Chancroid: new developments in an old disease.
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Chancroid↗
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Treating chancroid: summary of studies in South Africa.
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HIV Seropositivity↗
Herpes simplex virus in clinically suspected chancroid in Nairobi, Kenya.
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Africa↗
Partial characterization of the major lipooligosaccharide from a strain of Haemophilus ducreyi, the causative agent of chancroid, a genital ulcer disease.
The first preliminary structure of a surface lipooligosaccharide from Haemophilus ducreyi has been determined. The major oligosaccharide was released by mild acid hydrolysis and analyzed by liquid secondary ion and tandem mass spectrometry. The mass spectral data combined with composition and methylation analysis yielded the most probable structure; Gal1----4GlcNAc1----3Gal1----4Hep1----6Glc1----( Hep1----2Hep1----)3,4Hep1---- KDO, where the reducing terminal 3-deoxy-D-manno-octulosonic acid (or KDO) exists in an anhydro form. This anhydro species results from the elimination of a phosphate from C-4 of KDO during mild acid hydrolysis. The core heptose trisaccharide consists of L-glycero-D-manno-heptose, but analysis of the peracetylated sugars indicated that the 1,4-linked heptose is likely D-glycero-D-manno-heptose. The monoclonal antibody 3F11 generated against Neisseria gonorrhoeae also binds to this lipooligosaccharide and suggests that the terminal trisaccharide is Gal beta 1----4GlcNAc beta 1----3Gal beta 1----, an epitope found in the glycose moiety of the human erythrocyte glycosphingolipid lactoneotetraglycosylceramide. Mass spectrometric and composition analysis of the lipid A moiety shows that it is similar to the lipid A of Haemophilus influenzae strain I-69 Rd-/b+ proposed by Helander et al. (Helander, I. M., Lindner, B., Brade, H., Altmann, K., Lindberg, A. A., Rietschel, E. T., and Zähringer, U. (1988) Eur. J. Biochem. 177, 483-492). Electrospray mass spectrometric analysis of the intact O-deacylated lipooligosaccharides gave an average Mr of 2710, and supported an overall structure consisting of the above nonasaccharide linked directly to a diphosphorylated lipid A moiety through the single KDO which is phosphorylated. This structure should provide a framework to investigate the roles of lipooligosaccharides in the host immunochemical response and pathology of H. ducreyi infection, a leading cause of genital ulcer disease.
Carbohydrate Sequence↗
Presumptive specific clinical diagnosis of genital ulcer disease (GUD) in a primary health care setting in Nairobi.
Of 22,274 patients 12 years of age or older attending a primary health care clinic in Nairobi, 1076 (4.8%) complained of symptoms suggesting a sexually transmitted disease (STD). Of these, 518 females and 462 males underwent complete clinical evaluation, and 78% had objective microbiologic or clinical evidence of STD, including 168 (17.1%) with genital ulcer disease (GUD). Presumptive specific clinical diagnoses on initial physical examination in cases of GUD were chancroid (131 patients), syphilis (25), genital herpes (15) and lymphogranuloma venereum (LGV) (1). Clinical diagnoses correlated only weakly with microbiological and serological diagnoses. Haemophilus ducreyi was isolated from 51 (41%) of the 125 with a clinical diagnosis of chancroid, and 4 (22%) of 18 with a diagnosis of syphilis, herpes, or LGV (P = 0.13). The rapid plasma reagin (RPR) test was reactive in 6 (24%) of 25 with a clinical diagnosis of syphilis, 18 (12.3%) of 146 with a diagnosis of chancroid or herpes, and 37 (4.7%) of 786 without a genital ulcer (P < 0.001, GUD vs no GUD). Sensitivity, specificity, and positive predictive value for presumptive clinical diagnosis of chancroid, relative to H. ducreyi isolation, were 93%, 16%, and 41%; and for diagnosis of syphilis, relative to reactive RPR, were 25%, 88% and 25%. Specific treatment based on presumptive specific clinical diagnosis frequently was inadequate for syphilis among patients with GUD and reactive RPR test. Syndromic treatment of GUD with antimicrobial combinations active against both chancroid and syphilis would be preferable to treatment with single drugs based on presumptive specific clinical diagnoses for this population.
Anti-Bacterial Agents↗
Clinical and in situ cellular responses to Haemophilus ducreyi in the presence or absence of HIV infection.
We aimed to determine if the clinical and histological features of chancroid are altered by HIV infection. Male patients presenting to the Nairobi special treatment clinic with a clinical diagnosis of chancroid were eligible for the study. A detailed history, physical examination, swabs for Haemophilus ducreyi culture and blood for HIV serology, syphilis serology and CD4 counts were obtained from all patients. Punch biopsies from an ulcer were obtained from 10 patients and either fixed in 10% formalin or snap frozen in Optimum Cutting Temperature (OCT) medium compound at -70 degrees C. Patients were treated with erythromycin and followed for 3 weeks. Chi-square and Student's t-test were used to determine if the clinical and laboratory features of chancroid differed between HIV-seropositive and seronegative individuals. Cox regression survival analysis was used to determine if HIV infection altered cure rates of chancroid at 21 days. Immunohistochemical staining was performed using lymphocytic and macrophage markers and tissue sections were analysed by 2 pathologists in a blinded manner. Between February and November 1994, 109 HIV-seropositive and 211 HIV-seronegative individuals were enrolled in the study. HIV patients had ulcers of longer duration than HIV-seronegative patients (P=0.03). Although cure rates were similar at 3 weeks, HIV patients had lower cure rates at 1 week (23% v 54%, P=0.002). A dense interstitial and perivascular inflammatory infiltrate extending from the reticular to deep dermis was present in all biopsies. This consisted of equal amounts of CD4 and CD8 T-lymphocytes as well as macrophages. The histological and immunohistochemical picture was identical for HIV-positive and negative patients. HIV infection slows the healing rates of chancroid ulcers despite appropriate antibiotic therapy. This clinical difference cannot be attributed to an altered histopathological response to HIV infection. Additional studies are needed to elucidate the mechanisms responsible for this finding.
AIDS-Related Opportunistic Infections↗
Recent changes in the epidemiology of genital ulcer disease in the United States. The crack cocaine connection.
The incidence of syphilis and chancroid began to increase in the United States among heterosexuals in the mid-1980s, with most cases reported among minorities living in Eastern cities and in the South. A number of studies have established a link between increasing syphilis incidence rates and cocaine use, specifically the smoked form of the drug, which is known as "crack." A similar link was hypothesized for chancroid, but supporting data became available only recently. In New Orleans, we showed that Haemophilus ducreyi infection in male patients was strongly associated with crack cocaine use. However, our studies also demonstrated that drug use by the patient actually was a marker for a more important risk factor: sexual exposure to a cocaine-using woman. Thus, although the details of the relationships among crack, sexual behavior, and the size and nature of core transmitter groups are not known, it is clear that crack cocaine abuse is the driving force behind the recent syphilis and chancroid epidemics in the United States. Although it is not possible to predict the effects of these events on human immunodeficiency virus (HIV) transmission, the potential for significant synergism between them exists. New approaches to HIV surveillance should be developed taking this possibility into account. During the last 3 to 4 years, incidence rates of syphilis and chancroid have fallen in the United States, despite continued problems throughout the country with crack cocaine abuse. However, our studies and those of others have shown how difficult it is to recognize chancroid clinically, suggesting that the disease may be grossly underreported.(ABSTRACT TRUNCATED AT 250 WORDS)
Chancroid↗
Specificity of the immune response to Haemophilus ducreyi.
The specificity of the antibody response to Haemophilus ducreyi in sera from patients attending a sexually transmitted disease clinic in South Africa has been studied using immunoblotting. Patients with chancroid were shown to have higher levels of IgG (mean 0.74, SD 0.34) to H. ducreyi than those with no history of chancroid (mean 0.34, SD 0.19). The pattern of the antibody specificity was highly variable between patients with culture proven chancroid but there was no observed strain specificity. In comparison, the patterns obtained using sera from patients without known exposure to H. ducreyi showed less variation between patients and were of less intensity at the dilution used. Sera from patients with chancroid recognised epitopes on proteins that varied in molecular weight between strains, particularly of 60-66kDa (10 of 36 patients) and 25-27kDa (8 of 36 patients). In addition epitopes were recognised on the GroEL and/or DnaK heat shock proteins in 13 of 36 sera tested. There was no apparent change in the epitopes recognised on proteins between the homologous and heterologous strains. Patterns of antibody specificity in sequential sera only varied in one of six patients tested.
Antibodies, Bacterial↗
The clinical diagnosis of genital ulcer disease in men.
We report the sensitivity and specificity of physical examination findings for diagnosing primary syphilis, chancroid, and genital herpes. The physical features of genital ulcers in 446 men were measured in accordance with a quantitative scale. Two hundred-twenty of these men had an established, single microbiological diagnosis. Forty-five (20%) had primary syphilis, 118 (54%) had chancroid, and 57 (26%) had genital herpes. There was considerable overlap in the clinical presentation of these three diseases. The classic clinical sign complex attributed to primary syphilis (painless, indurated, clean-based ulcers) was only 31% sensitive but 98% specific. The classic presentation of a chancroid ulcer (a deep, undermined, purulent ulcer) was only 34% sensitive but 94% specific. The classic description of genital herpes ulcers (multiple, shallow, tender ulcers) was only 35% sensitive but 94% specific. Inguinal lymph node findings did not contribute significantly to clinical diagnostic accuracy. These data indicate that the clinical diagnosis of genital ulcer disease can be made with reasonable certainty only for a minority of patients. Rapid, sensitive, and specific diagnostic tests for syphilis, chancroid, and genital herpes are needed.
Adolescent↗
Use of an enzyme immunoassay to detect serum IgG antibodies to Haemophilus ducreyi.
An experimental enzyme immunoassay (EIA) for detecting serum IgG antibody to Haemophilus ducreyi was developed using an ultrasonicated whole-cell antigen. The mean optical densities (OD) for sera from men with proven chancroid from Nairobi (47 patients) and Bangkok (72 patients) were significantly higher than those obtained from Nairobi men with genital ulcers not due to H. ducreyi, from Nairobi men with urethritis, from pregnant women in Nairobi, and from European men with sexually transmitted disease. When an OD of 0.500 was taken as the cutoff value, 89% and 55% of men with proven chancroid in Nairobi and Bangkok, respectively, were positive for H. ducreyi antibody, as compared with 2%-17% in the control groups. A rise in OD was observed in five of 18 patients with clinical chancroid. These results confirm the development of circulating antibodies in chancroid and suggest that this EIA may be useful for the diagnosis and epidemiological study of H. ducreyi infection.
Antibodies, Bacterial↗
The clinical diagnosis of genital ulcer disease in men in the tropics.
Since the clinical diagnosis of genital ulcers without laboratory confirmation is not reliable in developed countries, we postulated that clinical diagnosis alone would be no more reliable in developing countries. A presumptive clinical diagnosis of chancroid, genital herpes, syphilis, or lymphogranuloma venereum was made for 100 male patients at the Special Treatment Clinic in Nairobi, Kenya. This diagnosis was then compared to the final diagnosis determined by laboratory identification of the pathogen, by culture, or by serologic response. In 64 patients, a final diagnosis of either chancroid, syphilis, or genital herpes was established. The diagnostic accuracy varied from 75% for chancroid to 42% for syphilis and 43% for herpes. The overall diagnostic accuracy was 66%. The predictive values of positive clinical diagnoses were 84% for chancroid, 60% for syphilis, and 75% for herpes. Thus, clinical diagnosis of genital ulcer disease was not sufficiently reliable in this study.
Chancre↗
Haemophilus ducreyi infection in south Florida: a rare disease on the rise?
Increased numbers of patients with genital ulcers sought medical attention in the Palm Beach County, Florida, Sexually Transmitted Disease clinics from Aug 1, 1982 to Aug 31, 1983. We established that a small proportion of subsequent cases of genital ulcers were caused by Haemophilus ducreyi, the etiologic agent associated with chancroid. We also set up a surveillance system to monitor this sexually transmitted infection, and have illuminated several recent cases of chancroid occurring in that area. This outbreak of chancroid suggest that clinicians practicing in south Florida consider chancroid (generally a rare disease in the United States) in their differential diagnoses of genital ulcers.
Adult↗
Haemophilus ducreyi inhibits phagocytosis by U-937 cells, a human macrophage-like cell line.
Haemophilus ducreyi is a gram-negative obligate human pathogen that causes the genital ulcer disease chancroid. Chancroid lesions are deep necrotic ulcers with an immune cell infiltrate that includes macrophages. Despite the presence of these phagocytic cells, chancroid ulcers can persist for months and live H. ducreyi can be isolated from these lesions. To analyze the interaction of H. ducreyi with macrophages, we investigated the ability of H. ducreyi strain 35000 to adhere to, invade, and survive within U-937 cells, a human macrophage-like cell line. We found that although H. ducreyi strain 35000 adhered efficiently to U-937 cells, few bacteria were internalized, suggesting that H. ducreyi avoids phagocytosis by human macrophages. The few bacteria that were phagocytosed in these experiments were rapidly killed. We also found that H. ducreyi inhibits the phagocytosis of a secondary target (opsonized sheep red blood cells). Antiphagocytic activity was found in logarithmic, stationary-phase, and plate-grown cultures and was associated with whole, live bacteria but not with heat-killed cultures, sonicates, or culture supernatants. Phagocytosis was significantly inhibited after a 15-min exposure to H. ducreyi, and a multiplicity of infection of approximately 1 CFU per macrophage was sufficient to cause a significant reduction in phagocytosis by U-937 cells. Finally, all of nine H. ducreyi strains tested were antiphagocytic, suggesting that this is a common virulence mechanism for this organism. This finding suggests a mechanism by which H. ducreyi avoids killing and clearance by macrophages in chancroid lesions and inguinal lymph nodes.
Animals↗
Development of a rapid immunodiagnostic test for Haemophilus ducreyi.
Haemophilus ducreyi is the etiologic agent of chancroid, a sexually transmitted disease that increases the rate of transmission of human immunodeficiency virus. Chancroid ulcerations are difficult to distinguish from those produced by syphilis and herpes. Diagnosis based solely on clinical grounds is inaccurate, and culture is insensitive. Highly sensitive PCR has largely superseded culture as the preferred method of laboratory diagnosis; however, neither culture nor PCR is feasible where chancroid is endemic. We developed a rapid (15-min) diagnostic test based on monoclonal antibodies (MAbs) to the hemoglobin receptor of H. ducreyi, HgbA. This outer membrane protein is conserved in all strains of H. ducreyi tested and is required for the establishment of experimental human infection. MAbs to HgbA were generated and tested for cross-reactivity against a panel of geographically diverse strains. Three MAbs were found to be unique and noncompetitive and bound to all strains of H. ducreyi tested. Using an immunochromatography format, we evaluated the sensitivity and specificity of the test using geographically diverse strains of H. ducreyi, other Haemophilus strains, and other bacteria known to superinfect genital ulcers. All H. ducreyi strains were positive, and all other bacteria were negative, resulting in a specificity of 100%. The minimum number of CFU of H. ducreyi detected was 2 x 10(6) CFU, and the minimum amount of purified HgbA protein detected was 8.5 ng. Although this level of sensitivity may not be sufficient to detect H. ducreyi in all clinical specimens, further work to increase the sensitivity could potentially make this a valuable bedside tool in areas where chancroid is endemic.
Antibodies, Monoclonal↗
Use of an adsorption enzyme immunoassay to evaluate the Haemophilus ducreyi specific and cross-reactive humoral immune response of humans.
Serodiagnosis of chancroid is limited by the cross-reactivity of Haemophilus ducreyi with Haemophilus influenzae and Haemophilus parainfluenzae. This research describes an adsorption enzyme immunoassay (EIA) that assesses the humoral immune response of North Americans and Africans to H. ducreyi. Adsorption effectively removed anti-H. influenzae and anti-H. parainfluenzae antibodies, revealing that North American control sera had no residual anti-H. ducreyi reactivity. However, African control sera still had a residual anti-H. ducreyi response. Assessment of the duration of the humoral immune response in sera from African patients with chancroid showed that the humoral antibodies persisted for up to 8 months after the diagnosis. This may explain the lack of specificity of the adsorption EIA in areas where chancroid is endemic. The detection of the humoral immune response was affected by the strain of H. ducreyi used, with indigent strains being most useful. Using H. ducreyi 35000 for Canadian sera, the sensitivity of the adsorption EIA was 100% and the specificity was 88%. For African sera, H. ducreyi strain R018 was used, and the adsorption EIA had a sensitivity of 81% and a specificity of only 23%. These data reveal that the existing humoral response in a country where chancroid is endemic differs from that in a country where it is not, and that care must be used interpreting unadsorbed humoral immune responses. The adsorption EIA approach may prove useful as an epidemiologic tool for definition of existing (past and present) levels of exposure to H. ducreyi.
Adolescent↗
Characterization of the hemolytic activity of Haemophilus ducreyi.
H. ducreyi is the causative agent of chancroid, a genital ulcer disease most prevalent in developing countries. Chancroid enhances the heterosexual transmission of human immunodeficiency virus and is identified in focal outbreaks in the United States, but little is known about its pathogenesis. We studied the hemolysin produced by H. ducreyi because this molecule might be an important virulence factor in the pathogenesis of chancroid. Ten strains of H. ducreyi were tested on newly devised blood agar plates and were found to have hemolytic activity. We examined the hemolytic activity of H. ducreyi 35000 further and found that it was heat labile, cell associated, greatest at pH 7.0, and produced in logarithmic- but not stationary-phase cultures. Using transposons Tn916 and Tn1545-delta 3, we have isolated three classes of transposon mutants of strain 35000: those with no detectable hemolytic activity, those with reduced hemolytic activity, and those with enhanced hemolytic activity. Transposon insertions in the nonhemolytic mutants were located in a DNA sequence which hybridized to the Proteus mirabilis hemolysin gene. Analysis of clones containing overlapping sections of this region served to further localize the H. ducreyi hemolysin gene and allow its expression in Escherichia coli and complementation of the nonhemolytic defect in an H. ducreyi mutant. These experiments indicate that H. ducreyi 35000 produces a hemolysin that is related to the calcium-independent hemolysin produced by P. mirabilis. Further experiments are needed to define the similarity of the H. ducreyi hemolysin to other calcium-independent hemolysins and to determine its role in the pathogenesis of chancroid.
Cloning, Molecular↗