Lymphocutaneous (LC) ‒ It is the most common clinical form, accounting for 46% to 92% of cases.36 Clinically, it starts with the appearance, days to a few months after the trauma, of a small erythematous papule or pustule at the site of fungus inoculation. It is also called sporotichotic or inoculation chancre and usually is asymptomatic, tends to increase in size in a few weeks, and becomes nodular. Eventually, central liquefaction occurs, with fistulization or ulceration and subsequent drainage of purulent material (gummy lesion). After a few days to weeks, new papulonodular, erythematous, rosary-like lesions appear in the regional lymphatic pathway, which may be ascending or descending, depending on regional drainage (Fig. 1A). Similarly to the inoculation chancre, these lesions can become gummy and ulcerate. Although it occurs in any area of ​​the skin, places exposed to trauma, especially the upper and lower limbs, and the face, especially in children, are the most affected ones.37

Figure 1.

Clinical forms of human sporotrichosis. (A) Lymphocutaneous – inoculation chancre in the index finger and skin lesions in the ascending regional lymphatic pathway. (B) Fixed cutaneous form – verrucous lesion on the dorsum of the hand.

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Fixed cutaneous (FC) – It is the second most frequent clinical form, corresponding, on average, to 25% of cases. After the trauma, inoculation chancre appears, which does not show regional lymphatic progression, probably due to greater host resistance or a lower degree of thermotolerance and virulence of the fungal strain. The initial lesion may progress to ulceration, with irregular borders and varying sizes, or a verrucous appearance, with or without perforations for drainage of purulent material (Fig. 1B). The formation of a nodule is not rare; fluctuation and suppuration can occur, or it can be covered by scaly crusts. Sometimes small satellite papules around the initial lesion can be seen. In this form, the exposed sites of the body are also the most affected ones.37

Multiple inoculation ‒ It presents with multiple, polymorphic skin lesions in non-contiguous sites without systemic involvement. This clinical form has gained evidence with the emergence of zoonotic cases related to sick cats, in which the occurrence of multiple traumas is possible, due to scratches and bites. Overall, it affects immunocompetent individuals who usually report, consistently, the occurrence of multiple traumas; lesions appear almost simultaneously or in sequence.9 It is the least common cutaneous form.37,38

Although any mucosa can be affected by Sporothrix spp., the ocular mucosa is the most commonly affected, due to greater exposure. The proximity between humans and domestic cats has increased the frequency of this clinical presentation, especially in children. When the animals sneeze, aerosols from the animals reach the human ocular mucosa, or, after touching the animal or fomites, the individuals bring the contaminated hands to the eyes.37,39 The most characteristic clinical picture is granulomatous conjunctivitis, characterized by vegetating lesions on the palpebral and/or bulbar conjunctiva, and there may be enanthema and purulent discharge (Fig. 2A, B).40 It is possible for skin lesions to coexist on the eyelid ipsilateral to conjunctivitis. The presence of satellite lymphadenopathy, associated with ipsilateral granulomatous conjunctivitis, characterizes Parinaud's oculoglandular syndrome, often mistaken for cat-scratch disease.41 The involvement of the lacrimal sac can lead to dacryocystitis as a sequel.42 Episcleritis, uveitis, choroiditis, and other retrobulbar lesions rarely occur; these are often related to hematogenous spread in immunosuppressed patients, characterizing the systemic form with cutaneous/mucosal manifestation.40

Figure 2.

Clinical forms of human sporotrichosis. (A) Mucosal – bulbar conjunctiva lesion. (B) Mucosal – tarsal conjunctiva lesion, with pus.

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The involvement of other types of mucosa is less common, with the nasal mucosa being the second most affected region. There are reports of lesions in the palate, pharynx and trachea.43

It is the most common clinical manifestation after the skin and the mucosa. The osteoarticular involvement usually occurs from the contiguous skin lesion, and is usually unifocal.44 In these cases, the most important risk factors are lesions in the extremities, especially hands and feet, due to the close anatomical proximity between the skin and the osteoarticular system and osteometabolic frailty, especially in the elderly or chronic users of corticosteroids; and bite wounds, due to the greater depth of the inoculum (Fig. 3A).

Figure 3.

Radiological images in human sporotrichosis. (A) Osteoarticular form – resorption of the distal phalanx of the little finger caused by a cat bite (plain radiography). (B) Systemic form with osteoarticular manifestation – osteolytic lesions in the tibial medulla by hematogenous spread in a patient with systemic sporotrichosis and AIDS (plain radiography). (C) Pulmonary – cavity in the upper lobe of the right lung and extensive pulmonary opacity with a fibroretractile appearance (computed tomography). (D) Neurosporotrichosis – meningitis in a patient with systemic sporotrichosis and AIDS. Increase in the dimensions of the ventricular system, mainly in the supratentorial region (tetraventricular hydrocephalus), ventriculoperitoneal shunt catheter (computed tomography).

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In unifocal osteoarticular lesions, joint involvement with cartilage destruction is observed, eventually showing synovial joint effusion, and osteolytic lesions, usually of the distal short bones of the hands and feet. It manifests with pain, swelling, and functional limitation. Other phlogistic signs such as flushing and heat are usually milder when compared to infections of bacterial etiology. Sporothrix spp. are frequently isolated from synovial fluid or fragments. Positive serology for Sporothrix ssp. has been demonstrated in synovial fluid.44

Osteoarticular involvement occurs in approximately 1% of the large series.37 In the largest of them, which included 41 cases, there was a predominance of multifocal bone involvement, associated with immunosuppression, especially AIDS, probably due to a selection bias by the profile of care in a referral center.45

Other manifestations are the involvement of the tendons, due to the contiguity of a skin lesion, characterized by tenosynovitis of the extensor and/or flexor tendons, particularly in the hands, regardless of bone and joint involvement. Imaging findings are characteristic and have been observed in zoonotic transmission, sometimes when the skin lesions have already healed.

To evaluate osteoarticular involvement in patients with extremity lesions, radiographic assessment is recommended, especially in cases of bite wounds associated with significant swelling or pain that is disproportionate to the skin condition. In these cases, bacterial osteomyelitis is considered a differential diagnosis due to the composition of the microbiota in the oral cavity of cats. Generally, in bacterial osteomyelitis, the findings are more acute, inflammatory, with a purulent exudate that has a foul odor, and are not always located as close to the entry point as in sporotrichosis. Ultrasound examination is indicated to evaluate tenosynovitis in cases with functional limitations that involve movements related to a specific tendon.46

In the systemic form, which is rarer, other organs are affected, with or without skin lesions. It is accepted that, occasionally, the point of entry may be pulmonary with hematogenous spread of the pathogen, the traditional concept of 'systemic mycosis' proposed by Rippon, or it may show hematogenous spread from a cutaneous or osteoarticular lesion.47 Although there are no specific risk factors, patients with HIV/AIDS, with CD4+ counts < 200 cells/mm3, malnourished individuals, alcoholics, diabetics, transplant recipients, patients with hematological malignant neoplasias, in chronic use of immunosuppressive medications such as corticosteroids, which deplete cellular immunity, anti-TNF, and immunobiological, in addition to immunosenescence, are more predisposed to the development of systemic forms and may progress to death.48 Although Sporothrix spp. are primary pathogens, an opportunistic behavior of this mycosis can be observed in conditions of significant cellular immunity suppression, which may be an AIDS-defining disease.42 The systemic forms are rarely seen in immunocompetent individuals, which can be attributed to more virulent strains of the fungus or primary host immunodeficiency.49

With skin/mucosal involvement ‒ It must not be confused with primary cutaneous foci from multiple inocula or from primary mucosal inoculation. Hematogenous spread to the skin/mucosa is suspected when there are many skin lesions, dispersed in areas that are most often protected from trauma, such as the trunk, shoulders, proximal thighs, gluteal region, genitals, and face, especially the centrofacial region, or deep eye lesions, with reduced visual acuity, associated with a decline in the general status and underlying immunosuppression.50 Disseminated skin lesions may represent the only manifestation of hematogenous spread or be associated with the involvement of other organs, when they may be related to more severe conditions of immunosuppression, particularly HIV-induced cases.51,52

They present with varied morphology, usually ulcerated, suppurative lesions, without odor or significant inflammatory reaction, which differentiates them from a secondary bacterial condition. Because they are suppurative, they are often covered by crusts, consisting of solidified pus and blood on the surface. Other types of skin lesions seen in these disseminated conditions are papules, nodules, verrucous plaques, necrotic, vegetative, tumor-like, and molluscum-like lesions.52,53 Cold abscesses have been described in alcoholic patients.50

Mucosal involvement in systemic sporotrichosis, secondary to hematogenous spread, most often involves the nasal and oral (palate) mucosa. When the eye is affected by hematogenous spread, usually in immunosuppressed patients, posterior chamber involvement with chorioretinitis is observed.54,55 Therefore, fundus examination is recommended in all patients with systemic sporotrichosis and clinical signs of hematogenous spread.

With osteoarticular involvement ‒ The involvement of the osteoarticular system through the hematogenous route is usually associated with invasive and intensely disseminated disease, particularly in AIDS patients, but it can also be seen in other immunosuppressive conditions.45 In these cases, there is multifocal involvement of long bones, with osteolytic lesions (Fig. 3B). Clinically, there is pain and functional limitation, and there may rarely be inflammatory signs, considering the low potential of inflammatory cell immune response in these patients.

Multifocal bone sporotrichosis is often oligosymptomatic, due to the depletion of cellular immunity. Systematic osteoarticular screening is essential, preferably by bone scintigraphy or, when this is not available, skeletal inventory with plain radiography of all long bones, in addition to the bones of the hands, wrists, feet, and ankles in patients at risk, especially those with AIDS.45

Pulmonary ‒ The involvement can be primary, through the inhalation of conidia and other infective propagules of Sporothrix spp., or secondary to hematogenous spread, usually from a primary cutaneous focus. When primary, it may be limited to the lung, as in chronic obstructive pulmonary disease (COPD), or spread from the lungs, which is common in immunosuppressed patients.56 In these cases, it is difficult to identify whether the dissemination occurred from that organ or from the skin. The history of trauma preceding the clinical picture can help to define the probable route of spread. It usually manifests as two clinical patterns:

Primary pulmonary ‒ patients have an underlying lung disease, usually smokers with COPD, with one or multiple cavitated lesions, associated with lung parenchyma fibrosis and architectural destruction (Fig. 3C).

Multifocal pulmonary ‒ it occurs in an immunosuppressed patient with sporotrichosis in other organs, in which the lesions are not normally cavitated.56 Immunosuppression due to chronic alcoholism and cavitated pulmonary lesions has been reported in a patient with disseminated sporotrichosis.57

Cavitated lesions confound the diagnosis of pulmonary tuberculosis, contributing to the underdiagnosis of pulmonary sporotrichosis, particularly in endemic regions.57 The main respiratory symptom is a persistent, dry, or productive cough for more than two weeks, similar to tuberculosis. The investigation includes a plain chest X-ray and CT scan, mycological examination, and sputum smear microscopy to exclude tuberculosis, mycobacteriosis, and other mycoses. Patients with AIDS may be oligosymptomatic.

Neurological (neurosporotrichosis) ‒ Involvement of the central nervous system (CNS) by Sporothrix spp. is a rare and severe condition. It usually occurs in more invasive pictures of the disease, particularly associated with AIDS, by hematogenous spread through the blood-brain barrier. In addition to host susceptibility, some Sporothrix species show greater virulence with neurotropism, especially S. brasiliensis strains. In neurosporotrichosis, subacute to chronic meningitis is usually present, although meningeal irritation may be mild or asymptomatic when there is significant depletion of cellular immunity (Fig. 3D). Early lumbar puncture to investigate CNS involvement should be routine in patients with AIDS and clinical signs of systemic sporotrichosis.58 On the other hand, neurological symptoms with more overt signs of meningismus may occur in immune reconstitution inflammatory syndrome (IRIS), which facilitates diagnostic suspicion.59 In neurosporotrichosis, the cerebrospinal fluid may be clear. There is an increase in cellularity at the expense of mononuclear cells, hyperproteinorrhachia, and hypoglycorrhachia. Due to the low parasitic load of Sporothrix spp. in the CNS, the isolation and identification of the fungus in culture samples is rare. In these cases, molecular methods seem to be promising for diagnostic investigation.

Sepsis ‒ It occurs when there is organ dysfunction due to generalized infection caused by Sporothrix spp. Although present in several organs, the isolation of the fungus from blood culture samples is uncommon. It constitutes the progression of other systemic forms in patients with a low capacity to react to infection, most commonly observed in association with AIDS. Any organ or system can be affected in sepsis caused by Sporothrix spp.

Patients with sporotrichosis cutaneous/mucosal lesions may develop hypersensitivity reactions in the course of the disease. These reaction forms have been seen most frequently in the zoonotic sporotrichosis epidemic, with erythema nodosum, erythema multiforme, and Sweet syndrome being the most common ones (Fig. 4A, B).60,61 Reactive arthritis as a form of hypersensitivity, is overall polyarticular and migratory, disappearing before or after specific therapy.62 The immunoreactive forms are usually associated with milder and more localized sporotrichosis, which probably demonstrates better immunological control of the disease, although it is sometimes incapacitating. Exuberant reactive lesions may mask the specific lesions and the forme-fruste (subclinical form) of sporotrichosis.

Figure 4.

Immunoreactive forms of human sporotrichosis. (A) Erythema nodosum in the lower limbs (specific sporotrichosis lesion near the knee). (B) Sweet syndrome.

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As in other diseases, there may be more than one form of clinical presentation in the same patient. For example, cutaneous and mucosal, cutaneous and osteoarticular, cutaneous and immunoreactive. One should not confound cases with mixed involvement of the skin, mucosa, and osteoarticular system with systemic sporotrichosis, whose involvement occurs by hematogenous spread.

Children ‒ They have a higher risk of illness due to close contact with domestic cats and because they may present with atypical clinical conditions. The habit of petting domestic animals close to the facial region makes this topography prone to a greater risk of infection. Often, these atypical presentations delay the diagnosis, with a consequent higher risk of sequelae. On the other hand, children have a better immune response profile and cases are usually limited.

Pregnant woman – There is some difficulty related to the therapeutic management, as most pharmacological treatments are contraindicated.63 The possibility of fetal injury by the infection is also questioned.

Elderly ‒ Living with animals at home and the common comorbidities identified in this age group can lead to a greater risk of infection, potentially severe, and difficulty in therapeutic management, either because of the comorbidities themselves, such as diabetes mellitus or because of the drugs with which itraconazole, the first choice in the treatment of sporotrichosis, interacts. Osteometabolic frailty, which is typical of this age group, is also a risk factor for systemic and difficult-to-manage forms.9

Immunosuppressed patients ‒ Systemic sporotrichosis in patients with underlying immunosuppressive conditions, particularly HIV/AIDS, should be carefully evaluated by a multidisciplinary team, with the routine evaluation of multiple organs being recommended, and emphasis on nasal, oral and ocular mucosa (fundus examination), bones, joints, lungs and CNS.

Any clinical specimen is suitable, although pus is the best material for the diagnosis.9,65 It can be obtained by puncture of abscesses using a needle (Fig. 5) or by deep manual expression of lesions, especially after crust removal. These sampling methods are simple, fast, and cost-effective. If this is not possible, a biopsy of the lesion is the method of choice. For that purpose, one can collect material through a punch biopsy or use a scalpel to obtain a spindle-shaped biopsy. When in doubt about the diagnosis of sporotrichosis, the best technique is the spindle-shaped biopsy, as the histopathological examination will differentiate it from other diseases, whether infectious or not. Another advantage of the spindle-shaped biopsy is the correspondence between the samples that will be sent for culture for fungi and common microorganisms or mycobacteria and the histopathological examination. In both cases, the depth of the biopsy is essential for the correct diagnosis and it should extend to the subcutaneous tissue. Fig. 6 outlines the division of the sampled fragment and the transportation of the material to the respective laboratory.

Figure 5.

Sampling. (A) Purulent exudate, sampled by puncturing a skin abscess, in human sporotrichosis. (B) Material (pus) to be sent for mycological examination.

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Figure 6.

Flowchart for the collection and transportation of material sampled by biopsy, for the diagnosis of human sporotrichosis. The illustration was partially based on Servier Medical Art elements, licensed by Creative Commons Attribution 3.0 Unported License.

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Direct mycological examination (DME) – It has low sensitivity and specificity in human sporotrichosis, especially in the LC and FC forms.

Isolation ‒ It is the reference method for the definitive diagnosis of sporotrichosis from clinical specimens in culture media. On Sabouraud dextrose agar and Mycosel agar media, Sporothrix spp. appear in 3 to 6 days, at 25° to 28 °C, in samples from skin lesions, and in 10 to 19 days from other organic materials. This may vary according to the species. 66

The histopathological pattern is usually granulomatous, most often suppurative, but epithelioid granulomas not otherwise specified, tuberculoid, in palisade, foreign body, and sarcoid granulomas may also be seen in decreasing order of frequency. In most cases, lymphocytes and plasma cells complement the inflammatory infiltrate.71 Special histological staining techniques, such as PAS and Gomori-Grocott silver methenamine, are used when there is clinical suspicion and a compatible histopathological picture. Sporothrix spp. show considerable variation in shape and relative size; from round to elliptical, from 2 to more than 6 μm in their major axes, and navicular with approximately 3 × 10 μm (Fig. 7C, D). Narrow-based budding is relatively frequent, usually single, rarely double or multiple, sometimes elongated, and club-shaped. But they can be oblong, of uniform width, including at the base, not showing a club-like shape. Additionally, the occurrence of misaligned budding in relation to the major axis of the mother cell, considered characteristic of Sporothrix spp, is important.72 If there is an abundance of fungal elements, immunosuppression or other mycoses are suspected, especially histoplasmosis (fungal elements are smaller) or cryptococcosis (capsulated and slightly larger fungus).

Asteroid bodies are extracellular structures, most often found inside abscesses, and correspond to the deposit of immunoglobulins around a yeast-like fungal cell. It represents one of the manifestations of the Splendore-Höeppli phenomenon, and it is observed as hyaline, fibrillar, or club-shaped material, in a radial arrangement, eosinophilic in H&E and PAS-positive staining.73

Histopathological features of erythema nodosum and Sweet syndrome associated with sporotrichosis may be indistinguishable from those seen in lesions related to other causes.74 However, in erythema nodosum, significant lobular involvement was reported in one case. In Sweet syndrome, epithelioid differentiation of histiocytes has been observed, which may indicate the histiocytoid variant.75

Two standardized methods are used to test the susceptibility of Sporothrix species to antifungals: the Clinical and Laboratory Standards Institute (CLSI) which proposes the microdilution method using inoculum obtained from the filamentous form of Sporothrix spp., and the European Committee on Antifungal Susceptibility Testing (EUCAST).76 Fluconazole, flucytosine, and echinocandins do not inhibit the growth of Sporothrix spp. in vitro; therefore, their inclusion in the AST is unnecessary.67,76 Some Sporothrix strains can be inhibited by voriconazole. Itraconazole, terbinafine, posaconazole, and amphotericin B have varied antifungal susceptibility profiles, which justifies their inclusion in all ASTs of human pathogenic Sporothrix species, given the possibility of a high minimum inhibitory concentration (MIC).77 The cutoff values ​​for clinical isolates of S. brasiliensis and S. schenckii according to the CLSI methodology are, respectively, amphotericin B, 4 and 4 μg/mL; itraconazole, 2 and 2 μg/mL; posaconazole, 2 and 2 μg/mL and voriconazole, 64 and 32 μg/mL. Additional cutoff values for S. brasiliensis include ketoconazole, 2 μg/mL and terbinafine, 0.12 μg/mL.76

Treatment-refractory cases are not necessarily associated with high MIC or the development of in vitro resistance during antifungal treatment. On the other hand, sporotrichosis caused by non-wild-type strains, that is, with high MIC values, tends to require longer treatment duration and higher doses of antifungals than those recommended in the literature, in addition to the possibility of the development of sequelae.78

Intradermal test (sporotrichin) – It detects a delayed-type hypersensitivity reaction using crude antigen obtained from S. schenckii cultures.79 It allows a presumptive diagnosis and may indicate previous exposure to Sporothrix spp. or occur by cross-reaction with other fungi. It is used in epidemiological investigations in endemic areas, although it is only available in research centers. In disseminated disease, the test may be negative due to anergy.80,81

Serology – It is an alternative tool in the laboratory diagnosis of sporotrichosis, useful for systemic and atypical forms, and as a diagnostic screening tool.23,44 Enzyme immunoassays, mainly enzyme-linked immunosorbent assay (ELISA) and immunoblotting are more sensitive, with faster results.82 ELISA, which uses the SsCBF (Sporothrix schenckii Con A-Binding Fraction) antigenic fraction, has a specificity of 90% and a sensitivity of 80%.82,83 It can be applied to the analysis of different biological samples, in addition to blood, such as synovial fluid and cerebrospinal fluid, resulting in efficient clinical-serological correlation and cure control.44,62 The enzyme immunoassay with S. brasiliensis exoantigens, despite its simple methodology, showed variations in results.

The monitoring of antibody titers may indicate relapse or failure of the established treatment; however, it is not commercially available for use in humans.83

Fig. 8 shows an updated flowchart for the laboratory diagnosis of human sporotrichosis.

Figure 8.

Flowchart for the laboratory diagnosis of human sporotrichosis, with estimated time for the processing of each method. GMS (Gomori-Grocott silver methenamine); CMA (cornmeal agar); 'C'‘C’, Carbon source; ITS, Internal Transcript Spacer; PCR, Polymerase Chain Reaction; qPCR, real-time quantitative PCR; RCA, Rolling Circle Amplification; AFLP, Amplified Fragment Length Polymorphism; RAPD, Random amplification of polymorphic DNA. Modified from Orofino-Costa et al., 2017.9

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It ranges from one to 12 months or longer, with a mean of 3 to 4 months in most published series.2,85 Although some authors still recommend it, maintaining the treatment for 2 to 4 weeks after the lesions resolve is unnecessary. The identification of a clinical cure is crucial and is characterized by complete re-epithelialization, absence of exudation, crusts, infiltration, desquamation, or significant erythema. At this point, treatment can be discontinued without harm. Fibrosis, milia, hypertrophic scarring, mild erythema, pruritus, and local tenderness do not denote disease activity.9

There are scarce data on the use of the new azoles in rescue therapy in cases that are refractory to conventional treatment.99 Isavuconazole, which has been approved in Brazil, has in vitro activity against S. brasiliensis, but there are few studies about it.100 Miltefosine, a phospholipid analog used to treat cutaneous and visceral leishmaniasis, has been tested in vitro and indicated as a possible therapeutic option, especially for patients who do not respond to conventional antifungals.101 Ongoing research evaluates whether herbal medicines and old drugs with other therapeutic indications can be useful for the treatment of human sporotrichosis, but still without practical perspectives.

Different modalities are used alone or in combination with systemic treatment and are useful for patients with intolerance or contraindication to systemic drugs, or poor response to therapy.102

Thermotherapy – It is most commonly used in pregnant women with uncomplicated clinical manifestations of sporotrichosis.63,103,104 It is based on the thermal intolerance of the Sporothrix species at temperatures above 39 °C.3 The heat source can be a hot water bottle, infrared source, or another method, aiming to reach a temperature of 42 to 43 °C for 20 to 30 minutes, three times a day.105 It promotes systemic drug permeation through vasodilation if used concomitantly.

Cryosurgery – Performed with liquid nitrogen in the proper equipment, with a non-contact spray tip, in two freeze/thaw cycles, monthly, until a clinical cure is achieved. The freezing time depends on the size and thickness of the lesion, approximately 10 to 30 seconds (Supplementary Material - video). The number of sessions depends on the clinical course. It is useful for the early treatment of verrucous and vegetating lesions. It is possible that penetration of systemic antifungals into the skin lesion may increase due to epidermal necrosis and consequent exposure of fungal antigens to the host immune system, shortening treatment time.106

Electrosurgery – for refractory cases, it is an exceptional resource, maintaining the systemic antifungal perioperatively and postoperatively to prevent dissemination.107 It is performed by a specialized professional and when associated with curettage, it constitutes an easy and simple method, maintaining local function and aesthetics. It can be indicated in places where cryosurgery offers a higher risk of complications, such as the nose and ears, for example.

Others – drainage or puncture of encysted/abscessed lesions and isolated curettage of verrucous-crusted lesions may help in the treatment of skin lesions by reducing the parasite pool, although there are no studies on these methods. There have been reports of successful use of photodynamic therapy, either alone or in combination with intermittent doses of itraconazole. 108

Recommendations in special situations:

• 1)

  Start treatment of the localized clinical forms found in immunocompetent patients with the lowest dose of each drug and wait at least one month for the clinical evolution. Rarely, larger doses of itraconazole or terbinafine are needed. If the patient does not progress well, it is better to associate other drugs or another therapeutic modality. Likewise, start with the lowest effective dose of KI. Higher initial doses increase toxicity and are no guarantee of rapid therapeutic response.

• 2)

  In classic cases of sporotrichosis with low therapeutic response, investigate the use of medications that reduce the absorption of itraconazole. If possible, measure the serum level of the drug, as it is an erratically absorbed medication. The use of proton-pump inhibitors is an example, as they reduce the absorption of itraconazole. Verify the concomitant medications on the itraconazole interactions list. Also, consider whether the antifungal was a compounding medication or if there was low adherence.

• 3)

  If there are drug interactions or contraindications to itraconazole, terbinafine or KI are effective treatment options. Both are well tolerated and have a low potential for interactions with other medications.

• 4)

  Give preference to terbinafine and KI for the treatment of children.

• 5)

  Be careful when medicating women of childbearing age, as systemic antifungals can decrease the concentration of oral contraceptives. The additional use of barrier contraceptive methods is advised.

• 6)

  Due to the teratogenic potential of azoles and the contraindication to the use of KI, it is advisable, during pregnancy and lactation, to use adjuvant physical methods for the treatment, with amphotericin B being reserved for severe cases only.2,102,104

• 7)

  In osteoarticular lesions, the initial dose of itraconazole should be 400 mg/day for six months.2,46,109,110 After this period, it can be discontinued if cure is achieved, except in HIV/AIDS patients, when the drug should be maintained until CD4+ >200 cells/μL. If there are still signs or symptoms, the treatment continues with 200 to 400 mg/day for another six months (authors' personal experience). A synovectomy is eventually required.2,111

• 8)

  There is still no consensus regarding the medication, dose and duration of treatment for pulmonary sporotrichosis, which should be guided by the clinical presentation severity. Mild cases can be treated with oral itraconazole and more severe cases with amphotericin B, followed by itraconazole. Most authors recommend a 6–12 month duration.2,56,112,113

• 9)

  Surgical intervention is recommended for patients with localized lung involvement and/or those with radiological features of cavity disease.56,112 Superior results are obtained with early surgery in combination with amphotericin B when compared to using drugs only.56,113,114

• 10)

  The administration of oral corticosteroids, such as prednisone, in symptomatic immunoreactive forms, plays an important role in neutralizing the exacerbated immune response, prescribed at a loading dose of 20 to 40 mg/day, or 0.5 mg/kg/day, providing it does not exceed 40 mg/day. Low doses, 20 mg/day, are usually sufficient. The corticosteroid withdrawal regimen is controversial, which can be carried out in 7 to 14 days, or by tapering off to prevent a recurrence.63,74,75 Erythema nodosum requires slower weaning. Mild and localized, oligosymptomatic cases can be treated with an antifungal associated with a non-steroidal anti-inflammatory drug (NSAID) or with KI alone, due to its immunomodulatory mechanism.

• 11)

  There may be a paradoxical response with exacerbation of the clinical picture, including the development of new lesions, at the beginning of the antifungal therapy. This phenomenon is due to the inflammatory process resulting from the release of antigens and the consequent immune response of the host. Treatment should preferably be performed with an antifungal agent associated with NSAIDs or potassium iodide alone, avoiding corticosteroids in these cases, due to the risk of worsening the infection or even the potential for invasion, especially of bones, in lesions located in the extremities. Reserve corticosteroids for moderate to severe immunoreactive forms, always associated with antifungal therapy. The emergence of new nodules in the lymphatic pathway may not mean worsening, but only a mechanism for the body to eliminate the disease.

• 12)

  The use of topical corticosteroids is contraindicated for sporotrichosis lesions, as they reduce local immunity and promote centrifugal growth or deepening of the lesion. Topical medications should be avoided because, in addition to having no effect, they can cause contact dermatitis. Washing the lesion with soap and water, without much friction, is sufficient, and the use of topical antiseptics is not necessary. Open lesions should be occluded to prevent myiasis, preferably by changing the dressing twice a day. Mineral oil or liquid petroleum jelly can be used with the dressing so that the gauze pad does not adhere to the lesion. If there are signs of secondary bacterial infection, systemic antibiotics should be preferred.

• 13)

  Controlling chronic diseases, reducing alcohol intake, and discontinuing steroid or anti-TNF use are important measures in all systemic forms of sporotrichosis, when possible.48

• 14)

  Try to reduce the dose of immunosuppressants and, if possible, discontinue the use of anti-TNFs in patients with autoimmune diseases. For that purpose, it is advisable to establish good communication between the medical teams involved in the treatment. Reducing the dose of immunosuppressants in transplant recipients may be the key to the successful treatment of sporotrichosis.48,100

• 15)

  Serum levels of calcineurin inhibitors (tacrolimus and cyclosporine) increase significantly after treatment with itraconazole is initiated, so the monitoring of serum concentrations should be stringent.100

• 16)

  Amphotericin B is the main drug used to treat severe, visceral, and life-threatening systemic sporotrichosis, although the therapeutic response is not as favorable as in other systemic mycoses.2,48,98,115 Treatment maintenance after the administration of amphotericin B is usually carried out with itraconazole for a period of 12 months.

• 17)

  Lipid formulations of amphotericin B constitute a more tolerable alternative to the conventional one; however, their superiority in terms of efficacy has not been proven for sporotrichosis.

• 18)

  Patients with HIV/AIDS seem to have a worse prognosis, requiring high doses of itraconazole, amphotericin B, and hospitalization due to lesion extension and/or comorbidities.42,98,116,117

• 19)

  Beware of drug interactions between itraconazole and antiretroviral drugs such as efavirenz, ritonavir, and darunavir.48 The impact of implementing antiretroviral therapy (ART) during sporotrichosis is unknown and the best time for starting remains uncertain. Due to the predisposition to meningitis in IRIS, it is suggested to delay starting ART, similar to tuberculosis and cryptococcosis, in patients considered to be at high risk: neurological impairment, low CD4+ T-cell count, and high viral load.118

• 20)

  Lipid formulations of amphotericin B are the first choice in neurosporotrichosis, followed by maintenance with itraconazole for 12 months.2 Treatment withdrawal depends on the remission of the neurological signs and symptoms, and cerebrospinal fluid (CSF) cellularity should be monitored every 3 to 6 months until normal levels are reached (authors' experience).

• 21)

  The risk of recurrence of meningeal sporotrichosis is high in these patients; thus, it is prudent to maintain suppressive antifungal therapy or discontinue after a CD4+ T-cell count > 200 cells/μL in at least two separate measurements, with an interval of six months between them (authors’ experience).118 Generally, prolonged or even lifelong suppressive therapy with itraconazole at a dose of 200 mg/day is indicated when immunosuppression cannot be controlled, both in meningeal and disseminated involvement.2,49,119,120

Sporothrix spp. are found in the environment; therefore, control and prophylaxis measures should be adopted, contemplating the concept of one health, especially in areas of higher prevalence, with a high concentration of people with little access to education, health, and sanitary conditions.122 These measures comprehend the use of adequate gloves, clothing, and footwear for handling plants and animals with cutaneous and/or mucosal lesions or when performing rural work, periodic cleaning of backyards, removal of construction material, and decomposing organic matter debris. Responsible care for animals should be encouraged, by treating the sick ones, and separating them from other animals and humans in the household, until the cure is achieved. Try neutering/spaying the cats, to avoid their going out for hunting, fighting, walking, or mating. Find viable means for the cremation of dead animals to prevent the fungus from perpetuating in nature. Actively offer information on the mode of transmission and prophylaxis of the disease to the owners of sick animals, aiming to encourage assisted treatment without abandonment.3 The abandonment of animals and the neglect of their care contribute to the perpetuation and increase of the epidemic.