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Selected sexually transmitted diseases and their relationship to HIV.

Although sexually transmitted diseases (STDs) are underreported and underrecognized, they are a major source of morbidity, mortality, and represent a major socioeconomic cost in developing and industrialized nations. Individuals who develop STDs are often coinfected with human immunodeficiency virus (HIV). Coinfection with HIV both facilitates the natural history of STDs and worsens the clinical picture. The objective of this article is to provide a review to the practicing clinician on the epidemiology, clinical manifestations, methods of diagnosis, and treatment for four cutaneous STDs--chancroid, genital herpes, granuloma inguinale, and lymphogranuloma venereum--in coinfected HIV patients.

Chancroid↗

Binding of Haemophilus ducreyi to carbohydrate receptors is mediated by the 58.5-kDa GroEL heat shock protein.

The bacterium Haemophilus ducreyi causes the sexually transmitted disease chancroid, which is characterized by the appearance of mucocutaneous, persistent ulcers on the external genitals. To identify carbohydrate receptors that mediate the attachment of this pathogen to host cells, we investigated the binding of 35S-methionine-labeled H. ducreyi strains to a panel of defined glycosphingolipids that were separated on thin layer chromatography plates. H. ducreyi bound to lactosylceramide, gangliotriaosylceramide, gangliotetraosylceramide, neolactotetraosylceramide, the GM3 ganglioside, and sulfatide. To elucidate the role of the surface-located 58.5-kDa GroEL heat shock protein (HSP) of H. ducreyi in attachment, we investigated the binding of purified HSP to the same panel of glycosphingolipids. Our results suggest that the 58.5-kDa GroEL HSP of H. ducreyi is responsible for the attachment of this bacterium to the majority of the tested glycosphingolipids, and thus represents a potential bacterial adhesin.

Attachment Sites, Microbiological↗

Haemophilus ducreyi.

Haemophilus ducreyi is the etiologic agent of chancroid, an infection which is endemic in tropical and subtropical areas of the world and which is becoming more prevalent in Europe and North America. Recently, several strains have demonstrated resistance to several antimicrobials by plasmid acquisition and cell envelope alteration making control of the spread of this organism a challenge. Equally challenging is the growth of this organism in the clinical microbiology laboratory because of its in vitro fastidious nature. Currently, the therapy of choice for Haemophilus ducreyi infection is trimethoprim sulfamethoxazole or erythromycin. Plasmid enumeration and restriction endonuclease fingerprinting in addition to outer membrane protein profiles may provide a basis for subtyping which would be useful in epidemiologic studies.

Animals↗

The immune response to Haemophilus ducreyi resembles a delayed-type hypersensitivity reaction throughout experimental infection of human subjects.

Previous work in 3 subjects infected for 2 weeks indicated that experimental infection with Haemophilus ducreyi recruits CD4 cells to the skin at the pustular stage of disease. In order to describe the kinetics of the host response, 23 subjects were infected at 2 sites with a standardized dose of H. ducreyi. Subjects were biopsied 1 or 4 days after inoculation or when they developed a painful pustular lesion (days 7-14). Papules and pustules contained a predominant T cell infiltrate that consisted of CD45RO and CD4 cells of the alpha beta lineage. Both papules and pustules contained mixed or T helper 1 type cytokine mRNA and interleukin-8 and tumor necrosis factor-alpha mRNA. Although the subjects had no history of chancroid, their immune responses resembled delayed-type hypersensitivity reactions that occurred within 24 h of inoculation and persisted throughout the course of experimental infection.

Adult↗

Detection and discrimination of herpes simplex viruses, Haemophilus ducreyi, Treponema pallidum, and Calymmatobacterium (Klebsiella) granulomatis from genital ulcers.

BACKGROUND: Genital ulcer disease (GUD) is commonly caused by pathogens for which suitable therapies exist, but clinical and laboratory diagnoses may be problematic. This collaborative project was undertaken to address the need for a rapid, economical, and sensitive approach to the detection and diagnosis of GUD using noninvasive techniques to sample genital ulcers. METHODS: The genital ulcer disease multiplex polymerase chain reaction (GUMP) was developed as an inhouse nucleic acid amplification technique targeting serious causes of GUD, namely, herpes simplex viruses (HSVs), H. ducreyi, Treponema pallidum, and Klebsiella species. In addition, the GUMP assay included an endogenous internal control. Amplification products from GUMP were detected by enzyme linked amplicon hybridization assay (ELAHA). RESULTS: GUMP-ELAHA was sensitive and specific in detecting a target microbe in 34.3% of specimens, including 1 detection of HSV-1, three detections of HSV-2, and 18 detections of T. pallidum. No H. ducreyi has been detected in Australia since 1998, and none was detected here. No Calymmatobacterium (Klebsiella) granulomatis was detected in the study, but there were 3 detections during ongoing diagnostic use of GUMP-ELAHA in 2004 and 2005. The presence of C. granulomatis was confirmed by restriction enzyme digestion and nucleotide sequencing of the 16S rRNA gene for phylogenetic analysis. CONCLUSIONS: GUMP-ELAHA permitted comprehensive detection of common and rare causes of GUD and incorporated noninvasive sampling techniques. Data obtained by using GUMP-ELAHA will aid specific treatment of GUD and better define the prevalence of each microbe among at-risk populations with a view to the eradication of chancroid and donovanosis in Australia.

Calymmatobacterium↗

Molecular methods for the diagnosis of genital ulcer disease in a sexually transmitted disease clinic population in northern Thailand: predominance of herpes simplex virus infection.

A multiplex polymerase chain reaction (M-PCR) assay that simultaneously detects the three major causes of genital ulcer disease (GUD), Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus, was used to evaluate swab specimens for 38 sequential patients with GUD at a Thai sexually transmitted disease clinic. Subjects received clinical diagnoses and syndromic treatment. Swab specimens for H. ducreyi cultures and M-PCR were obtained. No H. ducreyi cultures were positive. Of 38 M-PCR specimens, 31 (81.6%) were positive for HSV, 1 (2.3%) for both HSV and T. pallidum, and none for H. ducreyi or T. pallidum alone; 6 (15.8%) were negative for all 3 pathogens. Clinical diagnoses corresponded poorly to M-PCR findings; none of 5 suspected cases of chancroid were positive by M-PCR and none of 1 for syphilis, but 21 of 24 suspected herpes lesions were confirmed by M-PCR. Human immunodeficiency virus infection status was known for 24 of 38 subjects; 11 (45.8%) were seropositive, and all 11 had HSV by M-PCR. HSV appeared to be the most common pathogen overall.

Chancroid↗

Evaluation of an isogenic hemolysin-deficient mutant in the human model of Haemophilus ducreyi infection.

Haemophilus ducreyi causes the genital ulcerative disease chancroid. One putative virulence factor of H. ducreyi is a pore-forming hemolysin that displays toxicity against human fibroblasts and keratinocytes. In order to test the role of the hemolysin in pathogenesis, an isogenic hemolysin-deficient mutant was constructed, designated 35000HP-RSM1. The lipooligosaccharide, outer membrane protein patterns, and growth attributes of 35000HP-RSM1 were identical to its parent, 35000HP. Human subjects were challenged on the upper arm with the isogenic isolates in a double-blinded, randomized, escalating dose-response study. Pustules developed at a similar rate at sites inoculated with the mutant or parent. The cellular infiltrate and bacterial load in lesions were also similar. These results indicate the hemolysin does not play a role in pustule formation. Due to the limitations of this model, the role of the hemolysin at later stages of infection could not be determined.

Adult↗

Role of ceftriaxone in sexually transmitted diseases.

Ceftriaxone is a third-generation cephalosporin with antibacterial and pharmacokinetic characteristics that make it an excellent choice for the treatment of gonococcal infection and chancroid. Adverse effects are unusual. Clinical efficacy in all reported studies has been excellent. Additional studies are required for further elucidation of the role of ceftriaxone in the treatment of pelvic inflammatory disease and syphilis. Chlamydial infections are not altered by ceftriaxone, and additional treatment is necessary if Chlamydia is present concurrently with Neisseria gonorrhoeae.

Ceftriaxone↗

A prospective clinical and bacteriologic study of inguinal buboes in Thai men.

One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989. The median duration of preceding symptoms was 7 days (range, 1-62 days). The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinal lymphadenopathy, and 31 (27%) had concurrent active genital ulcers. There was no history of genital ulceration in 66 (58%) of the patients. Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy. Saline (1 mL) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative. Syphilis serology was positive in only one case. Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid. If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.

Adolescent↗

The microbiological flora of penile ulcerations.

The penile ulcerations of 100 consecutive men were tested for microorganisms. A polymicrobial flora was identified in the ulcers of 97 men. The microorganisms recovered from these ulcers included combinations of anaerobic and aerobic bacteria (including Mycoplasma), herpes simplex virus, yeasts, and filamentous fungi. Fifty-three study entrants had microorganisms, identified by culture or serologic tests, that were considered primary in ulcer pathogenesis. Herpes simplex virus was the most prevalent and Treponema pallidum was the next most prevalent pathogen identified. Of our patients, 5% had two recognized pathogens confirmed by laboratory tests, and only one of these was suspected at clinical examination. In addition, the study suggests that microorganisms other than Haemophilus ducreyi can produce ulcers with a morphology mimicking chancroid.

Adolescent↗

Characterization of cell proteins of Haemophilus ducreyi by polyacrylamide gel electrophoresis.

The whole-cell proteins of 105 clinical isolates of Haemophilus ducreyi from several geographic sources (North America, Africa, Asia, and Europe) were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The protein profiles were reproducible and unaffected by repeated subculturing or age of culture. At least seven different subtypes were determined by proteins in the molecular weight range of 24,000-50,000. These proteins are located in the outer membrane of the cell, as determined by SDS-PAGE of the sarcosinate-insoluble membrane preparations of these strains. Thirteen isolates from a Winnipeg, Manitoba, Canada, outbreak of chancroid had identical patterns, suggesting a common origin. Although H ducreyi shares a number of proteins in common with other Haemophilus species, the protein profiles appear to be species specific. Heterogeneity in the protein composition of H ducreyi has provided a basis for subtyping, which could be of value in future epidemiologic studies.

Bacterial Proteins↗

A temperature-dependent rabbit model for production of dermal lesions by Haemophilus ducreyi.

The fact that optimal in vitro growth of Haemophilus ducreyi occurs at 33 degrees C prompted evaluation of the effect of temperature on the ability of this organism to produce skin lesions in rabbits after intradermal inoculation. Animals housed at a reduced ambient temperature (15-17 degrees C) consistently developed necrotic lesions when injected intradermally with 10(5) cfu of H. ducreyi; this inoculum did not produce necrotic lesions in animals housed at normal room temperature (23-25 degrees C). Lesion production in this new model was dependent on both viability of the H. ducreyi inoculum and replication of these organisms after intradermal injection. Histopathologic examination of the lesions revealed that H. ducreyi infection of the rabbit dermis evolves from an acute inflammatory reaction to abscess formation. Evaluation of three additional strains of H. ducreyi in this model confirmed that lesion formation was not bacterial strain-dependent. This new temperature-dependent rabbit model for productive H. ducreyi infection will facilitate investigation of the molecular pathogenesis of chancroid.

Animals↗

Comparison of clinical diagnosis and standard laboratory and molecular methods for the diagnosis of genital ulcer disease in Lesotho: association with human immunodeficiency virus infection.

A multiplex polymerase chain reaction (M-PCR) assay for Haemophilus ducreyi, Treponema pallidum, and herpes simplex virus (HSV) was compared with clinical and standard laboratory methods for the diagnosis of genital ulcer disease (GUD) in 105 patients; 36% were human immunodeficiency virus (HIV)-seropositive. Chancroid (80%), syphilis (8%), and genital herpes (8%) were the most frequent diagnoses. H. ducreyi and HSV were isolated from ulcers of 43% and 18% of patients, respectively; in 35%, all cultures were negative and the laboratory diagnosis indeterminate. M-PCR detected H. ducreyi, T. pallidum, and HSV in 56%, 23%, and 26% of patients, respectively; (no definitive diagnosis, 6%). The proportion of patients with more than one agent was 4% by culture and 17% by M-PCR (P = .002). Resolved sensitivities of M-PCR for H. ducreyi and HSV cultures were 95% and 93%, respectively. The sensitivities of H. ducreyi and HSV cultures were 75% and 60%, respectively. HSV, detected in 47% of specimens from HIV-infected versus 16% from HIV-uninfected patients (P < .001), may be emerging as a more frequent cause of GUD.

Adolescent↗

Antibiotic susceptibilities and plasmid profiles of Haemophilus ducreyi isolates from southern Africa.

Thirty-eight strains of Haemophilus ducreyi isolated in southern Africa were tested in vitro against 15 antimicrobial agents including those frequently used for the treatment of chancroid. In addition, newer compounds which possess characteristics consistent with their possible use as single-dose therapy for the disease were tested. All isolates were found to be resistant to penicillin as a result of beta-lactamase production. The majority of strains were also resistant to tetracycline, sulphamethoxazole and trimethoprim, but susceptible to co-trimoxazole, erythromycin, spectinomycin, ceftriaxone, ceftizoxime, cefodizime, ciprofloxacin, fleroxacin, rifampicin, rifabutin and FCE 22250. beta-Lactamase production appeared to be associated with the presence of low molecular weight plasmids (5.7 or 7 Md). Sulphonamide resistance appeared to be either chromosomally-mediated or due to the presence of a 4.9 Md plasmid. No evidence of plasmid-mediated tetracycline resistance was observed.

Anti-Bacterial Agents↗

Haemophilus ducreyi: clinical disease and pathogenesis.

Haemophilus ducreyi causes the sexually transmitted disease chancroid, which facilitates the transmission of HIV infection. This review focuses on recent advances in the epidemiology, diagnosis, treatment and pathogenesis of this disease.

Anti-Bacterial Agents↗

Routinely reported sexually transmitted diseases presage the evolution of the AIDS epidemic.

Because AIDS is largely transmitted through sexual intercourse, the descriptive epidemiology of sexually transmitted diseases of short incubation period could presage the incidence trend of AIDS after a time interval that approximates the incubation period of the disease. We have evaluated this hypothesis using data from the 50 states in the United States routinely reported to the Centers of Disease Control and Prevention from 1979 to 1994. We have estimated the dependence of the slope of the annual incidence rate of AIDS over the period 1987-1994 on the intercept and the slope of one or more of three common sexually transmitted diseases: gonorrhea, chancroid, and syphilis. When the parameters of two sexually transmitted diseases were used as predictor variables, the adjusted multiple correlation coefficient (Radj) ranged from 0.70 to 0.77. When the parameters of all three sexually transmitted diseases studied were used in the regression model, the Radj reached a high value of 0.79. We conclude that incidence data of three common sexually transmitted diseases during an 8-year period presage the evolution of the AIDS epidemic during the subsequent 8-year period.

Acquired Immunodeficiency Syndrome↗

Vitamin A and risk of HIV-1 seroconversion among Kenyan men with genital ulcers.

BACKGROUND: Vitamin A is involved in normal immune function and the maintenance of mucosal integrity through complex effects on cellular differentiation. OBJECTIVE: We sought to determine whether serum vitamin A levels were associated with altered susceptibility to primary infection with HIV-1 in men with high-risk sexual behaviour and genital ulcers who presented for treatment at an STD clinic in Nairobi, Kenya. METHODS: HIV-1 seronegative men were prospectively followed. Vitamin A levels at study entry were compared among 38 men who HIV-1 seroconverted versus 94 controls who remained HIV seronegative. RESULTS: Vitamin A deficiency (retinol less than 20 microg/dl) was very common and was present in 50% of HIV-1 seroconverters versus 76% of persistent seronegatives. Seroconversion was independently associated with a retinol level greater than 20 microg/dl (HR 2.43, 95% CI 1.25-4.70, P = 0.009), and a genital ulcer aetiology caused by Haemophilus ducreyi (HR 3.49, 95% CI 1.03-11.67, P = 0.04). Circumcision was independently associated with protection (HR 0.46, 95% CI 0.23-0.93, P = 0.03). CONCLUSION: Vitamin A deficiency was not associated with an increased risk of HIV-1 infection among men with concurrent STD. A decreased risk of HIV-1 seroconversion was independently associated with lower retinol levels. The effects of vitamin A on macrophage and lymphoid cell differentiation may paradoxically increase mucosal susceptibility to HIV-1 in some vulnerable individuals, such as men with genital ulcers. Lack of circumcision and chancroid are confirmed as important co-factors for heterosexual HIV-1 transmission. The role of vitamin A in heterosexual HIV-1 transmission requires further study.

Adult↗

Etiology of genital ulcerations in Swaziland.

The etiology of genital ulcer disease was determined among 155 consecutive new cases in Mbabane, Swaziland. In contrast to genital ulcerations in industrialized countries, chancroid was the most common diagnosis (44% of cases), as established on clinical grounds and by exclusion of other etiologies. Primary syphilis and genital herpes accounted for only 17% and 12% of the cases, respectively. Lymphogranuloma venereum was found in 13% of the patients, and in 15% of cases no diagnosis was made.

Chancroid↗