Sporotrichosis

Sporotrichosis is a subacute to chronic granulomatous infection caused by thermally dimorphic fungi of the genus Sporothrix. It usually follows traumatic inoculation of the fungus into the skin and subcutaneous tissue, producing a nodular or ulcerated lesion that spreads along lymphatics. Inhalation causes pulmonary disease, and haematogenous dissemination occurs in immunosuppressed hosts.

It is the commonest subcutaneous mycosis worldwide. It occurs in all continents, with hyperendemic areas in the Americas (Brazil, Peru, Mexico, Colombia), southern Africa (South Africa), parts of Asia and Australia. Zoonotic transmission from cats has produced a large epidemic in Brazil.

The agent was traditionally called Sporothrix schenckii alone. Molecular analysis separates a clinical clade of related species, called the Sporothrix schenckii complex.

Virulence, drug susceptibility and clinical pattern differ between species, and species identification needs sequencing of the calmodulin gene or equivalent molecular methods. Routine laboratories report Sporothrix schenckii complex.

Colonies at 25 to 30 degrees Celsius are initially smooth, moist and white to cream, and become wrinkled, leathery and dark brown to black as conidia mature. Growth takes 3 to 7 days, and cultures are held up to 4 weeks. Conversion to the yeast phase at 37 degrees Celsius on brain heart infusion agar confirms thermal dimorphism. Mould phase cultures produce infectious conidia, and they are a laboratory hazard handled in a biological safety cabinet.

• Soil, decaying wood, hay, straw, sphagnum moss, rose thorns and other plant material: the classical sources. Disease follows thorn and splinter injury, gardening, handling of moss, agriculture, forestry and floristry. Reported outbreaks followed exposure to sphagnum moss and to timbers in gold mines in South Africa, where infection reached more than 3000 miners in the 1940s.
• Animals: diseased cats, which carry large numbers of yeast cells in skin lesions, nasal secretions and under the claws, transmit infection to humans through scratches and bites and by direct contact. Sporothrix brasiliensis has established an animal to human epidemic, with cats, dogs, and the people who care for them affected. Armadillo hunting and digging in Latin America are associated with infection, and rodents, horses and other animals are occasionally infected.
• Inhalation: conidia reach the lung, mainly in patients with chronic lung disease, alcohol use disorder or immunosuppression.
• Person to person transmission is rare, with isolated case reports after contact with lesions.
• Laboratory acquired infection follows needle stick and aerosol exposure.

Risk factors for severe disease: alcohol use disorder, diabetes, chronic obstructive pulmonary disease, corticosteroid therapy, malignancy, transplantation, HIV, and malnutrition.

Inoculated conidia convert to yeast at body temperature in the dermis and subcutis. Yeast cells are phagocytosed and killed by neutrophils and macrophages, and a granulomatous reaction forms. The fungus has few documented virulence factors, but these are known:

• Cell wall peptidorhamnomannan and glycoprotein gp70 (an adhesin binding extracellular matrix).
• Melanin in conidia and yeasts, which protects against oxidative and phagocytic killing.
• Thermotolerance: the capacity of an isolate to grow at 35 to 37 degrees Celsius correlates with the tendency to disseminate. Strains that grow poorly at 37 degrees Celsius cause fixed cutaneous disease on cooler skin.
• Adhesion to host extracellular matrix, and exoenzymes.

Immune control depends on Th1 and Th17 responses with interferon gamma activated macrophages. Antibody responses also occur and have limited protective value. Hypersensitivity (erythema nodosum, erythema multiforme, Sweet syndrome, reactive arthritis) arises in a minority and is associated with strong immunity and, particularly, with Sporothrix brasiliensis infection.

Few organisms are present in tissue of immunocompetent patients, and the tissue reaction is pyogranulomatous.

Disseminated disease in HIV typically occurs when the CD4 count is below 200 cells per microlitre, with multiple skin lesions and sometimes meningitis. Immune reconstitution inflammatory syndrome has been reported after antiretroviral therapy.

• Culture is the diagnostic standard. Pus, aspirate, ulcer scrapings, biopsy, synovial fluid, sputum, and, in disseminated disease, blood or CSF are inoculated on Sabouraud dextrose agar with chloramphenicol, with or without cycloheximide, at 25 to 30 degrees Celsius. Growth appears in 3 to 7 days, sometimes up to 4 weeks. Confirmation by conversion to yeast on brain heart infusion agar at 37 degrees Celsius, or by sequencing. Contaminants are excluded by thin hyphae with rosette conidia and by the dimorphic behaviour.
• Direct microscopy: potassium hydroxide or Gram stain of pus often shows no organisms in the immunocompetent patient, because the organism burden is low. Cigar shaped yeasts are more readily found in cats, in Sporothrix brasiliensis infection and in the immunosuppressed patient. Fluorescent antibody staining of pus is more sensitive than KOH.
• Histopathology: a mixed pyogranulomatous reaction with a central suppurative zone, a surrounding tuberculoid zone of epithelioid cells and giant cells, and an outer syphilitoid zone of lymphocytes and plasma cells. Periodic acid Schiff and Grocott methenamine silver reveal a few round to cigar shaped yeasts. Asteroid bodies (a yeast cell surrounded by radiating eosinophilic Splendore Hoeppli material) are seen in some cases and support the diagnosis but are not specific, because the same reaction occurs around other organisms. Fungal elements may be scarce, and culture of the biopsy is always paired with histology.
• Serology: enzyme immunoassay against yeast antigens is available in some centres and is useful in extracutaneous disease. It is not standardised.
• Molecular testing: PCR and sequencing identify species, and calmodulin sequencing is preferred for species level identification.
• Imaging: chest radiograph or CT for pulmonary disease, which may show cavitation in the upper lobes, fibrosis and pleural thickening. Plain radiographs show osteolytic lesions in osteoarticular disease.
• Cerebrospinal fluid: suspected neurological disease needs a lumbar puncture. CSF culture is positive in only a minority of cases, and large volumes (at least 10 mL) and repeated samples increase the yield.
• Blood cultures: positive in a minority of cases of disseminated disease in advanced HIV.
• Sporotrichin skin test: no longer used.

The choice of drug depends on site and severity, host immunity, pregnancy and species. Treatment is long, and it continues until clinical resolution and then for at least 2 to 4 weeks afterwards.

Cutaneous and lymphocutaneous disease

Itraconazole capsules are taken with food and an acidic drink, and oral solution is taken on an empty stomach. Serum levels are checked after 2 weeks where available, with a trough target of at least 1 microgram per mL by chromatography, and absorption problems are common. Potassium iodide causes iodism (metallic taste, rhinorrhoea, salivary gland swelling, acneiform rash, nausea), thyroid disease and hypersensitivity, and is avoided in pregnancy, and in thyroid disease.

Sporothrix brasiliensis disease responds to itraconazole, with longer courses needed in extensive disease. Terbinafine and itraconazole are combined in refractory disease, or where itraconazole fails or has poor absorption.

Pulmonary disease

• Severe or life threatening disease: liposomal amphotericin B 3 to 5 mg per kg daily (or amphotericin B deoxycholate 0.7 to 1 mg per kg daily) for 2 to 6 weeks until a favourable response, then itraconazole 200 mg twice daily for a total of at least 12 months.
• Mild to moderate disease: itraconazole 200 mg three times daily for 3 days, then 200 mg twice daily for at least 12 months.
• Surgical resection of a localised cavity is considered in cavitary disease, with antifungal cover.

Osteoarticular disease

Itraconazole 200 mg twice daily for at least 12 months. Severe disease starts with liposomal amphotericin B 3 to 5 mg per kg daily, then itraconazole. Surgical debridement is often needed in destructive disease.

Disseminated disease and meningitis

• Disseminated disease: liposomal amphotericin B 3 to 5 mg per kg daily until improvement, followed by itraconazole 200 mg twice daily for a total of at least 12 months.
• Meningitis: liposomal amphotericin B 5 mg per kg daily for 4 to 6 weeks, followed by itraconazole 200 mg twice daily for at least 12 months.
• HIV: lifelong suppressive itraconazole 200 mg daily is continued while CD4 count remains low, and is stopped only after immune recovery, with specialist advice.

Special populations

• Pregnancy: azoles, terbinafine and potassium iodide are avoided. Local hyperthermia is used for cutaneous disease, and amphotericin B for severe disease. Treatment with itraconazole is started after delivery in cutaneous disease.
• Children: itraconazole 6 to 10 mg per kg daily (maximum 400 mg daily), or saturated potassium iodide starting at 1 drop three times daily and rising to 1 mL three times daily.
• Zoonotic disease: infected cats are treated with itraconazole for months, with veterinary supervision. Carcasses are buried deeply or cremated. Hands are washed after handling and gloves worn when handling infected animals.

Monitoring and drug safety

• Itraconazole: hepatotoxicity, negative inotropy (avoid in heart failure), and strong CYP3A4 inhibition. It is avoided with simvastatin, lovastatin, oral midazolam, triazolam and other interacting drugs. Liver tests are checked at baseline, at 2 to 4 weeks, and every 1 to 3 months afterwards.
• Amphotericin B: nephrotoxicity, hypokalaemia and hypomagnesaemia, infusion reactions, and anaemia. Monitoring of renal function and electrolytes is essential.
• Terbinafine: hepatotoxicity, and taste disturbance.

Prevention

Gloves and long sleeves when handling soil, moss, hay, rose bushes and thorny plants. Avoidance of straw and sphagnum moss for packing without protection. Protective clothing for armadillo hunters and miners. Veterinary management of infected cats.