Ocular Sporotrichosis

Sporotrichosis is a subacute or chronic mycosis predominant in tropical and subtropical regions. It is an infection of subcutaneous tissue caused by Sporothrix fungus species, but occasionally resulting in an extracutaneous condition, including osteoarticular, pulmonary, nervous central system, and ocular disease. Cases of ocular sporotrichosis are rare, but reports have been increasing in recent decades. Ocular infections usually occur in hyperendemic areas of sporotrichosis. For its classification, anatomic criteria are used. The clinical presentation is the infection in the ocular adnexal and intraocular infection. Ocular adnexa infections include palpebral, conjunctivitis, and infections of the lacrimal sac. Intraocular infection includes exogenous or endogenous endophthalmitis. Most infections in the ocular adnexal have been reported in Brazil, China and Peru, and intraocular infections are limited to the USA and Brazil. Diagnosis is performed from Sporothrix isolation in the mycological examination from ocular or skin samples. Both sporotrichosis in the ocular adnexa and intraocular infection can mimic several infectious and non-infectious medical conditions. Ocular adnexa infections are treated with potassium iodide and itraconazole. The intraocular infection is treated with amphotericin B. This review describes the clinical findings and epidemiological, diagnosis, and treatment of ocular sporotrichosis.


Introduction
Sporotrichosis is a subacute or chronic infection predominant in the subcutaneous tissue [1]. It is caused by Sporothrix species fungal and is predominant in tropical and subtropical regions [2,3]. Most cases are reported from Brazil, China, Peru, and Mexico [2,4]. The upper limbs, lower limbs, and the face are affected [1,3]. Occasionally, it can also result in an extracutaneous infection, including osteoarticular, pulmonary, nervous central system, and ocular infection [4][5][6][7]. Ocular infection due to Sporothrix manifests with a lesion in the ocular adnexa or the deep eyeball structures, causing endophthalmitis [8,9]. Cases of ocular sporotrichosis are rare, but reports have been increasing in recent decades [8][9][10][11][12]. Intraocular infection due to Sporothrix could be a sight-threatening condition that may result in vision loss. To date, little is known about the epidemiology, clinical findings, and outcomes of ocular sporotrichosis. The purpose of this review is to discuss the epidemiology, the aspects related to etiology, main clinical manifestations, diagnosis, and management of ocular sporotrichosis.

Epidemiology and Etiology
Sporotrichosis is a significant health problem in tropical and subtropical regions. Sporotrichosis has a wide geographic distribution worldwide, but most cases have been reported in retrospective studies from Brazil, China, Mexico, and Peru ( Figure 1) [2,4,[13][14][15][16].

Epidemiology and Etiology
Sporotrichosis is a significant health problem in tropical and subtropical regions. Sporotrichosis has a wide geographic distribution worldwide, but most cases have been reported in retrospective studies from Brazil, China, Mexico, and Peru ( Figure 1) [2,4,[13][14][15][16]. Sporotrichosis has been described in humans and animals like cats in Brazil, the United States, Malaysia, and Argentina. Isolated cases in cats also have been reported in Germany, Japan, Mexico, Spain, India, and Australia [17][18][19][20]. Brazil seems to be the most endemic country for sporotrichosis in the world. More than 5000 human cases and 5113 feline cases have been reported in Brazil from 1998 to 2018 [13]. In retrospective studies from China, 2000 cases were recorded in 9 years [14], and more than 1800 cases in Peru [21]. Ocular infections due to Sporothrix occur in hyperendemic areas. Most infections in the eyelid have been reported in China and Peru [8,11], and conjunctival sporotrichosis in Brazil, a hyperendemic area of zoonotic transmission [12]. Intraocular infections are limited to the USA and Brazil (Figure 1) [9]. Ocular sporotrichosis affects all age groups and both sexes [8,9,11,12]. Although Sporothrix can enter the skin or eye via a traumatic inoculation with vegetal material or a wood splinter, or contact with cats or cats with sporotrichosis, most cases occur in the absence of predisposing factors. Infections are usually caused by S. schenckii, S. globosa, and S. brasiliensis. Rare pathogens include S. pallida and S. mexicana. S. globosa causes about 99.3% of cases in Asia, 94% in Australia and South Africa by S. schenckii, 88% in Brazil by S. brasiliensis, and 89% in South and Central America and North America by S. schenckii [2,3]. All these species grow in the soil at temperatures of 6.6-28.84 °C and 37.5-99.06% humidity, and associated with a variety of plants, flowers, decaying material, woody debris, reed leaves, corn stalks, leaves, and wood crumbs, potentially facilitating its establishment and proliferation in the environment [22]. S. schenckii and S. brasiliensis constitute the causal agents of ocular sporotrichosis [8,9,11,12], but the causal agent has not been typified in most cases. Additionally, a case of fungal keratitis was caused by S. pallida, a rare human pathogen [23]. Infections are usually caused by S. schenckii, S. globosa, and S. brasiliensis. Rare pathogens include S. pallida and S. mexicana. S. globosa causes about 99.3% of cases in Asia, 94% in Australia and South Africa by S. schenckii, 88% in Brazil by S. brasiliensis, and 89% in South and Central America and North America by S. schenckii [2,3]. All these species grow in the soil at temperatures of 6.6-28.84 • C and 37.5-99.06% humidity, and associated with a variety of plants, flowers, decaying material, woody debris, reed leaves, corn stalks, leaves, and wood crumbs, potentially facilitating its establishment and proliferation in the environment [22]. S. schenckii and S. brasiliensis constitute the causal agents of ocular sporotrichosis [8,9,11,12], but the causal agent has not been typified in most cases. Additionally, a case of fungal keratitis was caused by S. pallida, a rare human pathogen [23].

Clinical Presentation
Classically, cutaneous sporotrichosis presents with lymphocutaneous, fixed, and disseminated lesions. Nearly 80% of the affected patients show the lymphocutaneous form [1,6]. After traumatic implantation, the lesion may ulcerate and progress along the regional lymphangitic channels. Later, these nodules may ulcerate. The fixed cutaneous sporotrichosis is a single ulcer with no regional lymphatic spreading [1,6]. Disseminated or hematogenous sporotrichosis is rare and usually seen in immunocompromised patients as J. Fungi 2021, 7, 951 3 of 20 an opportunist infection. Disseminated sporotrichosis can extend to various organs and systems, including the central nervous system, osteoarticular tissue, pulmonary, and ocular, progressing to fungemia [5,24]. Extracutaneous sporotrichosis is rare and often develops ocular, pulmonary, and central nervous system involvement ( Figure 2) [5,7].

Clinical Presentation
Classically, cutaneous sporotrichosis presents with lymphocutaneous, fixed, and disseminated lesions. Nearly 80% of the affected patients show the lymphocutaneous form [1,6]. After traumatic implantation, the lesion may ulcerate and progress along the regional lymphangitic channels. Later, these nodules may ulcerate. The fixed cutaneous sporotrichosis is a single ulcer with no regional lymphatic spreading [1,6]. Disseminated or hematogenous sporotrichosis is rare and usually seen in immunocompromised patients as an opportunist infection. Disseminated sporotrichosis can extend to various organs and systems, including the central nervous system, osteoarticular tissue, pulmonary, and ocular, progressing to fungemia [5,24]. Extracutaneous sporotrichosis is rare and often develops ocular, pulmonary, and central nervous system involvement ( Figure 2) [5,7]. For the classification of ocular sporotrichosis, anatomic criteria and the source of infection are used. The clinical presentation of ocular sporotrichosis is ocular adnexal infection and intraocular infection ( Figure 2). Ocular adnexa infections include palpebral, conjunctivitis, and disorders of the lacrimal sac ( Figure 3A-H). The intraocular disease consists of exogenous or endogenous endophthalmitis. Most ocular conditions include skin lesions, except for primary conjunctivitis, dacryocystitis, and exogenous endophthalmitis ( Figure 2). The site of infection, the factors as traumatic inoculation, the residence in the hyperendemic area and host factors that include immune responses determines the clinical outcome of infection (Table 1).

Ocular Adnexa Sporotrichosis
The term ocular adnexa includes the tissues and structures surrounding the eye, including the orbital soft tissue, lacrimal system, conjunctiva, eyelids, and eyebrows [25]. Sporotrichosis in the ocular adnexa consists of a group of infections that can be classi-fied into (1) palpebral infections, one group of infections of the dermis around the eyes, (2) conjunctivitis, one group of infections of the bulbar and palpebral conjunctiva, and (3) infections of the lacrimal system. The eyelid and conjunctiva are more affected in sporotrichosis in the ocular adnexa [8,12], followed by a lacrimal sac that is less affected [8]. Usually, dermatologists manage palpebral lesions and infections of the conjunctiva and lacrimal system by ophthalmologists with oculoplastic expertise.

Sporotrichosis Palpebral
Eyelid sporotrichosis is caused by S. schenckii and also by S. brasiliensis and S. globosa ( Table 2) [8,11,[26][27][28][29][30][31][32][33][34][35][36]. Among the adnexa ocular, 82% of these cases are limited to the eyelids [8]. A case series reported the epidemiologic characteristics and clinical features of 72 patients with eyelid sporotrichosis in Jilin, China. This study included 43 children and 29 adults between 2 months and 80 years. Fixed cutaneous lesion occurred in 57%, lymphocutaneous in 35%, and disseminated in 8% of cases. The 43% of patients had a history of trauma caused by vegetal material and wood [11]. A systematic review included 19 patients with eyelid sporotrichosis and 2 in eyebrows in a hyperendemic area in Peru. In this study, 57.1% of patients were male, and 87.5% were between 0 and 14 years. Lymphocutaneous lesion occurred in 62% and fixed form in 38% of cases [8]. A series of 16 cases of eyelid sporotrichosis has also been reported in another Peruvian hyperendemic area (La Libertad). In this series, most of the cases were lymphocutaneous [29]. Other case series in China reported 10 cases of eyelid sporotrichosis, lymphocutaneous (6 cases), fixed cutaneous (3 cases), and eyelid abscess (1 case) [28]. In Brazil, case reports of sporotrichosis in eyelids are increasing [10,26]. Isolated cases also have been reported in Mexico, Costa Rica, Japan, Argentina, Malaysia, and Australia (Table 2) [30][31][32][33][34][35]. The eyelid lesions may be primary, or their involvement may be part of lymphocutaneous or disseminated lesions. These lesions start as a small subcutaneous nodule at the site of an inoculation that later is ulcerated or spreads along the regional lymphangitic channels.
Skin eyelid lesions may be papular, nodular, ulcerative, or infiltrative (plaque-like) or may show a combination of these features ( Table 2) [8]. However, not all eyelid lesions present with these characteristic clinical manifestations. In China, some eyelid lesions were granuloma annulare-like plaque, abscess, and cyst-like lesions [12,28].
In patients with disseminated infection, eyelid lesions were manifested as a cluster of papules and verrucous plaques [12,28]. The eyelid is the first line of defense for the eye. Therefore, palpable lymphadenopathy or an ulcerated lesion in the periocular region in pediatric patients or some adults from endemic and hyperendemic areas are a suggestive finding of palpebral sporotrichosis. These epidemiological and clinical features may prompt clinicians to consider sporotrichosis in eyelids and facilitate the diagnosis, management, and differentiation of other periocular infections.
The tarsal conjunctiva was more frequently affected than the bulbar (49 cases, 87.5% versus six patients, 10.7%, respectively) ( Table 4). Eyelid involvement was reported in 18 cases (33.3%), the lower eyelid being more affected than the upper one (18 cases (32.1%) versus four patients (7.1%), respectively). In 50% of the cases (28 subjects), a Parinaud oculoglandular syndrome was integrated. The most frequently reported lymph node involvement was preauricular lymphadenopathy (14 cases, 25%), although the affected lymph nodes were not specified in 18 patients (32.1%) ( Table 3). The response to treatment was favorable in cases of palpebral and bulbar disease (79% and 75%, respectively), although the doses of itraconazole used show great variability according to the severity of the case and the low number of patients and clinical studies, it does not allow for more informed conclusions (Table 4).

Dacryocystitis Due to Sporothrix
Among the ocular adnexa, infection of the lacrimal sac due to Sporothrix is infrequent. To date, only six cases have been identified in the published literature [56][57][58]. There are five cases in Brazil, a hyperendemic area of sporotrichosis associated with zoonotic transmission [56,57], and one in Jilin, China [58]. The age of the cases ranged from 2 to 41 years, and five were women. Both the right and left eyes were affected similarly, and three cases presented compromise of the conjunctiva [56,58]. Sporothrix spp., the causal agent, has been identified in four patients, but S. schenckii (1 case) and S. brasiliensis (1 case) have been identified in culture. Among these cases, no trauma associated with ocular implantation has been identified [56][57][58]. Exceptionally, in one case, contact lens use was reported [58], and in other cases, contact with cats [56,57] with no specific history of injury.

Exogenous Endophthalmitis
Exogenous endophthalmitis due to Sporothrix is less frequent than endogenous endophthalmitis [9]. Exogenous endophthalmitis occurs after eye trauma penetrating, although most exogenous cases do not report penetrating ocular trauma [59][60][61][62][63][64][65]. All patients have been reported in the USA, and Sporothrix spp. is the most common etiological agent [9,[59][60][61][62][63][64][65]. Risk factors include delay in treatment and the presence of a lacerating injury resulting from the ocular trauma [60]. The clinical presentation may be subacute or chronic. Anterior uveitis is a clinical manifestation that is more common in exogenous endophthalmitis, including granulomatous uveitis and scleritis [59][60][61][62][63][64][65]. Clinical findings can be nonspecific, emulating non-infectious forms of uveitis. Usually, exogenous endophthalmitis results from prolonged chronic fungal infection/uncontrolled, since most case reports are diagnosed within 100 days of symptom onset (Table 5). Patients often present with decreased vision and redness, and some also have eye pain, leading to a delay in diagnosis and treatment [62][63][64][65]. An eye examination usually reveals a hypopyon and intraocular inflammation [63][64][65]. Exogenous endophthalmitis is a severe eye infection. These cases are medical emergencies, as delay in treatment may result in permanent vision loss.

Endogenous Endophthalmitis
Endogenous endophthalmitis due to Sporothrix is a severe but uncommon cause of intraocular inflammation [66][67][68][69][70][71][72][73][74]. This disease is caused by hematogenous dissemination of the Sporothrix fungus spread of cutaneous or disseminated sporotrichosis to the eye. S. schenckii is the most common cause of endogenous endophthalmitis [66,[69][70][71][72][73][74], although there have been cases reported of endogenous endophthalmitis caused by S. brasiliensis, an emergent pathogen associated with the zoonotic transmission of sporotrichosis in Brazil [67,68]. The clinical findings include choroiditis, chorioretinitis, uveitis, and retinitis [67,70,73,74]. A systematic review reveals that posterior uveitis seems to be a clinical manifestation more common in endogenous endophthalmitis caused by Sporothrix, especially in HIV-infected patients from hyperendemic areas (Table 5) [9]. The initial manifestation is usually posterior uveitis since it is highly vascular, and as a consequence, the intraocular infection usually starts in the posterior segment. Multifocal choroiditis due to S. brasiliensis was also reported in five eyes of three immunocompromised patients with disseminated sporotrichosis in Brazil [68]. In contrast to patients with exogenous endophthalmitis, all patients with endogenous endophthalmitis have an identifiable systemic infection. Systemic infections include sporotrichosis disseminated, osteoarticular, and widespread multiorgan dissemination (including cutaneous, osteoarticular, and pulmonary) [66][67][68][69][70][71][72][73][74]. Patients with endogenous endophthalmitis may present with varying inflammation, decreased vision, and visual loss in some cases. In some cases, diagnosis delay can worsen ocular outcomes, as the disease can disseminate anterior or posterior uveitis to endogenous endophthalmitis [74].

Differential Diagnoses
Ocular sporotrichosis can mimic a broad spectrum of diseases that are infectious and non-infectious. In endemic and hyperendemic area, it is vital to differentiate ocular sporotrichosis from other endemic diseases. Diagnosis must be confirmed by mycological examination. The differential diagnoses for sporotrichosis in ocular adnexa include palpebral lesions caused by the fungus and conjunctivitis caused by bacterial or viral infections. Intraocular sporotrichosis should be included in the differential diagnosis for ocular inflammation, endophthalmitis, choroiditis, retinitis, and uveitis caused by bacterial and fungal infections or viral (Table 6).  • Pseudoendophthalmitis from intravitreal injections, uveal melanoma, retinoblastoma, and sarcoidosis.
In the patient samples, the observation of Sporothirx spp. yeasts are made with direct or fresh examination with conventional stains including Giemsa, PAS, and Grocott (KOH (10%) or NaOH (4%) is rarely used due to poor results); the observation of yeast in cigar-shaped buds or small boats is characteristic, but infrequently seen (5-10%), except in disseminated cases and immunosuppressed patients. Cat and dog cases have many yeasts; however, this is frequent only in the ocular conjunctiva samples in human subjects [1,5,10,12,47].
Like direct examination, biopsy (skin) is not pathognomonic; on rare occasions, asteroid bodies with yeasts may appear. In general, the histopathological image is a combination of suppurative granulomatous conformation and pyogenic reaction, and to a lesser extent, a tuberculoid granuloma can be observed. Large numbers of yeast can only be observed in disseminated cases that affect the eye and adjacent structures [5,75].
Other supporting tests are the intradermal reaction (IDR) with sporotrichin M (mycelial); it should be noted that it is not a standardized test (performed in-house), and in many countries, it is not authorized. It is carried out with the polysaccharide metabolic fraction of S. schenckii (peptide-rhamnomannan); it is applied intradermal (dilution 1:2000, averaging 5 × 10 7 cells/mL) [5,75,76]. The reading is done with the same criteria as the PPD. This test is immensely guiding in above 90%. Serology has little value, more useful in disseminated cases; the most used techniques are precipitins, agglutinins, and complement fixation [1,5].
Molecular biology is of great importance in the identification of strains from tissue samples (biopsies) through the amplification of DNA fragments, with PCR tests (chitin synthetase gene, ChS1, 26S rDNA gene, and topoisomerase II gene), and PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) [1,75]. Proteomic identification, particularly with MALDI-TOF MS techniques, makes it possible to effectively and rapidly identify the five species of Sporothrix [1,75].

Treatment
Like cutaneous sporotrichosis, the primary ocular condition or associated by extension of cutaneous or disseminated cases is managed as follows: Itraconazole is the drug considered of choice by the North American Guidelines for the Treatment of Sporotrichosis, especially for lymphangitic and disseminated cases, and it is regarded as the first option in ocular disease cases [77]. It is used at doses of 100-300 mg/day, depending on the weight and conditions of the patient; the treatment time fluctuates between four and six months, with minimal collateral effects, and it is essential to mention that its absorption depends on gastric pH and food [5,77].
Another highly active drug is potassium iodide (KI). It is the therapy of choice in underdeveloped countries due to its excellent efficacy, low side effects, easy administration, and low cost [1,5,78]. It is generally managed in a saturated solution of KI and drops starting with 2-20 three times a day; in the various series, tanning is obtained within 2-3 months of treatment; there are some cases with rapid responses (15 days). In general, the most critical side effect is gastritis, and to a lesser degree, rhinitis, bronchitis, urticaria, and erythema nodosum. It should be mentioned that KI is prepared as a magisterial formula. In disseminated cases and immunosuppressed patients, they do not respond [78][79][80]. In ocular cases, it also has been administered in combination with KI and itraconazole, especially in those that did not respond well to monotherapy [81].
Amphotericin B is the treatment of choice for systemic, disseminated sporotrichosis cases and must be administered in the hospital. Management with liposomal amphotericin B is suggested, at a standard dose of 3 mg/kg/day, with a range of 3-5 mg/kg/day. For amphotericin B deoxycholate the dose is 0.25-0.75 mg/kg/day. Treatment time is variable and depends more on side effects (kidney) [1,5,77]. Systemic amphotericin B alone or in combination with an oral antifungal is the treatment most commonly used in intraocular infections. It can also be used the intravitreal and systemic antifungal or amphotericin B. It is important to note that for the management of amphotericin B, the patient must be hospitalized, and remember that the most important collateral effects are phlebitis and especially kidney damage; for topical management, it is usually an irritating drug in the mucous membranes [9,77]. The subconjunctival and oral agents show poor intraocular penetration; therefore, intravitreal and systemic antifungal therapy should be considered in cases of endophthalmitis. Cases of exogenous endophthalmitis have worse ocular outcomes and complications compared with endogenous endophthalmitis. The endophthalmitis complications include blindness and irreversible vision loss [9,[60][61][62][63][64].
Another of the drugs used is terbinafine, at doses of 250-500 mg/day; the responses are variable, and it is considered a less active drug than itraconazole but with fewer drug interactions and side effects [1,5]. There are varying results with the administration of fluconazole; its dose is 200-400 mg/day [1]. The use of corticosteroids in cases surrounding the eye is beneficial to avoid the appearance of keloid and fibrous lesions, and they should always be associated with systemic antifungals. The most widely used is prednisone at doses of 10-25 mg/day [5].

Conclusions
Sporotrichosis is an emerging mycosis subcutaneous around the world, which occasionally can result in an ocular infection. Traumatic inoculation with vegetable material, contact with cats, HIV infection, residence in hyperendemic areas, and disseminated infection are associated with this disease. Ocular lesions must be classified using anatomic criteria and the source of infection. There are two defined types of lesions: ocular adnexal lesions, including palpebral lesions, conjunctivitis, and dacryocystitis, and intraocular infection that include endophthalmitis, uveitis, and choroiditis. The diagnosis is based on suggestive ocular findings and mycological examination from ocular or skin samples. Itraconazole and KI are the most used antifungal agents in treating sporotrichosis in adnexa ocular, and amphotericin B is the antifungal agent for treating intraocular infection. Ocular adnexal lesions have an excellent clinical outcome, whereas intraocular infections may have worse results and complications. This review has identified some key points to improve ocular sporotrichosis s clinical, epidemiological, and therapeutic aspects. These findings have public health implications and can assist healthcare providers involved in eye care.