Chancroid: An update

Arun C Inamadar, Aparna Palit

 Department of Dermatology, Venereology and Leprosy, BLDEA's SBMP Medical College, Bijapur - 586 103, Karnataka, India

Correspondence Address:
Arun C Inamadar
Department of Dermatology, Venereology and Leprosy, BLDEA's SBMP Medical College, Bijapur - 586 103, Karnataka
India

Introduction

Chancroid is a sexually transmissible genital ulcerative disease, caused by Haemophilus ducreyi. It is most prevalent in the developing countries of Asia, Africa and Latin America, especially among the people of low socioeconomic strata. In these geographic areas, annual incidence of chancroid may exceed to that of syphilis.[1] Though uncommon, occasional outbreaks of the disease have been reported from the United States and Europe, among the communities with high risk behaviour.

Because of the fact of epidemiological synergy, in the current era of HIV infection and AIDS epidemic, prompt diagnosis and adequate treatment of chancroid as well as other genital ulcerative diseases have gained immense importance.

Clinical issues

Incubation period of chancroid is short, between 3-7 days. Atypical chancroid lesion is characterised by the triad of undermined ulcer edge, purulent dirty gray base and moderate to severe pain. Multiple ulcers are seen in 50% of cases. All the three features are present in less than 50% of the sufferers. Untreated cases of chancroid have been reported to persist for months to years.[2] Painful, inflammatory inguinal lymphadenopathy, mostly unilateral, is seen in about 30-60% cases which may undergo suppuration.

Obviously symptomatic disease, directly related to the ulcer and inguinal lymphadenopathy is common in males. Depending on the site, females may present with atypical symptoms like dysuria, dyspareunia, pain on defaecation, bleeding per rectum or vaginal discharge. Incidence of chancroid seems to be apparently higher in males, which may be attributed to the facts like,[1]

• Easily visible anatomy of male external genitalia.
• Asymptomatic vaginal or cervical ulcers in females.
• Less common occurrence of lymphadenitis and bubo formation in females.
• Spontaneous healing of lesions resulting from autoinoculation in dry areas (inner thighs), which are common in females.

Variations to the classical clinical presentation of chancroid are seen[3] like, transient, popular, dwarf, follicular varieties and those forming giat, serpiginous and phagadenic ulcers.

Clinical presentation of chancroid may simulate other STD.s[1] like donovanosis or condylomata Iota (exuberant granulomatous lesion), herpes genitalis (superficial cluster of lesions) or gonorrhoea (endourethral lesion).

Mild constitutional features may be seen during acute illness but systemic spread of the organism never occurs. Extragenital lesions, though rare, result from autoinoculation. Breast, thighs, fingers, anal canal and oral cavity are the sites involved. Anal ulcers in women result from drainage or autoinoculation and not necessarily due to anal intercourse.[1]

Cicatrix formation and phimosis may be a late complication of chancroid requiring circumcision.

Pathogenesis

The fact that H. ducreyi is a strict human pathogen, makes understanding of basic pathogenic mechanism of chancroid a challenging issue.

The potential virulence factors produced by H. ducreyi include[4],[5] fine tangled pill, lipooligosaccharide (Los), haemoglobin binding outer membrane protein (OMP), cell associated hemolysin, soluble cytolethal distending toxin (Hd -CDT) and cu-zu superoxide dismutase (Cu-Zw SOD). Exact mechanism of action of these factors is unknown. The pill help in adherence to the host cell. Hemolysin acts on RBCs, human foreskin fibroblasts and immune system cells relevant to chancroid lesion like, macrophages, T cells and B cells. The influx of these inflammatory cells is partly responsible for the tissue destruction characteristic of chancroid. Host immune system avoidance by H. ducreyi in chancroidal ulcers are provided by both hemolysin and Cu-Zn SOD.[7] CDT causes host cell cycle arrest at G-2 phase and hamper specific host response, contributing to the persistence of chancroid ulcer.[8],[9] OMP DSrA facilitates the ability of H. ducreyi to progress to pustular stage.[10]

The histopathology of infected site resembles a DTH response.[11] In in-vitro models of infection[12] H. ducreyi increases the reaction of pro-inflammatory cytokines IL-6 and IL-8.[12],[13] IL-8, a potent neutrophil chemoattractant, is responsible for local accumulation of neutrophils,[12],[13] hallmark of chancroid ulcer. Both IL-6 and IL-8 also produce keratinocyte proliferation in the tissue surrounding ulcer giving rise to acanthosis,[12] IL-6 also induces IL-2 receptor expression in T- cells, giving rise to TH1 type of CD4 T cells response. This is proved by the fact that there is increased urinary excretion of soluble IL-2 receptors in chancroid patients.[12]

Diagnostic issues

According to CDC guidelines,[14] definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media. Probable diagnosis for both clinical and surveillance purposes requires fulfilling the criteria,

a) Patient has one or more painful genital ulcers.

b) Syphilis and HSV infection excluded by appropriate laboratory tests.

Suggestive diagnosis can be made in presence of the pathognomonic features of chancroid, i.e., a combination of painful ulcers and tender regional lymphadenopathy.

Isolation and identification of H. ducreyi

1. Culture methods:[15] Most widely used media for culture of H. ducreyi are enriched gonococcal agar and enriched Mueller - Hinton chocolate agar. Sensitivity of the culture method is < 80%.

Non- culture detection methods:

1. Direct microscopy:[15] Typical appearance of the organism is detected by Gram stained smears of clinical specimen. Sensitivity is < 50% even in culture positive cases. False positive diagnosis is also frequent.

2. DNA amplification techniques:[16]

PCR-to amplify H. ducreyi 16s RNA gene. It is less sensitive in clinical specimens due to presence of Taq polymerase inhibitors. Multiplex PCR -(M-PCR) - Simultaneous DNA amplification of H. ducreyi, T. pallidum and HSV 1 and 2 are possible. It is more sensitive than other standard diagnostic tests.

3. Antigen detection assays (Immunofluorescence)[5],[16]

• Detection of monoclonal antibody (MAb) against 29 KDa outer membrane protein (OMP) of H. ducreyi. Positive in both culture+ve (>90%) and culture negative cases. It is a simple, rapid and sensitive method but may not be available in resource poor countries.
• Indirect IF, using MAb against lipooligosaccharide (LOS) of H. ducreyi was assessed by Ahmed et al[1],[2],[3],[4],[5],[6] and was found to be superior to bacterial culture. It is a good method to be used in population with high chancroid prevalence.

4. Nucleic acid probe techniques:[15],[16]

DNA- DNA hybridisation techniques using labelled H. ducreyi derived probes.

Usefulness of this method in clinical specimens has not been assessed widely.

5. Serological methods:[15],[16]

• Enzyme immuno assays (EIA): Using ultrasonicated whole cell antigen, purified LOS or OMP H. ducreyi as antigen.
• DOT Immunoblot
• Agglutination
• Compliment fixation test

Cross reacting antibodies to other haemophilus species complicates the interpretation of serological testing.

6. Mass spectrometric method (MALDI/TOFMS)[16]

It identifies H. ducreyi in short time (10 minutes). It is also helpful to detect the strain differences of the organism.

7. Tissue biopsy[10]

Though not diagnostic, characteristic histopathological findings are seen, it may be helpful in diagnosing non healing or atypical ulcers.

To summarise, till date, culture using specialised media is the most practised method for diagnosis of infection with H. ducreyi. It has the added advantage that antimicrobial sensitivity of the organism can be tested at the same time.[16] PCR is a superior method than other available means of diagnosis. M- PCR is very useful in rapid diagnosis of difficult genital ulcer disease syndrome. However, in the study conducted by Risbud et al[17] in diagnosis of GUD, M -PCR was not found to be superior to the clinical diagnosis alone or in combination with basic laboratory tests. Serology has limited usefulness in routine diagnosis of H. ducreyi infection, but it is helpful in epidemiological studies as a screening method for past infection.[16]

Chancroid and HIV synergy

Like other GUD, chancroidal ulcer is a major risk factor for heterosexual spread of HIV. Moreover, factors like lack of circumcision, prostitution, drug abuse (crack cocaine, alcohol) seem to be independent risk factors for transmission of both the diseases.[2],[3] Different retrospective seroprevalence surveys[18] have identified increased seroconversion rate in presence of H.ducreyi infection and it increases with number of previous ulcer episodes in a dose response relationship.[2]

The explanations for the enhanced HIV transmission in patients with chancroid ulcer may be due to the facts′ like,

• Genital ulcers act as both portals of entry and exit for (HIV can be detected on ulcer surface).

From the relatively few studies available[19] it is evident that, there are only minor research on such agents may cause an impact to cut down the incidence of multiple STDs in a patient as well as heterosexual transmission of HIV.

Molecular techniques can detect the presence of H. ducreyi DNA in clinical specimen. M-PCR[26] and nested single tube PCR techniques[27] have been shown to be more sensitive than standard methods. This can be extremely useful in designing locally appropriate syndromic management algorithm for genital ulcer.

Molecular techniques have also provided a better understanding to the pathogenesis of STDs. Such knowledge serves as an important basis for rational vaccine design and development.[23] Unless progress is made in developing models to study the pathogenesis of H. ducreyi infection, it is not likely that an effective vaccine against H. ducreyi will be developed in the near future.

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