritis cannot be reliably differentiated solely on clinical grounds. Symptoms include urethral discharge (often whitish and mucoid rather than frankly purulent), dysuria, and urethral itching. Physical examination may reveal meatal erythema and tenderness and a urethral exudate that is often demonstrable only by stripping of the urethra.

At least one-third of males with C. trachomatis urethral infection have no demonstrable signs or symptoms of urethritis. Use of nucleic acid amplification assays on first-void urine specimens to diagnose chlamydial infections in men has facilitated more broadly based testing for asymptomatic infection in males. As a result, asymptomatic chlamydial urethritis has been demonstrated in 5 to 10% of sexually active adolescent males screened in school-based clinics or community centers. Such patients generally have first-glass pyuria (≥15 leukocytes per 400× microscopic field in the sediment of first-void urine), a positive leukocyte esterase test, or an increased number of leukocytes on Gram-stained smear prepared from a urogenital swab inserted 1 to 2 cm into the anterior urethra. For the enumeration of leukocytes, the smear is first scanned at low power to identify areas of the slide containing the highest concentration of leukocytes. These areas are then examined under oil immersion (1000×). An average of four or more leukocytes in at least three of five 1000× (oil-immersion) fields is indicative of urethritis and correlates with the recovery of C. trachomatis. To differentiate between true urethritis and functional symptoms among symptomatic patients or to make a presumptive diagnosis of C. trachomatis infection in “high-risk” but asymptomatic men (e.g., male patients in STD clinics, sex partners of women with nongonococcal salpingitis or MPC, fathers of children with inclusion conjunctivitis), the examination of an endourethral specimen for increased leukocytes is useful if specific diagnostic tests for chlamydiae are not available. Alternatively, noninvasive screening for urethritis can be accomplished by testing of a first-void urine sample for pyuria, either by microscopy or by the leukocyte esterase test. Urine can also be directly tested for chlamydiae or gonococci by DNA amplification methods, as described below.

EPIDIDYMITIS

C. trachomatis is the foremost cause of epididymitis in sexually active heterosexual men <35 years of age, accounting for ~70% of cases. N. gonorrhoeae causes most of the remaining cases, and some men have simultaneous infections with both pathogens, usually accompanied by asymptomatic urethritis as defined above. In homosexual men, sexually transmitted coliform infection acquired via insertive rectal intercourse may cause epididymitis. Coliform bacteria and Pseudomonas aeruginosa, usually in association with preceding urologic instrumentation or surgery, are the most common causes of epididymitis in men over 35. Men with chlamydial epididymitis typically present with unilateral scrotal pain, fever, and epididymal tenderness or swelling on examination. The illness may be mild enough to treat on an outpatient basis with oral antibiotics or severe enough to require hospitalization and parenteral therapy. Testicular torsion should be excluded promptly by radionuclide scan, Doppler flow study, or surgical exploration in a teenager or young adult who presents with acute unilateral testicular pain without urethritis. The possibility of testicular tumor or chronic infection (e.g., tuberculosis) should be excluded when a patient with unilateral intrascrotal pain and swelling does not respond to appropriate antimicrobial therapy.

REITER'S SYNDROME

Reiter's syndrome consists of conjunctivitis, urethritis (or cervicitis in females), arthritis, and characteristic mucocutaneous lesions .C. trachomatis has been recovered from the urethra of up to 70% of men with untreated nondiarrheal Reiter's syndrome and associated urethritis. In the absence of overt urethritis, it is important to exclude subclinical urethritis in the men in whom this diagnosis is suspected.

The pathogenesis of Reiter's syndrome remains obscure. However, since more than 80% of affected patients have the HLA-B27 phenotype and since other mucosal infections (with Salmonella, Shigella, or Campylobacter, for example) produce an identical syndrome, chlamydial infection is thought to initiate an aberrant and hyperactive immune response that produces inflammation at the involved target organs in these genetically predisposed individuals. Evidence of exaggerated cell-mediated and humoral immune responses to chlamydial antigens in Reiter's syndrome supports this hypothesis. The presumptive demonstration of chlamydial elementary bodies and chlamydial DNA in the joint fluid and synovial tissue of patients with Reiter's syndrome suggests that chlamydiae may actually spread from genital to joint tissues in these patients, perhaps in macrophages.

PROCTITIS

C. trachomatis strains of either the genital immunotypes D through K or the LGV immunotypes cause proctitis in homosexual men who practice receptive anorectal intercourse. In the United States, the vast majority of cases are due to immunotypes D through K and present either as asymptomatic infection or as mild proctitis not unlike gonococcal proctitis. These infections may develop in heterosexual women as well. Patients present with mild rectal pain, mucous discharge, tenesmus, and (occasionally) bleeding. Nearly all have neutrophils in their rectal Gram's stain. Anoscopy in these non-LGV cases of chlamydial proctitis reveals mild, patchy mucosal friability and mucopurulent discharge, and the disease process is limited to the distal rectum. LGV strains produce more severe ulcerative proctitis or proctocolitis that can be confused clinically with HSV proctitis (severe rectal pain, bleeding, discharge, and tenesmus) and that histologically resembles Crohn's disease in that giant cell formation and granulomas can be seen. In the United States, these cases occur almost exclusively in homosexual men.

MUCOPURULENT CERVICITIS

Although many women with C. trachomatis infection of the cervix have no symptoms or signs, a careful speculum examination reveals evidence of MPC in 30 to 50% of cases. As is discussed more fully in, MPC is associated with yellow mucopurulent endocervical discharge and with ≥20 neutrophils per 1000× microscopic field within strands of cervical mucus on a thinly smeared, Gram-stained preparation of endocervical exudate. Other characteristic findings include edema of the zone of cervical ectopy and a propensity of the mucosa to bleed on minor trauma—e.g., when specimens are collected with a swab. A Pap smear shows increased numbers of neutrophils as well as a characteristic pattern of mononuclear inflammatory cells, including plasma cells, transformed lymphocytes, and histiocytes. Cervical biopsy shows a predominantly mononuclear cell infiltrate of the subepithelial stroma, often with follicular cervicitis.

PELVIC INFLAMMATORY DISEASE (PID)

In the United States, C. trachomatis has been identified in the fallopian tubes or endometrium of up to 50% of women with PID, and its role as an important etiologic agent in this syndrome is well accepted. PID occurs via ascending intraluminal spread of C. trachomatis from the lower genital tract. MPC is thus followed by endometritis, endosalpingitis, and finally pelvic peritonitis. Evidence of MPC is usually found in women with laparoscopically verified salpingitis. Similarly, endometritis, demonstrated by endometrial biopsy showing plasma cell infiltration of the endometrial epithelium, is documented in most women with laparoscopically verified chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can also occur in the absence of clinical evidence of salpingitis: ~40 to 50% of women with MPC have plasma cell endometritis. Histologic evidence of endometritis has been correlated with an “endometritis syndrome” consisting of vaginal bleeding, lower abdominal pain, and uterine tenderness in the absence of adnexal tenderness. Chlamydial salpingitis produces milder symptoms than does gonococcal salpingitis and may be associated with less marked adnexal tenderness. Thus mild adnexal or uterine tenderness in sexually active women with cervicitis suggests PID.

Infertility associated with fallopian-tube scarring has been strongly linked to antecedent C. trachomatis infection in serologic studies. Since many infertile women with tubal scarring and antichlamydial antibody have no history of PID, it appears that subclinical tubal infection (“silent salpingitis”) may produce scarring. Studies in animals and humans with salpingitis and tubal scarring suggest the continuing presence of persistent, slowly replicating chlamydial infection in tubal tissue. While the pathogenesis of Chlamydia-induced tubal scarring remains poorly understood, antibodies to the chlamydial 60-kDa heat-shock protein have been correlated with tubal infertility, ectopic pregnancy, and Fitz-Hugh–Curtis syndrome (see below). Thus this antigen may initiate an immune-mediated process that ultimately damages the fallopian tube. Host genetic susceptibility, as defined by HLA type, may also play an important role.

Perihepatitis, or the Fitz-Hugh–Curtis syndrome, was originally described as a complication of gonococcal PID. The syndrome should be suspected whenever a young, sexually active woman presents with an illness resembling cholecystitis (fever and right-upper-quadrant pain of subacute or acute onset). Symptoms and signs of salpingitis may be minimal. Cultural and/or serologic evidence of C. trachomatis infection is found in three-quarters of women with this syndrome.

URETHRAL SYNDROME IN WOMEN

In the absence of infection with uropathogens such as coliforms or Staphylococcus saprophyticus, C. trachomatis is the pathogen most commonly isolated from college women with dysuria, frequency, and pyuria. Chlamydia can also be isolated from the urethra of women without symptoms of urethritis, and up to 25% of female STD clinic patients with chlamydial urogenital infection have cultures positive for C. trachomatis from the urethra only.

C. TRACHOMATIS INFECTION IN PREGNANCY AND THE NEONATAL PERIOD

Studies in the United States have demonstrated that 5 to 25% of pregnant women have C. trachomatis infections of the cervix. In these studies, approximately one-half to two-thirds of children exposed during birth have acquired C. trachomatis infection. Roughly half of the infected infants (or 25% of the group exposed) have developed clinical evidence of inclusion conjunctivitis. In addition to infecting the eye, C. trachomatis has been isolated frequently and persistently from the nasopharynx, rectum, and vagina of such infants, occasionally for periods exceeding 1 year in the absence of treatment. Pneumonia develops in ~10% of children infected perinatally, and otitis media may in some cases result from perinatally acquired chlamydial infection.

Neonatal chlamydial conjunctivitis has an acute onset 5 to 14 days after birth and often produces a profuse mucopurulent discharge. However, it is impossible to differentiate chlamydial conjunctivitis from other forms of neonatal conjunctivitis (such as that due to N. gonorrhoeae, Haemophilus influenzae, Streptococcus pneumoniae, or HSV) on clinical grounds; thus laboratory diagnosis is required. Inclusions within epithelial cells are often detected in Giemsa-stained conjunctival smears, but these smears are considerably less sensitive than cultures, antigen detection tests, or nucleic acid hybridization tests for chlamydiae. Gram-stained smears may show gonococci or occasional small gram-negative coccobacilli in Haemophilus conjunctivitis, but smears should be accompanied by cultures for these agents.

C. trachomatis causes a distinctive pneumonia syndrome in infants. Recent epidemiologic studies have linked chlamydial pulmonary infection in infants with increased occurrence of subacute lung disease (bronchitis, asthma, wheezing) in later childhood.

Lymphogranuloma Venereum

DEFINITION

LGV is a sexually transmitted infection caused by C. trachomatis strains of the L₁, L₂, and L₃ serovars. In the United States, most cases are caused by L₂ organisms. Acute LGV is characterized by a transient primary genital lesion followed by multilocular suppurative regional lymphadenopathy. Patients exposed via insertive rectal intercourse may develop hemorrhagic proctitis with regional lymphadenitis. Acute LGV is almost always associated with systemic symptoms such as fever and leukocytosis but is rarely associated with systemic complications such as meningoencephalitis. After a period of years, late complications include genital elephantiasis due to lymphatic involvement; strictures; and fistulas of the penis, urethra, and rectum.

EPIDEMIOLOGY

LGV is usually sexually transmitted, but occasional transmission by nonsexual personal contact, fomites, or laboratory accidents has been documented. Laboratory work involving the creation of aerosols of LGV organisms (e.g., sonication, homogenization) must be conducted only with appropriate measures for biologic containment.

The peak incidence of LGV corresponds to the age of greatest sexual activity: the second and third decades of life. The worldwide incidence of LGV is falling, but the disease is still endemic and a major cause of morbidity in Asia, Africa, South America, and parts of the Caribbean. In the Bahamas, an apparent outbreak of LGV has been described in association with a concurrent increase in heterosexual infection with HIV. However, the reported incidence of LGV in the United States has been only 0.1 case per 100,000 persons for more than a decade.

The frequency of infection following exposure is believed to be much lower than that for gonorrhea and syphilis. Early manifestations are recognized far more often in men than in women, who usually present with late complications. In the United States, where the reported male-to-female ratio of cases is 3.4:1, most cases have involved homosexually active men and persons returning from abroad (travelers, sailors, and military personnel). The main reservoir of infection, although it has not been directly demonstrated, is presumed to be asymptomatically infected individuals.

CLINICAL MANIFESTATIONS

A primary genital lesion develops from 3 days to 3 weeks after exposure. It is a small, painless vesicle or nonindurated ulcer or papule located on the penis in men and on the labia, posterior vagina, or fourchette in women. The primary lesion is noticed by fewer than one-third of men with LGV and only rarely by women. It heals in a few days without scarring and, even when noticed, is usually recognized as LGV only in retrospect. LGV strains of C. trachomatis have occasionally been recovered from genital ulcers and from the urethra of men and the endocervix of women who present with inguinal adenopathy; these areas may be the primary site of infection in some cases.

Primary anal or rectal infection develops after receptive anorectal intercourse. In women, rectal infection with LGV (or non-LGV) strains of C. trachomatis presumably can also arise by the contiguous spread of infected secretions along the perineum (as in rectal gonococcal infections in women) or perhaps by spread to the rectum via the pelvic lymphatics.

From the site of the primary urethral, genital, anal, or rectal infection, the organism spreads via the regional lymphatics. Penile, vulvar, or anal infection can lead to inguinal and femoral lymphadenitis. Rectal infection produces hypogastric and deep iliac lymphadenitis. Upper vaginal or cervical infection results in enlargement of the obturator and iliac nodes.

The most common presenting picture in heterosexual men is the inguinal syndrome, which is characterized by painful inguinal lymphadenopathy beginning 2 to 6 weeks after presumed exposure; in rare instances, the onset comes after a few months. The inguinal adenopathy is unilateral in two-thirds of cases, and palpable enlargement of the iliac and femoral nodes is often evident on the same side as the enlarged inguinal nodes. The nodes are initially discrete, but progressive periadenitis results in a matted mass of nodes that becomes fluctuant and suppurative. The overlying skin becomes fixed, inflamed, and thin and finally develops multiple draining fistulas. Extensive enlargement of chains of inguinal nodes above and below the inguinal ligament (“the sign of the groove”) is not specific and, although not uncommon, is documented in only a minority of cases. On histologic examination, infected nodes are initially found to have characteristic small stellate abscesses surrounded by histiocytes. These abscesses coalesce to form large, necrotic, suppurative foci. Spontaneous healing usually takes place after several months; inguinal scars or granulomatous masses of various sizes persist for life. Massive pelvic lymphadenopathy may lead to exploratory laparotomy.

As cultures and serologic tests for C. trachomatis are being used more often, increasing numbers of cases of LGV proctitis are being recognized in homosexual men. Such patients present with anorectal pain and mucopurulent, bloody rectal discharge. Although these patients may complain of diarrhea, they are often referring not to diarrhea but rather to frequent, painful, unsuccessful attempts at defecation (tenesmus). Sigmoidoscopy reveals ulcerative proctitis or proctocolitis, with purulent exudate and mucosal bleeding. The histopathologic findings in the rectal mucosa include granulomas with giant cells, crypt abscesses, and extensive inflammation. These clinical, sigmoidoscopic, and histopathologic findings may closely resemble those of Crohn's disease of the rectum.

Constitutional symptoms are common during the stage of regional lymphadenopathy and, in cases of proctitis, may include fever, chills, headache, meningismus, anorexia, myalgias, and arthralgias. These findings in the presence of lymphadenopathy are sometimes mistakenly interpreted as representing malignant lymphoma. Other systemic complications are infrequent but include arthritis with sterile effusion, aseptic meningitis, meningoencephalitis, conjunctivitis, hepatitis, and erythema nodosum. Chlamydiae have been recovered from the cerebrospinal fluid and in one case were isolated from the blood of a patient with severe constitutional symptoms—a result indicating the dissemination of infection. Laboratory-acquired infections suspected of being due to the inhalation of aerosols have been associated with mediastinal lymphadenitis, pneumonitis, and pleural effusion.

Complications of untreated anorectal infection include perirectal abscess; fistula in ano; and rectovaginal, rectovesical, and ischiorectal fistulas. Secondary bacterial infection probably contributes to these complications. Rectal stricture is a late complication of anorectal infection and usually develops 2 to 6 cm from the anal orifice—i.e., at a site within reach on digital rectal examination. Proximal extension of the stricture for several centimeters may lead to a mistaken clinical and radiographic diagnosis of carcinoma.

A small percentage of cases of LGV in men present as chronic progressive infiltrative, ulcerative, or fistular lesions of the penis, urethra, or scrotum. Associated lymphatic obstruction may produce elephantiasis. When urethral stricture occurs, it usually involves the posterior urethra and causes incontinence or difficulty with urination.

Approach to the Diagnosis and Treatment of C. trachomatis Genital Infections

Four types of laboratory procedure are available to confirm C. trachomatis infection: direct microscopic examination of tissue scrapings for typical intracytoplasmic inclusions or elementary bodies; isolation of the organism in cell culture; detection of chlamydial antigens or nucleic acid by immunologic or hybridization methods; and detection of antibody in serum or in local secretions.

Except in conjunctivitis, direct microscopic examination of Giemsa-stained cell scrapings for typical inclusions has an unacceptably low degree of sensitivity, and false-positive interpretations by inexperienced observers are common. Even for conjunctivitis, this approach has been replaced by direct fluorescent antibody staining of conjunctival smears to identify chlamydial elementary bodies with specific monoclonal antibodies (see below).

Cell culture techniques for isolation of C. trachomatis are available in most large medical centers but not in other clinical settings. In addition to limited availability, other disadvantages of cell culture include its low and variable level of sensitivity (60 to 80%), its requirement for rigorous transport conditions, and its high cost and technically demanding nature. Therefore, nonculture alternatives involving antigen detection or nucleic acid hybridization have been developed. In the direct immunofluorescent antibody (DFA) slide test, potentially infected genital or ocular secretions are smeared onto a slide, fixed, and stained with fluorescein-conjugated monoclonal antibody specific for chlamydial antigens. The observation of fluorescing elementary bodies confirms the diagnosis. Enzyme-linked immunosorbent assay (ELISA) techniques for the detection of chlamydial antigens provide another alternative to culture. The reported sensitivity and specificity of these tests for genital infections (as compared with culture) have been 60 to 80% and 97 to 99%, respectively, in high-risk populations. Assays with nucleic acid probes have also been developed for chlamydial diagnosis. One such test uses DNA-RNA hybridization and appears to be approximately equal to the best ELISAs in terms of sensitivity and specificity. Nucleic acid probes have also been developed for use in amplification assays such as LCR and PCR. These tests are now the most sensitive chlamydial diagnostic methods available, being the first nonculture assays to surpass culture itself in sensitivity. In addition, the ability of these tests to detect chlamydial genes in urine with a high degree of sensitivity and specificity allows—for the first time—the use of urine specimens rather than conventional urethral and cervical swabs. The use of urine specimens is particularly appealing for public-health chlamydial screening programs because of the ease of sample collection, even in community-based settings.

Serologic tests are of limited usefulness in the diagnosis of chlamydial oculogenital infections. The complement fixation test with heat-stable, genus-specific antigen has been used with some success to diagnose LGV but is insensitive in infections due to non-LGV strains of C. trachomatis. The microimmunofluorescence (micro-IF) test with C. trachomatis antigens is more sensitive but is generally available only in research laboratories. The test measures antibodies by serovar specificity and by immunoglobulin class (IgM, IgG, IgA, secretory IgA) in both serum and local secretions. Serologic diagnosis by the micro-IF test may be useful in infant pneumonia (in which high-titer IgM antibody and/or fourfold rises in titer are often demonstrated), in chlamydial salpingitis (especially Fitz-Hugh–Curtis syndrome), and in LGV. In all of these more invasive syndromes, high antibody levels are present.

Table 1 summarizes the diagnostic tests of choice for patients with suspected C. trachomatis infection. It is clear that, in most settings and for most purposes, sensitivity and specificity will be greatest with nucleic acid amplification techniques. For patients to whom medicolegal considerations may apply (victims of sexual or child abuse), cultures or nucleic acid amplification methods should always be used. In men with suspected urethritis, PCR or LCR testing of a first-void urine specimen offers a more sensitive and noninvasive diagnostic method than the use of urethral swabs. For the diagnosis of urogenital (cervical or urethral) infections in women, testing of a first-void urine specimen by nucleic acid amplification methods is at least as sensitive as testing of a cervical swab. Patient-collected vaginal swabs tested by PCR or LCR have also been used successfully. Since chlamydial diagnostic testing has become more widely available and is now more sensitive and specific than in the past, its use for specific diagnosis in patients with suspected chlamydial syndromes (such as MPC, NGU, and PID) and their partners should be promoted. High priority should also be given to the screening of asymptomatic high-risk women who would not otherwise receive treatment for presumptive chlamydial infection, especially those seen in high-risk settings (e.g., STD clinics or abortion clinics) and those with a high-risk profile (e.g., sexually active and ≤21 years of age, new sex partner within the preceding 2 months, or more than one current sex partner). Similar screening programs should be used to detect and treat asymptomatic urethritis in high-risk adolescent males. Where implemented, screening programs of this type have been associated with reductions in the prevalence of chlamydial infection and of its complications, such as PID.

TREATMENT

Until the introduction of azithromycin, chlamydial infections could not be eradicated by single-dose or short-term antimicrobial regimens. In most uncomplicated infections in adults, a 7-day course of treatment

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with doxycycline or tetracycline must be given for genital infections. A 2-week course is recommended for complicated chlamydial infections (e.g., PID, epididymitis) and at least a 3-week course of doxycycline (100 mg orally bid) or erythromycin base (500 mg orally qid) for LGV. Failure of treatment of genital infections with a tetracycline usually indicates poor compliance or reinfection rather than the involvement of a drug-resistant strain. To date, clinically significant drug resistance has not been observed in C. trachomatis infection.

Therapy for C. trachomatis urethritis is more efficacious than therapy for nonchlamydial NGU. C. trachomatis is eradicated from the urethra in nearly all cases by treatment with tetracycline hydrochloride (500 mg qid for 7 days) or doxycycline (100 mg by mouth bid for 7 days).

Eradication of C. trachomatis from the cervix by tetracycline and doxycycline, with doses and durations similar to those specified above for urethritis, has been demonstrated. Erythromycin base (500 mg qid for 10 to 14 days) is the regimen of choice for pregnant women with C. trachomatis infection. Amoxicillin (500 mg tid for 10 days) has also been used successfully in pregnant women. Tetracycline hydrochloride (500 mg qid) or doxycycline (100 mg bid) for 14 days produces clinical and microbiologic cure of epididymitis and PID associated with C. trachomatis infection, but in this situation a tetracycline should always be used together with a drug that is highly effective against gonorrhea.

Azithromycin is highly active against C. trachomatis, exhibits prolonged bioavailability, is concentrated intracellularly, and has made possible single-dose therapy for chlamydial infection for the first time. In comparative trials, a 1-g single dose of azithromycin has been as effective as 7 days of doxycycline therapy for uncomplicated chlamydial infection. Azithromycin causes fewer adverse gastrointestinal reactions than do older macrolides such as erythromycin. The single-dose regimen of azithromycin has great appeal for the treatment of patients with uncomplicated chlamydial infection (especially those without symptoms and those with a likelihood of poor compliance) and of sexual partners of infected patients. These advantages must be weighed against the considerably greater cost of azithromycin. Whenever possible, the single 1-g dose should be given as directly observed therapy. Although not approved by the U.S. Food and Drug Administration for the treatment of pregnant women, the 1-g single-dose regimen of azithromycin appears to be safe and effective for this purpose.

Of the newer fluoroquinolones, ofloxacin (300 mg by mouth bid for 7 days) has been shown to be as effective as doxycycline for the treatment of chlamydial infection and appears to be safe and well tolerated. It cannot be used in pregnancy.

Treatment of Sex Partners

The continued high prevalence of chlamydial infections in most parts of the United States is due primarily to the failure to diagnose—and therefore treat—patients with symptomatic or asymptomatic infection and their sex partners. C. trachomatis urethral or cervical infection has been well documented in a high proportion of the sex partners of patients with NGU, epididymitis, Reiter's syndrome, salpingitis, or endocervicitis. If possible, confirmatory laboratory tests for Chlamydia should be undertaken in these individuals, but even those without positive tests or evidence of clinical disease who have recently been exposed to proven or possible chlamydial infection (e.g., NGU) should be offered therapy.

Treatment of Neonates and Infants

In neonates with conjunctivitis or infants with pneumonia, erythromycin ethylsuccinate or estolate can be given orally in a dose of 50 mg/kg per day, preferably in four divided doses, for 2 weeks. Careful attention must be given to compliance with therapy—a frequent problem. Relapses of eye infection are common following treatment with topical erythromycin or tetracycline ophthalmic ointment and may also occur after oral erythromycin therapy. Thus follow-up cultures should be performed after treatment. Both parents should be examined for C. trachomatis infection and, if diagnostic testing is not readily available, should be treated with doxycycline or azithromycin.

Prevention

Efforts to develop a vaccine for chlamydial infection have not yet been successful. Early diagnosis and treatment shorten the duration of infectiousness and therefore constitute primary prevention of chlamydial infection. By the early 1990s, one of the 10 regions of the United States (Region X, the Pacific Northwest) had formally undertaken a chlamydial control program involving widespread screening of women attending family planning clinics. Approximately 500,000 tests per year were conducted at 150 such clinics throughout the region in women meeting the criteria for high risk. Within 5 years, the prevalence of chlamydial infection had been reduced by >30% in this population. While most regions of the United States have now initiated similar programs, some family planning and STD clinics still do not offer chlamydial testing. The availability of highly sensitive and specific diagnostic tests that can be done with urine specimens and of single-dose therapy makes it feasible to mount an effective chlamydial control program nationwide, with screening of high-risk persons both in traditional health care settings and in novel community- and school-based settings.

TRACHOMA AND ADULT INCLUSION CONJUNCTIVITIS

Definition

Trachoma is a chronic conjunctivitis associated with infection by C. trachomatis serovar A, B, Ba, or C. It has been responsible for an estimated 20 million cases of blindness throughout the world and remains an important cause of preventable blindness. Inclusion conjunctivitis is an acute ocular infection caused by sexually transmitted C. trachomatis strains (usually serovars D through K) in adults exposed to infected genital secretions and in their newborn offspring.

Epidemiology

In trachoma-endemic areas where the classic eye disease is seen, transmission is from eye to eye via hands, flies, towels, and other fomites and usually involves serovar A, B, Ba, or C. The worldwide incidence and severity of trachoma have decreased dramatically during the past 35 years, mainly as a result of improving hygienic and economic conditions. Endemic trachoma is still the major cause of preventable blindness in northern Africa, sub-Saharan Africa, the Middle East, and parts of Asia. Transmission occurs primarily through close personal contact, particularly among young children in rural communities with limited water supplies. In endemic areas, trachoma is associated with repeated exposure and reinfection, but the infection can also become chronic and persistent. Acute relapse of old trachoma occasionally follows treatment with cortisone eye ointment or develops in very old persons who were exposed in their youth.

Clinical Manifestations

Both endemic trachoma and adult inclusion conjunctivitis present initially as a conjunctivitis characterized by small lymphoid follicles in the conjunctiva. In regions with hyperendemic classic blinding trachoma, the disease usually starts insidiously before the age of 2 years. Reinfection is common and probably contributes to the pathogenesis of trachoma. Studies using PCR techniques indicate that chlamydial DNA is often present in the ocular secretions of patients with trachoma, even in the absence of positive cultures. Thus persistent infection may be more common than was previously thought.

The cornea becomes involved, with inflammatory leukocytic infiltrations and superficial vascularization (pannus formation). As the inflammation continues, conjunctival scarring eventually distorts the eyelids, causing them to turn inward so that the inturned lashes constantly abrade the eyeball (trichiasis and entropion); eventually the corneal epithelium is abraded and may ulcerate, with subsequent corneal scarring and blindness. Destruction of the conjunctival goblet cells, lacrimal ducts, and lacrimal gland may produce a “dry-eye” syndrome, with resultant corneal opacity due to drying (xerosis) or secondary bacterial corneal ulcers.

Communities with blinding trachoma often experience seasonal epidemics of conjunctivitis due to H. influenzae that contribute to the intensity of the inflammatory process. In such areas the active infectious process usually resolves spontaneously in affected persons between 10 and 15 years of age, but the conjunctival scars continue to shrink, producing trichiasis and entropion and subsequent corneal scarring in adults. In areas with milder and less prevalent disease, the process may be much slower, with active disease continuing into adulthood; blindness is rare in these cases.

Eye infection with genital C. trachomatis strains in sexually active young adults presents as the acute onset of unilateral follicular conjunctivitis and preauricular lymphadenopathy similar to that seen in acute adenovirus or herpesvirus conjunctivitis. If untreated, the disease may persist for 6 weeks to 2 years. It is frequently associated with corneal inflammation in the form of discrete opacities (“infiltrates”), punctate epithelial erosions, and minor degrees of superficial corneal vascularization. Very rarely, conjunctival scarring and eyelid distortion occur, particularly in patients treated for many months with topical glucocorticoids. Recurrent eye infections develop most often in patients whose sexual consorts are not treated with antimicrobials.

Diagnosis

The clinical diagnosis of classic trachoma can be made if two of the following signs are present: (1) lymphoid follicles on the upper tarsal conjunctiva; (2) typical conjunctival scarring; (3) vascular pannus; or (4) limbal follicles or their sequelae, Herbert's pits.

The clinical diagnosis of endemic trachoma should be confirmed by laboratory tests in children with more marked degrees of inflammation. Intracytoplasmic chlamydial inclusions are found in 10 to 60% of Giemsa-stained conjunctival smears in such populations, but chlamydial PCR or LCR is more sensitive and is often positive when smears or cultures are negative. Follicular conjunctivitis in adult Europeans or Americans living in trachomatous regions is rarely due to trachoma.

TREATMENT

Public health control programs for endemic trachoma have consisted of the mass application of tetracycline or erythromycin ointment to the eyes of all children in affected communities for 21 to 60 days or on an intermittent schedule. These programs also include surgical correction of inturned eyelids by a mobile surgical team that visits each locale. Mass treatment of entire villages with single-dose azithromycin may be an alternative approach.

Adult inclusion conjunctivitis responds well to treatment with full doses of oral tetracycline or erythromycin administered for 3 weeks. Simultaneous treatment of all sexual consorts of the patient is also necessary to prevent ocular reinfection and to avoid genital disease due to chlamydial infection. Topical antibiotic treatment is not required for patients who receive systemic antibiotics.

Prevention

Efforts to develop a trachoma vaccine have not yet been successful. General hygienic measures associated with improved living standards are effective in the elimination of endemic trachoma. An adequate water supply for personal cleanliness may be a key factor. In some areas the reduction of numbers of flies in the household is important.

C. PSITTACI INFECTIONS

Definition

Psittacosis is primarily an infectious disease of birds and mammals that is caused by C. psittaci. Transmission of infection from birds to humans results in a febrile illness characterized by pneumonitis and systemic manifestations. Inapparent infections or mild influenza-like illnesses may also occur. The term ornithosis is sometimes applied to infections contracted from birds other than parrots or parakeets, but psittacosis is the preferred generic term for all forms of the disease.

Epidemiology

Almost any avian species can harbor C. psittaci. Psittacine birds (parrots, parakeets, budgerigars) are most commonly infected, but human cases have been traced to contact with pigeons, ducks, turkeys, chickens, and many other birds. Psittacosis may be considered an occupational disease of pet-shop owners, poultry workers, pigeon fanciers, taxidermists, veterinarians, and zoo attendants. During the past 20 years, there has been an increase in incidence, with cases and outbreaks occurring primarily among employees of poultry-processing plants. It is suspected that many cases go undiagnosed and unreported.

The agent is present in nasal secretions, excreta, tissues, and feathers of infected birds. Although the disease can be fatal, infected birds frequently show only minor evidence of illness, such as ruffled feathers, lethargy, and anorexia. Asymptomatic avian carriers are common, and complete recovery may be followed by continued shedding of the organism for many months.

Psittacosis is almost always transmitted to humans by the respiratory route. On rare occasions the disease may be acquired from the bite of a pet bird. Prolonged contact is not essential for transmission of the disease; a few minutes spent in an environment previously occupied by an infected bird has resulted in human infection. In one outbreak, gardening rather than direct exposure to birds was associated with infection. A psittacosis-like agent has been transmitted among hospital personnel, with severe and sometimes fatal infections. There is evidence that these “human” strains are more virulent than avian organisms. There is no record of infection acquired by the ingestion of poultry products.

Pathogenesis

The psittacosis agent gains entrance to the body through the upper part of the respiratory tract, spreads via the bloodstream, and eventually localizes in the pulmonary alveoli and in the reticuloendothelial cells of the spleen and liver. Invasion of the lung probably takes place by way of the bloodstream rather than by direct extension from the upper air passages. A lymphocytic inflammatory response occurs on both the interstitial and the respiratory surfaces of the alveoli as well as in the perivascular spaces. The alveolar walls and interstitial tissues of the lung are thickened, edematous, necrotic, and occasionally hemorrhagic. Histologic examination of the affected areas reveals alveolar spaces filled with fluid, erythrocytes, and lymphocytes. The picture is not pathognomonic of psittacosis unless macrophages containing characteristic cytoplasmic inclusion bodies (Levinthal-Coles-Lillie bodies) can be identified. The respiratory epithelium of the bronchi and bronchioles usually remains intact.

Clinical Manifestations

The clinical manifestations and course of psittacosis are extremely variable. After an incubation period of 7 to 14 days or longer, the disease may start abruptly with shaking chills and fever, with temperatures ranging as high as 40.5°C (105°F); however, the onset is often gradual, with fever increasing over a 3- to 4-day period. Headache is almost always a prominent symptom; it is usually diffuse and excruciating and is often the patient's chief complaint.

Many patients present with a dry hacking cough that is usually nonproductive, but small amounts of mucoid or bloody sputum may be raised as the disease progresses. Cough may begin early in the course of the disease or as late as 5 days after the onset of fever. Chest pain, pleurisy with effusion, or a friction rub may all occur but are rare. Pericarditis and myocarditis have been reported. Most patients have a normal or slightly increased respiratory rate; marked dyspnea with cyanosis occurs only in severe psittacosis with extensive pulmonary involvement. In psittacosis, as in mycoplasmal pneumonias, the physical signs of pneumonitis tend to be less prominent than symptoms and x-ray findings would suggest. The initial examination may reveal fine sibilant rales, or clinical evidence of pneumonia may be completely lacking. Rales usually become audible and more numerous as the illness progresses. Signs of frank pulmonary consolidation are usually absent. Symptoms of upper respiratory tract infection are not prominent, although mild sore throat, pharyngitis, and cervical adenopathy are often documented; on occasion, the last may be the only manifestation of illness. Epistaxis is encountered early in the course of nearly one-fourth of cases. Photophobia is also a common complaint.

Patients often report generalized myalgia, and spasm and stiffness of the muscles of the back and neck may lead to an erroneous diagnosis of meningitis. Lethargy, mental depression, agitation, insomnia, and disorientation have been prominent features of the illness in some

epidemics but not in others; delirium and stupor develop near the end of the first week in severe cases. Occasional patients are comatose when first seen, and the diagnosis of psittacosis may be elusive in these cases. Gastrointestinal manifestations such as abdominal pain, nausea, vomiting, or diarrhea are noted in some cases; constipation and abdominal distention sometimes occur as late complications. Icterus, the result of severe hepatic involvement, is a rare and ominous finding. A faint macular rash (Horder's spots) resembling the rose spots of typhoid fever has been described.

Patients without cough or other clinical evidence of respiratory involvement present with fever of unknown origin. The pulse rate is slow in relation to the fever. When splenomegaly is noted in a patient with acute pneumonitis, psittacosis should be considered; the reported incidence of splenomegaly in this disease ranges from 10 to 70%. Nontender hepatic enlargement also occurs, but jaundice is rare. Thrombophlebitis is not unusual during convalescence; indeed, pulmonary infarction is sometimes a late complication and may be fatal.

In untreated cases of psittacosis, sustained or mildly remittent fever persists for 10 days to 3 weeks or occasionally for as long as 3 months. Over this period, the respiratory manifestations gradually abate. Psittacosis contracted from parrots or parakeets is more likely to be a severe, prolonged illness than infection acquired from pigeons or barnyard fowl. Relapses occur but are rare. Occasional patients develop endocarditis, and C. psittaci infection should be considered in cases of culture-negative endocarditis. Secondary bacterial infections are uncommon. Immunity to reinfection is probably permanent.

Laboratory Findings

The chest x-ray in psittacosis is nonspecific and may show pneumonic lesions that are usually patchy in appearance but can be hazy, diffuse, homogeneous, lobar, atelectatic, wedge-shaped, nodular, or miliary. The white blood cell count is normal or moderately decreased in the acute phase of the disease but may rise in convalescence. The erythrocyte sedimentation rate frequently is not elevated. Transient proteinuria is common. The cerebrospinal fluid sometimes contains a few mononuclear cells but is otherwise normal. Despite hepatomegaly, the results of liver function tests are generally normal or only mildly elevated.

The diagnosis can be confirmed only by isolation of the causative microorganism or by serologic studies. The agent is present in the blood during the acute phase of the disease and in the bronchial secretions for weeks or sometimes years after infection, but it is difficult to isolate. Further, the organism is hazardous to work with in the laboratory, and most clinical laboratories do not offer culture for C. psittaci. Thus psittacosis is most readily diagnosed by the demonstration of a rising titer of complement fixation antibody in the serum of a patient with a compatible clinical syndrome. Both an acute-phase and a convalescent-phase specimen should always be tested. C. trachomatis, C. psittaci, and C. pneumoniae all share a genus-specific “group” antigen, which is the basis of the complement fixation test. Thus acute infections with C. trachomatis or C. pneumoniae can also produce titer rises in this test. However, these three species have different major outer-membrane proteins that are the principal antigens in the micro-IF test. If there is doubt as to the interpretation of the complement fixation test, the micro-IF test can be used to differentiate among these antigens. The prompt initiation of treatment with tetracycline has been shown to delay an antibody rise in convalescence for several weeks or months.

Differential Diagnosis

A history of exposure to birds may be the only clinical basis for differentiating psittacosis from a variety of infectious and noninfectious febrile disorders. The list of pulmonary diseases that may be confused with psittacosis includes Mycoplasma pneumonia, C. pneumoniae pneumonia, legionellosis, viral pneumonia, Q fever, coccidioidomycosis, tuberculosis, enterovirus infection, carcinoma of the lung with bronchial obstruction, and common bacterial pneumonias. In the early stages, before pneumonitis appears, psittacosis may be mistaken for influenza, typhoid fever, miliary tuberculosis, or infectious mononucleosis.

TREATMENT

The tetracyclines are consistently effective in the treatment of psittacosis. Defervescence and alleviation of symptoms usually take place within 24 to 48 h after the institution of therapy with 2 g daily in four divided doses. To avoid relapse, treatment should probably be continued for at least 7 to 14 days after defervescence. In severe cases, hospitalization and pulmonary intensive care may be indicated. Sulfonamides are not active against C. psittaci. Erythromycin can be used in patients allergic to or intolerant of tetracyclines.

C. PNEUMONIAE INFECTIONS

Definition

A third chlamydial species that causes disease in humans, C. pneumoniae, has been described in the past quarter century. C. pneumoniae can be distinguished from the other two species on the basis of DNA hybridization and elementary body morphology. Although C. pneumoniae can be grown in a variety of cell cultures, it is considerably more difficult to culture than other chlamydiae, especially from clinical specimens. HL cells appear to be the most effective cell line for isolation of C. pneumoniae.

Epidemiology

Knowledge of the epidemiology of C. pneumoniae infections has been derived primarily from serologic studies. Infections begin to occur in late childhood, achieve peak incidence in young adults, but continue throughout adult life. Seroprevalence in the many adult populations that have been tested throughout the world exceeds 40%—a figure suggesting that C. pneumoniae infections are ubiquitous. Secondary episodes (reinfections) appear to occur commonly in older adults throughout life. C. pneumoniae also produces epidemics of pneumonia and respiratory illness, especially in close residential quarters such as military barracks. The incidence of infections outside of epidemics remains poorly defined. Transmission appears to be from person to person, probably primarily in schools and family units.

Pathogenesis

Little is known about the pathogenesis of C. pneumoniae infection. The infection begins in the upper respiratory tract and in many persons is a long-lived asymptomatic condition of the upper respiratory mucosal surfaces. However, in at least some individuals, the organism is transported to distant sites—perhaps within macrophages—since evidence exists for replication within arteries and synovial membranes of joints. A C. pneumoniae outer-membrane protein may induce host immune responses whose cross-reaction with human proteins results in an autoimmune reaction.

Clinical Manifestations

The clinical spectrum of C. pneumoniae infection includes acute pharyngitis, sinusitis, bronchitis, and pneumonitis, primarily in young adults. The clinical manifestations of primary infection appear to be more severe and prolonged than those of reinfection. The pneumonitis resembles that of M. pneumoniae pneumonia in that leukocytosis is frequently lacking and patients often have prominent antecedent upper respiratory tract symptoms, fever, nonproductive cough, a mild to moderate degree of illness, minimal findings on chest auscultation, and small segmental infiltrates on chest x-ray. In elderly patients, pneumonia due to C. pneumoniae can be especially severe and may necessitate hospitalization and respiratory support.

Epidemiologic studies have demonstrated an association between serologic evidence of C. pneumoniae infection and atherosclerotic disease of the coronary and other arteries. In addition, C. pneumoniae has been identified in atherosclerotic plaques by electron microscopy, DNA hybridization, and immunocytochemistry. The organism has been recovered in culture from atheromatous plaque—a result indicating the presence of viable replicating bacteria in vessels. Evidence from animal models supports the hypothesis that C. pneumoniae infection of the upper respiratory tract is followed by recovery of the organism from atheromatous lesions in the aorta and that the infection accelerates the process of atherosclerosis, especially in hypercholesterolemic animals. Antimicrobial treatment of the infected animals reverses the increased risk of atherosclerosis. In humans, two small trials in patients with unstable angina or recent myocardial infarction also suggested that antibiotics reduce subsequent untoward cardiac events. Larger trials have been initiated to determine more definitively whether antibiotics affect the risk of atherosclerosis.

Diagnosis

Diagnosis of C. pneumoniae infection is currently difficult because cell culture techniques are not available for routine clinical use and nonculture tests using antigen detection methods or DNA probes have not been developed for commercial use. Acute- and convalescent-phase sera can be tested for chlamydial complement fixation antibody to make a retrospective diagnosis. However, this test does not distinguish C. pneumoniae infection from infection due to C. trachomatis or C. psittaci.

TREATMENT

Although controlled treatment trials have not been conducted, C. pneumoniae is inhibited in vitro by erythromycin and tetracycline. Recommended therapy consists of 2 g per day of either agent for 10 to 14 days. Other macrolides, such as azithromycin, and some fluoroquinolones, such as levofloxacin, also appear to be effective.

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