What is Donovanosis

Donovanosis also called granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). Donovanosis occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa ¹. Donovanosis is a sexually transmitted infection that can rarely have non-sexual modes of transmission. It is classically associated with genital ulcers that demonstrate Donovan bodies on tissue smear samples ². Clinically, granuloma inguinale or donovanosis is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudobuboes) also might occur. The lesions are highly vascular (i.e., beefy red appearance) and bleed. Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intra-abdominal organs, bones, or the mouth. The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens. All patients presenting with possible donovanosis or sexually transmitted infection should be considered for HIV testing ³.

The Centers for Disease Control and Prevention (CDC) recommend that treatment should last until all lesions are healed. First-line treatment is azithromycin 1 g followed by 500 mg daily ⁴. Relapses can occur 6 to 18 months after seemingly successful treatment. Some alternative treatment regimens are doxycycline 100 mg twice per day, ciprofloxacin 750 mg twice per day, erythromycin 500 mg 4 times per day, and sulfamethoxazole/trimethoprim twice per day. Patients that are slow to respond can also be given gentamicin 500 mg every 8 hours. Erythromycin is the medication of choice in pregnancy. There is no change in the recommendations for HIV positive patients. The 2016 European Guidelines for donovanosis treatment state that antibiotics should continue for a minimum of three weeks and until symptom resolution ⁵. They also recommend azithromycin as a first-line treatment that can be given as 1 g initially then 500 mg daily or 1 g weekly. Children should be given azithromycin 20 mg/kg for a disease treatment course or prophylaxis for 3 days if exposed during birth. The first study to demonstrate the effectiveness of azithromycin was performed by Bowden et al. between June 1994 and March 1995 in Australia. Seven patients received 1 g azithromycin weekly for 4 weeks, and 4 patients received 500 mg azithromycin daily for 7 days. After 6 weeks, 3 patients from the first regimen and 1 patient from the second were healed, and all other participants in the study were significantly improved. Azithromycin was shown to be effective against donovanosis and has the added benefit of short, intermittent dosing, which may facilitate treating endemic populations. Medication alone may be the only treatment required. Surgery may be needed for extensive tissue destruction. Patients require consistent monitoring for disease resolution and possible recurrence ⁵.

Figure 1. Donovanosis male

Figure 2. Donovanosis female

Donovanosis causes

The bacteria that causes donovanosis is known as Klebsiella granulomatis comb. nov., but there has been significant debate over the most appropriate nomenclature ⁶. The causative agent of donovanosis was originally named Calymmatobacterium granulomatis by Aragao and Vianna in Brazil. After the original naming, it was found to have similarities to other Klebsiella species in respect to testing, structural aspects, and histologic appearance. Carter et al. ⁷ reclassified this bacteria in 1999 from Calymmatobaacterium to Klebsiella based on genes 16 SrRNA and phoE. K. granulomatis is a gram-negative coccobacillus. It is intracellular and encapsulated. It has been demonstrated to function as a facultative aerobe. The first effective treatment used was emetic tartar in Brazil. The first successful culture was in the mid-1990s by using peripheral blood monocytes and human epithelial cell lines ⁸.

How is donovanosis transmitted?

The transmission of donovanosis has been debated due to its apparent association with sexual contact despite reports of infection without sexual contact history. As of 1947, it has generally been accepted as a sexually transmitted infection based on a literature review done at the time. There is usually a history of sexual exposure before the lesion develops. There are also high rates of infection among age groups with increased sexual activity. Donovanosis has been diagnosed in women with lesions primarily located on the cervix, and men who have sex with men have a higher incidence of anal lesions ². A piece of evidence that tends to point away from donovanosis as a sexually transmitted infection is the low rates of sex workers affected. Also, there have been some cases of fecal transmission and children infected in nonsexual ways. There are case reports of children infected by sitting on adult’s laps and neonates infected during vaginal delivery. Some other risk factors are poor hygiene and low socioeconomic status. Also, the rate of transmission is thought to be low in general ⁸.

Govender et al. ⁹ reported 2 cases where young children were diagnosed with donovanosis with no history of sexual exposure. An 8-month-old female presented with a right ear mass and discharge. She was initially treated with antibiotics and surgical resection but did not follow up for 8 months. When she presented again, she was found to have progressed in symptomatology and had a new right temporal lobe abscess. She required a craniectomy to drain the abscess as well as a mastoidectomy. Tissue was removed during the surgery for analysis, and the diagnosis of granuloma inguinale was made. Questioning of the parents revealed no signs or symptoms of sexual abuse. No gynecological exam was performed on the patient’s mother, so it is unknown if she had a genital ulcer. The patient was treated with erythromycin with noted improvement in the right temporal lobe lesion noted on computed tomography prior to discharge. The patient and her family were unavailable for follow up after discharge ⁸.

Another case of a 5-month-old male with left ear discharge was also described. In addition to discharge from the ear, he also had a lower motor neuron cranial nerve VII palsy, mass at the external auditory meatus, and a friable retroauricular abscess. Tissue samples obtained during the surgical resection of the mass revealed granuloma inguinale. Gynecological exam of the mother showed a cervical lesion confirmed to by granuloma inguinale histologically. Again, there were no signs of sexual abuse in this case. There are no documented cases of granuloma inguinale in children in the United States. The cases that have been reported in other locals have mostly been children 1 to 4 years of age. The incubation period of donovanosis is uncertain but estimated to be around 50 days based on human experimental infections. In general, the incubation period is recorded as 1 to 365 days due to lack of data ⁹.

Donovanosis prevention

The incidence of donovanosis has been decreasing worldwide most likely due to the realized role in HIV transmission. There have been multiple programs in the United States, Australia, and Papua New Guinea that have reduced disease prevalence. One program in Papua New Guinea involved mandatory inpatient treatment and utilized security guards in the wards to ensure completion of treatment ¹⁰. Efforts in Australia have almost eradicated the disease. In the mid-1990s, a proactive approach to disease eradication was initiated. There were 115 cases of donovanosis noted within the aboriginal population in 1995. The Tri-State HIV/STI initiative implemented a Donovanosis Project Officer in 1997 to manage surveillance, diagnosis, and treatment. The prevalence significantly decreased over the following 3 years. In 2001, the National Donovanosis Eradication Committee was established after several organizations noted disease eradication was a worthy goal and possible. Both government and nongovernment agencies were involved, and they implemented a multidisciplinary approach. The goal of eradication was changed to elimination after realizing that eradication would require a global initiative. Elimination was defined as no new cases reported to the National Notifiable Disease Surveillance System (NNDSS) for 3 years. This second initiative utilized four Project Officers. As of 2004, there were only 5 reported cases of donovanosis ¹¹. Donovanosis has been targeted for eradication due to the risk of HIV transmission with genital ulcer disease. O’Farrell ¹² looked at STD clinics in Durban, South Africa and found higher rates of HIV-1 positivity in men with donovanosis as the duration of the lesions presence increased. There was a 5000-fold increase in the positive HIV-1 rates in men with donovanosis versus men with gonorrhea for greater than 3 months. Men with donovanosis are considered “super-spreaders” in regards to spreading HIV if they have the disease or acquiring the disease if they have genital lesions ¹². Since the incubation period is uncertain but estimated to be around 50 days, the CDC recommends treating anyone who has sexual contact with someone diagnosed with donovanosis within 60 days. It is unclear at this time if prophylaxis is useful in this setting. The 2016 European Guidelines also recommend prophylaxis for neonates exposed during vaginal birth ⁵.

Donovanosis symptoms

Donovanosis lesions usually start as a painless papule or subcutaneous nodule. The lesions develop the classic “beefy-red” appearance due to their high vascularity. The initial lesion takes on an ulcerative morphology after minor trauma. There is usually no regional lymphadenopathy. Developing subcutaneous granulomas known as pseudobuboes is possible. The lesions are progressive in an outward direction from the center. The borders of the lesions are sometimes described as “snake-like” in appearance. Self-inoculation is possible and may create mirror-image lesions in the same general location, usually across skin folds ⁸. Patients often delayed seeking health care for many reasons, and therefore, they usually present with a more progressed lesion ¹². There are 4 types of lesions. Classic ulcerogranulomatous lesions are the most common with beefy-red, non-tender ulcers that bleed easily. The second type is hypertrophic or verrucous with irregular raise edges and dry texture. The third type is necrotic, offensive-smelling, deep ulceration that causes tissue destruction. The last type is sclerotic or cicatricial with fibrous and scar tissue. The genitals are affected in 90% of cases and the inguinal region in 10% of cases. The most common sites where men are affected are the prepuce, coronal sulcus, frenum, glans, and anus. The most common sites where women are affected are the labia minora, fourchette, cervix, and upper genital tract. Pregnant patients experience quicker progression of donovanosis lesions and respond slower to treatment compared to the general population. Extragenital lesions occur on the lips, gums, cheek, palate, pharynx, larynx, and chest 6% of the time ¹⁰.

Donovanosis diagnosis

Diagnosis can be made by an experienced physician in endemic areas but may be difficult in other areas of the world. In nonendemic areas, the diagnosis will require a high index of suspicion. The diagnosis is confirmed by identifying Donovan bodies in a tissue smear. PCR testing is possible but is not widely available. It is seen in the research setting and often used during eradication programs. There are serologic tests that can be used for population studies, but they are not accurate enough to diagnose an individual ⁸.

The causative organism of granuloma inguinale or donovanosis is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared molecular tests for the detection of Klebsiella granulomatis DNA exist, but such an assay might be useful when undertaken by laboratories that have conducted a Clinical Laboratory Improvement Amendments (CLIA) verification study.

Donovanosis treatment

Several antimicrobial regimens have been effective, but only a limited number of controlled trials have been published ¹³. Treatment has been shown to halt progression of lesions, and healing typically proceeds inward from the ulcer margins; prolonged therapy is usually required to permit granulation and re-epithelialization of the ulcers. Relapse can occur 6–18 months after apparently effective therapy.

Recommended regimen ⁴:

• Azithromycin 1 g orally once per week or 500 mg daily for at least 3 weeks and until all lesions have completely healed

Alternative Regimens

• Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed
  OR
• Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed
  OR
• Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed
  OR
• Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed

The addition of another antibiotic to these regimens can be considered if improvement is not evident within the first few days of therapy. Addition of an aminoglycoside to these regimens is an option (gentamicin 1 mg/kg IV every 8 hours).

Other management considerations

Persons should be followed clinically until signs and symptoms have resolved. All persons who receive a diagnosis of granuloma inguinale should be tested for HIV ⁴.

Follow-up

Patients should be followed clinically until signs and symptoms resolve ⁴.

Management of Sex Partners

Persons who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient’s symptoms should be examined and offered therapy. However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established ⁴.

Special Considerations

Pregnancy

Doxycycline should be avoided in the second and third trimester of pregnancy because of the risk for discoloration of teeth and bones, but is compatible with breastfeeding ¹⁴. Data suggest that ciprofloxacin presents a low risk to the fetus during pregnancy ¹⁴. Sulfonamides are associated with rare but serious kernicterus in those with G6PD deficiency and should be avoided in third trimester and during breastfeeding ¹⁴. For these reasons, pregnant and lactating women should be treated with a macrolide regimen (erythromycin or azithromycin). The addition of an aminoglycoside (gentamicin 1 mg/kg IV every 8 hours) can be considered if improvement is not evident within the first few days of therapy.

HIV Infection

Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who do not have HIV infection. The addition of an aminoglycoside (gentamicin 1 mg/kg IV every 8 hours) can be considered if improvement is not evident within the first few days of therapy.

References

1. Velho PE, Souza EM, Belda Junior W. Donovanosis. The Brazilian Journal of Infectious Diseases 2008;12:521–5.
2. O’Farrell N. Donovanosis. Sex Transm Infect. 2002 Dec;78(6):452-7
3. Santiago-Wickey JN, Crosby B. Granuloma Inguinale (Donovanosis) [Updated 2019 Jan 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513306
4. Granuloma Inguinale (Donovanosis). 2015 Sexually Transmitted Diseases Treatment Guidelines. https://www.cdc.gov/std/tg2015/donovanosis.htm
5. O’Farrell N, Moi H. 2016 European guideline on donovanosis. Int J STD AIDS. 2016 Jul;27(8):605-7.
6. Santiago-Wickey JN, Crosby B. Granuloma Inguinale (Donovanosis) [Updated 2019 Jan 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513306
7. Phylogenetic evidence for reclassification of Calymmatobacterium granulomatis as Klebsiella granulomatis comb. nov. International Journal of Systematic Bacteriology (1 999), 49, 1695-1 700 https://ijs.microbiologyresearch.org/content/journal/ijsem/10.1099/00207713-49-4-1695
8. Velho PE, Souza EM, Belda Junior W. Donovanosis. Braz J Infect Dis. 2008 Dec;12(6):521-5.
9. Govender D, Naidoo K, Chetty R. Granuloma inguinale (donovanosis): an unusual cause of otitis media and mastoiditis in children. Am. J. Clin. Pathol. 1997 Nov;108(5):510-4.
10. O’Farrell N. Donovanosis. Sex Transm Infect. 2002 Dec;78(6):452-7.
11. Bowden FJ., National Donovanosis Eradication Advisory Committee. Donovanosis in Australia: going, going… Sex Transm Infect. 2005 Oct;81(5):365-6.
12. O’Farrell N. Global eradication of donovanosis: an opportunity for limiting the spread of HIV-1 infection. Genitourin Med. 1995 Feb;71(1):27-31.
13. O’Farrell N. Donovanosis. Sex Transm Infect 2002;78:452–7.
14. Briggs GC, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation, 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.