Chlamydial And Mycoplasmal Infections

Epidemiology, Pathology, and Clinical Manifestations

Humans are the only known natural host for all strains of C. trachomatis . The clinical manifestations and organ specificity of human infections with C. trachomatis are determined by both the mechanism of transmission and the properties of the infecting strain. Epidemiologically, C. trachomatis infections are divided into three categories: classic trachoma, sexually transmitted infections of adults, and perinatal ocular and respiratory tract infections.

Classic trachoma is an important cause of blindness in areas where public sanitation is inadequate and personal hygiene is poor ( ; ). The disease is due to repeated infections of the conjunctiva, resulting in a pathologic sequence over time of follicular conjunctivitis, subepithelial scarring, contraction of the scar resulting in turning inward of the eyelid (entropion), rubbing of the eyelashes on the cornea (trichiasis) with subsequent corneal injury, and corneal scarring with opacification and reduced vision. Typically, acute infection is transmitted among children via fingers, fomites, and probably flies, and most children become chronically infected within a few years of birth. Conjunctival scarring usually becomes evident by the second or third decade of life, and blindness can occur anywhere from 10 to 40 years after the first infection ( ). It is interesting to note that other species of the Chlamydiaceae ( C. psittaci and C. pneumonia ) may also be involved in the pathogenesis of trachoma ( ).

C. trachomatis –induced sexually transmitted infections of adults include LGV and urethritis/cervicitis and associated complications. LGV is endemic in Asia, Africa, and South America. In the United States, although approximately 500 cases are reported each year, the true incidence is much higher; the disease affects males more frequently than females and is most common in persons of low socioeconomic status living in the southeastern states, in men who have sex with men (MSM), and in persons who have visited LGV-endemic countries outside the United States. LGV is transmitted sexually, although transmission by fomites and by aerosols produced during laboratory accidents has caused pneumonitis, pleural effusions, and mediastinal or hilar lymphadenopathy ( ). Reservoirs of infection probably are persons with asymptomatic or ignored symptomatic urethral, cervical, or anorectal infection.

LGV is the only infection caused by C. trachomatis that produces multisystem involvement and constitutional manifestations. During the primary phase, a small, painless vesicle or a nonindurated papule or ulcer develops, often on the external genitalia, 3 days to 3 weeks after exposure, and heals quickly without scarring. If transmission is rectal, an acute proctitis is often the first manifestation. An outbreak of LGV proctitis in MSM was first noticed in Europe at the beginning of this century and is due to infection with a unique LGV variant (labeled “L2b”) ( ). Genomic similarity to isolates obtained from patients in the early 1980s in the United States suggests a silent ongoing epidemic in this population caused by this unique variant ( ). More recently several large outbreaks of LGV proctocolitis have been reported among MSM ( ; ; ; ). Moreover, the rates of LGV infections among MSM in New York City clinics are continuously increasing, trends having almost doubled over an 8-year period (16.6% LGV positivity rate as determined by LGV-specific testing of submitted C. trachomatis –positive anorectal specimens in 2012–2015 vs 8.7% LGV positivity rate in 2008–2011) ( ). These data are consistent with the estimation that LGV-associated genotypes cause 10% to 20% of all C. trachomatis– positive anorectal cases among MSM. Given the fact that none of the LGV-specific tests are commercially available and the evidence that asymptomatic LGV infections are not uncommon ( ; ; ; ), it is likely that a significant proportion of LGV cases are currently underdiagnosed.

The secondary stage, characterized by suppurative regional lymphadenopathy, fever, chills, anorexia, headache, myalgias, and arthralgias, begins 2 to 6 weeks after exposure. The primary ulcer or papule often resolves before the secondary stage, but an acute proctitis may persist. Histologic examination of affected lymph nodes shows granulomas surrounding stellate abscesses. Involved lymph nodes become matted and eventually suppurate, producing draining fistulas that heal with scarring over several months. Fibrosis and resultant abnormal lymphatic drainage are responsible for the urethral or rectal strictures or induration and lymphedema of the genitalia that develop during the third stage.

Non-LGV C. trachomatis infection is the most common notifiable condition in the United States, the most common bacterial cause of STD in the United States, and its prevalence continues to rise (Centers for Disease Control and Prevention ). In 2017, 1,708,569 cases of the C. trachomatis infection were reported, resulting in a rate of 528.8 cases/100,000 population, an increase of 22% compared with a rate of 446.6 cases/100,000 population in 2013; and an increase of 6.8% compared to the rate in the previous year 2016. The rates have increased in all states, among both females and males, and among all racial and ethnic groups ( ).

The clinical spectrum of sexually transmitted infections due to non-LGV strains of C. trachomatis is similar to disease caused by Neisseria gonorrhoeae . In men, C. trachomatis is responsible for 30% to 50% of cases of nongonococcal urethritis (NGU), but as many as 85% to 90% of men who harbor C. trachomatis in the urethra are asymptomatic ( ). Urethritis caused by C. trachomatis can present with dysuria and scant mucoid or mucopurulent discharge that rarely can progress to epididymitis. Among MSM, non-LGV strains of C. trachomatis have been associated with proctitis in up to 15% of all cases ( ). Clinical manifestations of chlamydial proctitis, which can vary from asymptomatic to anorectal pain with mucopurulent discharge, have considerable overlap with manifestations of LGV proctitis. However, it is important to identify the specific pathogen, since a much longer duration of antibiotic therapy is required to treat genotypes associated with LGV.

In addition to occasionally causing reactive arthritis associated with HLA-B27, C. trachomatis can also sometimes cause eye and/or skin symptoms (Reiter syndrome) and rarely perihepatitis. Although more common in men, cases of Reiter syndrome have been reported in women and children. Genital infection with C. trachomatis is diagnosed more often in women than in men, with a rate of 687.4/100,000 reported for women in the United States in 2013, about twice the rate among men ( ), a rate difference that is thought, at least in part, to reflect the greater number of women screened for this infection. Infection of the endocervix with C. trachomatis is often asymptomatic, but at least one-third of infected women have signs of infection on physical examination. The most common sign is mucopurulent cervicitis, which can spread to the urethra and urinary bladder, resulting in the acute urethral syndrome of abacteriuric pyuria, or to the endometrium and fallopian tubes, producing endometritis or salpingitis. Untreated infections of the upper reproductive tract may progress to pelvic inflammatory disease (PID) or may cause scarring and dysfunction of the oviduct transport system, which could result in infertility, ectopic pregnancy, or chronic pelvic pain. Intraperitoneal spread of the infection may cause acute peritonitis, perihepatitis (Fitz-Hugh-Curtis syndrome), periappendicitis, or perisplenitis. A portion (1–5%) of patients with urogenital infection with C. trachomatis will develop a reactive sterile arthritis predominantly in large joints that is usually self-limited but may develop a chronic relapsing course ( ; ). Chlamydial infection in pregnancy has been associated with preterm labor, premature rupture of membranes, low birth weight, neonatal death, and postpartum endometritis. In women, it is not uncommon for C. trachomatis to spread to the rectum, causing chlamydial proctitis. A small percentage of adults with chlamydial genital infections develop inclusion conjunctivitis from autoinoculation.

In developed countries, where sexually transmitted infection with C. trachomatis is epidemic, the organism may be transmitted from infected mother to infant during passage through the birth canal. Data from studies in North America indicate that 60% to 70% of infants exposed to C. trachomatis during vaginal delivery become infected with the organism, whereas infection after cesarean section is uncommon ( ). Rates of chlamydial infection are highest among adolescents and young adults. In 2017, almost two-thirds of reported cases were in individuals aged 15 to 24 years, and the rates were highest among women 15 to 19 years of age (3265.7 cases/100,000 women) and 20 to 24 years of age (3985.8 cases/100,000 women) ( ). During 2013 to 2017, the infection rates in women 15 to 24 years of age increased 8.8%, and rates in men increased almost 40% ( ). It is thought that reported cases for men are generally lower due to smaller numbers of men screened for C. trachomatis infection. It is unclear how much availability of commercial assays for urine (e.g., first-void urine) and extragenital testing (e.g., pharyngeal and rectal swabs) has contributed/will contribute to the better detection in men.

C. trachomatis is recovered from the conjunctiva of infected infants after 1 to 2 weeks and from the nasopharynx soon thereafter. The rate of isolation from the conjunctiva falls by 5 to 6 weeks, but C. trachomatis can be recovered from the nasopharynx, conjunctiva, rectum, and vagina (usually without producing symptoms) for several months.

Inclusion conjunctivitis, the most common manifestation of infection with C. trachomatis in infants, develops in nearly 80% of infants whose conjunctival culture or cytologic examination demonstrates the organism ( ), and among those with conjunctivitis, approximately 50% will have a nasopharyngeal infection. A mucopurulent discharge appears 2 to 25 days after birth, and the conjunctiva becomes inflamed and edematous. Severity ranges from a mild infection with scant discharge to copious mucopurulent discharge with severe swelling and pseudomembrane formation.

Approximately 20% to 30% of infants who acquire infection with C. trachomatis at birth develop interstitial pneumonitis. The illness begins at between 2 weeks and 3 months of age (peak, 3–6 weeks) with nasal congestion, followed by a distinctive staccato cough with tachypnea and rales but no fever. Hyperinflation with interstitial or alveolar infiltrates on chest radiograph and peripheral eosinophilia are frequently seen. About one-half of patients have or have had conjunctivitis. Symptoms last several weeks, but inspiratory rales and chest roentgenographic changes may persist for months.

Recently, it was shown that C. trachomatis genital infection in women results in a shift in microbiota toward anaerobic bacteria, an increased production of lactoferrin, interleukin 6 (IL-6), IL-1α, interferon-α (IFN-α), and IFN-β, and decreased production of IFN-γ ( ). Another study examined and compared cytokines in cervical secretions from women with chlamydial infection involving only the cervix with those obtained from women with chlamydial infection involving both cervix and endometrium. It was proposed that polarization of the host immune response toward T-helper (Th) 1 phenotype and related cytokines is associated with protection against ascending infection and reinfection, while polarization toward humoral, type I interferon, Th 17 phenotype, and involved cytokines is associated with susceptibility to C. trachomatis ( ). The unique LPS structure of C. trachomatis , which is capable of preventing initiation of both canonic and noncanonic innate immune signals, was suggested as a contributing factor to the high incidence of asymptomatic C. trachomatis infections ( ).

Epidemiology

Infection caused by Chlamydophila (formerly Chlamydia ) psittaci (also called psittacosis, parrot fever, or ornithosis) occurs worldwide. C. psittaci has seven genotypes (A–F, E/B), all of which are infective for humans. Psittacine birds are considered the major reservoir, but most species of birds can be infected with the organism. Infected birds may be obviously ill and may die of the disease, but frequently they have mild signs such as anorexia, diarrhea, lethargy, and ruffled feathers. Human illness is sporadic and has been associated with exposure to parrots, canaries, pigeons, sparrows, ducks, cockatiels, fowl (especially turkeys), and occasionally mammals. Owners of pet birds account for about one-half of the cases reported in the United States each year. During the past decade, fewer than 10 confirmed cases were reported annually in the United States, which likely is an underrepresentation because patients with mild illness may not seek medical attention or be reported ( ). Pet shop employees, pigeon fanciers, zoo workers, veterinarians, and others who work with birds are at increased risk for infection. Outbreaks have occurred among poultry processing plant workers, principally among workers who killed the birds and plucked their feathers and those who eviscerated carcasses, with a mortality of about 1%, even with appropriate therapy ( ; ). Before the discovery of antibiotics, the mortality rate for human infection was 15% to 20%. Over the past several decades, the prevalence of psittacosis in the United States has declined dramatically as a result of adding tetracycline to poultry feed, requiring medication of commercially imported psittacine birds before entering the country, and domestic breeding of parakeets.

C. psittaci is present in the blood, tissues, excreta, and feathers of infected birds and may be shed for months after acute infection. Transmission to humans occurs via inhalation of infectious aerosols derived from feces, fecal dust, and secretions of C. psittaci –infected birds, but may result from handling contaminated plumage or tissues, from bird bites, or from mouth-to-beak contact. Contact with birds does not have to be close or prolonged. Person-to-person spread of C. psittaci has never been demonstrated ( ).

Pathogenesis and Pathology

C. psittaci enters the body via the respiratory tract and is transported to the macrophages of the liver and spleen, where the organisms replicate. They then enter the blood and travel to the lungs, the primary target of infection, and other organs. Histologic examination of lung tissue shows lymphocytes in the alveolar and interstitial spaces and mucous plugging of the bronchioles. Small hemorrhages and macrophages with intracytoplasmic inclusions may be seen. The hilar lymph nodes, liver, and spleen may be enlarged and may contain foci of necrosis; in fatal cases, the myocardium, pericardium, meninges, brain, and adrenal glands may be involved.

Clinical Manifestations

After an incubation period of 1 to 2 weeks, psittacosis may begin abruptly with chills and fever, or it may begin more gradually with increasing fever and malaise. Persistent dry, hacking cough, occasionally productive of blood-streaked mucoid sputum, is prominent. The heart rate is often slow relative to body temperature, and a diffuse, severe headache is usual. Malaise, anorexia, painful myalgias, and arthralgias are common, and a macular rash (Horder spots) resembling the rose spots of typhoid fever may occur. Decreased mentation may develop at the end of the first week of illness, and some may have gastrointestinal complaints. C. psittaci is a rare cause of destructive endocarditis; most affected persons have a history of rheumatic heart disease or congenital valvular abnormalities ( ). Myocarditis, hepatitis, and neurologic complications have been reported, some of which with fatal outcome ( ).