Sporotrichosis in Mexico

Sporotrichosis is an endemic mycosis caused by the species of the Sporothrix genus, and it is considered one of the most frequent subcutaneous mycoses in Mexico. This mycosis has become a relevant fungal infection in the last two decades. Today, much is known of its epidemiology and distribution, and its taxonomy has undergone revisions. New clinical species have been identified and classified through molecular tools, and they now include Sporothrix schenckii sensu stricto, Sporothrix brasiliensis, Sporothrix globosa, and Sporothrix luriei. In this article, we present a systematic review of sporotrichosis in Mexico that analyzes its epidemiology, geographic distribution, and diagnosis. The results show that the most common clinical presentation of sporotrichosis in Mexico is the lymphocutaneous form, with a higher incidence in the 0–15 age range, mainly in males, and for which trauma with plants is the most frequent source of infection. In Mexico, the laboratory diagnosis of sporotrichosis is mainly carried out using conventional methods, but in recent years, several researchers have used molecular methods to identify the Sporothrix species. The treatment of choice depends mainly on the clinical form of the disease, the host’s immunological status, and the species of Sporothrix involved. Despite the significance of this mycosis in Mexico, public information about sporotrichosis is scarce, and it is not considered reportable according to Mexico’s epidemiological national system, the “Sistema Nacional de Vigilancia Epidemiológica.” Due to the lack of data in Mexico regarding the epidemiology of this disease, we present a systematic review of sporotrichosis in Mexico, between 1914 and 2019, that analyzes its epidemiology, geographic distribution, and diagnosis.


Introduction
Sporotrichosis is an infection caused by the thermodimorphic fungi of the genus Sporothrix. The disease is characterized by nodular lesions in the skin and in the subcutaneous tissue, that subsequently ulcerate, mainly affecting the lymphocutaneous system, but rarely other organs. The transmission pathways are associated with organic matter, animal excreta, or also zoonosis [1][2][3]. Sporotrichosis is usually acquired through traumatic inoculation with fomites (spines, debris), contaminated soil, and animal scratches [1,[4][5][6]. Because plant thorns or bushes are often the source of the infection, the disease is commonly known as the "rosebush mycosis" or the "gardener's mycosis" [6]. Rarely can it be acquired by inhalation of spores and produce a primary lung infection [1,7]. This mycosis is also widely prevalent in endothermic animals, such as cats, occasionally dogs, armadillos, rats, birds, and parrots, which are a source of zoonotic transmission [5]. Years ago, it has been shown that sporotrichosis can evolve as a severe disseminated disease with visceral and osteoarticular involvement, particularly in individuals with AIDS, individuals receiving immunosuppressive treatments, and other causes of immunodeficiencies, such as diabetes and chronic alcoholism [1,8].
Sporotrichosis can be classified as cutaneous (which is the most common form) or extracutaneous [1,6]. However, there are other classification approaches based on the clinical characteristics of the infection, and they are divided as follows: skin (lymphocutaneous, fixed cutaneous, and multiple microconidia, while in rich media such as blood and chocolate agar at 37°C, the fungus forms yeast colonies of elongated blastoconidia [6]. The direct examination of biological samples with 10% potassium hydroxide is useless for the diagnosis of human sporotrichosis, due to the scarcity of fungal elements in the lesions, particularly in the lymphocutaneous and fixed cutaneous forms. However, it is convenient to discard other sporotrichoid skin infections [15]. The histopathological analysis is another alternative method, mainly for disseminated forms [16].
In this article, we present a review of sporotrichosis in Mexico through a systematic revision of articles including the following criteria: the epidemiological data of the patients, such as age, gender, geographic origin, diagnosis, and treatment, published from 1914 to 2019.

Methods
The databases used in the search were Scopus, PubMed, ScienceDirect, MEDLINE, and SciELO, as well as the archives from the Faculty of Medicine Library, UNAM. The search was performed using the words Sporothrix, Sporothrix schenckii, and sporotrichosis.

S. schenckii
Rojas et al.  S. globosa (4) Ochoa-Reyes et al. [ Table 2). The laboratory diagnosis of sporotrichosis is mainly carried out using conventional methods (sample culture, isolation of the etiologic agent, macro-and micromorphology, histopathology, and sporotrichin skin test (ST)). Thirty-seven of the articles reviewed included at least one of the aforementioned diagnostic tests, and in 75% of them, immunodiagnostic methods were present; 14 papers reported the use of ST, three used the indirect immunofluorescence assay (IFA), one used the immunodiffusion method, and another one used the Enzyme-Linked Immunosorbent Assay (ELISA) method (Table 1). Finally, the revision evidenced that the most frequently employed treatment for sporotrichosis in Mexico is potassium iodide, even though the treatment of choice (itraconazole, terbinafine, amphotericin B, and others) mainly depends on the clinical form of the disease, the host's immunological status, and the species of Sporothrix involved (Table 1).

Discussion
Sporotrichosis is considered one of the most frequent subcutaneous mycoses in Mexico. For a long time, it ranked second after mycetoma, but most of the cases reported for mycetoma are caused by Nocardia brasiliensis and not by fungal species [56].
Despite the significance of this mycosis in Mexico, public information about sporotrichosis is scarce, and it is not considered a reportable disease according to the Mexican epidemiological national system, the "Sistema Nacional de Vigilancia Epidemiológica" [57].
Several studies consider lymphocutaneous and fixed sporotrichosis as the most frequent forms. The results of this review showed that the lymphocutaneous sporotrichosis is the most frequent form in Mexico. The possibility that the immune system of each individual, or the species or strain of Sporothrix is related to the clinical presentation is a hypothesis that is still under discussion and study [13].
Regarding the prevalence by gender or age, our results show that the most affected age group is between 0 to 15 years. These results are in accordance with those obtained in a retrospective study conducted by Ramírez-Soto et al. [58] in Peru, which showed that 62% of the cases of sporotrichosis involved children under 14 years of age. Our results are also consistent with the findings from another epidemiology study done in Venezuela, where 34.5% of the sporotrichosis cases diagnosed included patients aged < 15 years [59]. However, the infection depends on the exposure to the fungus, and it is more related to specific occupational and recreational activities in each country. As observed in this review, the highest frequency of the disease was recorded in students, possibly due to their participation in outdoor recreational activities, during which they may suffer from trauma involving material contaminated by the fungus. In India and Japan, there is a higher prevalence of sporotrichosis in females, due to their role in agricultural activities [60]. Likewise, in Brazil, females are most frequently infected, either by zoonotic transmission or by trauma with thorns or bushes [61,62]. On the other hand, in South Africa, the incidence rate in males is higher than that in females, with a 3:1 ratio, because males participate more frequently in outdoor activities and activities related to mining [63]. Lastly, in Asian countries, such as China and India, sporotrichosis is more common in females than in males [64].
In this review, most of the cases did not offer information about the source of infection. A few cases, in which this data was reported, were attributed to skin trauma with plant sticks, cat scratches, bites and scratches from squirrels, rat bites, trauma with debris, and spider bites. In the 40 studies analyzed, the most frequently reported source of infection was skin  trauma with plant sticks (Table 1). It is worth mentioning that most of the areas where sporotrichosis cases occur are temperate, forested mountainous areas, with altitudes of approximately ± 2000 m.a.s.l. and summer rains. According to a meta-analysis performed by Ramirez-Soto et al. [58], Sporothrix spp. have specific ecological niches within endemic areas, and they grow in soils between 6.6 and 28.84°C, and a relative humidity between 37.5 and 99.06%. Concerning the diagnosis of sporotrichosis, phenotypic identification requires 5 to 7 days for culture growth and an additional 10 to 21 days for the physiological test [14]. In Mexico, paraclinical diagnosis of sporotrichosis is mainly carried out using conventional methods (sample culture, isolation of the etiologic agent, macro-and micromorphology, histopathology, and ST); thus, most of the records used for this review considered S. schenckii as the only etiological agent.
Immunodiagnostic methods have emerged as an alternative for the diagnosis of sporotrichosis. At first, precipitation and agglutination methods were used [65], but recently, immunoenzymatic assays have been considered new options [66,67]. These tests are based on the use of antigens obtained from epitopes located on the surface of the Sporothrix cell wall, related to N-and O-linked oligosaccharides of peptidorhamnomannan [68,69], where the O-linked pentasaccharide has been the primary epitope identified in the peptidorhamnomannan fraction [69]. Although purified antigens have been obtained for serological tests, they have significant limitations, such as low reproducibility and cross-reactivity. Until now, no immunological method has allowed for the identification of Sporothrix at the species level. Another immunological method widely used in epidemiological studies is the skin test (ST) with sporotrichin. This test determines if the patient has been in contact with the etiologic agent [70].
Molecular tools have shown that Sporothrix is a complex fungus formed by phylogenetically related cryptic species, some of them considered of medical relevance, such as S. brasiliensis, S. schenckii sensu stricto, S. globosa, S. mexicana, S. luriei, and S. pallida [6,88]. New evidence derived from a population genetic analysis of Mexican native isolates has shed light on an indeterminate clade within S. schenckii, which is the species involved in most of the sporotrichosis cases in Mexico [72]. As for S. globose and S. schenckii sensu lato and sensu stricto, they have a worldwide distribution [5]. In Asian countries, S. globosa is the predominant endemic species, with a prevalence of 99.3% [64], while in Brazil, S. brasiliensis has displaced S. schenckii as the most prevalent species [89].
In vitro studies have shown that Sporothrix species differ in virulence and antifungal susceptibility [75,90], suggesting that the combination of different antifungals can generate a favorable response [91]. Potassium iodide and/or itraconazole (ITC) are the first-line treatments for fixed cutaneous and lymphocutaneous sporotrichosis [92]. Terbinafine has been considered the second-line treatment for lymphocutaneous and cutaneous sporotrichosis, in addition to being an excellent therapeutic option for patients with contraindications to the use of itraconazole or potassium iodide [6,93]. Amphotericin B is used in the disseminated, systemic, pulmonary, and osteoarticular forms [92,94]. In pregnant or lactating women with fixed cutaneous sporotrichosis, the use of local thermotherapy (42-43°C) is recommended, due to the thermolability of the fungus, and amphotericin B is recommended in severe cases. Immunosuppressed patients generally require life-long suppressive therapy [95]. The duration and treatment are based on the "Clinical Practice Guidelines for the Management of Sporotrichosis: 2007 Update by the Infectious Diseases Society of America" [94].

Conclusions
In Mexico, sporotrichosis has proven to be one of the most frequent subcutaneous mycoses. This study showed that the states with the highest number of cases are Jalisco, Mexico City, Puebla, Guerrero, and Guanajuato. The highest incidence of cases is reported in males, in the ≥ 0-15 age range, showing a lymphocutaneous clinical presentation, and for whom plant traumatisms is identified as the main source of infection. The commonly identified species were S. schenckii and S. globosa. The most frequently used treatment for sporotrichosis is potassium iodide. We emphasize that this is the first retrospective study in Mexico that has done an analysis of sporotrichosis' epidemiology, geographic distribution, and diagnosis reported between 1914 and 2019. This knowledge could be used to aid in the adoption of strategic public health policies aimed at controlling epidemics.
Acknowledgments The authors gratefully acknowledge the technical support of Hortensia Navarro Barranco.
Funding The authors received financial support from the División de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de México for the different projects involved in this revision.

Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of interest.
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