Granuloma Inguinale

01Pathophysiology

Granuloma inguinale is caused by Klebsiella granulomatis, an encapsulated, gram-negative, facultative intracellular organism. Transmission occurs primarily through direct sexual contact with an active lesion, though non-sexual transmission (e.g., fecal contamination, passage through an infected birth canal) has been documented in endemic areas. The incubation period ranges from 1 to 12 weeks but can extend to months.

After inoculation through microabrasions in the genital mucosa or skin, the organism is phagocytosed by tissue macrophages. However, instead of being destroyed, K. granulomatis survives and replicates within the macrophage vacuoles, forming the characteristic intracellular inclusion bodies known as Donovan bodies. This is the hallmark histological finding: clusters of organisms with bipolar condensation of chromatin, creating a "safety-pin" or "closed safety-pin" appearance within enlarged macrophages (also called "Donovan cells").

The ongoing intracellular infection triggers a robust chronic granulomatous inflammatory response. Dense infiltration by macrophages, plasma cells, and neutrophils leads to the formation of highly vascularized granulation tissue. This is why the ulcer appears beefy red and bleeds profusely on contact. The organism does not spread to regional lymph nodes, which explains the characteristic absence of true lymphadenopathy. Instead, subcutaneous extension of the granulomatous inflammation into the inguinal region can form pseudobuboes, firm subcutaneous swellings that mimic lymph node enlargement but are actually granulomas in the subcutaneous tissue, not within lymph nodes.

Without treatment, the disease is slowly destructive. Lesions expand outward by direct extension and auto-inoculation to adjacent skin folds. Chronic untreated disease can lead to tissue destruction, scarring, lymphatic obstruction (causing genital elephantiasis), secondary bacterial superinfection, and in rare cases, squamous cell carcinoma arising within long-standing lesions.

02Classification and Clinical Manifestation

There are four recognized morphological variants. Understanding these matters because the hypertrophic and necrotic variants can mimic malignancy or other STIs on the exam.

Distribution of lesions:

03Diagnostic Workup

The workup for granuloma inguinale begins with clinical suspicion based on the appearance of a painless, beefy-red, friable genital ulcer in the right epidemiologic context (endemic region, sexually active). The best initial step is to obtain a tissue crush preparation (also called a touch prep or smear): the clinician takes a small piece of clean granulation tissue from the ulcer edge, crushes it between two slides, and stains it with Wright or Giemsa stain. Finding Donovan bodies within macrophages confirms the diagnosis.

If the crush prep is equivocal or negative but suspicion remains high, a punch biopsy is the most accurate test. Histopathology will show the same Donovan bodies along with a characteristic mixed inflammatory infiltrate rich in plasma cells and macrophages, with prominent vascular proliferation. This histological picture explains the beefy-red, highly vascular appearance of the lesion.

PCR-based testing is available in some reference laboratories and offers superior sensitivity, but it is not yet a standard-of-care test in most clinical settings. Importantly, K. granulomatis cannot be reliably cultured, so culture plays no role in diagnosis. There is no useful serologic test.

Because genital ulcer diseases frequently co-exist, every patient should also undergo screening for syphilis (RPR/VDRL), HIV, HSV, and Chlamydia trachomatis (particularly the LGV serovars).

04Management and Treatment

Azithromycin is the preferred first-line agent due to its convenient dosing (once weekly), high tissue penetration, and intracellular accumulation within macrophages, which is critical because K. granulomatis is an intracellular organism. The minimum duration is 3 weeks, but treatment must continue until all lesions have fully healed with complete epithelialization. Stopping therapy based on a calendar date rather than clinical resolution is a common cause of relapse.

For patients who cannot tolerate or access azithromycin, doxycycline 100 mg twice daily is the next best option and is widely used. TMP-SMX and ciprofloxacin are also effective alternatives.

In pregnancy, doxycycline is contraindicated (tooth discoloration, bone growth inhibition in the fetus), ciprofloxacin is avoided (cartilage toxicity risk), and TMP-SMX should not be given near term (risk of neonatal kernicterus). The recommended agents are erythromycin base 500 mg four times daily or azithromycin.

In HIV-positive patients, response to therapy is often slower and relapses are more frequent. Current guidelines recommend adding parenteral gentamicin if no improvement is observed within the first few days, as adjunctive aminoglycoside therapy enhances intracellular killing.

All patients should be followed clinically until lesions resolve entirely. Sexual partners from the preceding 60 days should be examined and offered treatment if symptomatic.

If lesions do not respond, reconsider the diagnosis (biopsy to exclude malignancy) and screen again for co-infections.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students get questions on granuloma inguinale wrong is by confusing it with lymphogranuloma venereum (LGV). Both are tropical STIs with the word "granuloma" or "inguinal" in their names, and both can present with genital lesions and inguinal swelling. The critical distinction is the nature of the inguinal swelling: LGV causes true, painful lymphadenopathy (suppurative buboes from infected lymph nodes), while granuloma inguinale causes pseudobuboes (subcutaneous granulomatous nodules that are NOT within lymph nodes). If the vignette describes a painless genital ulcer with inguinal swelling but no fluctuant, tender lymph nodes, think Donovanosis, not LGV.

The second trap is confusing this with primary syphilis. Both present as painless genital ulcers. The discriminator is the ulcer quality: a syphilitic chancre is firm/indurated and clean with a smooth base, while a Donovanosis ulcer is soft, beefy-red, and bleeds easily. Additionally, the syphilitic chancre resolves spontaneously, whereas Donovanosis ulcers progressively enlarge without treatment.

A third pitfall involves the diagnostic test. Students may select "culture" as the answer for confirming the diagnosis, since culture is the gold standard for many bacterial infections. However, K. granulomatis cannot be reliably cultured in the clinical laboratory. The confirmatory diagnosis relies on visualization of Donovan bodies on tissue biopsy or crush preparation, not culture.

Finally, remember the treatment duration rule: therapy is not a fixed course but continues until all lesions have completely re-epithelialized. The minimum is 3 weeks, but stopping on a calendar date when ulcers are still open is the setup for relapse. In HIV-positive patients who fail initial therapy, the next step is adding gentamicin IV, not switching the oral antibiotic.

The core competency being tested is the ability to differentiate among the causes of genital ulcer disease using the pain/painless distinction, the presence or absence of lymphadenopathy, the ulcer morphology, and the correct confirmatory test for each entity.