Granuloma Inguinale

Granuloma inguinale (donovanosis) is a chronic, progressive, ulcerative genital disease caused by Klebsiella granulomatis (formerly Calymmatobacterium granulomatis), an encapsulated Gram-negative intracellular bacillus. It is endemic in limited areas: Papua New Guinea, parts of southern Africa (KwaZulu-Natal), India (Tamil Nadu), Brazil, the Caribbean, and among Indigenous Australians (nearly eliminated by programmes). It is rare elsewhere.

Epidemiology and transmission

• Low infectivity. Transmitted mainly through sexual contact (vaginal or anal), though non-sexual transmission is suspected in some cases (autoinoculation, children). Most cases occur in sexually active people aged 20 to 40, with poor hygiene and low socioeconomic status as risk factors. Incubation is variable, between 1 and 12 weeks (up to 6 months).
• Associated with increased HIV transmission through ulceration. Co-infection with HIV is frequent in some regions, and may worsen disease.
• Pathogenesis: bacteria enter through minor breaks in skin, are phagocytosed by macrophages and multiply within vacuoles, producing Donovan bodies (intracellular rods with bipolar staining, "safety pin" appearance). Ulceration with granulation tissue forms, and lymphatic obstruction with fibrosis leads to pseudoelephantiasis.

Complications

• Progressive tissue destruction, genital scarring and deformity, urethral and anal strictures, lymphatic obstruction with pseudoelephantiasis (genital elephantiasis), secondary bacterial infection and sepsis, fistulae, anaemia and malnutrition, malignant transformation (squamous cell carcinoma, in long-standing lesions), extragenital dissemination (rare, to bone, joint, liver, spleen, lungs), and increased HIV acquisition.
• Disease in pregnancy may be aggressive and may rarely infect neonates (vaginal delivery).

Beginning as one or more subcutaneous nodules or papules that ulcerate, with painless progression:

• Ulcerogranulomatous (classic, commonest): painless, progressive, beefy-red, friable ulcer with a granular base that bleeds easily on touch, rolled edges, with clear-cut borders. No adenopathy typically. Autoinoculation produces "kissing" lesions.
• Hypertrophic or verrucous: exuberant, raised, wart-like, with irregular edges.
• Necrotic: deep, foul-smelling ulcer with destruction of tissue.
• Sclerotic or cicatricial: fibrous bands and stricture formation.
• Satellite lesions and pseudobuboes (subcutaneous granulomas of the inguinal region mimicking lymphadenopathy, without true nodal enlargement) occur in about 10%.

Sites

• Men: prepuce, coronal sulcus, glans, frenulum, shaft, scrotum. Women: labia minora, fourchette, mons pubis, vaginal wall, and cervix (may mimic carcinoma).
• Anal region (MSM and receptive anal intercourse), groin, and thigh. Rarely extragenital (mouth, face, nose, gums).
• Systemic symptoms are usually absent. Pain is mild or absent unless secondary infection occurs.

Differential diagnosis

• Syphilis (painless but indurated, clean base), chancroid (painful, soft, with suppurative bubo), LGV, genital herpes, genital warts, squamous cell carcinoma, amoebiasis cutis, cutaneous tuberculosis, pyoderma gangrenosum, deep fungal infections, leishmaniasis, and Crohn disease.
• Red flags: persistent non-healing ulcer in an endemic area, ulcer with cervical lesion mimicking cancer, HIV co-infection, pregnancy, and signs of malignant change.

• The standard diagnosis is demonstration of Donovan bodies in tissue smears or biopsy:
• Tissue smear: after cleaning the lesion, crush a piece of granulation tissue from the edge on a glass slide, air dry, and stain with Giemsa, Wright, or Leishman. Donovan bodies appear as dark-staining, bipolar "safety pin" intracytoplasmic rods (1 to 2 micrometre) in large mononuclear cells (macrophages). Sensitivity is about 90 to 95% in expert hands.
• Biopsy: histology shows epithelial hyperplasia with ulceration and a dense subepithelial infiltrate of histiocytes, plasma cells and neutrophils with few lymphocytes. Warthin-Starry silver stain highlights organisms. Pseudoepitheliomatous hyperplasia may mimic carcinoma.
• Culture is not routinely available (requires egg yolk or monocyte cell culture).
• PCR (for the phoE gene) is available in reference labs, and not widely accessible.
• Concomitant testing: HIV, syphilis serology (and repeat at 3 months), HSV PCR, hepatitis B, NAAT for chlamydia and gonorrhoea, and pregnancy test.
• Biopsy is mandatory in long-standing, atypical, hypertrophic or non-responding lesions to exclude carcinoma, and in HIV-infected patients.

Antimicrobial therapy (duration at least 3 weeks, or until all lesions have completely healed)

• Azithromycin 1 g orally once weekly (preferred), or azithromycin 500 mg daily.
• Doxycycline 100 mg orally twice daily (alternative; contraindicated in pregnancy and young children).
• Ciprofloxacin 750 mg orally twice daily (alternative; not for pregnancy and children).
• Erythromycin base 500 mg orally four times daily (alternative, safe in pregnancy).
• Trimethoprim-sulfamethoxazole 160/800 mg orally twice daily (alternative).
• Add gentamicin 1 mg/kg IV every 8 hours to any of the regimens if lesions do not respond in the first few days, and in HIV-infected patients (consider as part of treatment).
• Pregnancy and lactation: azithromycin 1 g weekly or erythromycin. Add gentamicin for no response. Avoid tetracyclines, fluoroquinolones, and sulfonamides near term.
• Duration should continue until complete epithelialisation, usually 3 to 6 weeks or longer for extensive lesions. Relapse can occur 6 to 18 months after apparent cure, even with an effective regimen, so a longer course (weeks beyond healing) is sometimes advised.
• Lack of improvement within the first few days indicates the need to reconsider diagnosis, add an aminoglycoside, check adherence, or evaluate for coinfection, HIV, or malignancy.

Supportive and local care

• Local wound care with saline cleansing, topical antiseptic, dressings, treatment of secondary bacterial infection with systemic antibiotics (amoxicillin-clavulanate 625 mg three times daily), and analgesia.
• Nutritional support and treatment of anaemia.
• HIV: start antiretroviral therapy.
• Surgical procedures: debridement, skin grafting for extensive tissue loss, and reconstruction of strictures, fistulae and genital deformities after infection is controlled. Lymphoedema management. Biopsy and oncological resection for malignancy.

Follow-up

Weekly review until healed. Examine again at 3, 6 and 12 months for relapse. HIV and syphilis retesting at 3 months.

Partner management and prevention

Examine and offer presumptive treatment to all sexual partners within the previous 60 days (azithromycin 1 g weekly for 3 weeks, or syndromic therapy), given low infectivity and difficulty of diagnosis. Counsel on safer sex, condom use, hygiene, and early care. Public health reporting where required. National programmes in endemic regions (Australia, Papua New Guinea) have used syndromic management and screening for elimination.

Prognosis

Good with timely therapy, but delayed treatment results in scarring and deformity. Incomplete treatment is associated with recurrence, and ongoing monitoring for malignancy is advisable.