# 81 - 194 Chlamydial Infections

### 194 Chlamydial Infections

urogenital tract. The vagina yields the largest number of organisms; 
next most densely colonized are the periurethral area and the cervix. 
Ureaplasmas are isolated less often from urine than from the cervix, 
but M. hominis is found with approximately the same frequency at 
these two sites. Ureaplasmas are isolated from the vagina of 40–80% of 
sexually active, asymptomatic women and M. hominis from 21–70%. 
The two microorganisms are found concurrently in 31–60% of women. 
In men, colonization with each organism is less prevalent. A large U.S. 
prospective multicenter study of a nucleic acid amplification test 
for M. genitalium including male and female patients seeking care 
in diverse geographic regions found overall prevalence to be 10.3%. 
Mycoplasmas have been isolated from urine, semen, and the distal 
urethra of asymptomatic men.
■
■CLINICAL MANIFESTATIONS
Urethritis, Pyelonephritis, and Urinary Calculi 
In many 
episodes of Chlamydia-negative nongonococcal urethritis, ureaplasmas 
may be the causative agent. These organisms may also cause chronic 
voiding symptoms in women. The common presence of ureaplasmas in 
the urethra of asymptomatic men may suggest either that only certain 
serovars are pathogenic or that predisposing factors, such as lack of 
immunity, must exist in persons who develop symptomatic infection. 
Alternatively, disease may develop only upon initial exposure to urea­
plasmas. Ureaplasmas have been implicated in epididymitis. M. geni­
talium also appears to cause urethritis. M. genitalium and ureaplasmas 
do not have a known role in prostatitis. M. hominis does not appear to 
play a primary etiologic role in urethritis, epididymitis, or prostatitis.
Evidence suggests that M. hominis causes up to 5% of cases of acute 
pyelonephritis. Ureaplasmas have not been associated with this disease.
Ureaplasmas play a limited role in the production of urinary calculi. 
The frequency with which ureaplasmas reach the kidney, the predis­
posing factors that allow them to do so, and the relative frequency of 
urinary tract calculi induced by this organism (compared with other 
organisms) are not known.
Pelvic Inflammatory Disease 
M. hominis can cause pelvic 
inflammatory disease. In most episodes, M. hominis occurs as part of 
a polymicrobial infection, but the organism may play an independent 
role in a limited number of cases. Data also support an association of 
M. genitalium with pelvic inflammatory disease. Ureaplasmas are not 
thought to cause pelvic inflammatory disease.
Postpartum and Postabortal Infection 
Studies implicate 

M. hominis as the primary pathogen in ~5–10% of women who have post­
partum or postabortal fever; ureaplasmas have been implicated to a lesser 
degree. These infections are generally self-limited; however, if symptoms 
persist, specific antimicrobial therapy should be given. Ureaplasmas also 
appear to play a role in occasional postcesarean wound infections.
Nonurogenital Infection 
In rare instances, M. hominis causes 
nonurogenital infections, such as brain abscess, wound infection, 
poststernotomy mediastinitis, endocarditis, and neonatal meningitis. 
These infections are most common among immunocompromised 
and hypogammaglobulinemic patients. Ureaplasmas and M. hominis 
can cause septic arthritis in immunodeficient patients. Ureaplasmas 
probably cause neonatal pneumonitis; their possible causal role in 
the development of bronchopulmonary dysplasia—the chronic lung 
disease of premature infants—has been extensively investigated, with 
most studies indicating at least a significant association. It is unclear 
whether ureaplasmas and M. hominis cause infertility, spontaneous 
abortion, premature labor, low birth weight, or chorioamnionitis.
■
■DIAGNOSIS
Culture and PCR are both appropriate methods for the isolation of 
urogenital mycoplasmas. Culture of these organisms, however, requires 
special techniques and media that generally are available only at larger 
medical centers and reference laboratories. Serologic testing is not 
recommended for the clinical diagnosis of urogenital Mycoplasma 
infections. Antibiotic resistance testing to guide appropriate therapy is 
becoming more available to clinical practice.

TREATMENT
Urogenital Mycoplasma Infections
Because colonization with urogenital mycoplasmas is common, it 
appears at present that their isolation from the urogenital tract in 
the absence of disease generally does not warrant treatment.
Patients with recurrent urethritis or cervicitis after treatment 
failure of appropriate antibiotic therapy for sexually transmitted 
infections should receive M. genitalium testing. It is not recom­
mended to screen for M. genitalium in those who are asymptomatic. 
However, sex partners of patients with symptomatic M. genitalium 
infection should receive testing. Those with positive test results 
should receive treatment with antibiotics to possibly reduce the risk 
for reinfection.
Macrolides and doxycycline are considered the antimicrobial 
agents of choice for Ureaplasma infections (Table 193-2). Ure­
aplasma resistance to macrolides, doxycycline, quinolones, and 
chloramphenicol has been reported. M. hominis is resistant to mac­
rolides. Doxycycline is generally the drug of choice for M. hominis 
infections, although resistance has been reported. Clindamycin is 
generally active against M. hominis. Quinolones are active in vitro 
against M. hominis.
For M. genitalium, treatment failure and/or antibiotic resistance 
has increased for both azithromycin and moxifloxacin. The Centers 
for Disease Control and Prevention’s 2021 Sexually Transmitted 
Infections Treatment Guidelines recommend two-stage therapy 
based on antibiotic resistance testing, if available: doxycycline 100 mg 
orally 2 times per day for 7 days, followed by either azithromycin 
1 g orally initial dose, followed by 500 mg orally once daily for 3 
additional days (if macrolide sensitive), or moxifloxacin 400 mg 
orally once daily for 7 days (if macrolide resistant). If M. genitalium 
antibiotic resistance testing is not available, then doxycycline fol­
lowed by moxifloxacin is recommended. Test of cure for M. genita­
lium infection is not recommended for asymptomatic persons who 
received treatment with a recommended regimen.
CHAPTER 194
Chlamydial Infections
■
■FURTHER READING
Waites KB et al: Mycoplasma pneumoniae from the respiratory tract 
and beyond. Clin Microbiol Rev 30:747, 2017.
Waites KB et al: Macrolide-resistant Mycoplasma pneumoniae in the 
United States as determined from a national surveillance program. J 
Clin Microbiol 57:e00968, 2019.
Wang G et al: Global prevalence of resistance to macrolides in Myco­
plasma pneumoniae: A systematic review and meta-analysis. J Anti­
microb Chemother 77:2353, 2022.
Workowski KA et al: Sexually transmitted diseases treatment guide­
lines, 2021. MMWR Recomm Rep 70:1, 2021.
Matthew M. Hamill, Thomas C. Quinn

Chlamydial Infections
Chlamydiae are obligate intracellular bacteria that cause a wide variety 
of diseases in humans and nonhuman animals.
ETIOLOGIC AGENTS
The chlamydiae were originally classified as four species in the 
genus Chlamydia: C. trachomatis, C. pneumoniae, C. psittaci, and C. 
pecorum (the last species being found in ruminants). The C. psittaci 
group has been separated into three species: C. psittaci, C. felis, and C. 
abortus. The mouse pneumonitis strain (MoPn) is now classified as

C. muridarum, and the guinea pig inclusion conjunctivitis strain 
(GPIC) is now designated C. caviae.

C. trachomatis is divided into two biovars: trachoma and LGV (lym­
phogranuloma venereum). The trachoma biovar causes two major types 
of disease in humans: ocular trachoma, the leading infectious cause of 
preventable blindness in the developing world; and urogenital infections, 
which are predominantly sexually transmitted but can be neonatally 
transmitted. The 18 serovars of C. trachomatis fall into three groups: 
the trachoma serovars A, B, Ba, and C; the oculogenital serovars D–K; 
and the LGV serovars L1–L3. Serovars can be distinguished by serologic 
typing with monoclonal antibodies or by molecular gene typing. How­
ever, serovar identification usually is not important clinically, since the 
antibiotic susceptibility pattern is the same for all three groups. The one 
exception applies when LGV is suspected on clinical grounds; in this 
situation, serovar determination is important because a longer treatment 
duration is typically required for LGV strains.
BIOLOGY, GROWTH CYCLE, AND 
PATHOGENESIS
■
■BIOLOGY
During their intracellular growth, chlamydiae produce characteristic 
intracytoplasmic inclusions that can be visualized by direct fluorescent 
antibody or Giemsa staining of infected clinical material, such as con­
junctival scrapings or cervical or urethral epithelial cells. Chlamydiae 
are nonmotile, gram-negative, obligate intracellular bacteria that 
replicate within the cytoplasm of host cells, forming the characteristic 
membrane-bound inclusions that are the basis for some diagnostic 
tests. Originally considered to be large viruses, chlamydiae differ from 
viruses in possessing RNA and DNA as well as a cell wall that is quite 
similar in structure to the cell wall of typical gram-negative bacteria. 
However, chlamydiae lack peptidoglycan; their structural integrity 
depends on disulfide binding of outer-membrane proteins.
PART 5
Infectious Diseases
■
■GROWTH CYCLE
Among the defining characteristics of chlamydiae is a unique growth 
cycle that involves alternation between two highly specialized morpho­
logic forms (Figs. 194-1 and 194-2): the elementary body, which is the 
infectious form and is specifically adapted for extracellular survival, 
and the metabolically active and replicating reticulate body, which is 
not infectious, is adapted for an intracellular environment, and does 
not survive well outside the host cell. The biphasic growth cycle begins 
with attachment of the elementary body (diameter, 0.25–0.35 μm) at 
specific sites on the surface of the host cell. The elementary body enters 
the cell through a process similar to receptor-mediated endocytosis 
and resides in an inclusion, where the entire growth cycle is completed. 
The chlamydiae prevent phagosome–lysosome fusion. The inclusion 
membrane is modified by insertion of chlamydial antigens. Once the 
elementary body has entered the cell, it reorganizes into a reticulate 
body, which is larger (0.5–1 μm) and contains more RNA. After ~8 h, the 
reticulate body starts to divide by binary fission. The intracytoplasmic, 
membrane-bound inclusion body containing the reticulate bodies 
increases in size as the reticulate bodies multiply. Approximately 
18–24 h after infection of the cell, these reticulate bodies begin to 
become elementary bodies by a reorganization or condensation pro­
cess that is poorly understood. After rupture of the inclusion body, the 
elementary bodies are released to initiate another cycle of infection.
Chlamydiae are susceptible to many broad-spectrum antibiotics and 
possess a number of enzymes, but they have a very restricted metabolic 
capacity. None of these metabolic reactions result in the production of 
energy. Chlamydiae have thus been considered to be energy parasites 
that use the ATP produced by the host cell for their own metabolic 
functions. Many aspects of chlamydial molecular biology are not well 
understood, but the sequencing of several chlamydial genomes and 
new proteomics research have provided researchers with many relevant 
tools for elucidating the biology of the life cycle.
■
■PATHOGENESIS
Genital infections are primarily caused by C. trachomatis serovars 
D–K, with serovars D, E, and F involved most frequently. Molecular 

FIGURE 194-1  Chlamydial intracellular inclusions filled with smaller dense 
elementary bodies and larger reticulate bodies. (Reprinted with permission from WE 
Stamm: Chlamydial infections, in Harrison’s Principles of Internal Medicine, 17th ed. 
AS Fauci et al [eds]. New York, McGraw-Hill, 2008, p 1070.)
2. Initial inclusions
3. Fusion of inclusions;
    appearance of RBs
1. Uptake of
   chlamydial EBs
Cell membrane
Cell cytoplasm
Cell nucleus
4. Multiplication of RBs;
    enlargement of inclusion
6. Release
   of EBs
5. Conversion of
    RBs to EBs
8. Return to normal
   cycle with IFN-γ
   removal
7. Persistence associated
    with IFN-γ exposure;
    large aberrant RBs 
FIGURE 194-2  Chlamydial life cycle. EBs, elementary bodies; IFN-γ, interferon γ; 
RBs, reticulate bodies. (Reproduced with permission from WE Stamm: Chlamydial 
infections, in AS Fauci et al [eds]: Harrison’s Principles of Internal Medicine, 17th ed. 
New York, McGraw-Hill, 2008.)

typing of the major outer-membrane protein gene (omp1) from which 
serovar differences arise has been used to demonstrate that polymor­
phisms can occur in isolates from patients who are exposed frequently 
to multiple infections, while less variation is observed in isolates from 
less sexually active populations. Polymorphisms in the major outermembrane protein may provide antigenic variation, and the different 
forms allow persistence in the community because immunity to one is 
not protective against the others.
The trachoma biovar is essentially a parasite of squamocolumnar 
epithelial cells; the LGV biovar is more invasive and involves lymphoid 
cells. As is typical of chlamydiae, C. trachomatis strains are capable 
of causing chronic, clinically inapparent, asymptomatic infections. 
Because the duration of the chlamydial growth cycle is ~48–72 h, the 
incubation period of sexually transmitted chlamydial infections is 
relatively long—generally 1–3 weeks. C. trachomatis causes cell death 
as a result of its replicative cycle and can induce cell damage whenever 
it persists. However, few toxic effects are demonstrated, and cell death 
because of chlamydial replication is not sufficient to account for dis­
ease manifestations, the majority of which are due to immunopatho­
logic mechanisms or nonspecific host responses to the organism or its 
by-products.
In recent years, the entire genomes of various chlamydial species 
have been sequenced, the field of proteomics has become estab­
lished, host innate immunity has been more precisely delineated, 
and innovative host cell–chlamydial interaction studies have been 
conducted. As a result, many insights have been gained into how chla­
mydiae adapt and replicate in their intracellular environment and 
produce disease. These insights into pathogenesis include information 
on the regulation of gene expression, protein localization, the type III 
secretion system, the roles of CD4+ and CD8+ T lymphocytes in the 
host response, and T lymphocyte trafficking.
The chlamydial heat-shock protein, which shares antigenic epitopes 
with similar proteins of other bacteria and with human heat-shock 
protein, may sensitize the host, and repeated infections may cause host 
cell damage. Persistent or recurrent chlamydial infections are associ­
ated with fibrosis, scarring, and complications following simple squa­
mocolumnar epithelial infections. A common endpoint of these late 
consequences is scarring of mucous membranes. Genital complications 
can lead to pelvic inflammatory disease (PID) and its late consequences 
of tubal factor infertility, ectopic pregnancy, and chronic pelvic pain, 
while ocular infections may lead to blinding trachoma. High levels of 
antibody to human heat-shock protein have been associated with tubal 
factor infertility and ectopic pregnancy. Without adequate therapy, 
chlamydial infections may persist for several years, although symptoms—
if present—usually abate.
Pathogenic mechanisms of C. pneumoniae have yet to be completely 
elucidated. The same is true for C. psittaci, except that this agent 
infects cells very efficiently and causes disease that may reflect direct 
cytopathic effects.
C. TRACHOMATIS INFECTIONS
■
■GENITAL INFECTIONS (SEE ALSO CHAP. 141)
Spectrum 
Although chlamydiae cause a number of human dis­
eases, localized lower genital tract infections caused by C. trachomatis 
and the sequelae of such infections are the most important in terms 
of medical and economic impact. Oculogenital infections due to C. 
trachomatis serovars D–K are transmitted during sexual contact or 
from mother to baby during childbirth and are associated with many 
syndromes, including cervicitis, salpingitis, acute urethral syndrome, 
endometritis, ectopic pregnancy, infertility, and PID in female patients; 
urethritis, proctitis, and epididymitis in male patients; and reactive 
arthritis, conjunctivitis, and pneumonia in infants. Women bear the 
greatest burden of morbidity because of the serious sequelae of these 
infections. Untreated infections may lead to PID, and multiple episodes 
of PID can lead to tubal factor infertility and chronic pelvic pain. 
Studies estimate that up to 80–90% of women and >50% of men with 

C. trachomatis genital infections lack symptoms; other patients have 

very mild symptoms. Additionally, extragenital infection in the phar­
ynx and rectum is typically asymptomatic and may persist for years 
without treatment. Thus, a large reservoir of infected persons contin­
ues to transmit infection to sexual partners.

As their designations reflect, the LGV serovars (L1, L2, and L3) cause 
LGV, an invasive sexually transmitted infection (STI) characterized by 
a transient and typically painless genital ulcer followed by acute lymph­
adenitis with bubo formation and/or acute hemorrhagic proctitis (see 
“Lymphogranuloma Venereum,” below).
Epidemiology 
• 
GLOBAL EPIDEMIOLOGY  C. trachomatis geni­
tal infections are global in distribution. The World Health Organiza­
tion (WHO) estimated that in 2020, 50 million (95% uncertainty 
interval [UI] 36-67) prevalent cases in men and 77 million [UI 67-90] 
prevalent cases in women and 59 million [95% UI 34-90] new cases of 
chlamydia in men and 70[95% UI 44-98] new cases in women. These 
figures make chlamydial infection the most prevalent bacterial STI 
in the world. There are large differences by WHO region; in 2020 in 
the Americas, the male incidence (per 1000) was 48 (95% UI, 23–86), 
compared with 12 (95% UI, 5–25) in Southeast Asia. In women in the 
Americas, there were 68 (95% UI, 39–104) incident cases (per 1000) 
compared with 16 (95% UI, 7–28) in Southeast Asia. The associated 
morbidity is substantial, and the economic cost is high.
U.S. EPIDEMIOLOGY  In the United States, these infections are the 
most commonly reported of all infectious diseases. Chlamydia is noti­
fiable nationally and is reported to the U.S. Centers for Disease Control 
and Prevention (CDC). In 2022, 1,649,716 cases were reported to the 
CDC, representing a 5-year decline of 6.2%. As chlamydial infections 
are typically asymptomatic, case reports are profoundly influenced by 
screening coverage. The disruptions in STI-related screening, preven­
tion, and care activities during the COVID-19 pandemic necessitate 
that the trend for chlamydia surveillance data collected during the 
pandemic should be interpreted with caution. Higher rates among 
women than among men reflect the focus on expansion of screening 
programs for women during the past 25 years. Use of increasingly sen­
sitive diagnostic nucleic acid amplification tests, an increased emphasis 
on case reporting, and improvements in the information systems used 
have elevated the number of cases reported every year. The CDC and 
other professional organizations recommend annual screening of all 
sexually active women <25 years of age and women aged >25 years 
who are at increased risk of infection, as well as rescreening of previ­
ously infected individuals at 3 months. Additionally, the CDC recom­
mends that all pregnant women aged <25 years and those >25 years 
who are at increased risk be routinely screened for chlamydia during 
the first prenatal visit. Women who remain at risk for infection should 
be retested in the third trimester to prevent maternal complications 
and neonatal infection. In pregnancy, a test-of-cure is recommended 
4 weeks after treatment. The 2022 U.S. total case count corresponds 
to 495 cases per 100,000 population. Women have the highest infec­
tion rates (621.2 cases per 100,000) compared to the rate among men 
(363.7 cases per 100,000). With the increased availability of urine test­
ing and extragenital testing, men—including gay, bisexual, and other 
men who have sex with men (MSM)—are increasingly being tested for 
chlamydial infection. From 2021 to 2022, rates of chlamydial infection 
in men increased by 1.8%, whereas rates in women fell by 1.2% during 
this period. Chlamydia rates remain highest among adolescents and 
young adults; in 2022, 57.7% of all cases were reported among persons 
aged 15–24 years. Chlamydial infection rates vary considerably among 
different racial and ethnic populations as well as between states. For 
example, the rate in Louisiana per 100,000 population in 2022 was 
788.6, compared with 198.0 in Vermont; the rate among blacks/African 
Americans was 1113.3 per 100,000 population compared with 100.6 in 
Asians.
CHAPTER 194
Chlamydial Infections
The aforementioned statistics are based on case reporting; in 2018, 
the CDC estimated there were 4 million cases of chlamydia in the 
United States. Although screening programs have demonstrated reduc­
tions in PID rates, evidence is lacking to support general screening of 
young sexually active men. In contrast, sexually active MSM should 
undergo at least annual screening at anatomically exposed sites. Studies

based on screening surveys estimate that the U.S. prevalence of C. tra­
chomatis cervical infection was 5.9% and 8.8% among asymptomatic 
male and female college students, respectively; between 3.3 and 8.3% 
among prenatal patients; 7% for women seen in family planning clin­
ics; and >10% for women seen in STI clinics. In a cohort of female 
college students, incident chlamydial infection was also associated 
with bacterial vaginosis and high-risk human papillomavirus infection. 
The prevalence of C. trachomatis in the cervix of pregnant women is 
approximately six times higher than that of Neisseria gonorrhoeae. 
The prevalence of genital infection with either agent is highest among 
women who are between the ages of 20 and 24. Recurrent infections 
are common in groups with greater vulnerability to STIs and are 
often acquired from untreated sexual partners. The use of hormonal 
contraception and the presence of cervical ectopy are also associated 
with an increased risk. The proportion of infections that are asymp­
tomatic appears to be higher for C. trachomatis (83.9% in men, 87.1% 
in women) than for N. gonorrhoeae, (41.3% in men, 68.4% in women), 
and symptomatic C. trachomatis infections are clinically less severe. 
Mild or asymptomatic C. trachomatis infections of the fallopian tubes 
nonetheless cause ongoing tubal damage and infertility. The costs of 

C. trachomatis infections and their complications to the U.S. health care 
system have recently been estimated to be >$516.7 million annually.

Clinical Manifestations 
• 
NONGONOCOCCAL AND POSTGONO­
COCCAL URETHRITIS  C. trachomatis is the most common cause 
of nongonococcal urethritis (NGU) and postgonococcal urethritis 
(PGU). The designation PGU refers to NGU developing in men 2–3 
weeks after treatment of gonococcal urethritis with single doses of 
agents such as penicillin or cephalosporins, which lack antimicrobial 
activity against chlamydiae. Current treatment regimens for gonorrhea 
have evolved and now include combination therapy with ceftriaxone 
and doxycycline unless chlamydia has been excluded; if chlamydia 
has been excluded, then gonorrhea is treated with ceftriaxone mono­
therapy. Thus, both the incidence of PGU and the causative role of C. 
trachomatis in this syndrome have declined.
PART 5
Infectious Diseases
In the United States, most of the estimated 2 million cases of acute 
urethritis are NGU, and C. trachomatis is implicated in 30–50% of these 
cases. The cause of most of the remaining cases of NGU is due to Myco­
plasma genitalium; Trichomonas vaginalis and herpes simplex virus 
(HSV) cause some cases. Other etiologies include Haemophilus species, 
N. meningitidis, and adenovirus. The rate of involvement of C. tracho­
matis in urethral infection ranges from 3–7% among asymptomatic 
men to 15–20% among symptomatic men attending STI clinics. One 
multisite study of men in Baltimore, Seattle, Denver, and San Francisco 
reported an overall chlamydial prevalence of 7% in urine samples 
assessed by nucleic acid amplification tests (NAATs)—molecular tests 
that amplify the nucleic acids in clinical specimens. As in women, 
infection in men is age related, with young age most strongly associ­
ated with chlamydial urethritis. The prevalence among men is highest 
at 20–24 years of age. In STI clinics, urethritis is usually less prevalent 
among MSM than among heterosexual men.
NGU is diagnosed by documentation of leukocytes on urethral 
exudate and by exclusion of gonorrhea by Gram’s staining, NAAT, or 
culture. C. trachomatis urethritis is generally less severe than gonococ­
cal urethritis, although in any individual patient, these two forms of 
urethritis cannot reliably be 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 as well as a 
urethral exudate that is often demonstrable only by stripping or milk­
ing of the urethra.
At least one-third of male patients with C. trachomatis urethral 
infection have no evident signs or symptoms of urethritis. The avail­
ability of NAATs for first-void urine specimens has facilitated broaderbased testing for asymptomatic infection in male patients. As a result, 
asymptomatic chlamydial infection has been demonstrated in 5–10% 
of sexually active male adolescents screened at school-based clinics or 
community centers. Such patients generally have pyuria (≥15 leuko­
cytes per 400× microscopic field in the sediment of first-void urine), a 

positive leukocyte esterase test, or an increased number of leukocytes 
on a Gram-stained smear prepared from a urogenital swab inserted 
1–2 cm into the anterior urethra. When specific diagnostic tests for 
chlamydiae are not available, the examination of an endourethral speci­
men for increased leukocytes is useful in differentiating between true 
urethritis and functional symptoms in symptomatic patients. Alterna­
tively, urethritis can be assayed noninvasively by examination of a firstvoid urine sample for pyuria, either by microscopy or by the leukocyte 
esterase test. Urine (or a urethral swab) can also be tested directly for 
chlamydiae by DNA amplification methods (NAATs), as described 
below (see “Detection Methods”). Urine testing for urethral STIs in 
men is much more acceptable than endourethral swab collection.
EPIDIDYMITIS  Chlamydial urethritis may be followed by acute epi­
didymitis (<6 weeks’ duration), but this condition is rare, generally 
occurring in sexually active patients <35 years of age; in older men, 
epididymitis is usually associated with gram-negative bacterial infec­
tion and/or instrumentation procedures. An estimated 50–70% of cases 
of acute epididymitis are caused by C. trachomatis. The condition usu­
ally presents as unilateral scrotal pain with tenderness, swelling, and 
fever in a young man, often occurring in association with chlamydial 
urethritis. The illness may be mild enough to treat with oral antibiot­
ics on an outpatient basis or severe enough to require hospitalization 
and parenteral therapy. Testicular torsion should be excluded promptly 
by imaging 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 (>6 weeks’ duration) 
(e.g., tuberculosis) should be excluded when a patient with unilateral 
intrascrotal pain and swelling does not respond to appropriate antimi­
crobial therapy.
REACTIVE ARTHRITIS  Reactive arthritis consists of conjunctivitis, 
urethritis (or, in female patients, cervicitis), arthritis, and characteristic 
mucocutaneous lesions. It may develop in 1–2% of cases of NGU; the 
rate of chlamydia-induced arthritis has been estimated to be 4–15% 
and is thought to be the most common type of peripheral inflamma­
tory arthritis in young men. When reactive arthritis is triggered by 
an STI, it may also be referred to as sexually acquired reactive arthri­
tis (SARA). C. trachomatis has been recovered from the urethra of 
16–44% of patients with reactive arthritis and 69% of men with signs 
of urogenital inflammation at the time of examination. Antibodies 
to C. trachomatis have also been detected in 46–67% of patients with 
reactive arthritis, and Chlamydia-specific cell-mediated immunity has 
been documented in 72%. In addition, C. trachomatis has been isolated 
from synovial biopsy samples from 15 of 29 patients in a number of 
small series and from a smaller proportion of synovial fluid specimens. 
Chlamydial nucleic acids have been identified in synovial membranes 
and chlamydial elementary bodies in joint fluid. The pathogenesis of 
reactive arthritis is unclear, but this condition probably represents an 
abnormal host response to a number of infectious agents, including 
those associated with bacterial gastroenteritis (e.g., Salmonella, 
Shigella, Yersinia, or Campylobacter), or to infection with C. trachomatis 
or N. gonorrhoeae. An association between reactive arthritis and the 
HLA-B27 phenotype in white individuals has been described, but not 
in patients from sub-Saharan Africa, where the prevalence of HLAB27 is much lower. Since other mucosal infections produce an identi­
cal syndrome, chlamydial infection is thought to initiate an aberrant 
hyperreactive immune response that produces inflammation of the 
involved target organs in these genetically predisposed individuals. 
Evidence of exaggerated cell-mediated and humoral immune responses 
to chlamydial antigens in reactive arthritis supports this hypothesis. 
The finding of chlamydial elementary bodies and DNA in joint fluid 
and synovial tissue from patients with reactive arthritis suggests that 
chlamydiae may actually spread from genital to joint tissues in these 
patients—perhaps in macrophages.
NGU is the initial manifestation of reactive arthritis in 80% of 
patients, typically occurring within 14 days after sexual exposure. The 
urethritis may be mild and may even go unnoticed by the patient. 
Similarly, gonococcal urethritis may precede reactive arthritis, but coinfection with an agent of NGU is difficult to rule out. The urethral

discharge may be purulent or mucopurulent, and patients may or may 
not report dysuria. Accompanying prostatitis, usually asymptomatic, 
has been described. Arthritis usually begins ~4 weeks after the onset 
of urethritis but may develop sooner or, in a small percentage of 
cases, may actually precede urethritis. The knees are most frequently 
involved; next most commonly affected are the ankles and small joints 
of the feet. Sacroiliitis, either symmetrical or asymmetrical, is docu­
mented in two-thirds of patients. Mild bilateral conjunctivitis, iritis, 
keratitis, or uveitis is sometimes present but lasts for only a few days. 
Finally, dermatologic manifestations occur in up to 50% of patients. 
The initial lesions—usually papules with a central yellow spot—most 
often involve the soles and palms and, in ~25% of patients, eventually 
epithelialize and thicken to produce keratoderma blenorrhagicum. 
Circinate balanitis is usually painless and occurs in fewer than half of 
patients. The initial episode of reactive arthritis usually lasts 2–6 months.
PROCTITIS  Primary anal or rectal infections with C. trachomatis 
have been described in women and MSM who practice receptive anal 
intercourse. Symptoms are characterized by anorectal pain, a bloody 
mucopurulent discharge, and tenesmus. Oculogenital serovars D–K 
and LGV serovars L1, L2, and L3 have been found to cause proctitis. The 
LGV serovars are far more invasive and typically cause more severely 
symptomatic disease, including severe ulcerative proctocolitis that can 
be clinically confused with HSV proctitis. However, asymptomatic or 
paucisymptomatic LGV infection is increasingly recognized in MSM. 
Histologically, LGV proctitis may resemble Crohn’s disease in that 
giant cell formation and granulomas are detected. In the United States 
and Europe, cases of LGV proctitis occur almost exclusively in MSM, 
many of whom have HIV infection and other STI coinfections.
The less invasive non-LGV serovars of C. trachomatis cause mild 
proctitis. Many infected individuals are asymptomatic, and in these 
cases, infection is diagnosed only by routine NAAT of rectal swabs. The 
number of fecal leukocytes is usually abnormal in both asymptomatic 
and symptomatic cases. Sigmoidoscopy may yield normal findings or 
may reveal mild inflammatory changes or small erosions or follicles 
in the lower 10 cm of the rectum. Histologic examination of rectal 
biopsies generally shows anal crypts and prominent follicles as well as 
neutrophilic infiltration of the lamina propria. Chlamydial proctitis 
is best diagnosed by isolation of C. trachomatis from the rectum and 
documentation of a response to appropriate therapy. NAATs are the 
diagnostic test of choice.
MUCOPURULENT CERVICITIS  Although most women with chla­
mydial infections of the cervix have no symptoms, almost half gener­
ally have local signs of infection on examination. Cervicitis is usually 
characterized by the presence of a mucopurulent discharge, with >20 
neutrophils per microscopic field visible in strands of cervical mucus in 
a thinly smeared, Gram-stained preparation of endocervical exudate. 
Hypertrophic ectopy of the cervix may also be evident as an edematous 
area near the cervical os that is congested and bleeds easily on minor 
trauma (e.g., when a specimen is collected with a swab). A Papanico­
laou smear shows increased numbers of neutrophils as well as a char­
acteristic pattern of mononuclear inflammatory cells, including plasma 
cells, transformed lymphocytes, and histiocytes. Cervical biopsy shows 
a predominantly mononuclear cell infiltrate of the subepithelial 
stroma. Clinical experience and collaborative studies indicate that a 
cutoff of >30 polymorphonuclear leukocytes (PMNs)/1000× field in a 
Gram-stained smear of cervical mucus correlates best with chlamydial 
or gonococcal cervicitis. However, the wide availability of NAATs and 
limited access to microscopy outside of specialist centers has decreased 
the role of cervical mucus examination.
Clinical recognition of chlamydial cervicitis depends on a high 
index of suspicion and careful cervical examination. No genital symp­
toms are specifically correlated with chlamydial cervical infection. The 
differential diagnosis of a mucopurulent discharge from the endocer­
vical canal in a young, sexually active woman includes gonococcal 
endocervicitis, salpingitis, endometritis, and intrauterine contraceptive 
device–induced inflammation. Diagnosis of cervicitis is based on the 
presence of PMNs on a cervical swab as noted above; the presence of 
chlamydiae is confirmed by NAAT.

PELVIC INFLAMMATORY DISEASE  Inflammation of sections of the fal­
lopian tube is often referred to as salpingitis or PID. The proportion of 
acute salpingitis cases caused by C. trachomatis varies geographically 
and with the population studied. It has been estimated that C. tracho­
matis causes up to 50% of PID cases in the United States. Recent studies 
report that the proportions of PID cases attributable to N. gonorrhoeae 
or C. trachomatis is decreasing; approximately 50% of women diag­
nosed with acute PID tested positive for either organism. PID occurs 
via ascending intraluminal spread of C. trachomatis or N. gonorrhoeae 
from the lower genital tract. Mucopurulent cervicitis is often followed 
by endometritis, endosalpingitis, and finally pelvic peritonitis. Evidence 
of mucopurulent cervicitis is often found in women with laparoscopi­
cally verified salpingitis. Similarly, endometritis, demonstrated by an 
endometrial biopsy showing plasma cell infiltration of the endometrial 
epithelium, is documented in most women with laparoscopy-verified 
chlamydial (or gonococcal) salpingitis. Chlamydial endometritis can 
also occur in the absence of clinical evidence of salpingitis. Histologic 
evidence of endometritis has been correlated with a syndrome consist­
ing of vaginal bleeding, lower abdominal pain, and uterine tenderness 
in the absence of adnexal tenderness. Chlamydial salpingitis produces 
milder symptoms than gonococcal salpingitis and may be associated 
with less marked adnexal tenderness. Thus, mild adnexal or uterine 
tenderness in a sexually active woman with cervicitis may suggest 
chlamydial PID.

Screening and treating sexually active women for chlamydia and 
gonorrhea reduce their risk for PID. Chronic untreated endometrial 
and tubal inflammation can result in tubal scarring, impaired tubal 
function, tubal occlusion, and infertility, even among women who 
report no prior treatment for chlamydial infection. C. trachomatis has 
been particularly implicated in “subclinical” PID on the basis of a lack 
of history of PID among Chlamydia-seropositive women with tubal 
damage and detection of chlamydial DNA or antigen among asymp­
tomatic women with tubal infertility. These data suggest that the best 
method to prevent PID and its sequelae is surveillance and control of 
lower genital tract infections along with diagnosis and treatment of sex 
partners and prevention of reinfections. Promotion of early symptom 
recognition and health care presentation may reduce the frequency and 
severity of sequelae of PID.
CHAPTER 194
Chlamydial Infections
PERIHEPATITIS  Fitz-Hugh–Curtis syndrome was originally described 
as a complication of gonococcal PID. However, studies over the past 
several decades have suggested that chlamydial infection is more com­
monly associated with perihepatitis than is N. gonorrhoeae. Perihepati­
tis should be suspected in young, sexually active women who develop 
right-upper-quadrant pain, fever, or nausea. Evidence of salpingitis 
may or may not be found on examination. Frequently, perihepatitis 
is strongly associated with extensive tubal scarring, adhesions, and 
inflammation observed at laparoscopy, and high titers of antibody to 
the 57-kDa chlamydial heat-shock protein have been documented. 
Culture and/or serologic evidence of C. trachomatis has been found in 
three-fourths of women with this syndrome.
URETHRAL SYNDROME IN WOMEN  In the absence of infection with 
uropathogens such as coliforms or Staphylococcus saprophyticus, C. tra­
chomatis is the pathogen most commonly isolated from college women 
with dysuria, frequency, and pyuria. Screening studies can recover C. 
trachomatis at both the cervix and the urethra; in up to 25% of infected 
women, the organism is isolated only from the urethra. The urethral 
syndrome in women consists of dysuria and frequency in conjunction 
with chlamydial urethritis, pyuria, and no bacteriuria or urinary patho­
gens. Although symptoms of the urethral syndrome may develop in 
some women with chlamydial infection, the majority of women attend­
ing STI clinics for urethral chlamydial infection do not have dysuria 
or frequency. Even in women with chlamydial urethritis causing the 
acute urethral syndrome, signs of urethritis such as urethral discharge, 
meatal redness, and swelling are uncommon. However, mucopurulent 
cervicitis in a woman presenting with dysuria and frequency strongly 
suggests C. trachomatis urethritis. Other correlates of chlamydial 
urethral syndrome include a duration of dysuria of >7–10 days, lack 
of hematuria, and lack of suprapubic tenderness. Abnormal urethral

Gram’s stains showing >10 PMNs/1000× field in women with dysuria 
but without coliform bacteriuria support the diagnosis of chlamydial 
urethritis. Other possible diagnoses include gonococcal or trichomonal 
infection of the urethra.

INFECTION IN PREGNANCY AND THE NEONATAL PERIOD  Infections 
during pregnancy can be transmitted to infants during delivery. 
Approximately 20–30% of infants exposed to C. trachomatis in the 
birth canal develop conjunctivitis, and 10–15% subsequently develop 
pneumonia. All newborn infants receive ocular prophylaxis at birth to 
prevent ophthalmia neonatorum. The agents used to prevent gonococ­
cal eye infection are not effective against chlamydial conjunctivitis. 
The most effective measure to prevent neonatal chlamydial conjunc­
tivitis is through screening and treatment of chlamydial infections in 
pregnant women. Without treatment, conjunctivitis usually develops 
at 5–19 days of life and often results in a profuse mucopurulent dis­
charge. Roughly half of infected infants develop clinical evidence 
of inclusion conjunctivitis. However, it is impossible to differentiate 
chlamydial conjunctivitis from other forms of neonatal conjunctivitis 
(e.g., 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 or NAATs for chlamydiae. Gram-stained 
smears may show gonococci or occasional small gram-negative coc­
cobacilli in Haemophilus conjunctivitis, but smears should be accom­
panied by cultures or NAATs for these agents.
C. trachomatis has also been isolated frequently and persistently 
from the nasopharynx, rectum, and vagina of infected infants—occa­
sionally for >1 year in the absence of treatment. In some cases, otitis 
media results from perinatally acquired chlamydial infection. Pneumo­
nia may develop in infants from 2 weeks to 4 months of age. C. tracho­
matis is estimated to cause 20–30% of pneumonia cases in infants 
<6 months of age. Epidemiologic studies have linked chlamydial pul­
monary infection in infants with increased occurrence of subacute lung 
disease (bronchitis, asthma, wheezing) in later childhood.
PART 5
Infectious Diseases
LYMPHOGRANULOMA VENEREUM  C. trachomatis serovars L1, L2, and 
L3 cause LGV, an invasive systemic STI. The peak incidence of LGV 
corresponds with 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 parts of 
Asia, Africa, South America, and the Caribbean. LGV is rare in indus­
trialized countries; for more than a decade, the reported incidence in 
the United States has been only 0.1 case per 100,000 population. In the 
Bahamas, an apparent outbreak of LGV was described in association 
with a concurrent increase in heterosexual infection with HIV. Reports 
of outbreaks with the newly identified variant L2b in Europe, Australia, 
and the United States indicate that LGV is becoming more prevalent 
among MSM. These cases have usually presented as hemorrhagic proc­
tocolitis in HIV-positive men. However, LGV is increasingly described 
as an asymptomatic rectal infection in 30–50% of cases and is fre­
quently seen in MSM without HIV. More widespread use of NAATs for 
identification of rectal infections may have enhanced case recognition.
LGV begins as a small painless papule that tends to ulcerate at the 
site of inoculation, often escaping attention. This primary lesion heals 
in a few days without scarring and is usually recognized as LGV only in 
retrospect. LGV strains of C. trachomatis have occasionally been recov­
ered from genital ulcers and from the urethra of men and the endo­
cervix of women who present with inguinal adenopathy; these areas 
may be the primary sites of infection in some cases. Proctitis is more 
common among people who practice receptive anal intercourse, and an 
elevated white blood cell count in anorectal smears may predict LGV 
in these patients. Ulcer formation may facilitate transmission of HIV 
infection and other sexually transmitted and blood-borne infections.
As NAATs for C. trachomatis are standard of care in high-income 
settings, increasing numbers of cases of LGV proctitis are being rec­
ognized in MSM. Such patients present with anorectal pain and muco­
purulent, bloody rectal discharge. Sigmoidoscopy reveals ulcerative 
proctitis or proctocolitis, with purulent exudate and mucosal bleeding. 

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.
The most common presenting picture in heterosexual men and 
women is the inguinal syndrome, which is characterized by pain­
ful inguinal lymphadenopathy beginning 2–6 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 dis­
crete, but progressive periadenitis results in a matted mass of nodes 
that becomes fluctuant and suppurative. The overlying skin becomes 
fixed, inflamed, and thin, and multiple draining fistulas finally develop. 
Extensive enlargement of chains of inguinal nodes above and below 
the inguinal ligament (“the groove sign”) is not specific and, although 
not uncommon, is documented in only a minority of cases. Spontane­
ous 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.
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. Other 
systemic complications are infrequent but include arthritis with ster­
ile effusion, aseptic meningitis, meningoencephalitis, conjunctivitis, 
hepatitis, and erythema nodosum (Fig. A1-39). Complications of 
untreated anorectal infection include perirectal abscess; anal fistulas; 
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 devel­
ops 2–6 cm from the anal orifice—i.e., at a site within reach on digital 
rectal examination. 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 pro­
duce elephantiasis. When urethral stricture occurs, it usually involves 
the posterior urethra and causes incontinence or difficulty with urina­
tion. In women, esthiomene of the genitalia is a late, rare complication 
of untreated LGV infection resulting in massive labial elephantiasis and 
ulceration followed by scarring.
Diagnosis 
• 
DETECTION METHODS  Historically, chlamydiae 
were cultivated in the yolk sac of embryonated eggs. The organisms 
can be grown more easily in tissue culture, but cell culture—once con­
sidered the diagnostic gold standard—has been replaced by nonculture 
assays (Table 194-1). In general, culture for chlamydiae in clinical 
specimens is now performed only in specialized laboratories. The 
first nonculture assays, such as direct fluorescent antibody staining of 
clinical material and enzyme immunoassay (EIA), have been replaced 
by NAATs, which are currently recommended by the CDC as the 
diagnostic assays of choice. At present, numerous NAAT assays cleared 
by the U.S. Food and Drug Administration (FDA) are commercially 
available, some of which are available as high-throughput robotic plat­
forms. Three point-of-care rapid diagnostic assays are available; they 
are of increasing interest since patients can potentially be treated before 
leaving the clinic, thus preventing forward transmission while patients 
wait for results from tests with longer turnaround times. However, 
turnaround time and cost of goods currently limit their widespread 
adoption. Over-the-counter tests are also in development.
CHOICE OF SPECIMEN  Cervical and urethral swabs have traditionally 
been used for the diagnosis of STIs in female and male patients, respec­
tively. However, given the greatly increased sensitivity and specificity 
of NAATs, less invasive samples (e.g., urine for both sexes and vaginal 
swabs for women) can be used. For screening of women, the CDC now 
recommends that self-collected or clinician-collected vaginal swabs, 
which are slightly more sensitive than urine, be used; a recent analysis 
demonstrated the superiority of vaginal swabs over urine in women. 
Urine screening tests are often used in outreach screening programs, 
however. For symptomatic women undergoing a pelvic examination, 
cervical swab samples may be used because they have slightly higher

TABLE 194-1  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 ≥2 WBCs/high power field (HPF) in highprevalence settings (e.g., STI clinics) or ≥5 WBCs/HPF in 
lower-prevalence settings. No gram-negative intracellular 
diplococci (GNID). In the absence of microscopy: positive 
leukocyte esterase test on first catch urine
Epididymitis
Unilateral intrascrotal swelling, 
pain, tenderness; fever; NGU
Gram’s stain with ≥2 (or ≥5) WBCs/HPF; no GNID; 
urinalysis with pyuria
Women
Cervicitis
Mucopurulent cervical discharge, 
sustained endocervical bleeding 
easily induced by nontraumatic 
passage of a swab through the 
cervical os
Leukorrhea, defined as >10 WBCs/HPF on microscopic 
examination of vaginal fluid, might be a sensitive indicator 
of cervical inflammation with a high negative predictive 
value
Salpingitis
Lower abdominal pain, cervical 
motion tenderness, adnexal 
tenderness or masses
C. trachomatis always potentially present in salpingitis
Vaginal (or cervical) NAAT for C. trachomatis
Urethritis
Dysuria and frequency without 
hematuria
MPC; sterile pyuria; negative routine urine culture
Urine NAAT for C. trachomatis
Adults of Either Sex
Proctitis
Rectal pain, discharge, tenesmus, 
bleeding; history of receptive 
anorectal intercourse
Negative gonococcal NAAT and Gram’s stain; at least 1 
WBC/HPF in rectal Gram’s stain
Reactive arthritis
NGU, arthritis, conjunctivitis, typical 
skin lesions
Gram’s stain with ≥5 WBC/HPF; lack of GNID
Urine or vaginal NAAT for C. trachomatis
LGV
Regional adenopathy, primary 
lesion, proctitis, systemic symptoms
None
NAAT for C. trachomatis. Molecular testing 
for LGV is not widely available or not FDA 
cleared. If available, molecular PCR testing 
for C. trachomatis serovars L1, L2, or L3 can 
confirm diagnosis LGV
Neonates
Conjunctivitis
Purulent conjunctival discharge 
5–12 days after birth
Negative culture and Gram’s stain for gonococci, 
Haemophilus spp., pneumococci, staphylococci
Infant pneumonia
Subacute, afebrile pneumonia in 
infants aged 1–3 months
None
Chlamydial tissue culture, DFA, or NAAT (not 
FDA cleared) of nasopharyngeal specimen
aA 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: DFA, direct fluorescent antibody; FDA, U.S. Food and Drug Administration; HPF, high-power field; LGV, lymphogranuloma venereum; MPC, mucopurulent 
cervicitis; NAAT, nucleic acid amplification test; NGU, nongonococcal urethritis; PGU, postgonococcal urethritis; WBC, white blood cell.
Source: Based on Centers for Disease Control and Prevention Sexually Transmitted Infections Treatment Guidelines, 2021. https://www.cdc.gov/std/treatment-guidelines/
STI-Guidelines-2021.pdf.
chlamydial counts. For male patients, a first-catch 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. However, NAATs are not cleared 
by the FDA for detecting chlamydia from conjunctival swabs, and 
clinical laboratories should verify the procedure according to Clini­
cal Laboratory Improvement Amendments regulations. Samples from 
extragenital rectal and pharyngeal sites are used to detect chlamydiae 
by NAATs; in 2019, the CDC cleared the first NAATS for use on extra­
genital 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 except in 
pregnancy. However, because incidence studies have demonstrated that 
previous chlamydial infection increases the probability of becoming 

Urine NAAT for C. trachomatis
Urine NAAT for C. trachomatis
Vaginal (or cervical) NAAT for C. trachomatis
Rectal NAAT for C. trachomatis
CHAPTER 194
Chlamydial Infections
Tissue culture, conjunctival NAAT for C. 
trachomatis (not FDA cleared); DFA-stained 
scraping of conjunctival material
reinfected, the CDC does recommend that previously infected indi­
viduals 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 
high-titer 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 anti­
body 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 asymptom­
atic individuals.

TREATMENT
C. trachomatis Genital Infections
A 7-day course of oral doxycycline (100 mg twice daily) is the 
recommended regimen of treatment for uncomplicated chlamydial 
infections. A single 1-g oral dose of azithromycin or oral levofloxa­
cin 500 mg once daily for 7 days are alternatives. Doxycycline has 
slightly better efficacy than azithromycin in treatment of genital 
chlamydia infection and has demonstrated significantly higher 
microbiological cure rates in the treatment of rectal infection. 
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 adherence challenges) and of the sexual partners of infected 
patients. These advantages must be weighed against the lower 
efficacy and 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 regi­
men appears to be safe and effective for this purpose. Amoxicillin 
(500 mg three times daily for 7 days) can also be given as an alterna­
tive 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). Tradi­
tionally, a 3-week course of doxycycline (100 mg orally twice daily), 
azithromycin 1 g orally once weekly for 3 weeks, or erythromycin 
base (500 mg orally four times daily) is recommended treatment for 
both bubonic and anogenital LGV. However, several studies have 
demonstrated the efficacy of shorter-course treatment for LGV. 
Failure of treatment with a tetracycline in genital infections usually 
indicates limited adherence or reinfection rather than involvement 
of a drug-resistant strain. To date, clinically significant drug resis­
tance has not been observed in C. trachomatis.
PART 5
Infectious Diseases
Treatment or testing for chlamydiae should be considered among 
patients with N. gonorrhoeae because of the frequency of coinfection. Systemic treatment with erythromycin base or ethylsuc­
cinate has been recommended for ophthalmia neonatorum and 
for C. trachomatis pneumonia in infants. Data on azithromycin 
efficacy are limited, but it may be effective for use in neonates. For 
the treatment of adult inclusion conjunctivitis, a single 1-g dose of 
azithromycin was as effective as standard 10-day treatment with 
doxycycline.
SEX PARTNERS
The continued high prevalence of chlamydial infections in most 
parts of the United States is due primarily to the failure to diag­
nose—and therefore treat—patients with symptomatic or asymp­
tomatic 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, con­
firmatory laboratory tests for chlamydiae should be undertaken in 
these individuals, but even persons without positive tests or evi­
dence 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 
index patients receive treatment and are also provided with treat­
ment to give to their sex partner(s).
NEONATES AND INFANTS
In neonates with conjunctivitis or infants with pneumonia, eryth­
romycin ethylsuccinate or base 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 adherence to therapy—a fre­
quent problem. Relapses of eye infection may follow oral erythro­
mycin therapy. Thus, careful follow-up is required after treatment; 

the efficacy of erythromycin treatment for ophthalmia neonatorum 
is ~80%; therefore, a second course of therapy might be required. 
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., STI 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 STI clinics in 1993, the preva­
lence declined from 10% in the 1980s to <5% in 2000. Similar trends 
have occurred in association with screening programs elsewhere. In 
addition, screening can reduce 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 univer­
sal 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%. The avail­
ability 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 
individuals with increased vulnerability for STI acquisition in tradi­
tional 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. More recently, home-based, self-collected, mailin testing platforms have expanded the testing for chlamydia and other 
STIs outside of clinical settings. Since 2018, data have emerged on the 
efficacy of doxycycline postexposure prophylaxis. Efficacy data exist 
for MSM and transgender women, where a 200-mg single oral dose of 
doxycycline taken within 24–72 h of condomless sex reduced the risk 
of chlamydia acquisition by ~70–80%.
■
■TRACHOMA
Epidemiology 
Trachoma—a sequela of ocular disease predomi­
nantly in resource-limited areas—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 trachomaendemic areas. Foci of trachoma persist in Africa, Asia, Latin America, 
the Middle East, and the Pacific Rim. C. trachomatis serovars A, B, 
Ba, and C are isolated from patients with clinical trachoma in areas 
of endemicity in 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 sub­
continent, 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 fam­
ily members or between families with shared facilities. Eye-seeking 
flies (e.g., Musca sorbens) 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 aimed to eliminate blinding trachoma globally by 2020. The 
Neglected Tropical Disease road map 2021–2030 has set 2030 as the 
new target year for global elimination of trachoma as a public health 
problem.
Clinical Manifestations 
The clinical manifestations of trachoma 
include two phases: active trachoma (conjunctivitis) and cicatricial 
disease (conjunctival scarring). Both endemic trachoma and adult 
inclusion conjunctivitis present initially as conjunctivitis characterized 
by small lymphoid follicles in the conjunctiva. In regions with hyperen­
demic classic blinding trachoma, the disease usually starts insidiously 
before the age of 2 years. Reinfection is common and probably contrib­
utes 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 infil­
trations 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, opacification, 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 infec­
tious process usually resolves spontaneously in affected persons at 
10–15 years of age, but conjunctival scars continue to shrink, produc­
ing 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 (“infil­
trates”), 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 inflam­
mation. 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. While NAATS are the most sensitive 

and specific diagnostic assays they are prohibitively expensive and 
require laboratory infrastructure that are not available in most endemic 
regions. 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). Chlamydial resistance to azithromycin has not 
been documented. Topical tetracycline (1% eye ointment twice 
daily for 6 weeks) can be used as an alternative, but adherence 
rates are likely to be suboptimal. In the setting of eye infection with 
oculogenital strains, 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 reser­
voirs 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 poul­
try-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.
CHAPTER 194
Chlamydial Infections
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
True incidence and prevalence of psittacosis is difficult to ascertain, 
in part due to lack of routine testing and the varying performance of 
commonly used diagnostic tests. Since 2010, the CDC has typically 
received 10 reports annually of confirmed cases of psittacosis, although 
many more cases probably occur than are reported. Outbreaks have 
been observed in, for example, poultry plant workers. Control of psit­
tacosis 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. Hepatitis and neurologic complications can occur. 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. 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 chlamyd­
ial 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 chla­
mydiae, 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 consis­
tent 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. NAATs from respiratory samples are highly sensi­
tive and specific but are not widely available in laboratories. C. psittaci 
is now considered a biohazard category B biothreat agent and has been 
associated with laboratory-acquired infections.

TREATMENT
Psittacosis
The antibiotic of choice is doxycycline; the dosage for adults is 
100 mg twice a day, continued for 10–21 days; it is unclear if lon­
ger courses prevent relapse. Severely ill patients may need intra­
venous doxycycline and cardiovascular and respiratory support. 
Tetracycline (500 mg four times a day by mouth) and azithromycin 
250–500 mg by mouth daily for 7 days are alternative therapies. 
Erythromycin (500 mg four times a day by mouth) appears to be 
inferior to other agents in animal models.
PART 5
Infectious Diseases
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, but more 
typically 1–2%. PCR is the preferred method for diagnosis of acute 
infections. Serologic studies have linked C. pneumoniae to atheroscle­
rosis; isolation and PCR detection in cardiovascular tissues have also 
been reported. These findings suggest an expanded range of diseases 
and syndromes for C. pneumoniae. Large-scale case–cohort studies 
have demonstrated some association of C. pneumoniae with lung can­
cer, as evaluated by serology.
■
■EPIDEMIOLOGY
Primary infection occurs mainly in school-aged children and reinfec­
tion in adults. Seroprevalence rates of 40–70% show that C. pneu­
moniae is widespread in both industrialized and developing countries. 
Seropositivity usually is first detected at school age, and rates generally 
increase by ~10% per decade. About 50% of individuals have detectable 
antibody at 30 years of age, and most have detectable antibody by the 
eighth decade of life. Although, as mentioned, serologic evidence sug­
gests that C. pneumoniae may be associated with up to 10% of cases of 
community-acquired pneumonia, most of this evidence is based not on 
paired serum samples but rather on a single high IgG titer. Some doubt 
exists about the true prevalence and etiologic role of C. pneumoniae in 
atypical pneumonia, especially since reports of cross-reactivity have 
raised questions about the specificity of serology when only a single 
serum sample is used for diagnosis.
■
■PATHOGENESIS
Little is known about the pathogenesis of C. pneumoniae infection. It 
begins in the upper respiratory tract and may persist as a prolonged 
asymptomatic condition of the upper respiratory mucosal surfaces. 
However, evidence of replication within vascular endothelium and 
synovial membranes of joints shows that, in at least some individuals, 
the organism is transported to distant sites, perhaps within macro­
phages. A C. pneumoniae outer-membrane protein may induce host 

immune responses whose cross-reactivity with human proteins results 
in an autoimmune reaction.
The role of C. pneumoniae in the etiology of atherosclerosis has 
been discussed since 1988, when Finnish researchers presented 
serologic evidence of an association of this organism with coronary 
heart disease and acute myocardial infarction. Subsequently, the 
organism was identified in atherosclerotic lesions by culture, PCR, 
immunohistochemistry, and transmission electron microscopy; how­
ever, discrepant study results (including those of animal studies) and 
failure of large-scale treatment studies have raised doubts as to the 
etiologic role of C. pneumoniae in atherosclerosis. Epidemiologic 
studies have demonstrated an association between serologic evi­
dence 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 plaques—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 acceler­
ates 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 sug­
gested that antibiotics reduce the likelihood of subsequent cardiac 
events. However, larger-scale trials have not documented an effect of 
various antichlamydial regimens on the risk of these events.
■
■CLINICAL MANIFESTATIONS
C. pneumoniae was first reported as the etiologic agent of mild atypi­
cal pneumonia in military recruits and college students. 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 of C. pneu­
moniae pneumonia resembles that of Mycoplasma pneumonia in that 
leukocytosis is frequently lacking and patients often have prominent 
antecedent upper respiratory tract symptoms, fever, nonproductive 
cough, mild to moderate illness, minimal findings on chest ausculta­
tion, 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.
Chronic infection with C. pneumoniae has been reported among 
patients with chronic obstructive pulmonary disease and may play 
a role in the natural history of asthma, including exacerbations. The 
clinical symptoms of respiratory infections caused by C. pneumoniae 
are nonspecific and do not differ from those caused by other agents of 
atypical pneumonia, such as Mycoplasma pneumoniae.
■
■DIAGNOSIS
PCR amplification of respiratory secretions is the preferred method of 
diagnosis; several commercial assays are available. Serology and culture 
can be used to diagnose C. pneumoniae infection. Serology was the 
traditional diagnostic method. Serology is not FDA approved because 
of its poor predictive value and is not routinely used clinically. Cell cul­
ture, which can perform similarly to PCR and allows for antimicrobial 
susceptibility testing, is seldom used as most clinical laboratories are 
not equipped to culture Chlamydia spp. The organism is very difficult 
to grow in tissue cultures but has been cultivated in HeLa cells, HEp-2 
cells, and HL cells. Previously, the gold standard serologic test was the 
MIF test (see section on diagnosis of C. trachomatis genital infection, 
above). Any antibody titer >1:16 is considered significant evidence of 
exposure to chlamydiae. According to a CDC-sponsored expert work­
ing group, the diagnosis of acute C. pneumoniae infection requires 
demonstration of a fourfold rise in titer in paired serum samples. There 
are no official recommendations for diagnosis of chronic infections, 
although many research studies have used high titers of IgA as an 
indicator. The older CF tests and EIAs for LPS are not recommended,