Donovanosis

Salient features

 

·        Granuloma inguinale (GI) is a rare, chronic, progressive ulcerative disease that mainly affects the genital and perigenital skin.

·        GI is primarily contracted through sexual transmission.

·        GI is caused by infection with Klebsiella granulomatis, a gram-negative bacterium.

·        It affects mostly people of lower socioeconomic status living in tropical or subtropical areas.

·        Diagnosis confirmed by demonstrating intracellular Donovan bodies on histology.

  

Definition

 

Granuloma inguinale is a chronic, superficial, ulcerating disease of the genital, inguinal, and perianal areas. Granuloma inguinale is mildly contagious. The causative bacterial organism is Calymmatobacterium granulomatis. It is a cause of genital ulcer disease, may be followed by genital disfigurement, and has the potential for malignant change.

 

Epidemiology

 

Incidence and prevalence

 

The disease was initially described in India as ulcerations followed by elephantiasis of the genitalia. The microorganism was first identified in 1905 by Donovan, who noted the characteristic Donovan bodies in macrophages and epithelial cells of the stratum malpighii.

 

Age

 

The condition usually affects sexually active adults between the ages of 20 and 40 years.

 

Associated diseases

 

Granuloma inguinale may occur with other STIs and has been identified as a risk factor for the acquisition and transmission of HIV.

 

Pathogenesis

Donovanosis is causes by Klebsiella granulomatis (previously known as Calymmatobacterium granulomatis), an intracellular Gram-negative coccobacillus that stains well with Giemsa, Wright's, or silver stains but is periodic acid-Schiff-negative. The mature form is encapsulated, while the immature form is not. The immature nonencapsulated form may assume a closed-safety-pin appearance due to bipolar chromatin densities. K. granulomatis is a facultative organism that resides in the cytoplasm of large mononuclear cells.

 

Clinical features

 

The incubation period is considered to be between 1 and 360 days. Lesions appear in an average period of 50 days.

 

Four clinical types of lesions have been described:

1.   Ulcerogranulomatous: the most common type with painless beefy red ulcers with clean friable base that bleed when touched. Autoinoculation is common.

2.   Hypertrophic: usually with a raised irregular edge (relatively rare).

3.   Necrotic: offensive smelling ulcer causing tissue destruction.

4.   Sclerotic or cicatricial: dry ulcers that progress into scarring plaques. Lymphedema may be present.

 

At the site of primary inoculation, one or more papules or subcutaneous nodules develop and then evolves into an ulcer and gradually increases in size. Four clinical types have been described. The most common presentation is the ulcerogranulomatous type which presents as painless, broad, highly vascular, beefy red ulcers with a friable, granulation tissue–like base, which bleeds to touch. If untreated, the ulcers may extend to adjacent tissues via autoinoculation and form multiple ulcers. These ulcers are mirror images of each other and have been described as “kissing” lesions. The ulcers of GI may have smooth border or a raised irregular hypertrophic or verucous border resembling condyloma accuminata in the hypertrophiec type. The necrotic type often occurs in long-standing donovanosis and presents as a deep ulcer with copious gray, foul-smelling exudates and extensive destruction to surrounding tissue. The tissue overlying the regional lymph nodes may evolve into an abscess or pseudobubo (mimic enlarged lymph nodes) due to subcutaneous extension of granulomas that later ulcerates. The lymph nodes per se are not involved unless there are other ulcer pathogens present. In the rare dry cicatricial form, the lesions are non-bleeding ulcers that form band-like scars and lead to digital lymphedema due to constriction.

 

The genital region is affected in 90% of cases and the inguinal area in 10%.  The most common locations are on the coronal sulcus or inner aspect of the penile prepuce in uncircumcised men, on the anus in MSM, and the vulva in females. The disease progresses to the genitocrural and inguinal folds in males and to the perineal and perianal areas in females. Granuloma inguinale of the cervix presents as a proliferative growth and may mimic carcinoma.

 

Extra genital involvement has been reported in around 6% of the cases, occurring either as a primary infection or by spreading from a genital site by autoinoculation or systemic hematogenous dissemination. Primary extra genital sites reported include particularly the oral mucosa, and also the neck, scalp, chest, arms, and legs. Hematogenous dissemination may present with fever, anorexia, and weight loss. It may lead to the involvement of bones and visceral organs like including the intestines, liver, spleen, and lungs. The most commonly affected bone is the tibia, comprising more than 50% of reported cases.

 

Complications and co‐morbidities

 

Genital complications of donovanosis include genital swelling that may progress to pseudoelephantiasis, phimosis, paraphimosis, and progressive tissue destruction that may lead to the destruction of the whole penis or other involved organs. There is also an increased risk of squamous cell carcinoma in long-standing cases. More recently, squamous cell carcinoma (SCC) has developed in GI ulcerations of shorter duration in an HIV-infected patient.

In addition, the fact that GI ulcers are painless and bleed easily upon contact increases the risk of HIV transmission remarkably.

 

Disease course and prognosis

 

GI shows no tendency for spontaneous healing. Untreated lesions tend to be persistent, slowly extending and destructive. HIV augments continuation of the lesions with persistent ulcers for prolonged periods. If left untreated, GI may also extend to internal organs, including the ovaries, adnexa, uterus, epididymis, and bladder. Fistulas may form and lead to genital fibrosis and deformity. Systemic dissemination may be fatal, especially in cases of misdiagnosis.

 

Diagnosis and Laboratory Tests

 

Clinical diagnosis of donovanosis can be confirmed by the demonstration of Donovan bodies in smears from active lesions by Giemsa, Wright, or Leishman stains. The smears are prepared from tissue scrapings or touch preparations of biopsies taken from the advancing edge of the ulcer. Secondary bacterial infection and debris may affect the smear result; thus, it is recommended to wipe the ulcers gently with cotton swabs first before taking the smear but not to clean the ulcers with saline first.

 

Pathology

Histologically, ulceration with exuberant granulation tissue is evident. Pseudoepitheliomatous hyperplasia may be present at the ulcer edge. A diffuse infiltrate of histiocytes, plasma cells, and a few lymphocytes is present in the dermis, sometimes with small neutrophilic abscesses. Edema and endothelial cell swelling are often noted. The hypertrophic and the cicatricial forms of GI may exhibit fibrosis. The organisms are easier to find in properly done smears than in histologic sections. Clusters of Donovan bodies are seen in the vacuolated cytoplasm of the histiocytes of granulation tissue. Using Giemsa, Wright's, or silver stains, these Donovan bodies appear as “closed-safety-pin”-like structures measuring 1–2 microns in diameter. A modified version of Giemsa preparation such as Rapi-Diff can be used to stain tissue smear for a quick diagnosis. These Donovan bodies may also be occasionally found extracellularly or within neutrophils.

 

Treatment

 

Untreated ulcers do not resolve spontaneously. Appropriate antibiotic therapy should be initiated once a diagnosis is established to avoid complications that could result in serious sequelae.

 

Azithromycin is recommended as a first-line treatment as it is advantageous because it can be administered intermittently and on a weekly basis, while patients are under supervision. The patient should continue treatment for at least 3 weeks and until all clinically visible ulcers have completely healed. Serial biopsy specimens may be needed.

Doxycycline, trimethoprim–sulfamethoxazole, quinolones, and erythromycin (recommended during pregnancy) have also been shown to be effective in the treatment of donovanosis. For azithromycin, successful treatment with a daily dose of 500 mg for 1 week has been reported. However, the CDC 2015 guidelines recommend 1 g weekly or 500 mg daily for at least 3 weeks and until all lesions have completely healed.

For any of the regimens, the addition of an aminoglycoside (e.g. gentamicin 1 mg/kg IV q8h) should be considered if lesions do not respond within the first few days of therapy.

TREATMENT REGIMENS FOR DONOVANOSIS

Recommended:

Azithromycin, 1 g po once weekly – or – 500 mg po daily

Alternative:

Doxycycline, 100 mg po BID – or –   Trimethoprim–sulfamethoxazole, 1 double-strength (160 mg/800 mg) tablet po BID – or –   Ciprofloxacin, 750 mg po BID – or –   Erythromycin base, 500 mg po four times daily

Duration for all regimens: until all lesions completely healed (at least 3 weeks)

 

Relapse may occur 6–18 months after apparently effective treatment, requiring follow-up by the physician. Long-standing cases may be complicated by secondary bacterial infections or by fistulas and abscess formation, which require surgical intervention and render antibiotic treatment alone ineffective.

 

Prevention

Although donovanosis is uncommon in the partners of index cases, all sexual contact with a patient with GI in the previous 6 months need to be examined. Sexual partners need not be treated unless they develop signs and symptoms of GI.

Children born to mothers with untreated donovanosis need to receive prophylactic azithromycin at a dose of 20 mg/kg for 3 days.