Sporotrichosis

1. Sporotrichosis Prof. Alexandro Bonifaz, MD, PhD Dermatology Service & Mycology Department, Hospital General de México, “Dr. Eduardo Liceaga”, Balmis 148, Colonia Doctores, Ciudad de México 06726, Mexico

2. Intended Learning Outcomes To understand the epidemiology and pathogenesis of sporotrichosis To be aware of how the diagnosis of sporotrichosis is made To be able to treat confirm cases of sporotrichosis

3. Introduction • Sporotrichosis is an endemic, granulomatous, deep skin mycosis with a subacute or chronic course caused by the dimorphic fungi Sporothrix schenkii complex • Skin, subcutaneous tissues and lymphatic vessels are the most commonly involved structures • Bones, joints, and internal organs are rarely involved • Small and large outbreaks in humans have rarely been reported • Epidemics of sporotrichosis in animals have also been reported, hence can be viewed as a zoonosis • Infection can also occur in dogs, cats, birds, rodents and reptiles Arenas, R. et al. J. Fungi2018;4, 62. Lopes-Bezerraet al.Med Mycol2018;56, S126–S143 Bonifazet al. JDDG2010; 8:619-628 Chakrabarti et al. Med Mycol2015; 53: 3–14

4. Aetiology • Sporothrix schenkii sensulatois a thermally dimorphic fungus that is ubiquitously found in the environment • Soil • Decomposing vegetation • On plant materials • Woods • Sporothrix species present a saprophytic mycelium phase at room temperature (25–28◦C) and a yeast-like pathogenic phase at 36–37◦C • Sporothrix schenkii complex • Sporothrix schenkii sensustricto • Sporothrix brasiliensis (mainly cat-transmitted) • Sporothrix globosa • Sporothrix pallida (previously )albicans • Sporothrix mexicana • Sporothrix luriei The differences between these species relates to their antifungal susceptibility profiles and to a lesser extent their geographical distribution Lopes-Bezerraet al.Med Mycol2018;56, S126–S143 Bonifazet al. JDDG2010;8:619-628

5. Epidemiology: Global Distribution of Sporotrichosis • Sporotrichosis occurs in all continents; estimated burden of >40,000 cases annually • Most cases observed in hyper-endemic regions of Mexico, Peru, Colombia, Brazil, Uruguay, and Guatemala. • It has also been reported in many parts of Europe, especially Spain, France and Germany. Large number of cases outside of the Americas, often in outbreaks - have been reported from South Africa, Japan, and China Chakrabarti et al. Med Mycol. 2015; 53: 3–14

6. Epidemiology: Global Distribution of Sporotrichosis S. brasiliensis S. globosa S. schenkii clade IIa S. schenkii clade IIb Chakrabarti et al. Med Mycol. 2015; 53: 3–14

7. Feline-transmitted sporotrichosis • A large outbreak of cat-transmitted sporotrichosis is currently occurring in Brazil • In the state of Rio de Janeiro, the number of human cases jumped from 759 between 1998 and 2004 to more than 4000 in 2014 and 10,000 in 2017 mostly resulting from feline transmission • This outbreak is expanding to neighbouring Brazilian regions and countries Gremiãoet al. Med Mycol2015;53:15-21 Queiroz-Telleset al. Lancet Infect Dis2017;17:e367-77

8. Pathogenesis • Infection usually follows traumatic inoculation of Sporothrix conidia from a contaminated source (splinters, animal bites etc.) • Farmers, gardeners, livestock breeders , miners, veterinarians are the most at risk of sporotrichosis • A few cases of primary pulmonary and disseminated sporotrichosis following inhalation of fungal conidia have been reported • Incubation period is about 10 days, range 7-30 day • There is no gender preference, Male: Female of 1:1 • However, children (5-15 years) and young adults (<35 years) account for ~80% of the cases • Immunosuppression of all kinds facilitates dissemination Lopes-Bezerraet al.Med Mycol2018; 56: S126–S143 Bonifazet al. JDDG2010;8:619-628

9. Clinical Manifestations Extra-cutaneous manifestation Cutaneous manifestation • Extra-cutaneous sporotrichosis • Usually in the immunocompromised hosts • Following haematogenous dissemination of cutaneous foci to internal organs, joints & bones • Can also result from inhalation of Sporothrix conidia into the lungs • Lymphocutaneous sporotrichosis (~70%) • Lesions occur along lymphatic vessels up to the regional lymph nodes associated with pruritus and pain • Fixed cutaneous sporotrichosis (~25%) • Most limited form of sporotrichosis • Occurs in immunocompetent hosts • Characterized by a single vegetating or verrucous, sharply delineated plaque with an erythematous-violet border, covered by scales and crusts and usually asymptomatic • Disseminated cutaneous sporotrichosis • Usually in immunocompromised people • Affects mainly the face • Lesions consist of erythematous, violet and pruritic plaques • Haematogenous cutaneous sporotrichosis • Usually in the immunocompromised hosts • Muco-cutaneous presentation • Rarest form of cutaneous manifestation • Gummatous-like lesion, pain, ulceration, verrucous plaques Chakrabartiet al. Med Mycol2015; 53: 3–14 Bonifazet al. JDDG2010; 8:619-628

10. Clinical Manifestations Lymphocutaneous sporotrichosis Affects the extremities and the face with erythematous-violet, often ulcerated, gumma-like, subcutaneous, nodular lesions along lymphatic vessels up to the regional lymph nodes. This is associated with slight pruritus and pain. In exceptional cases lymphatic drainage may be impaired. In children it is located on the face uni- or bilaterally in 40% of cases Fixed cutaneous sporotrichosis Characterized by a single vegetating or verrucous, sharply delineated plaque with an erythematous-violet border, covered by scales and crusts and usually asymptomatic Bonifazet al. JDDG2010; 8:619-628

11. Diagnosis Direct microscopy • Samples: Skin lesions and body fluids • Reagent: 10-40% KOH • Stains: GMS, PAS, or gram stain • Observations: • Elongated yeast cells, 2-6µm in diameter • Asteroid bodies (Splendore–Hoeppli phenomenon): yeasts surrounded by immunoglobulins Fungal culture • Considered gold standard for diagnosis • Sabouraud dextrose agar, 28oC for 5-14 days • Dimorphism can be demonstrated on blood-chocolate agar or brain heart infusion agar at 37oC Colony: White-beige, with dark pigment in the center, membranous, radiated and fast growing Microscopy: thin, septate, branched hyphae (1–2µm in diameter) are observed with sympodulospores or radulospores, which gives the typical “daisy or peach flower” image Asteroid body (Splendore–Hoeppli phenomenon) Arenas, R. et al. J. Fungi2018;4, 62. Bonifazet al. JDDG2010;8:619-628 PAS, Periodic-Acid Schiff; GMS, Grocott’s Methenamine silver stain

12. Diagnosis • Histopathology • Sporothrix is rarely identified by histology • Culture is preferred diagnostic test • PAS and GMS are mandatory to illustrate yeast cells and elongated blastoconidia (cigar-shaped) • Rarely, asteroid bodies, or plasma cells, histicocytes, lymphocytes, and eosinophils can be found GMS stain showing cigar-shaped yeast cells Skin biopsy stained with GMS in which yeast can be observed (40x). Arenas, R. et al. J. Fungi2018, 4, 62.

13. Diagnosis • Sprorotrichin skin test • 0.1 mL of the antigen solution is injected and assessed 48 h later; it is considered a positive test when a lesion measuring ≥5 mm is formed. • The test can be false negative in patients with cellular immunity alterations, mainly AIDS, diabetes mellitus, and in patients with disseminated sporotrichosis • Antigen cross-reacts with H. capsulatum Positive sporotrichin test in a patient with lymphocutaneous sporotrichosis BonifazA. MicologíaMédicaBásica 5th Ed 2015;179–196. Madrid et al. Rev. Iberoam. Micol2009;26, 218–222.

14. Classification • Disease classification based on immune response has been proposed BonifazA. MicologíaMédicaBásica 5th Ed 2015;179–196. Madrid et al. Rev. Iberoam. Micol2009;26, 218–222.

15. Differential Diagnosis Chromoblastomycosis Non-tuberculous mycobacterial infection Cutaneous leishmaniasis • Other differential diagnoses includes: • Mycetoma (eumycetoma ) • Kaposi's sarcoma • Buruli ulcers (in endemic areas)

16. Treatment • Spontaneous resolution is rare • Therapy response is good for various antifungals, ~100% for cutaneous disease with itraconazole • Oral potassium Iodide is used in endemic areas due to good efficacy, safety and low costs • Treatment should be continued for 2-4 weeks after lesions have resolved Kauffman et al. IDSA guidelines Clin Infect Dis2007; 45 (10):1255–1265

17. Summary • Sporotrichosis is an implantation, endemic mycosis caused by the fungus Sporothrix schenkii species complex • Lymphocutaneous and fixed cutaneous lesions are the most common manifestations • Culture is the preferred diagnostic approach and allows antifungal susceptibility testing • Itraconazole is the oral triazole therapy of choice is uncomplicated cases of sporotrichosis • In severe cases, disseminated disease and in children and pregnancy, amphotericin B is the drug of choice

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