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Sporotrichosis
- 1. Name: Purshotam Kumar Sah Kanu Roll No.: MB 1318/075 Level: M.Sc Microbiology (3rd Sem) Central Department of Microbiology Tribhuvan University, Kirtipur Kathmandu, Nepal MB 609 Systemic and Diagnostic Mycology
- 2. Definition •Subcutaneous fungal infection, characterized by mobile tender nodules forming ulcer, may be followed by chronic sporotrichosis in the form of multiple hard nodules along lymphatic channels.
- 3. SPOROTRICHOSIS Sporotrichosis is a chronic infection characterised by nodular lesions and ulcers in the lymph nodes, skin or subcutaneous tissues and occasionally in the internal organs. The localised lesions are usually found on the hands, arms or legs. It is a chronic infection often limited to the cutaneous and subcutaneous tissues, and may rarely become disseminated. It is caused by a dimorphic fungus Sporothrix schenckii which lives as a saprophyte in the external milieu. It has been isolated from the soil, the plants and the wood.
- 4. S.schenckii is a dimorphic fungus found all over the world and occurs mainly in Central and SouthAmerica, parts of the USA andAfrica andAustralia. It is rare in Europe. The fungus is found in soil, decaying woods, thorns, and on infected animals including rats, cats, dogs, and horses.
- 5. Etiology: Causative Agent: It is caused by Sporothrix schenckii,a saprophyte in nature. Sporothrix schenckii(A dimorphic fungus). S.schenckii is a complex of several clinico- epidemiologically important species.These include S.albicans, S.brasiliensis (in Brazil), S. mexicana (in Mexico), S.globosa (in UK, Spain, Italy, China, Japan, USA, and India), and S.schenckii sensu stricto (“in the strict sense”)
- 6. Morphology: S.schenckii is a dimorphic fungus. In nature and in culture at 25 to 30°C, it develops as a mould with very thin (1-2 mm) septate hyphae; spore- bearing hyphae carry clusters of oval spores. The yeast phase is formed in tissue and in culture at 37°C, and is composed of spherical or cigar-shaped cells (1-3 × 3- 10 mm).
- 7. Cont.. In infected tissues, the fungus is seen as cigar shaped yeast cells, without mycelia. Sometimes ‘asteroid bodies’ are seen in the lesion, composed of a central fungus cell with eosinophilic material radiating from it. Spore is the infective stage of the fungus. It causes infection primarily on the hand or the forearm through direct contact of the skin by spores. Typically, infection is introduced in skin through a penetration of thorn.
- 8. Cont.. At the site of thorn injury, it causes a local pustule or ulcer with the nodules along the draining lymphatics. Frequently, the regional lymph nodes draining the ulcer enlarge, suppurate, and ulcerate. The primary lesion may remain localized or in the immunocompromised individuals may disseminate to involve the bones, joints, lung, and rarely the central nervous system. In infected tissue, the yeast appears as round, oval, or cigar shaped cells with irregular borders.
- 9. Cont.. Periodic acid-Schiff (PAS) or Gomori‟s methenamine silver (GMS) stain is useful to demonstrate these structures in the stained smears. The fungus on SDA at 25°C produces black and shiny colonies, which become wrinkled and foggy during course of time. The mold contains hyphae bearing flower-like structures of small conidia on delicate sterigmata. Laboratory diagnosis of sporotrichosis is made by demonstration of asteroid bodies in pus of the abscesses.
- 10. Cont.. Asteroid bodies consist of a central basophilic budding yeast cell with eosinophilic material, which radiates from the center. FIG. 72-4. Sclerotic bodies.
- 11. Pathogenesis • The fungus is a saprophyte found widely on plants, thorns and timber. Infection is acquired through thorn pricks or other minor injuries. Rare instances of transmission from patients and infected horses and rats have been recorded. Sporotrichosis most frequently presents as a nodular, ulcerating disease of the skin and subcutaneous tissues, with spread along local lymphatic channels but seldom extends beyond the regional lymph nodes. Most cases occur in the upper limb.
- 12. Cont… Human infections are mainly associated with S.schenckii sensu stricto, S.brasiliensis and S.globosa. S.brasiliensis and S.schenckii are the most virulent species in terms of mortality, tissue burden, and tissue damage with S. globosa being just next in virulence. Occupations such as agriculture, gardening, foresting, nursery and veterinary work are particularly at risk. Human infections have also been associated with insect bites, fish handling and bites of birds, cats, dogs, horses, reptiles. Occurrence of infection depends upon presence of abundant fungus in the environment and not portal of entry, age, gender, and race.
- 13. The disease frequently occurs in young individuals between 20 and 50 years of age. Only up to 60% of patients would recall history of prior injury. The incubation period varies from a few days to a few months (average 3 weeks).
- 14. Clinical Features The primary lesion is a small, indurated, progressively enlarging papulonodule, developing at inoculation site. It may ulcerate (sporotrichotic chancre) with or without transient satellite adenopathy. Clinical variants include a. lymphocutaneous sporotrichosis, b. fixed cutaneous sporotrichosis, or c. extracutaneous or systemic disease.
- 15. Extracutaneous dissemination may be in the form of osteoarticular, pulmonary, ocular or central nervous system disease; osteoarticular being the most common. Multifocal or disseminated cutaneous sporotrichosis means three or more lesions involving two different anatomical sites. Lymphocutaneous sporotrichosis is the classic form (Fig. 1) accounting for 70–80% of the cases. A string of nodules may appear along the draining lymphatics. Secondary lesions present as erythematous papules, nodules or plaques with smooth or verrucous surface. Some may soften, ulcerate and produce seropurulent discharge. They are mostly asymptomatic or mildly pruritic or painful.
- 16. In fixed cutaneous sporotrichosis, the infection remains confined to a single skin lesion at inoculation site (Fig. 2). Lesional morphology may be noduloulcerative or crusted erythematous to verrucous plaque (Fig. 3). Rare forms include those resembling keratoacanthoma, facial cellulitis, pyoderma gangrenosum, prurigo nodularis, soft tissue sarcoma, basal cell carcinoma, erysipeloid orrosacea. Involvement of exposed parts like extremities is common. This form is associated with high host resistance and better therapeutic outcome. It has been suggested that fixed cutaneous disease is caused by strains growing best at 35°C, whereas lymphocutaneous and extracutaneous disease is by strains that grow both at 35°C and 37°C.
- 17. The extracutaneous (systemic) form is a result of hematogenous spread in immunosuppressed patients. Manifestations include sinusitis, osteoarticular disease, meningitis and endophthalmitis. Pulmonary disease is rare and may manifest as cough, low- grade fever, weight loss, mediastinal lymphadenopathy and cavitation. Extracutaneous sporotrichosis has been reported as an emerging mycosis in human immunodeficiency virus (HIV) seropositive individuals in recent years.
- 18. Figs 1A and B: Cutaneous sporotrichosis. Lymphocutaneous sportrichosis involving upper limb; (A) Lower limb; (B) A string of noduloulcerative lesions appear along the lymphatics proximal to the initial inoculation (injury) site A B
- 19. Figs 2A to D: Cutaneous sporotrichosis: Fixed cutaneous sporotrichosis.A large indurated granulomatous plaque over forehead (A), Nasal bridge (B), Right cheek (C), Nose tip (D). Small papular lesions at the periphery of primary lesion are suggestive of destabilization of the lesion and results from trauma of surgery or manipulation of lesion
- 20. Figs 3A and B: Cutaneous sporotrichosis. (A) Ulcerative variant of cutaneous sportrichosis presenting as painless, nonhealing ulcers involving left mandibular area (B) Noduloulcerative lesions involving ear pinna and retroauricular area as a result of inoculation of Sporothrix schenckii following ear prick
- 21. Box 1: Differential diagnosis for cutaneous sporotrichosis • Cutaneous tuberculosis • Cutaneous leishmaniasis • Nocardiosis • Chromoblastomycosis • Paracoccidioidomycosis • Atypical mycobacteriosis
- 22. Laboratory Diagnosis Diagnosis is made by culture as frequently the fungus may not be demonstrable in pus or tissues. Collection of Infected Material: Pus should be aspirated from unruptured nodules. Swabs, scrapings or biopsies of ulcerated lesions should be collected in a sterile container. A. Micrscopic Examination: Direct microscopy is of little. Fine-needle aspiration cytology may show epithelioid cell granuloma, asteroid bodies and/or yeast cells and cigarshaped bodies [periodic acid Schiff (PAS) or Grocott‟s methanamine silver (GMS) stains]. The sensitivity/specificity of direct microscopic examination remains under evaluated as most studies consider it unhelpful due to paucity of fungal cells.
- 23. B. Culture: Culture of S.schenckii from pus or biopsy specimen on Sabouraud dextrose agar (SDA) or brain heart infusion agar is diagnostic. Growth is generally obtained in 3–5 days or within 2 weeks. Cultures on SDA at 25°C showcharacteristic colonies which are initially cream-colored turning brown/black after a few weeks (Fig. 4).
- 24. Cont… Lactophenol cotton blue (LCB) mounts demonstrate delicate branching septate hyphae with slender, short, conidiophores and surrounding pyriform conidia, in a flower-like arrangement. Individual thick-walled, dark brown conidia can also be seen attached directly to the hypha in a dense sleeve-like pattern (Fig. 5). The fungus exhibits temperature dimorphism. It is a mold at room temperature (26°C) and yeast in host tissues (37°C). Demonstration of this dimorphism helps to confirm the identity of S.schenckii. The fungus also produces melanin which may protect it against phagocytosis and extracellular proteinases.
- 25. Figs 4A and B: Cutaneous sporotrichosis: Sporothrix schenckii colony on Sabouraud’s glucose agar. Initial cream color (A) turns brown black (B) as it matures A B
- 26. Figs 5A to C: Cutaneous sporotrichosis: Sporothrix schenckii in delicate branching, mold form with pyriform conidia in (A) characteristic flower-like arrangement or; (B) dense sleeve-like pattern. Smears taken from culture in Sabouraud glucose agar at 25oC (Stain: Lactophenol cotton blue × 40); (C) yeast form from culture in brain heart infusion broth at 37oC (Gram stain × 40) A B C
- 27. C. Histology: Histological features are usually nonspecific. They may vary from acute on chronic inflammation with characteristic zonation to chronic epithelioid cell granuloma with foreign body or Langhans giant cells. There may also be nonspecific chronic granulomatous inflammatory cell infiltration (Fig. 6). Fixed cutaneous sporotrichosis shows central ulceration, hyperkeratosis at the edge, along with acanthosis and epidermal hyperplasia.
- 28. Neutrophilic abscesses may be seen. A dense cellular infiltrate comprising lymphocytes plasma cells, and variable number of epithelioid histiocytes, giant cells and eosinophils (mixed granulomatous cellular infiltrate) in upper and mid dermis may be seen. Occasionally, asteroid, cigar-shaped (1–2 . 4–5 μm), oval to round or single budding forms of the yeast can be visualized.
- 29. Asteroid bodies are seen in 40–85% of cases of chronic sporotrichosis. They are more frequent in lymphocutaneous variety. These are extracellular, 15–35 μm in diameter, bodies localized within abscesses. They are several fungal organisms enveloped by eosinophilic material radiating centrifugally in a sunburst fashion (Splendore-Hoeppli phenomenon). These are not pathognomonic; asteroid bodies can also be seen in other granulomatous and infectious diseases.
- 30. Histologically, nodules of lymphocutaneous sporotrichosis are organized into 3 concentric zones: the central necrotic zone containing amorphous debris and polymorphonuclear leukocytes (zone of chronic suppuration), the middle tuberculoid zone is composed of epithelioid cells, giant cells (predominantly Langhans type) and the outer zone comprising numerous plasma cells, lymphocytes and fibroblasts with prominent capillary hyperplasia and proliferation (syphiloid zone). In older lesions, this zonation may be indistinct. The fungal elements may vary from globose budding cells to cigar-shaped cells.
- 31. D. Serology: A latex agglutination test is of value for the diagnosis of the extracutaneous forms of sporotrichosis. The test has poor prognostic value since titres change little after successful therapy. E. Intradermal Test: A skin test with sporotrichin antigen is„positive in almost all patients with cutaneous sporotrichosis. It is performed by using sporotrichin or peptiderhamnomannan (PRM) antigens to detect delayed hypersensitivity. The diagnostic value is ambiguous as it is often positive in healthy people in endemic areas and may be negative in disseminated sporotrichosis.
- 32. F.Animal Inoculation: Rats are highly susceptible and can be infected by intraperitoneal or intratesticular inoculation.
- 33. Figs 6A to D: Cutaneous sporotrichosis: Histopathology - neutrophilic abscesses in the dermis with lymphoplasmacytic, epitheloid cell infiltrate. (A) Acute on chronic inflammation with characteristic central zone of chronic suppuration, middle tuberculoid inflammation zone comprising epitheloid and Langhans’ giant cells and outer syphiloid zone of lymphoplasmacytic cells, fibroblasts and capillary proliferation; (B) Chronic inflammatory cell infiltrate with foreign body giant cell reaction; (C) Epitheloid cell granuloma with a Langhans’ giant cell (D) (H & E, × 40) A B C D
- 34. Treatment Fixed cutaneous form is associated with high host resistance and minimal lesions may subside spontaneously. There are no well-controlled studies of treatment protocols. The treatment schedules recommended by Infectious Diseases Society ofAmerica are empirical (Table 3). Nevertheless, treatment needs to be continued for at least 4– 6 weeks after complete clinical remission. Oral administration of SSKI remains the treatment of choice for uncomplicated cutaneous sporotrichosis due to low cost and consistent efficacy.
- 35. Its mechanism of action remains unexplained; it may inhibit granuloma formation through immunologic as well as nonimmunologic mechanisms, exposing the fungus to host defences. The starting dose is 5 drops three times a day, subsequently increased daily by 5 drops up to a maximum of 30–40 drops thrice a day till complete regression. Development of metallic taste signifies threshold for maximum tolerable dose. The response is evident within 2 weeks with healing in 4–32 weeks. Adverse effects include metallic taste, flu-like syndrome, excessive lacrimation, gastrointestinal upset, parotid swelling, acneiform or papulopustular eruption, lesional pain and inflammation.
- 36. Rare side effects include hypothyroidism or hyperthyroidism, iododerma, cardiac irritability, vasculitis, pustular psoriasis, pulmonary edema, urticaria and angioedema, myalgia, lymphadenopathy and eosinophilia. Itraconazole is effective and well tolerated. Despite its high cost, it is currently the drug of choice with success rates of 90–100% (60–80% for osteoarticular sporotrichosis). Recommended dose is 200–400 mg/day for 3–6 months (1 year for osteoarticular and disseminated forms). It has good in vitro activity against S.brasiliensis; higher minimum inhibitory concentrations are recorded against other species.
- 37. Terbinafine, 500–1,000 mg/day, alone or in combination with SSKI, has been used effectively for 4–37 weeks. Though less effective than itraconazole, fluconazole, 400–600 mg/day, alone or in combination with SSKI, is other useful therapeutic option in patients intolerant to itraconazole. Amphotericin B (dose 0.5–1.0 mg/kg/day) is safe during pregnancy but due to its toxicity, it is reserved as a drug of choice for treating disseminated cutaneous, pulmonary or HIV-associated sporotrichosis. There is paucity of data for the use of posaconazole or ravuconazole; the former has shown good activity against all the species; the latter has activity limited only against S.brasiliensis.
- 38. Echinocandins have no activity and voriconazole is not recommended for treatment of sporotrichosis. The daily application of local heat (42–43°C) for weeks using wet heat or handheld pocket warmer or far infrared heater is recommended particularly in pregnant women. As there is no risk of dissemination of sporotrichosis or to the fetus, treatment is best delayed in pregnant patients.
- 39. Key Points • Most cases of sporotrichosis remain limited to skin/ subcutis and systemic dissemination is seen more often in immunosuppressed • Lymphocutaneous sporotrichosis is the commonest form and can be diagnosed readily • Spontaneous resolution is rare and treatment in all cases is imperative • Uncomplicated cutaneous disease is readily treated with SSKI or itraconazole while disseminated forms are difficult to treat and need more aggressive therapy with amphotericin B • Patients with immunosuppression may require suppressive therapy for life • Patient education for minimizing vocational exposure to source of infection, prolonged and regular treatment, and adverse effects of therapy is important.