Current Progress on Epidemiology, Diagnosis, and Treatment of Sporotrichosis and Their Future Trends

Abstract

Sporotrichosis, a human and animal disease caused by Sporothrix species, is the most important implantation mycosis worldwide. Sporothrix taxonomy has improved in recent years, allowing important advances in diagnosis, epidemiology, and treatment. Molecular epidemiology reveals that S. brasiliensis remains highly prevalent during the cat-transmitted sporotrichosis outbreaks in South America and that the spread of S. brasiliensis occurs through founder effects. Sporothrix globosa and S. schenckii are cosmopolitan on the move, causing major sapronoses in Asia and the Americas, respectively. In this emerging scenario, one-health approaches are required to develop a creative, effective, and sustainable response to tackle the spread of sporotrichosis. In the 21st century, it has become vital to speciate Sporothrix, and PCR is the main pillar of molecular diagnosis, aiming at the detection of the pathogen DNA from clinical samples through multiplex assays, whose sensitivity reaches remarkably three copies of the target. The treatment of sporotrichosis can be challenging, especially after the emergence of resistance to azoles and polyenes. Alternative drugs arising from discoveries or repositioning have entered the radar of basic research over the last decade and point to several molecules with antifungal potential, especially the hydrazone derivatives with great in vitro and in vivo activities. There are many promising developments for the near future, and in this review, we discuss how these trends can be applied to the Sporothrix-sporotrichosis system to mitigate the advance of an emerging and re-emerging disease.

Keywords: Sporothrix brasiliensis; Sporothrix globosa; Sporothrix schenckii; antifungal; diagnosis; epidemiology; implantation mycosis; sporotrichosis; subcutaneous mycosis; treatment.

Figure 1

Phylogenetic analysis of the main members of medical relevance in the genus Sporothrix using sequences from the partial calmodulin-encoding gene (exons 3–5) and the ITS region (ITS1/2+5.8s). In the clinical clade, S. brasiliensis is highly virulent for the warm-blooded vertebrate host, followed by S. schenckii, S. globosa, and S. luriei. In the environmental clade, S. chilensis, S. humicola, S. mexicana, and S. pallida are occasional pathogens with mild-pathogenic potential to mammals. Sporothrix phasma, a species with no virulence to mammals, was used as an outgroup in the phylogenetic analysis. Numbers close to the branches represent bootstraps values (ML/NJ).

Figure 2

Temporal evolution of feline sporotrichosis cases in Brazil between 1950 and 2022. The current scenario of sporotrichosis shows signs of frank expansion. The map was drawn based on case reports available on the literature [5,10,12,15,31,32,68,91,98,99,100,101,105,108,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153].

Figure 3

Founder effect events explain the expansion dynamics of cat-transmitted sporotrichosis. The molecular studies developed by de Carvalho et al. [101] offer new bases for proposing public policies to mitigate sporotrichosis. The S. brasiliensis genotypes (e.g., G1, G2, G3, G4, G5, Gn) infect cats living in the metropolitan region of Rio de Janeiro and are considered the parental population. Eventually, a sick cat infected with a single or a group of genotypes (e.g., G2 and G4) is taken to a new area (e.g., Pernambuco), where it will establish a founder population, transmitting S. brasiliensis to other cats (epizootics) or humans (zoonoses). A study of genetic diversity at time one (t1) will reveal that the founder population has less genetic diversity when compared to the parental population. However, the absence of sanitary barriers and the continuous exchange of diseased animals taken by their tutors from the parental-to-founder population will gradually (t2, t3, t4, tn) reconstitute the genetic diversity in the founding population and accelerate the pace of diversification.

Figure 4

A one-health approach to mitigating the spread of cat-transmitted sporotrichosis considers human health (1), animal health (2), and environmental health and safety (3).

Figure 5

The diagnosis of feline sporotrichosis can employ simple, fast, and inexpensive methods such as the quick Panoptic method. (A) Clinical aspect of feline sporotrichosis with ulcerated lesions in the cephalic region of a cat from the state of Espírito Santo, Brazil. (B,C) Feline macrophages infected with numerous S. brasiliensis yeasts cells (arrows), stained using the quick Panoptic method. Bar = 15 µm.

Figure 6

The molecular diagnosis of sporotrichosis relies on PCR. (A) Species-specific PCR is a fast and inexpensive method that combines conventional PCR and agarose gel electrophoresis to detect Sporothrix DNA, mainly in vitro culture samples [96]. Eventually, species-specific PCR is used for detection from clinical samples [249]. Although it has great specificity, the method has low sensitivity (up to 10–100 fg of DNA). (B) For the rapid and accurate diagnosis of human and feline sporotrichosis, a multiplex qPCR assay was developed for the simultaneous detection and speciation of S. brasiliensis, S. schenckii, and S. globosa from cultured DNA and clinical samples (up to 3 copies of the target) [238]. Ss54 = S. brasiliensis; Ss118 = S. schenckii; Ss06 = S. globosa.

Figure 7

The main antifungal agents used in treating sporotrichosis and their cellular targets are depicted. Azoles (e.g., itraconazole) and allylamines (e.g., terbinafine) are fungistatic drugs that slow fungal growth; the azoles by inhibiting cytochrome P-450-dependent synthesis of ergosterol (purple chart: sterol biosynthesis pathway) and the allylamines by competitive inhibition of squalene epoxidase, blocking the conversion of squalene to lanosterol. Amphotericin B is a fungicidal drug whose main target is the ergosterol molecule, producing pores in the plasma membrane (1), leading to the leakage of cytoplasmic material, sequestering (2), absorbing or extracting ergosterol from the membrane (4). Oxidative damage is reported as an alternative mode of action of AmB (3). The main adaptation that can lead to resistance in Sporothrix species is the increased expression of efflux pumps, especially to azoles, although other mechanisms may be involved. The illustration was partially based on Servier Medical Art elements and licensed under a Creative Commons Attribution 3.0 Unported License. ER: endoplasmic reticulum; ROS: reactive oxygen species.