Chancroid

 

Salient features

·        Chancroid is a sexually transmitted acute ulcerative disease usually localized at the anogenital area and often associated with inguinal adenitis or bubo.

·        Haemophilus ducreyi—a Gram-negative, facultative anaerobic coccobacillus—is the causative agent.

·        Chancroid is disappearing even from most countries where H. ducreyi was previously epidemic, with the exception of North India and Malawi.

·        Painful, soft ulcers with ragged undermined margins develop 1 to 2 weeks after inoculation (usually prepuce and frenulum in men and vulva, cervix, and perianal areas in women).

·        H. ducreyi facilitates the transmission of HIV.

·        Laboratory culture of H. ducreyi is problematic, but greater sensitivity can be expected by nucleic acid amplification methods, which are not routinely available.

·        Azithromycin and ceftriaxone are recommended as single-dose treatment, enhancing compliance.

 

Introduction

 

Chancroid is an acute ulcerative condition affecting the ano‐genital region, caused by the bacterium Haemophilus ducreyi and is often associated with visible lymphadenitis (buboes). The disease has generated renewed interest because of its capacity to facilitate HIV transmission and the organism's resistance to antimicrobial drugs.

 

Epidemiology

 

Incidence and prevalence

In most of the disease settings, commercial sex workers are the reservoir for the microorganism, and men are much more frequently affected than women (ratio 10: 1). In many low-income countries, chancroid is the most common cause of infectious genital ulcer disease, with frequencies even higher than those of genital herpes.

 

Age

 

The condition may be seen in sexually active individuals of all ages.

 

Sex

 

The condition is diagnosed more often in uncircumcised males. Subclinical infections may be more common in females.

 

Associated diseases

 

Co‐infections of H. ducreyi with Treponema pallidum or herpes simplex virus are common. Chancroid is also an important co‐factor in the transmission of HIV.

 

Transmission

The source of infection is almost always sexual contact with infected women who have genital ulcers. The transmission rate from females to males is not known, in contrast to a reported transmission rate from males to females of 70% per sex act, and untreated infected women are infectious for up to 45 days (while the clinical lesions are present). Asymptomatic carriers seem to be rare and there is no evidence that women harbor the organism for a significantly long period of time without clinical findings.

 

Chancroid and HIV

Chancroid and other diseases that produce genital ulcers are important risk factors for transmission of HIV. Men infected with HIV more often have had a history of genital ulcers compared with HIV-negative men. The risk of acquiring HIV after having sexual contact with HIV-positive women is highest for uncircumcised men with genital ulcer disease compared with circumcised men with and without genital ulcer disease (29% versus 6% versus 2%). In women, the risk of becoming infected with HIV also increases with the number of episodes of genital ulcer disease.

The presence of increased numbers of CD4⁺ lymphocytes and macrophages in ulcers due to infection with H. ducreyi provides an ideal opportunity for a latent HIV infection to become productive, with excretion of the virus into ulcer secretions. Genital lesions therefore become both a portal of viral entry for non-infected individuals and exit for HIV-infected persons.

 

Causative organism

 

The causative organism is H. ducreyi, a Gram‐negative facultative anaerobic coccobacillus of small size that shows a typical chaining pattern on Gram stain.

 

Pathogenesis

Trauma or micro abrasion to the skin or mucosa allows for penetration of the organism into the epidermis. There is a subsequent local tissue inflammation develop due to infiltration of lymphocytes, macrophages, and granulocytes in a primarily Th1 cell-mediated immune response combined with pyogenic inflammation.

Chancroid is associated with regional lymphadenitis due to the spread of the infection and resultant pyogenic inflammation. The intraepidermal lesion results in an erythematous papule, which eventually pustulates. The pustule undergoes central necrosis and enlarges, forming a pathognomonic, tender, non‐indurated ulcer with undermined margins and grey or yellow, necrotic, purulent exudates covering the base. Kissing ulcers result from autoinoculation of the skin opposing the primary ulcer. Regional lymph nodes become inflamed with subsequent periadenitis and resultant unilocular fluctuant buboes, which can rupture spontaneously to form a chronically discharging sinus.

 

Clinical features

 

History

 

The incubation period is usually short, between 3 and 10 days. No prodromal symptoms are known. There may be a history of recent sexual exposure with a commercial sex worker. Chancroid is characterized by painful ano‐genital ulceration and lymphadenitis with progression to bubo formation.

 

 

Presentation

 

The primary lesion starts as an inflammatory papule at the site of inoculation and soon progresses to a pustule.  Central necrosis of the pustule leads to an irregular-shaped, ragged ulcer with a red halo. The ulcer is deep, not shallow as in herpes; and spreads laterally, burrowing under the skin and giving the lesion an undermined edge and is sharply demarcated. The ulcer is usually covered by a necrotic, yellowish-gray exudate, and its base is composed of granulation tissue that bleeds readily on manipulation. In contrast to syphilis, chancroid ulcers are usually tender and or painful not indurated (soft chancre). The diameter varies from 1 mm to 2 cm. The ulcers are highly infectious, and autoinoculation from the primary ulcer may lead to the development of multiple or kissing ulcers on opposing skin surfaces and they can coalesce to form giant ulcers. Lesions are more common in uncircumcised men and half of the males present with a single ulcer and most lesions are found on the external or internal surface of the prepuce, on the frenulum, coronal sulcus, glans penis and penile shaft.  Edema of the prepuce is often seen. Perianal lesions may occur in men who have sex with men. Extragenital lesions can occur via autoinoculation. Lesions of the lips and oral cavity have been described. Rarely, if the chancre is localized in the urethra, Haemophilus ducreyi causes purulent urethritis.

In females the lesions are mostly localized on the vulva, especially on the fourchette, the labia minora, and the vestibule; they may also occur on the cervix or vaginal wall, or in the perianal area. Extragenital lesions of chancroid have been reported on the breasts, fingers, thighs, and inside the mouth. Trauma and abrasion may be important for such extragenital manifestations. Lesions in women are sometimes only mildly symptomatic and are more often multiple.

In both men and women, painful inguinal lymphadenitis (bubo) may develop within a few days to 2 weeks (average 1 week) after onset of the primary lesion. It is more often observed in men (about 40% of patients) and is usually unilateral, and erythema of the overlying skin is typical. Buboes can become fluctuant and may rupture spontaneously to form inguinal ulcers and sinuses. The pus of bubo is usually thick and creamy. Buboes are less common in female patients.

 

In HIV‐infected patients with more advanced immunosuppression, chancroidal lesions may be more persistent and slower to heal, and may be more numerous and fail to respond to single‐dose treatment regimens. Prompt diagnosis and treatment of chancroid may abrogate increases in HIV replication.

  

Differential diagnosis

 

The three classic etiologic agents for genital ulceration are (1) H. ducreyi, (2) Treponema pallidum, and (3) herpes simplex. The clinical appearance of the diseases caused by these three organisms can be extremely variable in both men and women, and therefore, clinical diagnosis of genital ulcer disease can be made with reasonable certainty only for a minority of patients.

 

 

DFA, direct fluorescent antibody assay; LGV, lymphogranuloma venereum

INFECTIOUS CAUSES OF GENITAL ULCER DISEASE
Disease	Incubation time	Clinical lesion	Diagnosis	Organism
Genital herpes	3–7 days	Vesicles, erosions, ulcers; history of herpes viral infection; painful	PCR, culture, DFA, Tzanck (if vesicles)	HSV 2 > 1
Primary syphilis	10–90 days, average 3 weeks	Non-purulent; usually single ulcer; indurated; relatively painless	Darkfield microscopy, serology, PCR	Treponema pallidum
Chancroid	3–10 days	Purulent; often multiple ulcers; soft, undermined edges; painful	Culture, PCR	Haemophilus ducreyi
LGV	3–12 days	Transient ulcer; indurated; painless	PCR, culture, serology	Chlamydia trachomatis serovars L1–3
Donovanosis	2–12 weeks	Chronic ulcer; indurated, beefy red, friable	Smears, histology	Klebsiella (Calymmatobacterium) granulomatis

 

 

Complications

In about half of the untreated patients, the course is that of spontaneous resolution without complications. Due to delay in treatment, various complications may occur.

 

·       Painful inguinal adenitis (up to 50%)

·       Spontaneous ruptures of inguinal buboes with occurrence of large abscesses and fistula formation (rare)

·       Spreading of Haemophilus ducreyi to distant sites (kissing ulcers and/or extragenital lesions due to autoinoculation) (in 50% of male patients)

·       Esophageal lesions in HIV patients

·       Acute conjunctivitis (very rare)

·       Bacterial super infection (including anaerobes) leading to extensive destruction (rare)

·       Scarring leading to phimosis (rare)

·       Erythema nodosum (very rare)

·       Enhanced HIV transmission (3–10-fold increased risk)

 

Prognosis and Clinical Course

 

The disease is self-limited and systemic spread does not occur. The time required for complete healing is related to the size of the ulcer; large ulcers may require 14 days. Complete resolution of fluctuant lymphadenopathy is slower than that of ulcers and may require needle aspiration through adjacent intact skin, even during successful therapy.  Occasionally, without treatment, genital ulcer and inguinal abscess have been reported to persist for years. Local pain is the most frequent complaint. If no clinical improvement is evident 1 week after the start of therapy, incorrect diagnosis, coinfection with another STI, concomitant HIV infection, poor compliance, or a resistant strain of H. ducreyi must be considered.

 

Pathology

Biopsies of chancroid classically have three vertical arranged zones of inflammation beneath the ulcers. The first zone has necrotic debris, fibrin and neutrophils. The middle zone is an area of granulation tissue, and the deepest zone contains dense lymphocytic and plasma cells infiltrate. Gram-negative coccobacilli are only rarely found with tissue Gram or Giemsa stains and are best seen with smears.

 

Diagnosis

The diagnosis should be suspected if there is a history of painful genital ulceration following the requisite incubation period and subsequent formation of unilateral buboes with or without sinus formation.

A probable diagnosis is made when all the following criteria are met:

1.   One or more painful genital ulcers are present.

2.   There is no evidence of T. pallidum infection by dark-field examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after the onset of ulcers.

3.   The clinical presentation, appearance of genital ulcers, and, if present, regional lymphadenopathy are typical for chancroid.

4.   A test result for herpes simplex virus performed on the ulcer exudate is negative. Patients should be tested for HIV infection and tested 3 months later for syphilis and HIV if initial results are negative.

 

Material is usually obtained with a cotton swab, on which the organism can only survive for a few hours without being refrigerated at 4°C. Direct examination of a smear of the exudate taken from the undermined border of an ulcer by Gram or Giemsa stain may be helpful. The bacilli are usually found in small clusters or parallel chains of two or three organisms streaming along strands of mucus. This pattern has been described as a “school-of-fish” or “railroad-track” appearance. This arrangement, said to be characteristic of H. ducreyi, is nevertheless not pathognomonic, because most genital ulcers have a polymicrobial flora.  Bacteria may be intracellular.

Herpes simplex genital ulcers can mimic chancroid. A herpes culture and Tzanck smear to look for virus-induced multinucleated giant cells help to establish the diagnosis. The histologic nature of chancroid is specific.

Accurate diagnosis of chancroid requires isolation of H. ducreyi on special culture media; small, non-mucoid semi opaque or translucent colonies appear after 24–72 hours if grown at 33–35°C in a 5–10% CO₂ atmosphere.

 

If culture is not possible or is inconclusive, diagnosis can be based on the clinical picture and the exclusion of other microorganisms that cause genital ulcer disease, such as syphilis or genital herpes, as well as on the epidemiologic data and response to therapy.

 

A multiplex PCR (M-PCR) assay has been developed by Roche Products for the simultaneous amplification of DNA targets from H. ducreyi, Treponema pallidum, and herpes simplex types 1 and 2, which seems to be a particularly attractive diagnostic tool in the investigation of patients presenting with genital ulcers. But this PCR-based method is not commercially available yet. In resource poor settings where diagnostic facilities are not readily available, the World Health Organization advocates the use of a syndromic management approach for patients with genital ulcer disease.

 

Treatment

Prompt antibiotic treatment is essential to reduce the risk of complications as well as the risk of acquisition and onward transmission of HIV.

The most active drugs against H. ducreyi are azithromycin, Ceftriaxone, Ciprofloxacin, and erythromycin with improvement of ulcers within 3 days and typically heal in 14 days or less, depending on the initial lesions. Worldwide, several isolates with intermediate resistance to either Ciprofloxacin or erythromycin have been reported. Ciprofloxacin is contraindicated in pregnant and lactating women.

Local treatment consists of antiseptic dressings (i.e., povidone-iodine). Suppurative fluctuant nodes should not be incised; if necessary, they can be punctured to prevent spontaneous rupture and sinus tract formation. A large syringe should be used and the fluctuant buboes entered laterally through normal skin. In patients with phimosis, a circumcision may be necessary when all active lesions have healed. In pregnancy, Ceftriaxone is the preferred drug, but azithromycin can be used as well.

Even after correct treatment, relapses occur in about 5% of patients and retreatment with the original regimen is recommended. Usually reinfection by an untreated sexual partner is the suspected cause of relapse.

 

Relation between HIV Infection and Chancroid

Genital ulcers promote the heterosexual transmission and acquisition of HIV-1. Effective treatment of genital ulcers can reduce the incidence of HIV-1, and this strategy has become a cornerstone of HIV prevention programs in many parts of the world.

In patients with HIV infection, the treatment recommendations are the same, but with a longer treatment course; close monitoring may be necessary because of delayed healing and possible treatment failures. Furthermore, it is shown that concomitant HIV infection has clinically significant effects on the course of the chancroid disease, and failure of single-dose or short-course therapy for chancroid in men is associated with HIV-1 seropositivity. Patients with chancroid should also be tested for HIV antibodies. In HIV-seropositive patients with culture-proven chancroid, the treatment recommendations are the same, but with a longer treatment course; close monitoring may be necessary because of delayed healing and possible treatment failures.

 

Prevention

The augmentation of the HIV epidemic by H. ducreyi has made chancroid control an urgent priority. Patients should be advised to abstain from sexual activity until all clinical lesions have cleared. Sexual contacts of the patient (within ten days of symptom presentation) should be examined and treated regardless of whether symptoms of the disease are present, since asymptomatic carriage of H. ducreyi is possible. Antibiotics may provide some protection from reinfection, since a single dose of azithromycin lasted as long as 2 months after treatment.

 

Regimens Actually Recommended by the CDC, WHO and by the European STD Guidelines (2011)

Antibiotics	Dosage	Limitations
1st line Azithromycin Or Ceftriaxone Or 2nd line Ciprofloxacin Or   Erythromycin base	1 g orally in a single dose 250 mg IM in a single dose   500 mg orally bd for 3 days   500 mg orally qds for 7 days	High cost, limited availability   Parenterally, may perform less well in HIV-positive patients   High cost, compliance, pregnancy   Compliance, gastrointestinal intolerance QT interval prolongation