Chancroid and human immunodeficiency virus infection – a review

Authors



Yetunde Mercy Olumide, md Department of Medicine College of Medicine University of Lagos P M B 12003, Lagos Nigeria
E-mail: mercyolumide2004@yahoo.co.uk

Introduction

Chancroid is an acute ulcerative disease usually occurring on the genital or anogenital areas, and is often associated with massive visible lymphadenitis (buboes). Haemophilus ducreyi, a Gram-negative facultative anaerobic coccobacillus requiring blood for its growth, causes the superficial ulcerations of chancroid and its associated suppurant regional lymphadenitis.

The disease has generated renewed interest because of its well-established capacity to amplify the transmission of human immunodeficiency virus (HIV) infection,1–3 and the organism's emerging resistance to drugs.4–7 Recent epidemiologic studies have implicated genital/anogenital ulcer disease as an important cofactor for the acquisition and transmission of HIV during sexual intercourse. The identification of such modifiable cofactors for HIV transmission has important implications for control programs. Better understanding of disease pathogenesis and improvement in its diagnostic techniques and control efforts have resulted from this renewed interest.

Epidemiology

Genital ulcer disease caused by H. ducreyi was estimated by the World Health Organization (WHO) in 1997 to have a prevalence of 6 million cases worldwide.8 It is endemic in the developing countries of Africa, Asia, and the Caribbean, where it causes 23–56% of genital ulcer disease.9–11 These countries have low socioeconomic indices and a weak public health infrastructure. They are also the countries being ravaged by the HIV pandemic, especially those with an adult HIV prevalence rate of greater than 8%.12 Chancroid disease, although uncommon in the industrialized countries of the Northern Hemisphere, was reported in several epidemics in the cities of New York, New Orleans, and Jackson in the USA in the 1980s to early 1990s.13–16 The number of cases has decreased since 1995.15

Prostitutes are the major reservoirs of H. ducreyi in epidemics in developed countries17 and in countries in which the disease is endemic. The common denominator for disease transmission is the exchange of sex for money or drugs. The use of crack cocaine and alcohol is also a major risk behavior for chancroid.18 In Nairobi, Kenya, the prevalence of genital ulcer disease amongst prostitutes is 5–25%, with H. ducreyi cultured in 50% of ulcers.17 Dada et al.19 reported an H. ducreyi seroprevalence of 86% amongst prostitutes with genital ulcer disease in Lagos.

The probability of transmitting chancroid from an infected to an uninfected person during a single sexual exposure is 0.35.19 In women, ulcers are often subclinical and sexual activity may continue, especially amongst commercial sex workers, who constitute efficient reservoirs for the infection. Asymptomatic infection reservoirs have not been proven.20 In a study searching for asymptomatic carriers amongst 213 commercial sex workers in Gambia using polymerase chain reaction (PCR), only four were found to be positive,21 comparable with the rate of H. ducreyi carriage found by culture.22 These individuals may be incubating chancroid or carrying the organism transiently following recent sexual exposure.23 Disease transmission is predominantly heterosexual, with males outnumbering females by ratios of 3 : 1–25 : 1.24 The causative organism has a short duration of infectivity and requires frequent contacts for spread within a population.12 Thus, it only survives in subgroups of the population with a sufficiently high turnover of sex partners (up to 15–20 sex partners per year).25 This has an implication for chancroid eradication, as the elimination of infection in this subgroup of the population would eradicate chancroid in the larger community.5,26

Pathogenesis

Trauma or microabrasion to the skin or mucosa is necessary for the penetration of the organism into the epidermis. The inoculum required for infection is on the order of 10,000.11,23 On infection, the organism incites a local tissue reaction, resulting in an initial intraepithelial lesion consisting of lymphocytes, macrophages, and granulocytes. There are also vesicular endothelial changes of swelling, proliferation, and erythrocyte extravasation.24 The cellular immune response to the bacillus is predominantly mononuclear, with infiltrates containing many CD4+ and CD8+ T lymphocytes and macrophages, with a paucity of B-lymphocyte lineage in lesional biopsy specimens.24 This predominant T-helper-1 (TH1) cell response is consistent with the observation of increased levels of soluble interleukin-2 receptors in the urine and semen of chancroid patients.27 These cytokines are secreted by CD4+ T lymphocytes. Lymphadenitis associated with chancroid is predominantly a pyogenic inflammatory response, with an unknown pathogenesis; and the paucity of organisms in the bubo pus is also unexplained.24 Virulence determinants in the organism include superoxide dismutase enzymes and hemolysin. Superoxide dismutase enzymes are thought to increase the survival and persistence of the pathogenic organism within the host,28 whereas hemolysin contributes to ulcer formation and the invasion of epithelial cells.29 The latter virulence determinant has immunogenic properties and is expressed both in vitro and in vivo by all known clinical strains of H10. ducreyi. These properties make hemolysin a possible candidate for vaccine development.30

The intraepidermal lesion results in an erythematous papule which eventually pustulates. Replication of the organism occurs during these stages, with shedding of bacteria intermittently even before ulceration, suggesting that the bacteria may be transmissible before ulceration.31 Many of the lesions may resolve spontaneously.24 The pustules undergo central necrosis and enlarge, forming the pathognomonic, tender, nonindurated ulcer, with undermined margins and gray or yellow necrotic purulent exudates covering the base. Kissing ulcers result from autoinoculation of the skin apposing the primary ulcer, as shown in Fig. 1. Regional lymph nodes, usually ipsilateral to the ulcer, become inflamed, with subsequent periadenitis and resultant unilocular fluctuant bubo, which can rupture spontaneously to form a chronically discharging sinus,30 as shown in Fig. 2.

Figure 1.

Multiple kissing ulcers

Figure 2.

Chancroid ulcer on the penile shaft with an ipsilateral ulcerating bubo

Clinical features

The incubation period of H. ducreyi is between 4 and 7 days with no prodromal symptoms. This may be longer with pre-existing HIV infection.32 There may be a history of recent sexual exposure, possibly with a commercial sex worker.

The primary lesion starts as a tender papule with an erythematous halo that evolves into a pustule. Central necrosis of the pustule leads to the characteristic painful, nonindurated, sharply defined ulcer with undermined edges. The ulcer of chancroid is classically described as a nonindurated soft sore, or “ulcus molle,” as distinct from the indurated ulcer of syphilis. Nevertheless, in most of our patients with poor personal hygiene, secondary polymicrobial infection often supervenes, so that the ulcer becomes indurated and more painful. The base of the ulcer is composed of friable granulation tissue covered by gray to yellowish exudates. Ulcers may be multiple and coalesce to form giant (> 2 cm) or serpiginous ulcers.33 Lesions may remain pustular (dwarfed chancroid), resembling folliculitis or pyogenic infection. Autoinoculation from the primary lesion/ulcer may lead to the development of multiple or kissing ulcers on apposing skin surfaces (Fig. 1).

Ulcers can be found on the prepuce, fraenulum, coronal sulcus, glans penis, and penile shaft in males. In females, the fourchette, labia, vestibule, clitoris, vaginal wall, cervix, and perianal skin may be involved. Extragenital lesions can occur on the breasts, fingers, thigh, and oral mucosa. Chancroid can be differentiated from other genital ulcer diseases by the classic chancroid triad of “undermined ulcer edge, purulent dirty gray base, and moderate to severe pain.”

Regional lymphadenitis (bubo) accompanies the ulcer in more than 40% of patients. It is usually unilateral, with erythema of the overlying skin. Buboes can become fluctuant and rupture spontaneously to form inguinal ulcers/sinuses, as shown in Fig. 3.

Figure 3.

Ruptured inguinal bubo with a sinus, but without an accompanying ulcer – transient chancroid

A serpiginously spreading ulceration with destruction of both skin and underlying soft tissue can also follow bubo ulceration. At times, the patient presents with bubo, the initial ulcer having healed – transient chancroid. Bubo formation is more common in males than in females. Unusual presentations of chancroid include acute purulent urethritis in males and vaginal fistulae complicating subclinical vaginal ulceration in females.

Diagnosis

A history of sexual intercourse and the formation of painful genital ulcers (following a requisite incubation period), and the development of unilateral, unilocular, fluctuant bubo, with or without a sinus, are the classic indicators in the diagnosis of chancroid.

The isolation of H. ducreyi is particularly difficult and often has a sensitivity of 80% or less. Most ulcers appear to be chancroid on clinical grounds, although the H. ducreyi isolation rate is only 23%, perhaps reflecting increased antimicrobial use.34 The use of PCR has revolutionized the laboratory diagnosis of chancroid,35 because alternative methods of diagnosis, such as Gram's stain and culture, are inaccurate and insensitive as H. ducreyi is a fastidious organism. Several serologic tests have been developed, including adsorption enzyme immunoassay (EIA) and lipooligosaccharide (LOS) EIA, to detect H. ducreyi infection. EIA detects both current and past H. ducreyi infection, whereas LOS EIA is more specific for current infection with H. ducreyi.36 The disadvantages of these tests are the high cost and the time between collection of the specimen and laboratory result, particularly if the PCR assay is performed off-site. The serologic tests also have the disadvantage of low specificity compared with PCR, and Totten et al.35 have suggested further evaluation of serologic tests to determine their suitability for the detection of chancroid in a given community.

Potential interactions and complications between sexually transmitted diseases (STDs) and HIV/acquired immunodeficiency syndrome (AIDS)

The potential interactions and complications between STDs and HIV/AIDS have received increasing attention in recent times worldwide.

Prior infection with a sexually transmitted organism may increase the probability of acquiring HIV infection, alter the clinical patterns and spectrum of HIV-associated opportunistic diseases, and alter the temporal cadence of HIV infection and progression to AIDS. Similarly, prior infection with HIV may increase the probability of infections with sexually transmissible organisms, increase the probability of clinical diseases developing in a dually infected person, alter the clinical patterns of STD, and alter the response to anti-STD chemotherapy. There are other potential interactions; for example, the normal commensals of the genital tract in HIV-positive individuals may be confused diagnostically with STD, STDs may confound HIV serology and vice versa, HIV-associated neuropathy may be confused with or exacerbate neuropathies caused by sexually transmissible organisms, neuropathies caused by antiretroviral chemotherapy may be confused with neuropathies caused by STD, invasive diagnostic methods for STD may spread HIV infection, STD workers may become increasingly involved with the problems of HIV counselling, and national policies on STDs may be amended because of endemic HIV infection.

Interactions between chancroid and HIV/AIDS

Effects of chancroid on HIV transmission and susceptibility

Chancroid facilitates the transmission of HIV by increasing both the infectiousness of HIV and the susceptibility to infection by the virus. Subjects with HIV infection and concomitant chancroid ulcer demonstrate increased infectiousness through the following:

  • 1There is increased HIV shedding into the genital tract from ulcer exudates. This has been demonstrated in a study of prostitutes in Nairobi, Kenya. Swabs of genital ulcers were cultured for HIV, and the virus was isolated from four of 36 ulcers, with 50% of patients having no HIV isolated from the cervical os. This observation suggests that the ulcer isolates were not a result of contamination from cervical secretions.36 Also, in Cote d’Ivoire, HIV-positive female sex workers with cervicovaginal ulcers had higher rates of HIV-I isolation from cervicovaginal lavage fluids than those without ulcer disease (66.8% vs. 21%). Adjustment for the level of immunosuppression did not alter these findings. Treatment for the ulcer reduced HIV-I detection to levels similar to those of individuals without genital ulcer disease.37
  • 2Genital ulcers bleed during intercourse, resulting in potential increases in viral shedding and HIV infectiousness.38
  • 3In men with genital ulcer disease, there is increased seminal fluid viral concentration, especially in those with nongonococcal urethritis. This is attributed to an increased plasma viral load from advanced disease or systemic immune activation by H. ducreyi.39

Chancroid genital ulcer disease increases susceptibility to HIV infection

  • 1Disruption of mucosal integrity provides a portal of entry for HIV.
  • 2Haemophilus ducreyi increases the presence and activation of HIV-susceptible cells in the genital tract. This is part of the organism's induced cellular immune response. Specifically, CD4+ T-helper cells and macrophages are found in significant numbers in both early lesions of chancroid and in the advancing edge of established ulcers.24 These cells are the primary targets of HIV.
  • 3Haemophilus ducreyi has also been found to increase CCR-5 receptor expression on macrophages,3 thus increasing the susceptibility of these cells to HIV invasion.
  • 4Specific T-cell-stimulating antigens have been demonstrated in H. ducreyi, and this can result in increased viral replication in these cells.40
  • 5A temporal sequence of chancroid infection and HIV seroconversion has been documented in 39 men who acquired STDs (89% chancroid) from female sex workers in Nairobi. Twenty-four were reported to have seroconverted, and those with genital ulcer disease were sometimes more likely to acquire HIV than those without genital ulcer disease after adjustment for sexual behavior.41 In New York, 14 HIV seroconversions were reported amongst 785 men attending an STD clinic. Forty per cent of the seroconversions were accounted for by patients with chancroid, although it was not a common cause of STD in the group.42
  • 6Invasive diagnostic/therapeutic procedures for chancroid may also spread HIV infection. These include bubo aspiration if not properly handled and herbalist's methods of bubo drainage, especially with the use of unsterilized blades for other subjects, e.g. in scarification and circumcision.

Effects of HIV on chancroid

  • 1HIV infection alters the clinical pattern of chancroid by prolonging the incubation period of H. ducreyi32 and increasing the number of genital ulcers. These ulcers also heal slowly and poorly.43,44 Extragenital sites are frequently affected, namely the thighs, anus, abdomen, hands, breasts, mouth, and feet.45–47 Furthermore, secondary invasion by Vincent organisms can complicate the disease.46,48–50
  • 2Chancroid chemotherapy is altered by concomitant HIV infection, with resultant slower healing on therapy and increased incidence of treatment failures.7 A longer course of treatment and closer monitoring are therefore advocated. Delayed or inappropriate treatment may lead to very serious complications, such as massive bleeding and amputation of the penis. Indeed, local communities have become familiar with this latter complication, which they call “reko reko” (penis cutter). The authors have also observed that HIV patients coinfected with H. ducreyi are more likely to have giant, persistent, serpiginous, phagedenic, penetrating, deep punched ulcers,33 as shown in Fig. 4.
Figure 4.

Deep punched out coronal ulcer in a human immunodeficiency virus-infected patient

Treatment

It is imperative that early, appropriate, and effective therapy is provided for the disease to reduce the viral infectiousness of patients with HIV, and to reduce the susceptibility of infection in their partners. Specific and prompt treatment to heal chancroidal ulcer is very important, but is limited by the ability to make both specific etiologic and presumptive etiologic diagnosis of the cause of genital ulcer disease. This has been addressed by WHO through the syndromic approach to the management of STDs.51 The principle is based on the use of a combination of antimicrobials that will treat all probable local etiologic agents. The approach uses clinical algorithms based on an STD syndrome to determine antimicrobial therapy. The process requires little or no clinical evaluation of the ulcer or laboratory investigations. Some countries, such as Nigeria,52 have developed manuals for health workers with modifications necessitated by local epidemiologic and drug sensitivity patterns. These charts also provide simple instructions for the follow-up of patients and their contacts. The syndromic approach has been validated by several studies for genital ulcer disease syndrome.53 Several antimicrobials are available for the treatment of chancroid, including ciprofloxacin, ceftriaxone, erythromycin, and azithromycin, which have activity against a number of organisms that cause STDs, including H. ducreyi.54–56 The broad spectrum of activity of these drugs is worth noting in the case of mixed infections. Single-dose regimens are preferred to ensure compliance, reduce cost, and limit the emergence of resistance. These agents are expensive, and it is a concern that cost will encourage the use of an inadequate or low dosage that will help force the selection of strains exhibiting resistance or reduced susceptibility, as has already been described for ceftriaxone and Neisseria gonorrhoeae. Algorithms for the case management of genital ulcer disease are shown in Fig. 5, and the four “C”s of good STD management are shown in Table 1.

Figure 5.

Genital ulcer disease syndromic flow chart

Table 1.  The four “C”s of good sexually transmitted disease (STD) management
Counselling You should:Compliance Encourage patient to:Condoms You should:Contact treatment Encourage patient to:
  1. The four “C”s should be emphasized to all patients regardless of the diagnosis, in order to encourage safe sexual practice.

Put yourself in your patient's place (show empathy)Avoid self-medicationInform patient of proper condom use as the only alternativeInform all sexual partner(s) in the last 3 months to seek medical treatment
Listen to patient and engage in dialogueEnsure completion of treatment regimen even after all the symptoms have disappeared, and inform patient not to share the medication with partnerEducate patient on consistent and correct condom useAvoid further spread of the infection to others
Counsel patient on the need to change risky behaviorAbstain from sex until treatment is completed and infection curedDemonstrate condom useAvoid reinfection
Educate patient on STD preventionFollow other instructionsProvide condoms to patientDiscuss the other three “C”s
Educate patient on the implications of untreated STDDiscuss the other three “C”sDiscuss the other three “C”s 
Discuss the other three “C”s   

There are several recommended and alternative regimens for the treatment of chancroid. Table 2 shows the WHO, Center for Disease Control and Prevention (CDC), and United Kingdom Clinical Effectiveness Group (CEG) recommendations.

Table 2.  Recommended drug treatment regimens for chancroid from the World Health Organization (WHO), the Center for Disease Control and Prevention (CDC), and the United Kingdom Clinical Effectiveness Group (CEG)
AntimicrobialDoseFrequencyDurationRouteRecommending body
Erythromycin500 mg3 times daily7 daysOralWHO
Erythromycin500 mg4 times daily7 daysOralCDC, CEG
Azithromycin1 gSingle doseOralCDC, CEG
Ceftriaxone250 mgSingle doseOralWHO, CEG
Ciprofloxacin500 mg2 times daily3 daysOralCDC

The emergence of therapeutic failures to trimethoprim in H. ducreyi is noteworthy.57,58 Treatment failures have been reported in individuals with immunosuppression caused by HIV infection, in uncircumcised individuals, and in Africans treated with single doses of either ceftriaxone7 or fleroxacin.59 These groups of patients should be followed up closely. Erythromycin or ceftriaxone can be used for pregnant women. Buboes that are fluctuant should be aspirated for symptomatic relief and to avoid complications of spontaneous rupture. Aspiration should be performed from a superior approach to prevent dripping of pus and fistula formation. Serologic tests for syphilis and HIV should be offered routinely at first contact and again after 3 months (window period).

Ancillary