ACP medicine, 3rd Edition

Infectious Disease

Diseases due to Chlamydia

Walter E. Stamm MD, FACP1

Professor

1Department of Medicine, and Head, Division of Allergy and Infectious Disease, University of Washington School of Medicine

The author has received grants for clinical research from ActivBiotics, Inc. and has served as advisor or consultant to Gen-Probe, Inc.

September 2006

The chlamydiae are obligate intracellular bacteria that produce a wide variety of infections in many mammalian and avian species.1 Three species of Chlamydia infect humans: C. trachomatis, C. psittaci, and C. pneumoniae [see Table 1]. C. trachomatis is exclusively a human pathogen and is transmitted from person to person via sexual contact, perinatal transmission, or close contact in households. C. trachomatiscauses trachoma in arid developing parts of the world and is a major cause of sexually transmitted and perinatal infections worldwide. In the United States, C. trachomatis infection is the most common reportable infectious disease, with 877,478 cases of genital chlamydial infection reported in 2003.2 C. psittaci, in contrast, is more widely distributed in nature, producing genital, conjunctival, intestinal, or respiratory infections in many avian and mammalian species.3 Humans are occasionally infected by avian strains after contact with infected birds, incurring a pneumonitis or a systemic infection termed psittacosis.

Table 1 Comparative Features of Chlamydia species

Species

C. trachomatis

C. psittaci

C. pneumoniae

Natural hosts

Humans

Birds, mammals

Humans

Mode of transmission

Sexual; close personal contact; maternal/infant

Zoonotic

Respiratory droplets

Typical diseases

STDs, LGV, trachoma

Pneumonia, psittacosis

Upper respiratory infections, pneumonia, atherosclerotic vascular disease

Risk groups

STDs: sexually active adolescents and young adults

Bird fanciers, pet-shop workers, veterinarians, animal and poultry workers

Young children, older adults

Trachoma: young children in arid, unhygienic, crowded conditions

 

 

Number of serotypes

18

Unknown

1

LGV—lymphogranuloma venereum  STDs—sexually transmitted diseases

  1. pneumoniae, the third chlamydial species that infects humans, was identified and characterized in the 1980s.4It is a fastidious organism that produces upper respiratory tract infection and pneumonitis in both children and adults.5Studies have also linked C. pneumoniaeinfection to atherosclerotic cardiovascular disease6 and perhaps to other illnesses, such as asthma and sarcoidosis.5 Transmission is believed to occur via aerosol droplets; no animal reservoir has been identified.

All chlamydiae share a unique life cycle characteristic of the genus [see Figure 1].7 The organism is transmitted in an extracellular nonreplicating form known as the elementary body. The elementary body adheres to and is phagocytosed into a host epithelial cell. Once inside the epithelial cell, the elementary body transforms into the intracellular replicative form of the organism, the reticulate body. Reticulate bodies divide by binary fission within membrane-bound vacuoles called inclusions. After approximately 36 hours, reticulate bodies condense into elementary bodies, the inclusion ruptures, and the elementary bodies disperse to infect adjacent epithelial cells or to be transmitted to other hosts. A unique feature of the chlamydial inclusion is its ability to resist lysosomal fusion; the mechanism of resistance is as yet unknown. The intracellular milieu also provides the organism with nutrients and serves as a refuge from host immune defense mechanisms.

 

Figure 1. Mechanism of Chlamydiae Infection

Life cycle of Chlamydia. (a) Chlamydiae are transmitted in an extracellular nonreplicating form known as the elementary body. The elementary body adheres to and is phagocytosed into a host epithelial cell. (b) Once inside the epithelial cell, the elementary body transforms into the intracellular replicative form of the organism, the reticulate body. (c) Reticulate bodies divide by binary fission within membrane-bound vacuoles called inclusions. (d) The reticulate bodies then reorganize into elementary bodies; multiplication stops. (e) After 35 to 40 hours, the inclusion ruptures, and elementary bodies are released to infect adjacent epithelial cells or to be transmitted to other hosts.

Although chlamydiae were initially thought to be large viruses, they in fact possess both DNA and RNA, have a cell wall and ribosomes similar to those of gram-negative bacteria, and are inhibited by a variety of antimicrobials (see below).7 C. trachomatis, C. psittaci, and C. pneumoniae all share a genus-specific lipopolysaccharide antigen. The commonly available complement fixation test for Chlamydia measures antibodies against this antigen. The three species can be differentiated serologically with the microimmunofluorescence test, which is directed against epitopes in the major outer membrane protein (MOMP).

Characteristically, chlamydial species produce chronic, persistent, and often asymptomatic infections of the epithelial lining of the eye, respiratory tract, and urogenital tract. Infection of epithelial cells induces secretion of cytokines and the initiation of an innate immune response. Induction and persistence of a chronic inflammatory response may eventually result in fibrosis, scarring, and other chronic sequelae of infection.8

In cell cultures, Chlamydia species are susceptible to many antimicrobials, including tetracycline, doxycycline, erythromycin, azithromycin, rifampin, clindamycin, ofloxacin, and levofloxacin. Although antibiotic-resistant strains of Chlamydia have been described, clinical antimicrobial resistance has yet to become a frequent problem in treating chlamydial infections.9

Diseases Due to C. trachomatis

Unlike C. pneumoniae, which appears to have only a single serotype, and C. psittaci, whose number of serotypes is unknown, C. trachomatishas at least 18 distinct serotypes (serovars).10 These serotypes confer tissue tropism and disease specificity: serovars A, B, Ba, and C are associated with trachoma, whereas serovars D through K are associated with sexually transmitted and perinatally acquired infections. Serovars L1, L2, and L3 are more invasive than the other serovars, spread to lymphatic tissue, and grow readily in macrophages; they produce the clinical syndromes of lymphogranuloma venereum and hemorrhagic proctocolitis. In addition to these more commonly reported syndromes, C. trachomatis has been reported as an infrequent cause of other infections, including endocarditis, peritonitis, pleuritis, and periappendicitis.11

Laboratory Diagnosis

Laboratory testing for C. trachomatis has evolved considerably over the past decade. Four types of confirmatory procedures are now available: (1) direct microscopic examination of swabs or tissue scrapings utilizing fluorescent antibody staining (DFA); (2) cell culture isolation of the organism; (3) detection of chlamydial antigens or genes in specimens by immunologic means or nucleic acid amplification testing; and (4) serologic testing for antibodies to C. trachomatis.

Except in cases of inclusion conjunctivitis, DFA has largely been abandoned for diagnosis of chlamydial infection. Even in inclusion conjunctivitis, nucleic acid amplification testing of conjunctival smears is probably a better choice because of its higher sensitivity. Cell culture techniques for isolation of Chlamydia are not widely available and have numerous drawbacks: culture has exacting requirements for specimen transport and is technically demanding and expensive; moreover, its sensitivity is only 60% to 80% of that of newer diagnostic tests.12 For those reasons, nonculture alternatives utilizing antigen or gene detection are the diagnostic methods of choice in most cases. The least expensive and most widely used of the nonculture tests are enzyme-linked immunoassays that detect chlamydial antigens on urethral or endocervical swabs. These tests, however, have limited sensitivity and specificity and cannot be used to test vaginal swabs or urine for Chlamydia.

The newer nucleic acid amplification tests, such as polymerase chain reaction (PCR) and transcription-mediated amplification (TMA), are the most sensitive and specific of the currently available tests.13 Ligase chain reaction (LCR), which also is very sensitive, was removed from the market in 2002. These tests are unique in being highly accurate, even when used on specimens that contain only small numbers of organisms (e.g., first-void urine samples or vaginal swabs). The ability to use such specimens is of particular importance because their ease of collection facilitates patient compliance and community-based screening programs.

Serologic tests are of little value in the diagnosis of most chlamydial ocular or genital infections.14 They are useful only in invasive syndromes such as pelvic inflammatory disease (PID), epididymitis, lymphogranuloma venereum, and infant pneumonia, which are associated with significant increases in both microimmunofluorescence and complement-fixing antibodies.

Sexually Transmitted Diseases

  1. trachomatisis the most common bacterial cause of sexually transmitted disease (STD) in the United States, being responsible for an estimated four million cases a year.2The spectrum of illness attributable to these infections parallels that of gonococcal infection. In men, the most common syndromes are nongonococcal urethritis and acute epididymitis. In women, mucopurulent cervicitis, urethritis, bartholinitis, acute salpingitis, and perihepatitis are the syndromes most commonly seen. Inclusion conjunctivitis, proctitis, and Reiter syndrome affect both sexes.

Sexually transmitted C. trachomatis infection has a widespread distribution and a high incidence and prevalence in adolescents and young adults in the United States and Europe.15 The age of peak incidence is the late teens and early 20s. A prospective cohort study of 14,322 persons between 18 and 26 years of age in the United States found that the overall prevalence of chlamydial infection was 4.19%.16 Women were more likely to be infected than men; the highest prevalences were found in African-American women (13.95%) and men (11%).16Prevalence has been reported at 3% to 8% in general medical clinics and urban high schools, 8.5% to 10% in asymptomatic female military personnel enrolled in a Chlamydia screening program, and as high as 15% to 20% in men and women attending STD clinics.17,18 C. trachomatis infection is frequently present in patients infected with Neisseria gonorrhoeae. In a cross-sectional study of five STD clinics, C. trochomatis was detected in 20% men and 42% women with laboratory-confirmed N. gonorrhoeae.19

The highest prevalences of chlamydial infection have been observed in persons who are single, have multiple sexual partners, are not using barrier contraception, report genital symptoms, have an infected sexual partner, or are attending a high-risk clinic such as an STD clinic. As many as 90% of infections in many settings may be asymptomatic and are thus discoverable only by screening. Recurrent chlamydial infections—often from untreated sexual partners—are common in high-risk groups.20

  1. trachomatisinitially infects the columnar epithelium of the genital tract and induces an inflammatory response that may persist for months or years. Serious sequelae, such as scarring of the fallopian tubes and damage to the upper genital tract, occur most often with repeated or persistent infections.21The mechanism through which repeated infection induces inflammation and subsequent complications is not clear. The C. trachomatis 60 kd heat shock protein has been implicated in these deleterious inflammatory responses and may induce antibodies that cross-react with human heat-shock protein. Other chlamydial proteins also may be important in this process.22 Host genetic susceptibility may also play a role: persons with particular HLA haplotypes (e.g., class II variant DQB1*06) appear to be more susceptible to scarring with either genital or ocular infection.23

Nongonococcal Urethritis

Diagnosis

Nongonococcal urethritis (NGU), the most common chlamydial urogenital infection in men, typically presents with burning pain on urination, urethral discharge, or urethral itching. A discharge from the urethra may be apparent on observation or may be visible only after stripping the urethra. The discharge is generally clear or mucoid, but it may be mucopurulent or purulent.24 However, up to half of the men with C. trachomatis infection of the urethra will have no clinical manifestations of urethritis, and 12% have no gram-stain evidence of urethral inflammation.25 Many of these patients will nevertheless have an increased number of leukocytes on Gram stain of a urethral smear. A presumptive diagnosis of NGU can be made on the basis of a leukocytic urethral exudate (≥ 4 polymorphonuclear leukocytes [PMNs] per 1,000 × oil-immersion field) in the absence of concurrent gonococcal infection by Gram stain or culture. About 40% of such cases of presumptive NGU are caused by Chlamydia; the remainder are caused by Ureaplasma urealyticum, Mycoplasma genitalium, and other microbes.26 The specific diagnosis of chlamydial infection can be confirmed by a nucleic acid amplification assay such as PCR, an antigen detection test, or culture.

Treatment

Men with presumed or confirmed NGU should be treated with oral doxycycline (100 mg twice a day for 7 days) or azithromycin (1 g as a single dose) [see Table 2]. The two regimens appear equally effective.27 The azithromycin regimen offers the advantage of single-dose therapy but is considerably more expensive.

Table 2 Antibiotic Therapy for Sexually Transmitted Diseases Caused by C. trachomatis

 

Disease

Drug

Typical Dose*

Cost/Mo ($)

Comments

Men

Nongonococcal urethritis

Azithromycin

1 g p.o. as a single dose

46

The regimens appear equally effective, but azithromycin is more expensive; sexual partners should be evaluated and empirically treated for chlamydial infection

Doxycycline

100 mg p.o., b.i.d., for 7 days

9

Epididymitis

Ofloxacin

300 mg p.o., b.i.d., for 10 days

80

Sexual partners should be evaluated and empirically treated for chlamydial infection

Ceftriaxone plus doxycycline

Ceftriaxone, 250 mg I.M.; doxycycline, 100 mg p.o., b.i.d., for 7 days

NA

Proctitis

Ceftriaxone plus doxycycline

Ceftriaxone, 125 mg I.M.; doxycycline, 100 mg p.o., b.i.d., for 7 days

NA

These infections occasionally develop in heterosexual women

Conjunctivitis

Azithromycin

1 g p.o. as a single dose

46

Sexual partners should be evaluated and empirically treated for chlamydial infection

Doxycycline

100 mg p.o., b.i.d., for 7 days

9

Women

Cervicitis

Azithromycin

1 g p.o. as a single dose

46

Sexual partners should be evaluated and empirically treated for chlamydial infection

Doxycycline

100 mg p.o., b.i.d., for 7 days

9

Amoxicillin

500 mg p.o., t.i.d., for 7 days

8

Urethritis

Azithromycin

1 g p.o. as a single dose

46

Untreated infections may last for months

Doxycycline

100 mg p.o., b.i.d., for 7 days

9

Salpingitis

Ofloxacin plus metronidazole

Ofloxacin, 400 mg p.o., b.i.d.; metronidazole, 500 mg p.o., b.i.d., for 14 days

135

Tubal infection may become chronic in spite of antibiotic therapy

Conjunctivitis

Azithromycin

1 g p.o. as a single dose

46

Sexual partners should be evaluated and empirically treated for chlamydial infection

Doxycycline

100 mg p.o., b.i.d., for 7 days

9

*For details, see 7:XIV Antimicrobial Therapy (especially Tables 3 and 4).
Costs are derived from online pharmaceutical sources and are intended to indicate relative costs of available therapies.
NA—not available

The prevalence of chlamydial infection in sexual partners has made partner notification and referral a standard practice; however, traditional partner referral is ineffective in ensuring that partners are treated. Two randomized, controlled studies found that medications given to the patient for use by the patient's partner (a strategy referred to as patient-delivered partner treatment) was superior to standard partner referral for the treatment of partners and the prevention of recurrence of C. trachomatis infection.28,29

Epididymitis

In 1% to 2% of men with chlamydial urethritis, the infection ascends in the genital tract to cause acute epididymitis. C. trachomatis is the major cause of acute epididymitis in heterosexual men younger than 35 years; other causes include Neisseria gonorrhoeae and, less commonly, urinary pathogens such as Escherichia coli or Pseudomonas aeruginosa.30 Urinary pathogens are a more common cause of epididymitis in homosexual men who practice rectal intercourse and in men older than 35 years who have had urologic instrumentation or surgery.

Diagnosis

Epididymitis caused by C. trachomatis typically presents as unilateral scrotal pain, fever, and epididymal tenderness and swelling. Testicular torsion should be excluded by a radionuclide scan or Doppler flow study if the diagnosis is in doubt.

Treatment

In some patients, epididymitis may be mild enough to be treated on an outpatient basis with oral antibiotics. In other cases, hospitalization is required for management of pain and initiation of parenteral antibiotics. Initial empirical therapy with ofloxacin, 300 mg orally or intravenously twice daily, is recommended by most experts until the etiologic agent is identified [see Table 2]. The Centers for Disease Control and Prevention (CDC) guidelines recommend the combination of ceftriaxone (250 mg I.M. as a single dose) plus doxycycline (100 mg orally twice a day for 10 days) for the treatment of acute epididymitis most likely caused by chlamydial or gonococcal infection.31

Mucopurulent Cervicitis

Endocervical infection with C. trachomatis is considered the female counterpart of male urethritis.32

Diagnosis

  1. trachomatiscervical infection is often clinically silent, although a careful speculum examination will reveal mucopurulent cervicitis in some cases. When clinical manifestations are present, they are nonspecific—for example, vaginal discharge, vaginal bleeding, lower abdominal pain, or dysuria. On examination, findings include a yellow or green mucopurulent discharge from the endocervical os, the presence of cervical ectropion, edema in the area of ectropion, and easily induced mucosal bleeding.32A Gram stain of the endocervical exudate typically shows large numbers of PMNs. Women with suspected mucopurulent cervicitis should be evaluated for both chlamydial and gonococcal infection.

Treatment

Chlamydial mucopurulent cervicitis is best treated with a single oral dose of 1 g of azithromycin [see Table 2].29 This regimen is effective and safe. Although more expensive than doxycycline, azithromycin is cost-effective because adolescents often fail to complete a 7-day course of doxycycline.33 Unlike doxycycline, azithromycin appears to be safe during pregnancy and is used for the treatment of chlamydial mucopurulent cervicitis or cervical infection in pregnant women.34 Amoxicillin (500 mg orally three times daily for 7 days) is comparable to azithromycin in the treatment of cervical C. trachomatis during pregnancy.35 Sexual partners of women found to have chlamydial cervical infection or mucopurulent cervicitis should be examined and empirically treated for chlamydial infection.

Acute Urethral Syndrome in Women

In women presenting with dysuria, frequency, and pyuria, C. trachomatis is the pathogen that is most commonly identified if urine cultures fail to find E. coli, Staphylococcus saprophyticus, or other uropathogens.36 Chlamydial infection should be considered to be the cause of so-called dysuria-pyuria syndrome when the urine culture does not demonstrate expected urinary bacterial pathogens, symptoms have been present for more than 7 days, the patient has a new sexual partner, or concomitant mucopurulent cervicitis is present on examination.36,37Recommended treatment is with oral azithromycin (1 g as a single dose) or doxycycline (100 mg twice a day for 7 days) [see Table 2].

Pelvic Inflammatory Disease

  1. trachomatisis thought to account for about half of all cases of PID in the United States.38Although PID caused by N. gonorrhoeaeinfection may be more acutely symptomatic, PID caused by C. trachomatis tends to be associated with higher rates of subsequent infertility.39,40 Ascending intraluminal spread of C. trachomatis from the lower genital tract can produce endometritis, endosalpingitis, and pelvic peritonitis. On examination, evidence of mucopurulent cervicitis is generally found in women who have laparoscopically verified salpingitis caused by C. trachomatis.

Diagnosis

Chlamydial salpingitis, which is considered more common than symptomatic PID, often produces fewer clinical symptoms and signs than gonococcal or anaerobic salpingitis.40,41 However, patients often present with lower abdominal pain, adnexal tenderness, vaginal discharge or bleeding, and uterine tenderness. They may or may not have fever.

Treatment

Empirical treatment of PID must provide antimicrobial coverage for the major pathogens, including C. trachomatis, N. gonorrhoeae, and vaginal anaerobes [see Table 2]. Screening of high-risk young women for chlamydial cervical infection followed by treatment has been shown to prevent subsequent PID in a prospective cohort study.42 Thus, chlamydial screening of all sexually active adolescent girls and women younger than 29 years who have new sexual partners is strongly recommended.43

Complications

Infertility and ectopic pregnancy are important sequelae of chlamydial tubal infection.39,40 Antecedent C. trachomatis PID has been linked to infertility from fallopian tube scarring. Demonstration of persistent, slowly replicating C. trachomatis in tubal tissue suggests that these patients may have chronic infection.40

Perihepatitis, or Fitzhugh-Curtis syndrome, develops in a subset of women with chlamydial salpingitis. These patients present with right upper quadrant pain, fever, and often adnexal tenderness. The diagnosis can be established with an endocervical nucleic acid amplification test for Chlamydia or by demonstration of high titers of antibody to C. trachomatis.

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 L3.44 Data from several clinical settings suggest that chlamydial proctitis is resurgent in homosexual and bisexual men in the United States.45,46 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. Acute proctitis among persons who have recently practiced receptive anal intercourse is usually sexually acquired. Such patients should be examined by anoscopy and evaluated for infection with herpes simplex virus, N. gonorrhoeae, Treponema pallidum, and C. trachomatis. Characteristically, a rectal Gram stain shows one or more PMNs per 1,000 × oil-immersion field, and anoscopy demonstrates a mucopurulent discharge and easily induced mucosal bleeding.44 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 have not been extensively studied, and these tests are not approved for the diagnosis of chlamydial proctitis.

Treatment

Treatment regimens for chlamydial proctitis have not been extensively studied. If an anorectal exudate is found on examination, or if polymorphonuclear leukocytes are found on a Gram-stained smear of anorectal secretions, the recommended empirical treatment is ceftriaxone (125 mg intramuscularly) plus doxycycline (100 mg orally twice a day for 7 days), pending results of additional laboratory tests [see Table 2].29

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 pathogenesis of Reiter syndrome is obscure, more than 80% of affected patients have the HLA B27 haplotype, so a genetic predisposition is clearly involved.47 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 proctitis with associated regional lymphadenitis.48 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. LVG infection in developed countries is rare. However, since 2003, an ongoing outbreak of LGV proctitis has been reported in industrialized countries, first in the Netherlands, then in neighboring European countries and the United Kingdom, and more recently in the United States and Canada; to date, all cases have involved men who have sex with men.49 It is uncertain whether the recent reports represent a new problem or one that has been present but undetected.50

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.51 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 industrialized countries, LGV proctitis has increasingly been recognized in homosexual men. The clinical course of LGV can be divided into three phases.52 In the first phase, disease involves the site of inoculation; in the second phase, the regional lymph nodes and sometimes the anorectum are involved; late sequelae affecting the genitals, the rectum, or both characterize the final phase. Patients present with rectal pain and mucopurulent, bloody rectal discharge. 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 lymphadenopathy, 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 resulting from associated lymphatic obstruction.29

Laboratory tests

LGV is most readily diagnosed serologically. Both the LGV complement fixation (CF) test and the microimmunofluorescence (MIF) test become strongly positive soon after the onset of lymphadenopathy. A positive serologic test for IgG antibodies, in the presence of a compatible clinical syndrome, is considered adequate for a presumptive diagnosis. Serial titers demonstrating a titer rise are confirmatory. A titer of greater than 1:256 rules in the diagnosis, whereas a titer less than 1:32 rules it out.52 MIF is more sensitive and specific than CF, but neither test can distinguish recent from past infection. For this reason, the results of serologic testing must be correlated with the clinical manifestations. Demonstration of C. trachomatis by culture or nucleic acid amplification tests from urethral or cervical specimens or from pus aspirated from buboes in a patient with a compatible syndrome also supports the diagnosis. PCR and other nucleic acid amplification tests appear to be useful but do not differentiate LGV and non-LGV strains; in addition, they have been evaluated only in limited situations.53,54

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,29,55 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.43 If not identified and treated, the infection may persist for months or years.56

The risk of acquiring C. trachomatis in an infant born vaginally to a woman with chlamydial cervicitis has been reported to be as high as 60% to 70%.57,58,59 However, these figures include asymptomatic newborns with colonization or only serologic evidence of infection. In infants from whom the organism has been isolated, the risk of conjunctivitis has been estimated to be 20% to 50%; the risk of pneumonia has been estimated to be 5% to 20%.

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 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.29 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.29,60

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 caused by 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

  1. 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.61Flies 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, greater availability of clean water, and increased efforts to control endemic disease.62

Pathogenesis

Severe, chronic, blinding trachoma is generally associated with repeated reinfection or persistent infection by trachoma-causing strains of C. trachomatis.63 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.61

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.64 With repeated episodes, the cornea becomes involved, with inflammatory infiltrates and pannus formation (superficial vascularization). Conjunctival scarring eventually develops and causes the eyelids to turn inward and abrade the eyeball.65 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; however, commercial assays are too expensive and complex for use in national programs, and researchers report the need for a rapid, reliable test to assist in endemic areas.66 Nucleic acid amplification testing frequently detects conjunctival C. trachomatis infection in persons without clinical signs of trachoma; however, it is unclear whether these persons are actually infected. A recent study indicated that 16S ribosomal RNA (rRNA) expression, a marker of chlamydial metabolic activity, appears useful in distinguishing between established infections and the presence of dead or subviable organisms.67

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.11 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.68 Personal cleanliness and a reduction in flies in villages may also be important.

Disease Due to C. psittaci

Psittacosis

  1. psittaciinfects 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 pneumonitis and a variety of systemic manifestations.69

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: 75 to 100 cases are reported each year in the United States,70 but it is likely that many cases, especially milder ones, go undiagnosed and thus unreported.

Pathogenesis

  1. psittacican 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.
  2. psittacienters humans via the upper respiratory tract and spreads throughout the body via the bloodstream, localizing primarily in pulmonary alveolar macrophages and the endothelial cells of the liver and spleen.71A 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.72 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, the absence of a pleural effusion, a relative bradycardia, the absence of neutrophilia, 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.70

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.70 Most patients respond to oral therapy using doxycycline (100 mg administered twice a day) or tetracycline hydrochloride (500 mg administered four times a day).70 For initial treatment of severely ill patients, doxycycline can be administered intravenously at a dosage of 4.4 mg/kg (2 mg/lb) body weight a day divided into two infusions daily (up to 100 mg a dose). Remission of symptoms usually is evident within 48 to 72 hours. However, relapse can occur, and treatment must continue for at least 10 to 14 days after fever abates. Erythromycin is probably the best alternative agent in patients in whom tetracycline is contraindicated.

Diseases Due to C. pneumoniae

  1. pneumoniaeis a recently described species that, as its name indicates, is associated primarily with respiratory tract infections. Initially,C. pneumoniaestrains 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 antigenic properties.73 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.74

Epidemiology

Because of the difficulty in isolating the organism, most epidemiologic studies have depended on microimmunofluorescence serologic studies. Such studies have indicated that C. pneumoniae infection is extremely prevalent, with approximately 40% to 75% of adults demonstrating seropositivity in almost all countries examined worldwide.75,76 Infections are uncommon until late childhood; the peak period of incidence appears to be between 10 and 20 years of age.77 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 infections 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.78

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.79 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

  1. pneumoniae, like other chlamydial species, can produce asymptomatic infection of the respiratory tract and endovascular tissues. C. pneumoniaewas 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. pneumoniaein infected tissues.80 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, otitis media, and asthma, but this is less extensively studied.81

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 have been frequent reports of an association between circulating C. pneumoniae antibody titers and coronary artery disease (CAD); however, several studies failed to find such an association. Most studies that do report an association with CAD have used the presence of IgG or IgA antibodies to C. pneumoniae as an indication of chronic infection.82 In addition, C. pneumoniae has been identified in atherosclerotic plaques by a variety of techniques, including electron microscopy, DNA hybridization, immunocytochemistry, and PCR.83 The organism has also been cultured from atherosclerotic plaques, demonstrating the presence of viable C. pneumoniae in the vessel wall.84

Two meta-analyses, which included 15 prospective trials evaluating IgG titers and 10 prospective trials evaluating IgA titers, found no significant association between CAD and IgG titers (odds ratio, 1.15; 95% confidence interval [CI], 0.97 to 1.36) and a significant but weak association with IgA titers (odds ratio, 1.25; 95% CI, 1.03 to 1.53).85,86 Nonetheless, the high frequency of infection found in human atherosclerotic tissue in comparison to normal tissue and the induction and progression of atherosclerotic-like inflammatory changes in animal models of atherosclerosis suggest an association between C. pneumoniae infection and cardiovascular disease.87

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.88 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. trachomatis 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 fluoroquinolones, such as levofloxacin. Most experts recommend tetracycline (2 g daily in four divided doses) or doxycycline (100 mg b.i.d.) as initial therapy.11Treatment should be given for at least 2 to 3 weeks. Azithromycin has proved to be effective against C. pneumoniae in the empirical treatment for community-acquired pneumonia89; the recommended dosage is 500 mg on day 1, followed by 250 mg a day for 4 days or 500 mg a day for 3 days. Many cases of C. pneumoniae pneumonia 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 has proved disappointing. The three largest and longest trials of antimicrobial therapy for C. pneumoniae-associated cardiovascular disease (involving a combined total of 16,000 patients) failed to show any significant reduction in coronary events.90,91,92 Antibiotics are not currently recommended for this indication.

Acknowledgment

Figure 1 Seward Hung

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Editors: Dale, David C.; Federman, Daniel D.