Granuloma inguinale

　　1. Etiology

　　Calymmatobacterium granulomatis belongs to the genus coccobacillus with Gram-negative staining, does not produce spores, has a capsule, no flagella, and is 1.5mm x 0.7mm in size. In tissue smears, the bacteria are encapsulated in the vacuole of large tissue cells, and sometimes in polymorphonuclear leukocytes or plasma cells. Its morphology and antigenicity are similar to the genus Klebsiella. It does not grow on artificial culture media, and it was reported to grow in the yolk sac of chicken embryos. Its bacteriological and biochemical characteristics have not been well determined. Electron microscopy confirms that its ultrastructure is similar to that of typical Gram-negative bacteria, and bacteriophage-like particles are found in Donovan bodies. Filamentous or vesicular protuberances can be seen on the wavy cell wall.

　　The encapsulated granuloma bacillus is pathogenic only to humans. The pathogen first forms a slowly progressing papule or subcutaneous nodule at the site of invasion, which later ulcerates and involves surrounding tissue, with a pathological basis of a large number of inflammatory cells infiltrating.

　　History and Progress: In 1882, McLeod first reported the disease, describing it as a crawling ulcer. In 1905, Donnovan first discovered the inclusion, stained bipolar in macrophages, in the damaged exudate, thereby proving that the causative agent is a cell body similar to Leishmania, known as Donovan body. In 1943, Anderson successfully cultivated it in the yolk sac of chicken embryos. In 1959, Goldberg successfully cultivated it in artificial culture medium.

　　Pathogen: The pathogen is Calymmatobacterium granulomatis, also known as Donnovan's bacillus, belonging to the genus Klebsiella. It is short rod-shaped, about 1.5mm in length, 0.5-0.7mm in width, with a capsule, no spores or flagella. Gram-negative. In damaged tissue cells, it appears as an oval inclusion with 20-30 bodies inside, known as Donovan bodies, reaching 1-2mm in size, presenting a blue-black needle-like shape. Wright-Giemsa staining or Warthin-Starry staining shows polar staining. Electron microscopy reveals common bacteriophages with intestinal bacteria, proving that this type of bacteria can be transmitted through a poor sanitary condition of fecal contamination environment, and also explains the pathogenic reason in males engaged in anal sex. It can be successfully cultivated in chick embryo yolk sac and artificial culture medium, but an animal infection model has not yet been established.

　　2. Pathogenesis

　　The encapsulated granuloma bacillus is pathogenic only to humans. The pathogen first forms a slowly progressing papule or subcutaneous nodule at the site of invasion, which later ulcerates and involves surrounding tissue, with a pathological basis of a large number of inflammatory cells infiltrating.

　　Complications:It can cause pseudo-lymphedema in the external genitalia such as the labia, clitoris, penis, and scrotum due to lymphatic obstruction. It can also cause narrowing of the urethra, vagina, anus, and other areas due to scars and adhesions. It can also lead to cancer and destruction of the external genitalia. Due to scar formation, lymphatic obstruction can occur, leading to elephantiasis in the penis, scrotum, and vulva. It can also cause narrowing of the urethra, vagina, rectum, or anus due to scar formation and tissue adhesion. Due to the persistent ulcers and fistula scars, squamous cell carcinoma may occur.

　　1. Onset:More common in males, with a male-to-female ratio of 2-3:1, most common in sexually active individuals aged 20-45 years.

　　2. Incubation period:Since transmission requires repeated contact, the incubation period is not fixed, ranging from 8 to 80 days.

　　3. Common sites:The damage is more common in the external genitalia, with males more often affected in the prepuce, coronal sulcus, frenulum, glans, and penis, while females are more commonly affected in the labia majora and minora, frenulum, perineum, and cervix. Both genders can be affected around the perianal area, with homosexuals being particularly prone. The infection can also spread to the nose, lips, oropharynx, limbs, chest, abdomen, buttocks, and internal organs such as the colon, liver, and kidneys, as well as to the epididymis, bone marrow, bones, and joints such as the orbital bone, tibia, clavicle, and sacroiliac joint.

　　4. Characteristics of skin lesions:The initial damage appears as painless, dark red, moist papules in the external genitalia, which gradually develop into subcutaneous nodules with a diameter of about 0.5 cm. The nodules can ulcerate to form ulcers. If mixed infection with the spirochete occurs, the tissue can rapidly necrose, and the ulcers continue to develop. The base can form proliferative beef-red velvet-like granulation tissue, which is harder in texture, with elevated edges, showing warty appearance, and is prone to bleeding upon contact. The surface is covered with seropurulent secretions, with a foul odor. If neglected, the ulcers may enlarge and deepen over time, affecting the urethra, anus, and other areas. Severe tissue destruction can lead to the formation of fistulas that are difficult to heal. Finally, due to fibrous tissue proliferation, hypertrophic scar nodules may form, but they do not heal completely, accompanied by hypopigmentation, ulcers, granulation tissue, and scar tissue, where the causative organisms can be found. Due to autoinoculation, scattered satellite-like small ulcers may appear around the damage.

　　5. Systemic dissemination:About 6% of patients may spread to other parts of the body through hematogenous or lymphatic routes, such as the skin of the face, oral cavity, chest, lower abdomen, and buttocks, and may also spread to organs such as the liver, colon, or epididymis.

　　6. Complications:Due to scar formation, it can lead to lymphatic obstruction, causing elephantiasis in the penis, scrotum, and female genitals, and can also cause stricture of the urethra, vagina, rectum, or anus due to scar formation and tissue adhesion. Due to the persistent and unhealed ulcers and fistula scars, squamous cell carcinoma may occur concurrently.

　　7. Pseudobubo:It occurs locally in the subcutaneous granuloma of the inguinal area, but not in lymph node enlargement, hence it is called pseudobubo. It can also develop into granulomatous ulcer, which is difficult to heal.

　　8. Course of the disease:The disease progresses slowly, may last for several years or even a dozen years, and cannot be cured spontaneously. The disease progresses rapidly during pregnancy, and a small number of late-stage patients may have malignant transformation, leading to squamous cell carcinoma.

　　Maintain regular treatment, avoid giving up halfway, and go to the hospital for a review or evaluation after completing the treatment. If symptoms persist or recur, go to the hospital immediately for examination. Avoid sexual contact and use barrier contraceptives such as condoms before the patient and their sexual partner are completely cured. It is also necessary to persist in checking and treating the sexual partners of the patients.

　　1. If the sexual partner of an inguinal granuloma patient has had sexual contact with the patient within 60 days before the onset of symptoms, they should be examined and treated.

　　2. Prevent inappropriate sexual behavior, avoid unclean sexual intercourse.

　　3. The medication should be continued until the lesion is completely resolved. Those who discontinue medication before 3 weeks may be cured, but there is a high risk of recurrence.

　　4. Pay attention to personal and family hygiene, fix the bed linen and hygiene supplies, etc.

　　1. Histopathological examination:It is a reliable method for diagnosing this disease. Tissue samples taken from the edge of active lesions show HE staining, revealing incomplete keratinization of the epidermis, disappearance of the granular layer, thickening of the stratum spinosum, formation of sponges, and pseudosquamous hyperplasia. The central area of the lesion may have atrophy and/or ulcer formation. In the thickened stratum spinosum, there is outward migration of polymorphonuclear leukocytes, forming focal small abscesses. The most characteristic histological change is the diffuse and high-density cell infiltration in the dermal papillae and upper dermis, edema, abundant vascular and endothelial hyperplasia, and infiltrating cells including a large number of plasma cells, histiocytes, varying amounts of erythrocytes extravasation, and sometimes lymphocytes and epithelioid cells or Langerhans giant cells. Most characteristic is that Giemsa staining can identify enlarged histiocytes (20-90μm) with multiple compartments, each compartment containing 1-20 Donovan bodies, which are 1-2μm in size, dark blue-black, resembling needles.

　　2. Cytological examination:Take about 1mm3 of tissue fragments from the biopsy, place them between two slides, and rotate in both directions to make a cell smear. After the smear dries in the air, fix it with methanol and perform Giemsa staining. Donovan bodies can be seen in mononuclear cells under the microscope (they can also sometimes be seen outside the cells).

　　3. Bacterial culture:Emulsify the tissue fragments obtained with a slide with sterile saline, inoculate them into the yolk sac of 5-day-old chick embryos, and incubate at 37℃ for 72 hours. The encapsulated bacteria of the granuloma will grow in the yolk sac fluid, and the needle-like pathogens can be displayed after staining.

　　4. Serological examination:There is no practical serological method. Complement fixation test can only detect antibodies with significant titer in the serum of patients with more than 3 months of disease course, and it has cross-reactivity with Klebsiella pneumoniae and Klebsiella rhinoscleromatis.

　　5. Histopathology:The center of the lesion is an ulcer with the edges showing hyperkeratosis or pseudo-squamous cell tumor-like hyperplasia. The ulcer edges have pseudo-squamous cell tumor-like hyperplasia, thickened stratum spinosum, elongated rete ridges, dense tissue cells, plasma cells, and a small amount of lymphocytes in the dermis. There are intercellular microabscesses with polymorphonuclear leukocytes. Gram staining shows scattered tissue cells with cytoplasm in a multicystic vesicular pattern, containing 1-20 oval bodies (Donovan bodies) with a diameter of 1-2 μm, which are of diagnostic value.

　　Nutritional and dietary recipes for granuloma inguinale

　　1. Peanut Red Bean Date Garlic Soup

　　Ingredients: 90 grams of peeled peanuts, 60 grams of red beans, and 60 grams of dried red dates; 30 grams of garlic.

　　Preparation: Boil all the ingredients together to make a soup.

　　Effect: tonify the body, nourish the blood, remove dampness, and detoxify.

　　Usage: Take in the morning and evening.

　　2. Chrysanthemum Flower Luffa Clam Soup

　　Ingredients: 30 grams of clam meat, 15 grams of chrysanthemum flower, and 10 grams of luffa sinensis.

　　Preparation: Boil the above three ingredients in an appropriate amount of water to make a decoction, and season with salt.

　　1. TCM treatment methods

　　Traditional Chinese medicine (TCM) makes a differential diagnosis based on the location of the primary sore, the severity of skin damage, the size of the granuloma, and the depth of the ulcer, considering whether there is pus and blood on the ulcer surface and the overall condition of the body. The tongue and pulse are also taken into account. Generally, the primary sore is often due to damp-heat and toxins, while the pseudo-horseshoe ulcer in the inguinal region is often associated with phlegm and heat accumulation. Granulomas are usually due to blood stasis, and later stages often involve deficiency of the liver and kidney yin.

　　1. Granuloma inguinale with damp-heat and toxic syndromeThe genitals may develop papules and subcutaneous nodules, which can be painful. The surface may quickly become eroded, forming ulcers with exudate, accompanied by fever and poor appetite. The tongue is red with a yellow coating, and the pulse is slippery and rapid. This is due to the invasion of the liver meridian by damp-heat toxins. Treatment should focus on clearing heat, promoting diuresis, and detoxifying.

　　The commonly used herbal formula is Ermio San combined with Wuwei Xiaodai Decoction: Huangbai 10g, Cangzhu 10g, Yiyiren 30g, Cheqianzi 10g, Tufuling 30g, Pugongying 30g, Yejuhua 10g, Tiankuizi 10g, Didingcao 10g. In this formula, Huangbai and Cangzhu are the main herbs for clearing heat and drying dampness; Yiyiren and Cheqianzi are combined with the main herbs to clear heat and eliminate dampness; Tufuling, Pugongying, Yejuhua, Tiankuizi, and Didingcao are used to clear heat and detoxify. For severe damp-heat, add 10g of Longdancao; for severe toxic heat, add 30g of Baihua She舌 grass; for those with concurrent phlegm-heat, add 10g of Chuanbei Mu.

　　2. Inguinal granuloma with phlegm-toxin accumulation syndromeIt can be seen in the formation of pseudo-horseshoe abscess in the inguinal area, with skin and kernel connected, some nodules merging into lumps, not moving when pushed, with自觉 pain, red tongue, yellow tongue coating, and wiry and slippery pulse. This is due to the accumulation of phlegm toxicity and the stasis of Qi and blood. Treatment should focus on clearing heat and detoxifying, and softening hard lumps and dispersing nodules.

　　The commonly used herbal formula is modified Wushen Decoction combined with Xiaolao Wan: Jinhuahua 10g, Lianqiao 10g, Huangbai 10g, Zexie 10g, Fuling 20g, Xuan Shen 20g, Jiangshai 30g (decoct first), Zhubei 10g, Xiangfu 10g, Chenpi 10g, Baijiangcan 10g, Qingpi 10g, Fahan 10g, Gancao 6g. In this formula, Jinhuahua, Lianqiao, and Huangbai are the main herbs for clearing heat and detoxifying; Zexie and Fuling are used to invigorate the spleen and eliminate dampness; Xuan Shen, Jiangshai, and Zhubei are used to soften hard lumps and disperse nodules; Xiangfu, Chenpi, Baijiangcan, Qingpi, Fahan, and Gancao are used in combination with the main herbs to regulate Qi and resolve phlegm. The whole formula works to clear heat and detoxify, soften hard lumps and disperse nodules. If there is severe toxic heat, add 30g of Baihua She舌 grass; for Yin deficiency, add 10g of Shengdi and Shashen; for hyperactivity of liver fire, add 10g of Huangqin and Qingdai.

　　3. Inguinal granuloma with Qi and blood stasis syndromeIt can be seen in the formation of granuloma in the perineum and inguinal area, with local pain, elevated granuloma, curled edges, relatively hard texture, often accompanied by general emaciation, lack of appetite, dark tongue, and wiry and thin pulse. This is due to the obstruction of Qi and blood, fighting with toxic heat and phlegm-dampness, hence the formation of granuloma in the perineum and inguinal area. The obstruction of Qi and blood leads to local pain. The elevated granuloma with curled edges and relatively hard texture is also a sign of Qi and blood stasis. Due to the obstruction of Qi and blood, blood stasis prevents the generation of Qi and blood, leading to general emaciation and lack of appetite. Dark tongue and wiry and thin pulse are also signs of Qi and blood stasis. Treatment should focus on activating blood circulation and removing blood stasis, and clearing heat and detoxifying.

　　The commonly used herbal formula is modified Xuefu Zhuyu Decoction combined with Wuwei Xiaodai Decoction: Chuanxiong 10g, Taoren 10g, Honghua 10g, Jiegeng 10g, Niuxi 10g, Yejuhua 20g, Tiankuizi 30g, Xuan Shen 20g, Pugongying 30g, Chishao 10g, Gancao 10g. In this formula, Chuanxiong, Taoren, Honghua, and Chishao are used to activate blood circulation and remove blood stasis; Jiegeng and Niuxi are used to harmonize Qi and blood, regulate Qi flow; Yejuhua, Tiankuizi, and Pugongying are used to clear heat and detoxify; Xuan Shen is used to soften hard lumps and disperse nodules; Gancao is used to harmonize the other herbs. For granulomas with hard texture, add 10g of Chuanshanjie and 10g of Dilong; for those with marked pain, add appropriate amounts of Sanqi powder and Yizhu.

　　4. Inguinal granuloma with liver and kidney deficiency syndromeIt can be seen in granuloma and ulceration, not healing for a long time, with remittent fever, pale complexion, fatigue, dizziness, shortness of breath, heat in the palms and soles, red tongue, thin coating, and thready and rapid pulse. This is due to insufficient liver and kidney, internal excess of虚 fire, so the skin and core溃破. Not healing for a long time, insufficient liver and kidney can have remittent fever, pale complexion, fatigue, dizziness, shortness of breath, heat in the palms and soles. Red tongue, thin coating, and thready and rapid pulse are all signs of insufficient liver and kidney. Treatment should focus on nourishing the liver and kidney.

　　Commonly used drugs are modified Liuwei Dihuang Wan: raw rehmannia 10g, fructus Corni 10g, rhizoma Dioscorea opposita 10g, alisma 10g, poria 10g, Cortex Moutan 10g, Ophiopogon japonicus 10g, Adenophora trachycarpa 10g, Lycium barbarum 10g, tangerine peel 10g, glycyrrhiza 10g. Raw rehmannia, fructus Corni, and rhizoma Dioscorea opposita are the main drugs, nourishing the Yin of the liver and kidney; alisma, poria, and Cortex Moutan are combined with the main drugs to relieve excess; Ophiopogon japonicus, Adenophora trachycarpa, and Lycium barbarum clear away the虚 heat; tangerine peel and glycyrrhiza harmonize the spleen and stomach. If the granuloma is hard, add 10g of穿山甲 and 20g of bupleurum; for those with toxic heat, add 30g of Taraxacum mongolicum and 30g of Hedysarum multiflorum.

　　2. Western medical treatment methods for inguinal granuloma

　　Antibiotics are effective for the disease, especially tetracycline, doxycycline, and streptomycin, with a general course of not less than 10-15 days, 500mg each time, four times a day. Penicillin is ineffective. The prognosis was poor in the past, but it has greatly improved due to the development and application of antibiotics in recent times.

　　1. Drug treatment

　　Starting in 1974, streptomycin was widely used in India to effectively treat the disease. Different countries use different drugs, such as chloramphenicol in Papua New Guinea, sulfamethoxazole/trimethoprim (sulfamethoxazole-trimethoprim) in South Africa, and methenamine in Brazil. The recommended treatment plan by the US Centers for Disease Control and Prevention is as follows:

　　Oral磺胺甲噁唑/甲氧苄啶 (sulfamethoxazole/trimethoprim, SMZ-TMP) 2 tablets, twice a day, for at least 3 weeks; or doxycycline 100mg, oral, twice a day, for at least 3 weeks. Alternative options include ciprofloxacin 750mg, oral, twice a day, for at least 3 weeks; or erythromycin 500mg, oral, four times a day, for at least 3 weeks.

　　If there is no improvement in the lesions after several days of treatment, it should be considered to add aminoglycoside antibiotics (such as gentamicin 1mg/kg, intravenous injection, once every 8 hours).

　　Sexual partners who have sexual contact with the patient or have similar clinical manifestations should be treated simultaneously. Pregnant and lactating women should be treated with erythromycin. Follow-up should be conducted during the treatment period until symptoms and signs disappear. In view of the long duration of the above drug treatment, some people have cured one patient with extensive genital and inguinal damage by taking azithromycin 500mg orally once a day for one week.

　　2. General Therapy

　　Sexual activity should be prohibited during treatment.

　　3. General Treatment

　　(1) Selection of Drugs: Tetracyclines, macrolides, ampicillin (ampicillin), or aminoglycosides are effective for this disease.

　　(2) Treatment Plan:

　　① 1.0g of sulfamethoxazole/trimethoprim (Bactrim), oral, 2 times/d, for 3-4 weeks.

　　① 0.5g of tetracycline, oral, 4 times/d, for 3-4 weeks; or 0.1g of doxycycline (doxycycline), oral, 2 times/d, for 3-4 weeks; or 0.1g of minocycline (minocycline), oral, 2 times/d, for 3-4 weeks.

　　② 0.5g of erythromycin, oral, 4 times/d, for 3 weeks; or 0.15g of roxithromycin, oral, 2 times/d, for 3 weeks; or 0.5g of clarithromycin, oral, 2 times/d, for 7-10 days; or 0.25g of azithromycin, oral, 1 time/d, for 7-10 days, with the initial dose of 1.0g.

　　③ 1.0g of streptomycin, intramuscular injection, 2 times/d, for 10 days; or 80,000 U of gentamicin, intramuscular injection, 2 times, for 3 weeks.

　　⑤ Ampicillin (ampicillin) can also be used. For those allergic to penicillin, lincomycin can be used.

　　⑥ There are also reports of treating the disease with norfloxacin (fluoroquinolone), ciprofloxacin (ciprofloxacin), azithromycin, ceftriaxone (ceftriaxone).

　　4. Local Treatment:Ulcers can be flushed with potassium permanganate solution, saline, or hydrogen peroxide solution, and then treated with antibiotic ointment. It should be changed daily to keep the passage unobstructed and the wound clean. Protective ointment can be applied externally around the ulcer to prevent auto-inoculation.

　　5. Surgical TreatmentFor those with advanced stage with tissue destruction, scars, and deformities, surgical treatment can be performed.

　　6. Management of Sexual Partners:Preventive treatment should be carried out for sexual partners who have had sexual contact with the patient in the past 3 months.

　　7. Observation of Efficacy:It can be judged by whether the clinical manifestations improve or whether the Donovan bodies persist.