Granuloma inguinale is a chronic bacterial infection that frequently is associated with other sexually transmitted diseases. Granuloma inguinale is characterized by intracellular inclusions in macrophages referred to as Donovan bodies. Granuloma inguinale usually affects the skin and mucous membranes in the genital region, where it results in nodular lesions that evolve into ulcers. The ulcers progressively expand and are locally destructive, as demonstrated in the image below.
The intracellular organism responsible for granuloma inguinale was initially described by Donovan over a century ago, and subsequently, the bacterium was classified in 1913 as Calymmatobacterium granulomatis. Although Anderson suggested that the organism be eponymously named Donovania granulomatosis, Carter et al discovered that the molecular structure of the causative organism was similar to Klebsiella species and reclassified the gram-negative pleomorphic bacillus as Klebsiella granulomatis.[1, 2]
The mode of transmission of granuloma inguinale primarily occurs through sexual contact; however, it is hypothesized to have low infectious capabilities because repeated exposure is necessary for clinical infection to occur. Additionally, granuloma inguinale may also be obtained through the fecal route or by passage through an infected birth canal.
Fewer than 100 cases of granuloma inguinale are reported annually, many of which are thought to be acquired during foreign travel.
International
Granuloma inguinale is rare in temperate climates, but it is common in the tropics and subtropics. Granuloma inguinale is endemic in Western New Guinea, the Caribbean, Southern India, South Africa, Southeast Asia, Australia, and Brazil.
Race
The incidence is higher in blacks than in whites in the United States. The incidence is higher in native persons than in Europeans in Western New Guinea. The incidence is higher in Hindus than in Muslims in India. These differences are more likely the result of disparities in socioeconomic status and living conditions than of a racial susceptibility.[3]
Sex
No sexual predominance is reported for granuloma inguinale.
Age
Granuloma inguinale most commonly is seen in sexually active people aged 20-40 years.
Relapse may occur up to 18 months after treatment. If untreated, the lesions may continue to expand for years. If granuloma inguinale remains untreated, secondary infections and lymphedema/elephantiasis may occur. Persistent granuloma inguinale lesions continue to expand and are locally destructive. Treated granuloma inguinale lesions tend to exhibit extensive fibrosis, resulting in strictures. Squamous cell carcinoma and less often basal cell carcinoma can develop in long-standing lesions and/or scars. Also see Complications.
For patient education resources, visit the Sexual Health Center and Pregnancy Center. Additionally, see the patient education articles Sexually Transmitted Diseases, Birth Control Overview, and Birth Control Methods.
The four main types of cutaneous lesions are as follows:
Nodular: The initial granuloma inguinale lesion is a papule or nodule that arises at the site of inoculation. The nodule is soft, often pruritic and erythematous, and eventually ulcerates. A nodule may be mistaken for a lymph node [ie, pseudobubo].
Ulcerovegetative (most common): These granuloma inguinale lesions develop from nodular lesions and consist of large, usually painless, expanding, suppurative ulcers. The ulcers have clean, friable bases with distinct, raised, rolled margins and have a tendency to bleed easily. The ulcers are "beefy red" and slowly expand centrifugally, eventually becoming more granulomatous with serpiginous borders. They are commonly located in the skin folds, and autoinoculation is a common feature, resulting in lesions on adjacent skin. Ulcers often become secondarily infected with other types of bacteria and emit a putrid odor.
Cicatricial: Dry ulcers evolve into cicatricial plaques and may be associated with lymphedema.
Hypertrophic or verrucous (relatively rare): This proliferative reaction, with the formation of large vegetating masses, may resemble genital warts.
Elephantiasislike swelling of the external genitalia is a frequent complication and is found most often in infected females in the late stage of granuloma inguinale.
Note the clinical penile images below.
View Image
Courtesy of Hon Pak, MD.
View Image
Courtesy of Hon Pak, MD.
View Image
Courtesy of Hon Pak, MD.
Distribution
The most common locations of granuloma inguinale lesions in men are the sulcocoronal and balanopreputial regions, as well as the anus. In women, granuloma inguinale lesions occur on the labia minora, the mons veneris, the fourchette, and/or the cervix.[4] Cervical involvement occurs in 10% of cases. Children are frequently infected via contact with an adult; however, this is not necessarily the result of sexual abuse.[3]
Extragenital involvement
Extragenital involvement occurs in 6% of granuloma inguinale cases. Autoinoculation or direct extension may lead to involvement of the lips, oral/gastrointestinal mucosa, scalp, abdomen, arms, legs, and bones. Recognition of extragenital donovanosis as a cause of lymphadenopathy is important in patients with HIV.[5]
Lymphadenopathy does not occur as a result of the primary infection with Klebsiella granulomatis, but, rather, it occurs from secondary bacterial infections. Pseudobuboes resemble lymph nodes, but they are just nodular lesions.
Disseminated lesions associated with systemic symptoms are frequently reported in endemic regions.[3] Hematogenous dissemination to the spleen, lungs, liver, bones, and the orbits may occur and occasionally results in death.
The most serious complication of granuloma inguinale is carcinoma, which is reported to occur in 0.25% of patients. This includes squamous cell carcinoma and basal cell carcinoma. Of note, squamous cell carcinoma is sometimes difficult to histologically distinguish from pseudoepitheliomatous hyperplasia associated with the lesions of granuloma inguinale. Furthermore, it is possible for granuloma inguinale and squamous cell carcinoma to coexist in the same lesion.[6, 7]
Once the lesions have healed, extensive fibrosis, stricture formation, and phimosis, leading to significant deformity and functional disability, may occur.
Elephantiasis of the genitals may develop secondary to lymphatic destruction.
Granuloma inguinale may also progress to involve extragenital sites, with potentially fatal systemic spread to the viscera.
Granuloma inguinale also increases the risk of acquiring HIV, and the risk is augmented with chronic lesions. Co-infection with HIV results in persistent ulcers that require intensive prolonged treatment with antibiotics.[3, 5]
Autoamputation of the penis has been reported in a man with long-standing granuloma inguinale associated with underlying HIV-2 infection.[8]
Although isolation of Klebsiella granulomatis has been reported, the organism is extremely fastidious and culture is beyond the capability of most laboratories. The easiest method to visualize the organism is via smears from the base of the ulcer. The organisms are seen within the cytoplasm of histiocytes. Characteristically, they exhibit bipolar staining, which has been likened to a safety-pin appearance, and are referred to as Donovan bodies. The organisms can occasionally be identified in tissue biopsy specimens with the use of special stains.
If a quick diagnosis is necessary, a smear can be performed. First, a cotton swab is gently rolled over the ulcer so as not to cause bleeding. The swab is then rolled over a glass slide. The slide is allowed to air dry and is then stained with Giemsa stain or pinacyanol to demonstrate Donovan bodies.
Alternatively, a crush preparation can be performed. A small piece of tissue should be obtained from the ulcer edge or base via punch biopsy, curettage, or a thin wedge resection. Next, the tissue is crushed between 2 glass slides, separated, and then air dried. A Wright-Giemsa, Warthin-Starry, toluidine blue, or Leishman stain may be used to demonstrate the Donovan bodies.
Lastly, a tissue biopsy specimen can be obtained; however, the organisms may be difficult to find in early or secondarily infected lesions, or on routine stained sections with hematoxylin and eosin. Thin, paraffin-embedded sections stained with Giemsa or silver stain may facilitate identification of the rod-shaped, encapsulated organisms within the macrophages.
Polymerase chain reaction techniques may be more sensitive; however, they are currently only used for scientific research.
An indirect immunofluorescent technique is available to test serum; however, it is not accurate enough for confirmatory diagnosis.
Culture of Klebsiella granulomatis from feces has been reported using a monocyte co-culture system and a modified Chlamydia culture.
Papanicolaou smears may identify Donovan bodies in patients undergoing routine cervical cytological screening.
Since granuloma inguinale is a sexually transmitted disease, a complete workup for other sexually transmitted disease should be considered.
The epidermis displays acanthosis at the ulcer edge, with pseudoepitheliomatous hyperplasia variably present. A dense dermal infiltrate of histiocytes and plasma cells is present, with a scattering of small neutrophilic abscesses. The macrophages are large and vacuolated, and they contain intracellular bacilli (ie, Donovan bodies), which are best visualized using special stains such as a Warthin-Starry, Wright-Giemsa, or Leishman stain. Klebsiella granulomatis does not stain well with hematoxylin and eosin.
Although various antimicrobial regimens have been used in the past and have been shown to be effective, there have only been a limited number of published controlled trials demonstrating the effectiveness of a particular therapeutic agent.
The current first-line drug according to the US Centers for Disease Control and Prevention (CDC) is azithromycin.[11] Alternative regimens include doxycycline, ciprofloxacin, erythromycin base, and trimethoprim-sulfamethoxazole. All antibiotics should be given for at least a 3-week course and continued until reepithelialization of the ulcer occurs and all signs of the disease have resolved. If the granuloma inguinale ulcers do not respond within the first days of therapy, add an aminoglycoside (eg, gentamicin 1 mg/kg IV q8h). Relapse of granuloma inguinale may occur 6-18 months after apparently effective therapy and treatment should be reinitiated at that time.
Since there have been past documented reports of tetracycline resistance, it is no longer recommended.[12]
Special considerations
The drugs of choice in pregnant and lactating women are macrolides (erythromycin or azithromycin). However, since erythromycin estolate has been associated with hepatotoxicity in as many as 10% of pregnancies, erythromycin base or erythromycin ethylsuccinate should be prescribed.[13, 14]
Doxycycline is classified as FDA category D and should be avoided in pregnancy, especially after 15 weeks’ gestation because of the risk of maternal hepatitis and brown discoloration of the infant’s deciduous teeth and inhibition of bone growth. It should also avoided in patients who are breastfeeding, since prolonged exposure beyond 3 weeks may also cause decreased bone growth.[15]
Ciprofloxacin is classified as FDA category C since animal studies indicate that it can be associated with damage to fetal cartilage. When given to breastfeeding women, observe for diarrhea in the infant since it can cause pseudomembranous colitis.[15]
Trimethoprim-sulfamethoxazole is also classified as FDA category C since there is a risk of cardiovascular defects when given in the first trimester, and it is associated with preterm delivery, low birth rate, and miscarriage. Sulfonamides are also associated with serious kernicterus in patients with G-6-P deficiency, and, when given in the third trimester of pregnancy, there is a higher risk of neonatal hyperbilirubinemia. Lastly, since trimethoprim is associated with depression of folate levels, supplementation of folate should be given if the medication must be used, especially during the first trimester.[15]
HIV-associated granuloma inguinale may take longer to heal, and the addition of a parenteral aminoglycoside to the regimen is highly recommended.[16] Note that malignant transformation and autoamputation have both been reported in HIV-positive patients with granuloma inguinale.[8, 17]
Sexual contacts within 60 days prior to onset of symptoms should be examined and offered therapy if clinical signs and symptoms are established; however, the value of empiric therapy in asymptomatic patients is uncertain.
Just as with immunocompetent patients with granuloma inguinale, patients with concomitant HIV infection or who are pregnant, the addition of a parenteral aminoglycoside (eg, gentamicin) should be considered if no improvement is seen within the first few days of standard antibiotic therapies.
Recommended dosing is as follows:
Azithromycin 1 g PO once a week or 500 mg/day for at least 3 weeks or until all lesions have completely healed
Doxycycline 100 mg PO twice a day for at least 3 weeks or until all lesions have completely healed
Erythromycin base 500 mg PO 4 times a day for at least 3 weeks or until all lesions have completely healed
Ciprofloxacin 750 mg PO twice a day for at least 3 weeks or until all lesions have completely healed
Trimethoprim-sulfamethoxazole 1 double strength (160 mg/800 mg) tablet PO twice a day for at least 3 weeks or until all lesions have completely healed
A clinical guideline summary is available from the US Centers for Disease Control and Prevention: 2015 Sexually Transmitted Diseases Treatment Guidelines-Granuloma Inguinale (Donovanosis).[18, 19]
Positive strides have been made in reducing the incidence of granuloma inguinale in endemic regions.
Australia and its surrounding indigenous areas have witnessed a decrease in the incidence of granuloma inguinale through the establishment of a National Donovanosis Eradication Advisory Committee. The committee consists of project officers representing different geographic areas who work closely with primary care healthcare providers.
The goal is to develop educational materials, conduct in-service teaching for staff in rural and remote areas, implement common protocols for treatment and diagnosis, and undertake active surveillance. Since the development of the committee in 2001, the number of new cases of granuloma inguinale has fallen to the lowest levels since the commencement of accurate epidemiological data collection.
This committee represents a proven model of public health intervention, using centralized officers with expertise in sexually transmitted infection who liaise with primary healthcare providers. A similar model may help reduce the incidence of disease in other endemic areas.[20]
Clinical Context:
Sulfamethoxazole inhibits the bacterial synthesis of dihydrofolic acid. Trimethoprim reversibly inhibits dihydrofolate reductase and blocks the production of tetrahydrofolic acid from dihydrofolic acid.
Clinical Context:
Doxycycline is a bacteriostatic tetracycline antibiotic that inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.
Clinical Context:
Ciprofloxacin is a bactericidal fluoroquinolone antibiotic that inhibits the bacterial enzymes topoisomerase II (DNA gyrase) and topoisomerase IV, which are required for bacterial DNA replication, transcription, repair, and recombination.
Clinical Context:
Erythromycin is a macrolide antibiotic that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits of susceptible organisms; it may be bacteriocidal or bacteriostatic depending on the concentration and type of microorganism.
Clinical Context:
Azithromycin is an azalide antibiotic (subclass of macrolide antibiotics) that inhibits bacterial protein synthesis by binding to the 50S ribosomal subunits of susceptible organisms; it may be bacteriocidal or bacteriostatic depending on the concentration and type of microorganism.
Elizabeth K Satter, MD, MPH, Dermatologist and Dermatopathologist
Disclosure: Nothing to disclose.
Specialty Editors
Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Disclosure: Nothing to disclose.
Paul Krusinski, MD, Director of Dermatology, Fletcher Allen Health Care; Professor, Department of Internal Medicine, University of Vermont College of Medicine
Disclosure: Nothing to disclose.
Chief Editor
Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Additional Contributors
James J Nordlund, MD, Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine
Disclosure: Nothing to disclose.
Jerry J Fasoldt, MD, Head of Medical Department, Senior Flight Surgeon, Naval Operational Support Center
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors, Clara-Dina Cokonis, Steven M. Manders, and Kari Williamson Boucher to the development and writing of this article. We also thank Hon Pak for the use of his clinical pictures.
Ramdial PK, Sing Y, Ramburan A, Bagratee JS, Naidu TK, et al. Nodal Donovanosis as the Sentinel Clue to Acquired Immunodeficiency Syndrome. J AIDS Clin Res. 2016. 7:614.
[Guideline] Centers for Disease Control and Prevention. 2015 Sexually Transmitted Diseases Treatment Guidelines-Granuloma inguinale (Donovanosis). Available at http://www.cdc.gov/std/tg2015/donovanosis.htm. June 4, 2015; Accessed: October 19, 2015.
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