Pathogenesis of Chlamydial Ocular Diseases
Deborah Dean
Chlamydial ocular infections include trachoma, adult inclusion conjunctivitis (paratrachoma), and neonatal inclusion conjunctivitis (also referred to as inclusion conjunctivitis of the newborn [ICN], neonatal inclusion blennorrhea or ophthalmia neonatorum). These diseases have been well described since antiquity, yet the infectious chlamydial particles responsible for each were not discovered until the first decade of the 20th century CE.1 Trachoma is a chronic ocular infection caused by Chlamydia trachomatis strains that are transmitted by hand to eye to hand contact. Recent investigations have also implicated Chlamydia pneumoniae and Chlamydia psittaci as additional pathogens that are responsible for trachomatous disease2.
Trachoma was first reported in China during the 27th century BCE in relation to a treatment for trichiasis. Trichiasis refers to one or more in-turned eyelashes that touch the globe of the eye and is a sequela of trachoma that occurs years to decades following infection. The Ebers Papyrus of 1800 BCE also made reference to trachomatous disease, but the actual term trachoma did not appear until the first century BCE, when it was used as the Greek word to describe rough swelling of the conjunctiva. During the Middle Ages, endemic trachoma in the Middle East was spread to Europe by the crusaders. Trachoma subsequently became a significant blinding disease of epidemic proportions among civilian and military populations during the Napoleonic era.
Although trachoma has disappeared from most developed countries of the world because of improved hygiene, sanitation, and economic development, it is estimated that more than 600 million inhabitants of Africa, the Eastern Mediterranean, parts of Central and South America, Asia, and Australia,3 are infected and at risk for disease. Of these 600 million, 150 million people have visual deficits. Approximately 6 million persons are already blind, and 10 million will require surgery for trichiasis to prevent progression of visual deficits and blindness.4
Adult and neonatal inclusion conjunctivitis is caused primarily by the sexually transmitted disease (STD) strains of Chlamydia trachomatis. The historic link between these chlamydial strains and STDs, as well as the ocular diseases, was not made until diagnostics were developed for Neisseria gonorrhoeae (GC). Once it became clear that many cases of cervicitis, neonatal conjunctivitis, and nongonococcal urethritis could not be attributed to GC, the involvement of another infectious agent was suspected. In 1907, Halberstaedter and von Prowazek5 identified typical chlamydial intracytoplasmic inclusions in conjunctival scrapings from an orangutan infected with a human trachoma strain. But it was not until 1957 that a trachoma strain was first isolated.6 Similar inclusions were later seen in scrapings from the genital tracts of the parents of an infant with neonatal conjunctivitis.7 The first strain responsible for chlamydial STDs was isolated in 1959.
Because the natural history of chlamydial STDs is not well understood, including the propensity for latent or persistent infections to reactivate and be transmitted, the true incidence and prevalence of adult and neonatal inclusion conjunctivitis are not known. Adult inclusion conjunctivitis is usually a unilateral, self-limited disease of presumed low prevalence, although chlamydial genital strains are the most common cause of STDs in the developed and developing world today. This disease can also be caused by other species of Chlamydia such as C. psittaci and C. pneumoniae.8,9,10 Neonatal conjunctivitis can be severe if untreated, and approximately 20% of infected neonates will develop pneumonitis within the first 6 months of life along with the long-term sequela of small airways disease in adulthood11.
The last two decades have provided scientific advances in almost all areas of chlamydial research. These include clinical, diagnostic, epidemiologic, physiologic, pathologic, microbiologic, genetic, genomic, and immunologic characteristics of chlamydial diseases. Furthermore, the advent of a new, simplified trachoma grading scheme12 and a more specific strain typing technique referred to as ompA genotyping13 in addition to multilocus gene typing techniques for C. trachomatis14,15 have enhanced the understanding of the clinical epidemiology, molecular epidemiology, transmission, risk factors, and prevalence of trachoma. However, the pathogenesis of trachomatous disease requires further study, and the best approach to designing an efficacious vaccine remains controversial.
TAXONOMY AND CLASSIFICATION
Chlamydia are prokaryotes. Chlamydial organisms were historically referred to as Bedsonia or Miyagawanella and were initially thought to be protozoa. Because of their small size and the problems encountered with propagation, they were subsequently thought to be viruses. In the 1960s they were classified as bacteria because Chlamydia express proteins (e.g., lipopolysaccharides) that are functionally analogous to other bacteria, divide by binary fission, are inhibited by antibacterial drugs, contain ribosomes, and are structurally and morphologically similar to Gram-negative bacteria.1 However, Chlamydia are only distantly related to other eubacterial orders based on phylogenies of ribosomal ribonucleic acid (rRNA) gene sequences.16
Chlamydiae comprise their own order, Chlamydiales; a single family, Chlamydiaceae; and one genus, Chlamydia. New genus and species designations were proposed for chlamydiae in 1999 based on sequence analysis of small segments of 16S and 23S rRNA.17,18 The proposal included expansion to two genera, Chlamydophila and Chlamydia. The former was proposed to comprise the species Chlamydophila pneumoniae19, Chlamydophila psittaci,20 Chlamydophila pecorum,1,21 Chlamydophila abortus, Chlamydophila caviae, and Chlamydophila felis. The genus Chlamydia was proposed to comprise the species C. trachomatis, C. muridarum,22,23 and C. suis. However, the rRNA analyses provide relatively constant evolutionary relationships that do not necessarily translate into biologically important designations for distinguishing one strain from another within a species or genus. This has become increasingly apparent from evidence of intragenic and intergenic recombination of the ompA gene for C. trachomatis (with new species designations for C. trachomatis and C. muridarum), C. psittaci (with new species designations for C. psittaci and C. abortus), and C. pneumoniae that affect persistence as well as tissue and host tropism for different strains.24 This is in addition to intraspecies and intergenomic recombination involving other genes for C. trachomatis strains25,26,27 and interspecies recombination involving other genes for C. caviae and C. muridarum.28 Furthermore, there is evidence for recombination events with acquisition of DNA from chlamydial or other organisms, including an invertible sequence in C. pneumoniae,29 insertion-sequence (IS)–like elements in C. trachomatis.25 glyA and murA gene inserts in C. trachomatis, C. muridarum, C. abortus, C. caviae, and C. pneumoniae30 and a tetracycline transposon in C. suis.31 Although the rate of or time frame for mutations and recombination events is not known for ompA or other genes, a new taxonomy may not be appropriate because these events do occur. Furthermore, genomic analyses of other organisms have revealed biologic relationships that are not reflected in the phylogenies of rRNA-based sequences.32 This continues to be an area of debate in the field of Chlamydia. However, in 2009, the Chlamydia field collectively proposed to retain the use of one genus, Chlamydia, for all species primarily because of the limitations of rRNA analyses.
C. trachomatis is made up of two biologic variants or biovars: trachoma and lymphogranuloma venereum (LGV). There is 87% to 99% deoxyribonucleic acid (DNA) homology among the human strains and biovars of C. trachomatis but only 30% homology for the nonhuman strains. C. trachomatis is currently known to infect only humans. The infections in humans include the conjunctiva and lower and upper genital tracts as well as the rectum and lymphatics that drain the perineum. These infections are caused by the 19 currently recognized serologic variants (serovars) of the trachoma and LGV biovars.
Serovars are defined by monoclonal and polyclonal antibodies that react to epitopes on the major outer membrane protein (MOMP) of C. trachomatis. Additional serovars presumably exist based on sequence data of the gene (ompA) that encodes for MOMP, but these strains have not been fully characterized to date.24 Serotyping has distinguished these serovars into different serogroups or classes: B class (serovars B, Ba, D, Da, E, L2, and L2a), Intermediate class (serovars F and G), and C class (serovars A, C, H, I, Ia, J, K, Ka, L1, and L3).1 Serovars A through K and Ba, Da, Ia, and Ka were previously referred to as trachoma-inclusion conjunctivitis (TRIC) strains.33 Trachoma is primarily caused by serovars A, B, Ba, and C, whereas adult and neonatal inclusion conjunctivitis are caused by serovars B or C, D through K, Da, Ia, Ka, L1, L2, L2a, and L3, which are the sexually transmitted strains of the organism. The LGV serovars tend to cause more severe disease and can invade regional lymphatics, whereas the non-LGV serovars are currently known to infect various epithelial type cells at ocular, respiratory, rectal, and genital mucosal surfaces.
Serotyping has been the most widely accepted technique for classifying C. trachomatis organisms. However, within the last decade, a new technique has been developed based on sequencing of ompA and is referred to as ompA genotyping1,34,35 (ompA was previously called omp1, but the nomenclature has changed to be consistent with that of other bacteria), in addition to multilocus sequence typing (MLST).14,15 These two techniques have been and continue to be invaluable for evaluating the molecular epidemiology, disease pathogenesis, and transmission dynamics of chlamydiae for STD and trachoma populations. However, MLST has been able to expand our understanding of specific strains that are associated with ocular versus invasive urogenital versus noninvasive prevalent urogenital infections as well as identify single nucleotide polymorphisms (SNPs) associated with each of these disease types.14 Furthermore, the chlamydial MLST scheme has been incorporated into the MLST website (mlst.net), which houses the MLST schemes for over 30 human pathogens, and can now be used to type specimens from different populations for global epidemiologic and evolutionary comparisons.14
DEVELOPMENTAL CELL CYCLE AND GENETICS
Chlamydia are obligate intracellular pathogens that require nutrients from the host cell for replication. They have a unique biphasic developmental cycle not found in any other bacteria. Chlamydia have two forms: the extracellular elementary body (EB; 0.3 μm in diameter), which is the infectious, spore-like particle of the organism; and the reticulate body (RB; 0.5–1.6 μm in diameter), which is the noninfectious metabolically active form. The outer membrane of the EB has disulfide, cross-linked cysteine residues on and between MOMP, as well as 12- and 60-kilodalton (kDa) cysteine-rich outer membrane proteins. These proteins provide a relatively rigid membrane that facilitates short-term viability of the organism outside the host cell. Once the EB comes in contact with susceptible eukaryotic epithelial cells, it attaches by divalent cations and polycations,36 possibly using heparin sulfate as a bridge between as yet unknown receptors on the EB and the cell surface37 or attaching via other unknown receptors. Heterologous serovars competitively inhibit attachment.38 The EB is taken up into a phagosome by receptor-mediated endocytosis,39 although pinocytosis and phagocytosis have also been described. There is ineffectual lysosomal fusion with the endophagosome, and hence intracellular survival is ensured. At this point in the cycle, the endophagosome is called an inclusion body.
The developmental cycle is regulated by transcriptional events.40 Cleavage of the disulfide bonds occurs within 6 to 8 hours of EB uptake and heralds the differentiation into the RB. The energy for RB replication, which occurs via binary fission41 starting at about 10 to 15 hours postinfection,42 comes from its own stores of adenosine triphosphate (ATP) and activated ATPase, as well as essential metabolites and phosphate compounds from the host cell that are transported across the inclusion body membrane.43 MOMP contains pore-like (porin) structures during the RB stage that are thought to facilitate this exchange.44 There appears to be a differential requirement for amino acids depending on the serovar: The LGV strains require methionine unlike the other STD strains, whereas the trachoma serovars require tryptophan. Some of the Chlamydia genomes contain genes encoding a partial tryptophan operon, which confers an interferon gamma (IFN-γ) escape mechanism. IFN-γ indirectly depletes tryptophan, which is essential for chlamydiae replication, through induction of indoleamine 2,3-dioxygenase (IDO) that degrades tryptophan. Oculotrophic strains lack a functional tryptophan synthase (unlike urogenic C. trachomatis) due to a frame shift mutation in one of the genes, trpA, that is required for enzyme function. Thus, the ocular strains are unable to use exogenous substrates such as indole to synthesize tryptophan.45,46 This limitation likely allows the organisms to more easily persist in infected tissue, resist antibiotics, and at some point, reactivate to promote disease. Leucine, phenylalanine, and valine, however, are necessary for growth for all known serovars and species of Chlamydia.47 As replication proceeds, the inclusion body expands and displaces the nucleus to the side of the cell. In addition, glycogen accumulates, which can be visualized by staining with iodine but is present only in C. trachomatis.
Within 36 to 72 hours, depending on the serovar, chromatin within the RB compacts down into an electron-dense nucleoid and, along with formation of membrane-bound disulfide bonds, produces an EB. The signal for these latter events is the reduction and oxidation of both intramolecular and intermolecular disulfide bonds.44 Anywhere from 100 to 1,000 EBs can be produced per infected cell.48 In many cases, the cell ruptures and dies releasing the infectious progeny, but the cell can also extrude the inclusion body by a process of exocytosis and thereby survive.
The EB is composed of several different proteins. MOMP comprises approximately 60% with a mass of 40 kDa49 and is the most immunogenic of the surface proteins. The mass of this protein does differ somewhat according to the serovar. Both the lipopolysaccharide (LPS) and MOMP have genus-specific determinants, whereas MOMP also contains serovar-, serogroup-, and species-specific epitopes. There are four variable segments (VSs) interspersed by five constant regions on MOMP.50 VS1, 2, and 4 are surface exposed and contain the serotyping epitopes of the organism, whereas VS3 has important T-cell determinants.36,51 Serovar-, subspecies-, and species-specific epitopes on MOMP have also been characterized for C. psittaci but do not appear to be immunogenic for C. pneumoniae. Limited data are available for the other species. The genus-specific epitope of LPS, shared by all species of Chlamydia, is a trisaccharide of 2-keto-3-deoxy-octanoic acid (KDO).52 This approximately 7,000-kDa glycolipid is similar to the LPS of enteric bacteria such as Salmonella typhimurium.53 Both the LPS and MOMP are expressed throughout the developmental cell cycle, whereas the 12- and 60–kDa proteins discussed previously are expressed only at the time when the RB condenses back into an EB.36
There are some important similarities and differences among the species of Chlamydia. Although they differ in host and host cell preference, genomic composition, epitopes, drug susceptibility, and metabolism, they are similar in morphology and structure. However, the EB of C. pneumoniae can appear pear-shaped, instead of round, with a large periplasmic space. In addition, when more than one EB enters a cell, the inclusion bodies usually fuse into a single body but can remain distinct for C. pneumoniae, C. psittaci, and C. pecorum. The size of these bodies can be variable, especially for C. psittaci. Recently, nonfusing inclusions of C. trachomatis have been identified that have mutations in the inclusion membrane protein A (IncA) gene (incA) and lack IncA expression in the inclusion membrane.54
Chlamydia contain a 7.5-kilobase (kb) plasmid that has been found in C. trachomatis, C. muridarum, C. caviae, C. felis, and C. psittaci strains. Yet, some C. trachomatis strains have been identified that do not contain the plasmid.55,56,57 The plasmid sequence is relatively conserved within a species but varies considerably between species. The function of the plasmid is not entirely known, although it is presumed to have a role in infectivity57 and replication.58 However, C. trachomatis strains that lack the plasmid can still be propagated in cell culture.59
Other genomic differences have been highlighted by the recent publications of the entire genomes of six C. trachomatis strains (human strains A/HAR13, B/Jali20, B/TW5/OT, D/UW3, L2/434, and L2b)60,61,62,63; four C. pneumoniae strains (TW183, CWL029, AR39, and J138)29,64,65; and one strain each of C. abortus (strain S26/3 from a ewe),66 C. caviae (strain guinea pig inclusion conjunctivitis, GPIC),28 C. muridarum (strain mouse pneumonitis, MoPn),29 and C. felis (strain Fe/C-56 from a cat).67 The genomes of C. pecorum, C. psittaci and C. suis have not yet been sequenced. Several open reading frames (ORFs) were found in each species that likely encode outer membrane proteins, including a polymorphic membrane protein (Pmp) gene (pmp) family including 9 genes for C. trachomatis, 21 for C. pneumoniae, 9 for C. muridarum, 17 for C. caviae, 18 for C. abortus, and 20 for C. felis. The pmp family is important because it is unique to the genus Chlamydia, constitutes a surprising 10% of the genome, and interspecies amino acid sequence homology is less than 50% compared with 70% to 80% for other surface proteins. Although the function(s) of these proteins are not completely understood, they are likely autotransporters important in host immune response and pathogenesis. This is supported by data that revealed differential immune responses to certain C. trachomatis Pmps in patients with chlamydial STDs.68,69,70 PmpD is considered a broadly cross-reactive neutralizing antigen that may be effective as a vaccine construct.71
All species of Chlamydia are susceptible to tetracyclines, except for C. suis strains that appear to have acquired a tetracycline resistance transposon from Helicobacter pylori.31 All serovars of C. trachomatis are susceptible to sulfonamides. However, few strains of C. psittaci and C. pneumoniae respond to treatment with sulfonamides.
EPIDEMIOLOGY AND PREDISPOSING FACTORS TO DISEASE
Trachoma
Trachoma is the leading infectious cause of preventable blindness in the world today and occurs as mesoendemic, endemic, or hyperendemic disease.1 The distribution is primarily in tropical developing countries of the world including North and sub-Saharan Africa, the Middle East, and the Northern Indian subcontinent where the highest affliction rates are reported.3 However, disease has also been reported in Southeast Asia and specific regions of Central and South America, Australia, and the South Pacific Islands.4 Of the more than 600 million people afflicted, approximately 150 million have visual deficits,4 and 12 million are predicted to be blind by the year 2020.72 However, the precise prevalence of disease or disease severity is not known because diagnostic surveys have not been conducted in many countries where trachoma is suspected nor have they been performed in many areas where trachoma is considered endemic or hyperendemic. Furthermore, diagnostic tests vary in sensitivity and specificity.
C. trachomatis is transmitted via eye to hand to eye contact where the primary reservoir of infection is the conjunctival mucosa. Other reservoirs include the nasopharynx, oropharynx, and rectum, but their role in infection and reinfection of the ocular mucosa is not completely understood.73 In one study, nasal secretions were not found to play a role in reinfection in a trachoma community in Tanzania,74 but additional studies are required. The STD strains of C. trachomatis are also present in these communities and may contribute to disease as has been suggested from nonhuman primate studies,75,76 findings in other trachoma populations,77,78 and recent research in a trachoma-endemic region of Nepal.2 It is important to consider that C. pneumoniae and C. psittaci are also likely involved in the pathogenesis of trachoma.2
The incubation period is not known but is thought to range from 5 to 12 days based on nonhuman primate studies.79 Children are considered the primary source of infection because they usually constitute more than 50% of the population and become easily infected from close contacts during frequent play and within small, crowded households. However, female caregivers can also serve as an important reservoir in which the infection is passed to them and then back to their children. Thus, children younger than 10 years are at greatest risk for infection and reinfection. Young women of childbearing age and other female caregivers are reported to have infection rates that range from 5% to 35%.2,73,74,80,81,82 These infections likely represent transmission within the household from and to children. Adult women develop more severe disease and sequelae than their male counterparts; repeat infection is considered an important factor in disease progression to trichiasis.
Patterns of trachomatous disease and disease severity are dependent on the degree of endemicity in villages or communities where C. trachomatis ocular infections occur. In hyperendemic areas, high prevalence rates of infection among children are found and reinfection is common. Indeed, most children by the age of 1 year have been infected at least once. Both sexes are equally at risk in childhood, but, because the rates of infection decline with age, adolescent and young adult females tend to have higher rates compared with their male counterparts. Hyperendemic communities have higher rates of conjunctival scarring, occurring as early as 4 years of age. Scarring is common in young adults and older age groups and progresses to trichiasis and entropion (in-turned eyelid) in many cases. These sequelae occur 10 to 40 years following the initial childhood disease.83 Trichiasis rates range from 8% to 17.5% depending on the geographic locale.84,85,86 Blindness occurs indirectly through corneal abrasion and bacterial superinfection of the abrasion, both of which may be facilitated by dry eyes, which is a common condition among older individuals. Furthermore, scarring of lacrimal glands and other periocular tissues from trachoma87,88 may contribute to dry eyes and accelerate disease progression. The corneal lesions typically heal by scarring and fibrosis. Trachoma is the primary cause of blindness in hyperendemic areas.
In mesoendemic or endemic communities, trachoma takes two forms. In one, the prevalence is low but there are some households in which infection rates are high, which provides a reservoir for repeat infection that can lead to the sequelae mentioned previously. In the other form, infection occurs later, starting at school age, and blindness is rare. However, the community rate of infection may be moderate to high.89,90 Where infection rates are declining, scarring in older individuals may still be present along with progression to trichiasis and blindness.
C. trachomatis cannot always be detected in all cases of active trachoma. In one report from Tanzania in which direct fluorescent antibody (DFA) and tissue culture tests were used, 43% of patients with follicular disease (TF) and 23% with intense inflammatory disease (TI) were negative for C. trachomatis.80 Similar findings have also been reported for newer nucleic acid amplification tests (NAAT) such as the ligase chain reaction (LCR)91 and the polymerase chain reaction (PCR)92 that have a higher sensitivity than DFA or culture. The most likely explanations for these findings are inadequate sampling of the conjunctiva, resolution of infection with residual inflammation, inflammation resulting from infections with other bacteria or other Chlamydiaceae organisms that are not detected by NAATs, or autoimmunity, or some combination thereof.1 In one study in the Gambia,93 household members were tested for chlamydiae every 2 weeks. Organisms were detected 2 weeks before onset of inflammation and for an additional 2 to 6 weeks after disease development in children. Clinical disease persisted for 30 weeks in children and for only 2 weeks in adults. In other studies, 5% to 24% of villagers without active disease were found to be infected,73,74,80,81,82 including 24% of children in Tanzania81 who were PCR positive but had no evidence for trachoma. Thus, the time at which the sample is obtained can be critical for detection of the organism.
The degree of inflammatory disease varies considerably from one child to the next but can remain constant at different time points for a particular child despite treatment. Historically, environmental factors were considered to be responsible.94 However, a combination of factors is now thought to contribute to this phenomenon: environmental conditions, infectious load of C. trachomatis,95 duration of infection,96 host immune response,1,97,98 and possibly host genetic susceptibility.99,100,101 Severe inflammatory disease and the duration of inflammation in childhood is thought to be a risk factor for progression to scarring, and trichiasis and entropion later in life. Thus, age is also an important risk factor for trachomatous disease.102 Additional interacting factors likely contribute. With age, there is continued exposure to the organism and risk of reinfection especially among females of childbearing age and female caregivers of all age groups. There can be changes in biologic susceptibility as in the development of dry eye syndrome that can occur from age or scarring. Also, host immune response to chlamydial antigens such as Hsp60 have been associated with trachomatous scarring,98,103 and this response may be potentiated with increasing age.98
Other risk factors for trachoma are low socioeconomic status, poor facial hygiene, more than one child in a bedroom, many children per household, lack of water or lack of use of water, and proximity to cows.80,104,105,106 Flies have historically been considered vectors for transmission in Africa. However, data from recent studies do not support the theory.107 In one study, fluorescein was used to stain the secretions in the eyes of children.108 Within 15 to 30 minutes, the legs and bodies of the flies were also stained with fluorescein. Eye-seeking flies such as Musca sorbens have been shown to land on the eyes of multiple children as was reported in a study in Africa,109 But, it is not clear how many infectious EBs can be carried on the flies, how long they are viable, and whether the inoculum is sufficient to cause infection. In the same study, only two of 395 flies that were caught from the eyes of children with C. trachomatis infections were positive for Chlamydia by PCR and the findings could not be confirmed.109 It is certainly possible that flies carry other bacteria from eye to eye, which might promote inflammatory disease and trachoma. Indeed, in many trachoma-endemic countries, there are seasonal outbreaks of conjunctivitis resulting from multiple bacterial species including Haemophilus influenzae, Haemophilus aegyptius, Streptococcus pneumoniae, Neisseria meningitidis, N. gonorrhoeae, and Moraxella spp. These infections may actually precede periods of increased trachoma prevalence rates. In a study in Tunisia,89 moderate to severe trachoma was found significantly more often among children with bacterial coinfections. Furthermore, pathogenic and nonpathogenic bacteria commonly colonize children who reside in trachoma areas. Coinfection of C. trachomatis with these bacteria may be one mechanism that is important for promoting severe inflammation, which results in conjunctival scarring and corneal vascularization years later.110 To further our understanding of trachoma pathogenesis, coinfection with Chlamydiaceae and other bacteria will be an important area of study.
The World Health Organization (WHO) in the late 1990s established the Alliance for the Global Elimination of Blinding Trachoma by the year 2020 (GET 2020).111 This collaborative alliance developed the SAFE strategy as a means to achieve this goal. The components of the strategy include surgery to correct trichiasis, oral antibiotics to treat C. trachomatis infections, facial cleanliness to decrease ocular infections with Chlamydia and other bacteria, and environment improvements such as latrines and access to clean water from deep wells. There are more than 20 countries that have instituted the SAFE program to date but often only the S and/or A programs are begun. Unfortunately, the rates of recurrence of trichiasis after surgery, irregardless of the type of procedure, range from 25% to 75% over the months to years postsurgery,112,113,114,115 In addition, infection rates return to pretreatment levels within 6 to 24 months of cessation of antibiotic therapy.116,117,118,119,120,121 These outcomes are likely multifactorial, reflecting the complicated nature of infections that may involve more than one Chlamydiaceae species requiring different lengths of treatment,8,9,122,123 the blunting of the immune response such that individuals are more rapidly susceptible to reinfection following treatment,116,124,125 and the ready source of organisms from untreated individuals and from animals that harbor C. pneumoniae and C. psittaci and can transmit these organisms to humans2
Adult Inclusion Conjunctivitis
Although chlamydial STDs account for more than 92 million cases annually worldwide126 with over 1 million occurring annually in the United States,127,128 the exact prevalence of adult inclusion conjunctivitis remains unknown. This is in part because infection is usually self-limited and does not always reach medical attention. The spread of chlamydial STD serovars is from hand to genital tract to eye contact or during sexual activity. However, there are reports of transmission occurring among family members from an infected neonate.33 Persons between the ages of 15 and 30 years are at highest risk for adult conjunctivitis.33 The incubation period is considered to be approximately 5 to 19 days, and disease may continue for months without treatment. There is usually complete resolution of disease following a 3-week course of systemic therapy with either tetracycline or erythromycin. A shorter course of treatment may be efficacious with other antibiotics such as azithromycin.
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