1449CHAPTER 189 Chlamydial Infections

clinician-collected vaginal swabs, which are slightly more sensitive

than urine, be used. Urine screening tests are often used in outreach

screening programs, however. For symptomatic women undergoing a

pelvic examination, cervical swab samples are desirable because they

have slightly higher chlamydial counts. For male patients, a urine specimen is the sample of choice, but self-collected penile-meatal swabs

have been shown to be very effective.

ALTERNATIVE SPECIMEN TYPES Ocular samples from babies and

adults can be assessed by NAATs. Samples from extragenital rectal and

pharyngeal sites have been used previously to detect chlamydiae by

NAATs with validation studies, but now several commercially available

NAAT tests have FDA clearance for extragenital samples.

OTHER DIAGNOSTIC ISSUES Because NAATs detect nucleic acids

instead of live organisms, they should be used with caution as testof-cure assays. Residual nucleic acid from cells rendered noninfective

by antibiotics may continue to yield a positive result in NAATs for

as long as 3 weeks after therapy when viable organisms have actually

been eradicated. Therefore, clinicians should not use NAATs for test

of cure until after 3 weeks. The CDC currently does not recommend a

test of cure after treatment for infection with C. trachomatis. However,

because incidence studies have demonstrated that previous chlamydial

infection increases the probability of becoming reinfected, the CDC

does recommend that previously infected individuals be rescreened

3 months after treatment.

SEROLOGY Serologic testing may be helpful in the diagnosis of LGV

and neonatal pneumonia caused by C. trachomatis. The serologic test

of choice is the microimmunofluorescence (MIF) test, in which hightiter purified elementary bodies mixed with embryonated chicken yolk

sac material are affixed to a glass microscope slide to which dilutions of

sera are applied. After incubation and washing, fluorescein-conjugated

IgG or IgM antibody is applied. The test is read with an epifluorescence

microscope, with the highest dilution of serum producing visible fluorescence designated as the titer. The MIF test is not widely available

except in research laboratories and is highly labor intensive. Although

the complement fixation (CF) test can also be used, it employs

lipopolysaccharide (LPS) as the antigen and therefore identifies the

pathogen only to the genus level. Single-point titers of >1:64 support

a diagnosis of LGV, for which it is difficult to demonstrate rising antibody titers—i.e., paired serum samples are difficult to obtain since the

disease often results in the patient’s being seen by the physician after

the acute stage. Any antibody titer of >1:16 is considered significant

evidence of exposure to chlamydiae. However, serologic testing is never

recommended for diagnosis of uncomplicated genital infections of the

cervix, urethra, and lower genital tract or for C. trachomatis screening

of asymptomatic individuals.

TREATMENT

C. trachomatis Genital Infections

A 7-day course of oral doxycycline (100 mg twice daily) or a

single 1-g oral dose of azithromycin are the primary recommended regimens of treatment for uncomplicated chlamydial

TABLE 189-1 Diagnostic Tests for Sexually Transmitted and Perinatal Chlamydia trachomatis Infection

INFECTION SUGGESTIVE SIGNS/SYMPTOMS PRESUMPTIVE DIAGNOSISa CONFIRMATORY TEST OF CHOICE

Men

NGU, PGU Discharge, dysuria Gram’s stain with >4 neutrophils per

oil-immersion field; no gonococci

Urine or urethral NAAT for C. trachomatis

Epididymitis Unilateral intrascrotal swelling, pain,

tenderness; fever; NGU

Gram’s stain with >4 neutrophils per

oil-immersion field; no gonococci;

urinalysis with pyuria

Urine or urethral NAAT for C. trachomatis

Women

Cervicitis Mucopurulent cervical discharge, bleeding and

edema of the zone of cervical ectopy

Cervical Gram’s stain with ≥20 neutrophils

per oil-immersion field in cervical mucus

Urine, cervical, or vaginal NAAT for

C. trachomatis

Salpingitis Lower abdominal pain, cervical motion

tenderness, adnexal tenderness or masses

C. trachomatis always potentially

present in salpingitis

Urine, cervical, or vaginal NAAT for

C. trachomatis

Urethritis Dysuria and frequency without hematuria MPC; sterile pyuria; negative routine

urine culture

Urine or urethral NAAT for C. trachomatis

Adults of Either Sex

Proctitis Rectal pain, discharge, tenesmus, bleeding;

history of receptive anorectal intercourse

Negative gonococcal culture and Gram’s

stain; at least 1 neutrophil per oil-immersion

field in rectal Gram’s stain

Rectal NAAT for C. trachomatis or culture

Reactive arthritis NGU, arthritis, conjunctivitis, typical skin lesions Gram’s stain with >4 neutrophils per

oil-immersion field; lack of gonococci

indicative of NGU

Urine or urethral NAAT for C. trachomatis

LGV Regional adenopathy, primary lesion, proctitis,

systemic symptoms

None Culture of LGV strain from node or rectum,

occasionally from urethra or cervix; NAAT

for C. trachomatis from these sites; LGV CF

titer, ≥1:64; MIF titer, ≥1:512

Neonates

Conjunctivitis Purulent conjunctival discharge 6–18 days after

delivery

Negative culture and Gram’s stain for

gonococci, Haemophilus spp., pneumococci,

staphylococci

Conjunctival NAAT for C. trachomatis;

FA-stained scraping of conjunctival material

Infant pneumonia Afebrile, staccato cough, diffuse rales, bilateral

hyperinflation, interstitial infiltrates

None Chlamydial culture or NAAT of sputum,

pharynx, eye, rectum; MIF antibody to

C. trachomatis—fourfold change in IgG or

IgM antibody titer

a

A presumptive diagnosis of chlamydial infection is often made in the syndromes listed when gonococci are not found. A positive test for Neisseria gonorrhoeae does not

exclude the involvement of C. trachomatis, which often is present in patients with gonorrhea.

Abbreviations: CF, complement-fixing; FA, fluorescent antibody; LGV, lymphogranuloma venereum; MIF, microimmunofluorescence; MPC, mucopurulent cervicitis; NAAT, nucleic acid

amplification test; NGU, nongonococcal urethritis; PGU, postgonococcal urethritis.

Source: Reproduced with permission from WE Stamm: Chlamydial infections, in AS Fauci et al [eds]: Harrison’s Principles of Internal Medicine, 17th ed. New York, McGrawHill, 2008.

1450 PART 5 Infectious Diseases

infections. Alternative 7-day oral regimens include erythromycin (500 mg four times daily), or a fluoroquinolone (ofloxacin,

300 mg twice daily; or levofloxacin, 500 mg/d) can be used. The

single 1-g oral dose of azithromycin is as effective as a 7-day

course of doxycycline for the treatment of uncomplicated genital

C. trachomatis infections in adults. 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 the 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 FDA for use in pregnancy,

this regimen appears to be safe and effective for this purpose.

Amoxicillin (500 mg three times daily for 7 days) or erythromycin (500 mg four times daily) can also be given as an alternative

to pregnant women. The fluoroquinolones are contraindicated

in pregnancy. A 2-week course of treatment is recommended for

complicated chlamydial infections (e.g., PID, epididymitis) and at

least a 3-week course of doxycycline (100 mg orally twice daily)

or erythromycin base (500 mg orally four times daily) for LGV.

Failure of treatment with a tetracycline in genital infections usually indicates poor compliance or reinfection rather than involvement of a drug-resistant strain. To date, clinically significant drug

resistance has not been observed in C. trachomatis.

Treatment or testing for chlamydiae should be considered

among N. gonorrhoeae–infected patients because of the frequency

of co-infection. Systemic treatment with erythromycin has been

recommended for ophthalmia neonatorum and for C. trachomatis

pneumonia in infants. For the treatment of adult inclusion conjunctivitis, a single 1-g dose of azithromycin was as effective as standard

10-day treatment with doxycycline. Recommended treatment regimens for both bubonic and anogenital LGV include tetracycline,

doxycycline, or erythromycin for 21 days.

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. Urethral or cervical infection with

C. trachomatis has been well documented in a high proportion

of the sex partners of patients with NGU, epididymitis, reactive

arthritis, salpingitis, and endocervicitis. If possible, confirmatory

laboratory tests for chlamydiae should be undertaken in these

individuals, but even persons 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.

A novel approach is partner-delivered therapy, in which infected

patients receive treatment and are also provided with single-dose

azithromycin to give to their sex partner(s).

NEONATES AND INFANTS

In neonates with conjunctivitis or infants with pneumonia, erythromycin ethylsuccinate or estolate can be given orally at a dosage

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 after topical

treatment with erythromycin or tetracycline ophthalmic ointment

and may also follow 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 Since many chlamydial infections are asymptomatic,

effective control and prevention must involve periodic screening of

individuals at risk. Selective cost-effective screening criteria have been

developed. Among women, young age (generally <25 years) is a critical

risk factor for chlamydial infections in nearly all studies. Other risk

factors include mucopurulent cervicitis; multiple, new, or symptomatic

male sex partners; and lack of barrier contraceptive use. In some settings, screening based on young age may be as sensitive as criteria that

incorporate behavioral and clinical measures. Another strategy is universal testing of all patients in high-prevalence clinic populations (e.g.,

STD clinics, juvenile detention facilities, and family planning clinics).

The effectiveness of selective screening in reducing the prevalence of

chlamydial infection among women has been demonstrated in several

studies. In the Pacific Northwest, where extensive screening began in

family planning clinics in 1998 and in STD clinics in 1993, the prevalence declined from 10% in the 1980s to <5% in 2000. Similar trends

have occurred in association with screening programs elsewhere. In

addition, screening can effect a reduction in upper genital tract disease.

In Seattle, women at a large health maintenance organization who were

screened for chlamydial infection on a routine basis had a lower incidence of symptomatic PID than did women who received standard care

and underwent more selective screening.

In settings with low to moderate prevalence, the prevalence at

which selective screening becomes more cost-effective than universal

screening must be defined. Most studies have concluded that universal screening is preferable in settings with a chlamydial prevalence of

>3–7%. Depending on the criteria used, selective screening is likely

to be more cost-effective when prevalence falls below 3%. Nearly all

regions of the United States have now initiated screening programs,

particularly in family planning and STD clinics. Along with singledose therapy, the availability of highly sensitive and specific diagnostic

NAATs using urine specimens and self-obtained vaginal swabs makes

it feasible to mount an effective nationwide Chlamydia control program, with screening of high-risk individuals in traditional health care

settings and in novel outreach and community-based settings. The

U.S. Preventive Services Task Force has named Chlamydia screening

as a Grade B recommendation, which means that private insurance

and Medicare will cover the cost of screening under the Affordable

Care Act.

■ TRACHOMA

Epidemiology Trachoma—a sequela of ocular disease in developing countries—continues to be a leading cause of preventable

infectious blindness worldwide. The WHO estimates that ~6 million

people have been blinded by trachoma and that ~1.3 million people

in developing countries still suffer from preventable blindness due to

trachoma; certainly, hundreds of millions live in trachoma-endemic

areas. Foci of trachoma persist in Australia, the South Pacific, and Latin

America. C. trachomatis serovars A, B, Ba, and C are isolated from

patients with clinical trachoma in areas of endemicity in developing

countries in Africa, the Middle East, Asia, and South America.

The trachoma-hyperendemic areas of the world are in northern

and sub-Saharan Africa, the Middle East, drier regions of the Indian

subcontinent, and Southeast Asia. In hyperendemic areas, the prevalence of trachoma is essentially 100% by the second or third year of

life. Active disease is most common among young children, who are

the reservoir for trachoma. By adulthood, active infection is infrequent

but sequelae result in blindness. In such areas, trachoma constitutes the

major cause of blindness.

Trachoma is transmitted through contact with discharges from the

eyes of infected patients. Transmission is most common under poor

hygienic conditions and most often takes place between family members or between families with shared facilities. Flies can also transfer

the mucopurulent ocular discharges, carrying the organisms on their

legs from one person to another. The International Trachoma Initiative

founded by the WHO in 1998 aims to eliminate blinding trachoma

globally by 2020.

Clinical Manifestations Both endemic trachoma and adult inclusion conjunctivitis present initially as conjunctivitis characterized by

small lymphoid follicles in the conjunctiva. In regions with hyperendemic classic blinding trachoma, the disease usually starts insidiously

1451CHAPTER 189 Chlamydial Infections

before the age of 2 years. Reinfection is common and probably contributes to the pathogenesis of trachoma. Studies using polymerase chain

reaction (PCR) or other NAATs 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 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 at

10–15 years of age, but conjunctival scars continue to shrink, producing trichiasis and entropion with 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 oculogenital C. trachomatis strains in sexually

active young adults presents as an acute onset of unilateral follicular

conjunctivitis and preauricular lymphadenopathy similar to that seen

in acute conjunctivitis caused by adenovirus or HSV. 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 partners are not treated with antimicrobial

agents.

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 pits. The clinical diagnosis of endemic trachoma should be confirmed by laboratory

tests in children with relatively marked degrees of inflammation. Intracytoplasmic chlamydial inclusions are found in 10–60% of Giemsa-stained

conjunctival smears in such populations, but chlamydial NAATs are

more sensitive and are often positive when smears or cultures are negative. Follicular conjunctivitis in European or American adults living in

trachomatous regions is rarely due to trachoma.

TREATMENT

Trachoma

Adult inclusion conjunctivitis responds well to treatment with the

same regimens used in uncomplicated genital infections—namely,

azithromycin (a 1-g single oral dose) or doxycycline (100 mg twice

daily for 7 days). Simultaneous treatment of all sexual partners is

necessary to prevent ocular reinfection and chlamydial genital disease. Topical antibiotic treatment is not required for patients who

receive systemic antibiotics.

PSITTACOSIS

Psittacine birds and many other avian species act as natural reservoirs for C. psittaci–type organisms, common pathogens in domestic

mammals and birds. The species C. psittaci, which now includes only

avian strains, affects humans only as a zoonosis. (The other strains

previously included in this species have been placed into different

species that reflect the animals they infect: C. abortus, C. muridarum,

C. suis, C. felis, and C. caviae.) Although all birds are susceptible, pet

birds (parrots, parakeets, macaws, and cockatiels) and poultry (turkeys

and ducks) are most frequently involved in transmission of C. psittaci

to humans. Exposure is greatest in poultry-processing workers and in

owners of pet birds. Infectious forms of the organisms are shed from

both symptomatic and apparently healthy birds and may remain viable

for several months. C. psittaci can be transmitted to humans by direct

contact with infected birds or by inhalation of aerosols from avian

nasal discharges and from infectious avian fecal or feather dust. Transmission from person to person has never been demonstrated.

The diagnosis is usually established serologically. Psittacosis in

humans may present as acute primary atypical pneumonia (which can

be fatal in up to 10% of untreated cases); as severe chronic pneumonia;

or as a mild illness or asymptomatic infection in persons exposed to

infected birds.

■ EPIDEMIOLOGY

Fewer than 50 confirmed cases of psittacosis are reported in the

United States each year, although many more cases probably occur

than are reported. Control of psittacosis depends on control of avian

sources of infection. A pandemic of psittacosis was once stopped by

banning shipment or importation of psittacine birds. Birds can receive

prophylaxis in the form of a tetracycline-containing feed. Imported

birds are currently quarantined for 30 days of treatment.

■ CLINICAL MANIFESTATIONS

Typical symptoms include fever, chills, muscular aches and pains,

severe headache, hepato- and/or splenomegaly, and gastrointestinal

symptoms. Cardiac complications may involve endocarditis and myocarditis. Fatal cases were common in the preantibiotic era. As a result

of quarantine of imported birds and improved veterinary-hygienic

measures, outbreaks and sporadic cases of psittacosis are now rare.

Severe pneumonia requiring management in an intensive care unit

may develop. Endocarditis, hepatitis, and neurologic complications

may occur, and fatal cases have been reported. The incubation period

is usually 5–19 days but can last as long as 28 days.

■ DIAGNOSIS

Previously, the most widely used serologic test for diagnosing chlamydial infections was the genus-specific CF test, in which assay of paired

serum specimens often shows fourfold or greater increases in antibody

titer. The CF test remains useful, but the gold standard of serologic

tests is now the MIF test, which is not widely available (see section

on diagnosis of C. trachomatis genital infection, above). Any antibody

titer above 1:16 is considered significant evidence of exposure to

chlamydiae, and a fourfold titer rise in paired sera in combination with

a clinically compatible syndrome can be used to diagnose psittacosis.

Some commercially available serologic tests based on measurement of

antibodies to LPS can be useful when the clinical diagnosis is consistent with bird exposure; however, since these tests are reactive for all

chlamydiae (i.e., all chlamydiae contain LPS), caution must be used in

their interpretation. C. psittaci is now considered a biohazard category

A biothreat agent and has been associated with laboratory-acquired

infections. The CDC does not recommend testing for this agent when

psittacosis is suspected, especially by culture.

TREATMENT

Psittacosis

The antibiotic of choice is tetracycline; the dosage for adults is 250 mg

four times a day, continued for at least 3 weeks to avoid relapse.

Severely ill patients may need cardiovascular and respiratory support. Erythromycin (500 mg four times a day by mouth) is an

alternative therapy.

C. PNEUMONIAE INFECTIONS

C. pneumoniae is a common cause of human respiratory diseases, such

as pneumonia and bronchitis. This organism reportedly accounts for

as many as 10% of cases of community-acquired pneumonia, most of