Sexually Transmitted Diseases - I. I. Mavrov 2005

Sexually Transmitted Diseases
Granuloma Inguinale (Donovanosis)

Granuloma inguinale (granuloma venereum), also known as donovanosis, is a chronic, slowly progressive sexually transmitted infection.

Etiology. The CAUSATIVE AGENT OF granuloma inguinale (*Calymmatobacterium granulomatis*) was discovered in 1905 by the Irish physician C. Donovan, who described intracellular inclusions in exudate samples taken from oral lesions in a patient who also presented with genital manifestations. For this reason, *Calymmatobacterium granulomatis* is sometimes referred to as Donovan bodies.

Currently, the pathogen of granuloma inguinale is classified within the family Enterobacteriaceae, as strains isolated from patients exhibit cross-reactivity with *Klebsiella pneumoniae* and *Escherichia coli* (I. Goldberg, 1964). *Calymmatobacterium granulomatis* appears as pleomorphic rods measuring 1–2 µm in length and 0.5–0.7 µm in width, with rounded ends. They occur singly or grouped in cyst-like arrangements and are typically encapsulated. The microbial Cells contain single or bipolar Chromatin accumulations, giving The Cell a characteristic safety-pin appearance. The Bacteria parasitize predominantly within macrophages and are easily identified by Giemsa staining, which colors the bacterial body blue, the chromatin inclusions dark blue or black, and surrounds the microorganism with a pink-staining capsule. With Wright's stain, the agents appear as bacillary bodies enclosed within well-defined, dense pink capsules. They stain poorly with other Dyes, are acid-sensitive, non-motile, and Gram-negative. Electron Microscopy of bacteria isolated from affected Tissues reveals a fibrillar capsule. They reproduce by binary fission.

Calymmatobacterium granulomatis grows on fresh egg-yolk media and, after adaptation, on other nutrient media as well. On Leventhal's Agar enriched with beef Heart broth, their colonies are shiny, reaching up to 1.5 µm in diameter. Gradually they turn gray, and later brownish. Donovan bodies can be cultivated in the infected yolk sacs of developing chicken embryos. The disease was successfully reproduced in healthy human volunteers through subcutaneous inoculation with exudate from patient lesions (C. Greenblatt et al., 1939).

Routes of transmission. Granuloma inguinale affects humans exclusively. Transmission occurs predominantly through sexual contact, and much less frequently via non-sexual domestic contact. Factors favoring the spread of infection include a humid climate and high ambient temperatures. Poor personal hygiene and promiscuous Sexual Behavior play a significant role in the onset and dissemination of the disease.

Epidemiology and general pathology. The disease is relatively widespread in the southern provinces of China, certain regions of Southeast Asia, Central and Southern Africa, India, Indonesia, Myanmar, and Vietnam. In the United States, granuloma inguinale is frequently reported along the Gulf Coast, the Mississippi delta, and the Atlantic coast and islands, with approximately 25% of cases diagnosed in other PARTS OF THE country (C. Clarke, 1957). In Brazil, it ranks fifth among Sexually Transmitted Diseases (V. Henrique et al., 1984). It is rarely encountered in Europe.

Several researchers report that the disease is more common in men than in women (R. Rasam, P. Rangian, 1954). However, R. S. Babayants (1984) notes that the condition is more prevalent among women. The highest incidence is observed in individuals aged 20 to 40 years.

Granuloma inguinale accounts for approximately 1.5% of all Sexually Transmitted Infections. From an epidemiological standpoint, the possibility of concurrent infection with Syphilis, Gonorrhea, urogenital chlamydia, or Chancroid must be considered.

The incubation period ranges from a few days to 3 months or more. In experimental inoculation of volunteers with lesion material, the incubation period varied from 17 to 50 days (R. Rasam, P. Rangian, 1954).

Donovan bodies penetrate through micro-abrasions in the Skin and mucous membranes, triggering an inflammatory response in the dermis or (less commonly) the subcutaneous tissue. The earliest manifestation of the disease is a small, raised papule about the size of a pea. The papule has a flat surface, the surrounding skin becomes macerated and moist, and within a few days, it begins to desquamate. Occasionally, the disease begins as a subcutaneous Swelling of varying sizes that softens to form a small abscess.

However, regardless of the initial primary lesion, it eventually softens, breaks down, and ulcerates. The resulting ulcer is painless, with a raised, soft, bright-raspberry-colored base, abundant granulation tissue, and jagged or scalloped borders.

Histological examination of biopsy specimens from such ulcers reveals an absence of necrotic debris and suppuration. At the edges of the ulcer, cellular infiltration extends into adjacent unaffected (normal) skin to varying depths, thereby reflecting the centrifugal spread of the infection from the involved dermal areas.

The infection can be transferred via contaminated hands to sites distant from the primary lesion. Specifically, cases of "secondary ulcers" on the hands and face are known to occur when the primary lesions are localized in the genital region. Researchers believe that the pathological process in donovanosis spreads *per continuitatem* or through autoinoculation. Hematogenous spread has been described, and lymphatic dissemination is also suspected. Individual susceptibility is thought to play a significant role in The Development of granuloma inguinale.

Calymmatobacterium granulomatis exhibits variable pathogenicity and morphological plasticity both within infected tissues and in culture, which explains the low contagiousness of donovanosis compared to other sexually transmitted diseases. It is quite possible that the causative agent is infectious only during a brief stage of its developmental cycle.

Many unresolved issues regarding the epidemiology of this disease remain. The low prevalence of donovanosis compared to syphilis or gonorrhea, coupled with its relatively long incubation period, accounts for the insufficient attention historically paid to the timely and thorough epidemiological screening of patients.

According to C. Sowmini and G. Nair (1973), among sexual partners where one has donovanosis, the other contracts the infection far more frequently than some authors claim. Detailed epidemiological contact tracing often reveals mild or subtle manifestations of the disease in many of these partners.

Diagnosis. The only reliable diagnostic method is the identification of Donovan bodies in material obtained from the margins of ulcers using a curette or forceps.

Bacterioscopic examination. Smears are prepared in the standard manner on Glass slides and stained using either the Giemsa or Wright method.

Microscopic examination of stained smears typically reveals erythrocytes, neutrophilic granulocytes, plasma cells, and lymphocytes. The most characteristic cytological feature is the presence of large, scattered mononuclear cells with round, oval, or Kidney-shaped nuclei. Macrophage size ranges from 20 to 60 µm (occasionally up to 90 µm) in diameter. Donovan bodies are relatively easy to detect within these cells and occur in two forms: encapsulated and non-encapsulated.

Stained encapsulated Donovan bodies are oval or kidney-shaped, 1–1.5 µm long and 0.5–0.7 µm wide, and surrounded by a clearly discernible dense pink capsule. The bacterial body stains blue, with dark blue or black chromatin inclusions visible inside the bacillus; these may be round or thread-like and are located centrally, peripherally, or at the poles. Non-encapsulated microorganisms appear as small, intensely stained bodies of various shapes: cocci, diplococci, or short rods. These immature, young forms measure 0.6–1 µm. Both encapsulated and non-encapsulated Donovan bodies reside within macrophages in clusters, scatters, or cyst-like formations, and both forms may coexist within a single cyst.

Cultures of Calymmatobacterium granulomatis are obtained by inoculating chicken embryos or by cultivating the Organism on fresh media. In the latter case, moist, shiny colonies typically appear within 24 hours. The donovanosis pathogen does not liquefy gelatin, yields a negative indole test, decolorizes litmus paper, and ferments and coagulates milk.

Donovan bodies are detected in skin and subcutaneous lesions in 90–95% of cases. They may be absent or difficult to identify in acute destructive lesions complicated by secondary fusospirochetal infection during very early disease manifestations, as well as in keloid-scar forms.

Histological examination is also of paramount importance. Key histological features of donovanosis include marginal epidermal hyperplasia and massive cellular infiltration of the dermis, interspersed with monocytes harboring Calymmatobacterium granulomatis. Characteristic alterations of the marginal epithelium comprise pronounced acanthosis, marked widening of intercellular spaces with The formation of exudate "islets" containing plasma cells, small numbers of segmented neutrophilic granulocytes, eosinophils, monocytes, and lymphocytes, alongside typical pseudoepitheliomatous hyperplasia. In some cases, this excessive, irregular epithelial proliferation mimics a malignant neoplasm.

Specific hallmarks of the disease include the state of the dermis, which displays a massive cellular reaction to Donovan bodies, resulting in exuberant granulation tissue growth and the arrangement of newly formed Blood Vessels in parallel bands. Histological analysis of early lesions reveals intense dermal cellular infiltration, desquamation of superficial epidermal layers, and edema of the deeper layers. As cellular infiltration in the dermal papillae progresses, the epithelial layers become damaged and eventually disappear. The skin and subcutis are frequently densely infiltrated with histiocytes, plasma cells, leukocytes, and, to a lesser extent, lymphocytes and a small number of fibroblasts. Within these infiltrates, small abscesses composed of segmented neutrophilic granulocytes are found. Pale cells—macrophages with faintly staining nuclei and foamy Cytoplasm packed with numerous pathogens—are also observed in histological preparations. These mononuclear cells are scattered in varying numbers throughout the upper layers of the affected tissue and the papillary dermis, with diameters ranging from 20 to 90 µm. Their nuclei are pyknotic and eccentrically placed. They are easily visualized with Giemsa staining (acquiring a deep red hue) and with hematoxylin and eosin.

In later Stages of the disease, particularly in hypertrophic forms, an excessive accumulation of Fibrous Connective Tissue is observed, with plasma cells, lymphocytes, and mononuclear cells populating the clefts between Collagen fibers. In sclerotic or cicatricial forms, thick bundles of hyalinized collagen fibers dominate the histological picture.

Differential diagnosis is performed with syphilis, to exclude which examinations for the presence of *Treponema pallidum* and serological monitoring are required; chancroid, which is confirmed by a short incubation period (3-5 days), multiple painful and easily bleeding ulcers with undermined and uneven edges, a moth-eaten base covered with purulent exudate, and the detection of *Haemophilus ducreyi* in ulcer discharges; inguinal lymphogranuloma, primarily affecting the Lymph Nodes (inguinal, genital, and rectal), caused by specific strains of *Chlamydia trachomatis* detected via characteristic intracellular inclusions in cell culture or chicken embryos, a positive Frei skin test and Formol-gel test, elevated body Temperature, headache, and joint pain; tropical filariasis, which causes genital elephantiasis without ulceration—diagnosis is supported by a history of frequent fever attacks, tumor-like tissue thickenings, and the detection of microfilariae in the patients' blood; Genital Tuberculosis, where genital ulcers differ from those in donovanosis, and biopsy reveals caseous necrosis, giant cells, and mycobacteria; and urogenital amebiasis, as amebic lesions of the external genitalia outwardly resemble donovanosis, and concurrent or sequential infection is possible (native unstained smears are examined to rule out amebiasis by identifying active, living *Entamoeba histolytica*).

Clinical Features. The disease is characterized by the development of granulomatous ulcerations of the skin and subcutaneous tissue (frequently extensive), predominantly in the genital and perineal regions. This condition goes by several names, which often leads medical students and physicians to confuse it with lymphogranuloma venereum or inguinal lymphogranuloma. Granuloma inguinale is commonly described under the following synonyms: Broca's donovanosis, tropical ulcerating granuloma, and the fifth venereal disease.

The disease begins insidiously. At the site of viral entry, inflamed, dense papules or vesicles appear with a slightly flattened surface, typically small and painless. They ulcerate to form single expanding ulcers with a velvety surface, or areas of granulomatous tissue with multiple coalescing round or oval ulcers. As a rule, the affected areas include the genitalia (glans Penis, foreskin, Clitoris, Labia minora), Perineum, perianal region, inguinal area, facial and trunk skin, hands, shins, and the mucous membranes of the Nose, Oral Cavity, Larynx, and Pharynx (see insert VIII, 5). The disease may acquire a systemic character, affecting other Organs and bodily systems (skin, fascia, Muscles, Liver, Spleen, Urinary Bladder, bones).

A typical donovanosis ulcer presents as an expanding mass of granulation tissue resembling a tumor, with notched or wavy edges sharply demarcated from the surrounding skin. It is usually soft to the Touch, though the surrounding skin may be edematous, thickened, and of a juicy, bright pink color; the base is clean with serous discharge or may be covered by a thin yellowish crust. With secondary infection, the ulcer acquires a "dirty" appearance, covered with scabs and necrotic masses. The simultaneous appearance of multiple ulcers is possible.

Donovanosis ulcers grow slowly but steadily at the periphery, potentially involving large areas of skin in the ulceration process. Discharge from the ulcers is scant, seropurulent, occasionally blood-tinged, and carries a characteristic foul odor. Despite the prominence of ulceration, the process is relatively painless, adenopathy is minimal or absent, and the patient's general condition remains undisturbed.

Additionally, As a result of autoinfection, opposing skin folds are frequently affected—the labia, intergluteal clefts, inguinoscrotal folds, and perineum. In men, the process often begins on the glans penis and spreads to the penile shaft, Scrotum, inguinoscrotal folds, thighs, and pubic area. In women, from the labia minora or clitoral frenulum (the most common primary sites), the process extends to the Labia Majora, Vagina, inner thighs, pubic region, rectum, and perineum. Besides the external genitalia, the vagina, cervix, and other Internal Organs may be involved. However, primary cervical lesions with extension to the vagina and external genitalia can also occur. Occasionally, pelvic organs are drawn into the pathological process.

Oral cavity donovanosis ranks second in frequency. It is notable for its pain, especially if the Teeth are involved. Extragenital donovanosis affects the Lips, Gums, Cheeks, palate, pharynx, larynx, nose, neck, and chest. These forms account for approximately 6% of all donovanosis cases (W. McCormack, 1980).

Systemic donovanosis affecting the bones, joints, liver, and spleen is rare and has been described in patients under specific conditions (post-abortion, Miscarriage, or surgery amidst severe debilitating illnesses). Hepatic abscesses containing Donovan bodies have been observed. Osteomyelitis with characteristic radiographic changes (multiple irregular osteomyelitic periosteal lesions with generalized demineralization of the limb bones) has been described in young women with cervical donovanosis. Visceral donovanosis involving the Lungs, as well as the spread of infection from the cervix to the urinary bladder, may also occur. Disseminated donovanosis is currently rare.

Complications are more frequently observed in women. Sequelae of donovanosis may include genital pseudo-elephantiasis, urethral, vaginal, and rectal strictures. Various genital deformities occur, particularly in men—phimosis, elephantiasis, penile necrosis, urethral and anal strictures, and other complications. Squamous Cell Carcinoma is extremely rare. In elderly patients, systemic granuloma inguinale and extensive lesions accompanied by comorbidities (secondary anemia, tuberculosis, Cancer) can be fatal.

Depending on clinical features and the predominance of specific symptoms, several Clinical forms of granuloma inguinale are distinguished: ulcerative, verrucous, exuberant, necrotic, sclerosing, mucosal, and mixed.

Ulcerative forms of donovanosis are the most common. Genital ulcers may be solitary or multiple, tending toward vegetation, serpiginous growth, and extension into the inguinal region. Ulcerative forms are subdivided into ulcerovevegetative, serpiginoulcerative, ulceroperforating, and keloid-scarring types. The latter is more frequently observed in women and is characterized by early, massive fibrous tissue formation. Due to rapid fibrosis, active ulcer islands become isolated and frequently break down. The fibrous tissue is coarse and inelastic, which can cause various genital deformities. Finding Donovan bodies in tissue smears is particularly difficult in this form.

The verrucous form occurs with equal frequency in both sexes. Lesions are typically extensive, involving the genitalia and adjacent areas. It is characterized by the appearance of prominent, pale pink, slightly bleeding warty growths at the Base of the ulcers. Ulcers are frequently widespread. The scant exudate dries to form a serosanguineous crust that adheres tightly to the granulation tissue. Ulcers are usually painless, with a torpid course. Hypertrophic and elephantiasic types are Variants of the verrucous form. In the hypertrophic type, the ulcer base is elevated above the surrounding skin and consists of large, coarse, pale pink granulation tissue, making the surface convex. The ulcer is painless, discharge is minimal, and it enlarges slowly, potentially persisting in this state for several months. The causative agent is difficult to detect in surface exudate, but is readily identified deep within the granulation tissue. The elephantiasic type is characterized by a tendency toward elephantiasis development.

The exuberant form is characterized by significant growth of bright red granulations with a velvety, glazed, moist surface. The granulations protrude above the skin surface, and the ulcer margin is thin and difficult to delineate. The surrounding skin is slightly edematous and infiltrated. Ulcer discharge is seropurulent, abundant, and has a specific unpleasant odor. Young, non-encapsulated forms of Donovan bodies predominate in the discharge, located both intracellularly within mononuclear cells and extracellularly. Smears reveal a high number of neutrophilic segmented granulocytes, within which *Calymmatobacterium granulomatis* can frequently be observed. Patients complain of pain in the lesion area and intolerable itching.

The necrotic form typically develops in patients with chronic, long-standing donovanosis and represents the most severe variant of the disease. Against the Background of a chronic course, an acute, rapidly spreading destructive inflammatory process suddenly arises, where pink granulation tissue is quickly replaced by gray-brown necrotic tissue with abundant thick, chocolate-colored discharge. This form most commonly results from secondary infection complicating donovanosis ulcers. Bacteriological examination OF the exudate reveals numerous pyogenic flora, fusospirochetal infection, etc., while Donovan bodies disappear from surface discharges.

Lesions rapidly extend peripherally and deeply, destroying tissues down to the fascia, muscles, and even bones. In women, the external genitalia, perineum, and perianal region can be completely destroyed. The rectovaginal septum frequently disintegrates, forming rectovaginal fistulas accompanied by septic cystitis. In men, penile necrosis can lead to complete destruction of the organ. The process is typically accompanied by regional lymphangitis and lymphadenitis. The patients' general condition deteriorates; they suffer from fever, chills, systemic toxic symptoms (weakness, malaise, headache), and acute secondary anemia may develop. As the infection further generalizes, the liver, spleen, Middle ear, and bones are affected. Without timely therapeutic intervention, necrotic donovanosis can be fatal.

The mixed form of donovanosis manifests when a single patient simultaneously exhibits symptoms characteristic of two or more of the aforementioned clinical variants.

Donovanosis most commonly runs a chronic course, typically lasting 2 to 4 years, although short-term (several months) and prolonged (up to 30–40 years) courses are possible. The tendency for recurrence after seemingly healed ulcers is quite high, often leading to new ulcers that follow the same developmental cycle as earlier ones.

The General condition of patients usually remains unaffected for a long time. Some complain of pain at the ulcer site, while others (especially women) report intolerable itching in the external genitalia. In some patients during late stages, sexual intercourse becomes difficult or entirely impossible. Patients with early signs of donovanosis are capable of a normal sex life. Infected women can conceive and give birth to healthy children, though Pregnancy frequently ends in miscarriage or abortion.

The disease can cause mechanical difficulties during urination, defecation, sexual intercourse, childbirth, and even walking in cases of extensive lesions of the genitalia, inguinal, or perianal regions. Pseudo-elephantiasis of the genitalia is noted in 15–20% of donovanosis patients, occurring most frequently in women. The cause of this complication is the mechanical compression of Lymphatic vessels by scar tissue, and pseudo-elephantiasis does not always correlate with the duration of the disease. For example, in women, early lesions (a few months old) sometimes cause elephantiasis of the labia majora, labia minora, or clitoris. Urethral, vaginal, or rectal stenosis may complicate the sclerosing form of donovanosis, causing difficulties with urination, defecation, and childbirth. During the healing of extensive genital lesions, adhesion of the labia majora and minora in women, and attachment of the penis to the scrotum in men, may be observed. Long-standing ulcers can induce other genital deformities (penile curvature, tissue destruction followed by scarring in the labial areas).

Oral cavity donovanosis may cause synechiae between the lips, cheeks, and gums, restricting Mouth opening, impairing swallowing, and causing severe distress to patients.

The condition of patients with late and complicated forms of donovanosis is extremely grave, as the disease is incurable in such stages, much like late-stage cancer or leprosy.

Treatment is prescribed after diagnosis confirmation. Co-trimoxazole is effective—a bactericidal drug containing trimethoprim and sulfamethoxazole, taken in tablets for 10 days (40 tablets). In addition to sulfonamides, Antibiotics have found widespread application, notably benzylpenicillin (total dose 5,000,000–7,000,000 IU) and streptomycin sulfate. The latter is administered intramuscularly at 1 mL twice daily for 12–14 days (average course dose 25–30 g). Concurrently, sulfonamides and antibiotics are recommended for topical application as powders or compresses on ulcers after preliminary cleansing with disinfectant solutions (hydrogen peroxide). General strengthening therapy and Vitamins are prescribed as indicated.

Preventive measures are identical to those for other sexually transmitted infections.