The source of lobomycosis infection is unknown. It was long believed that the disease was restricted to Brazil’s Amazon region because of its hot and humid climate, and that male forest workers were the main host population. However, the disease is not only present in Brazil, but also in forested areas of other countries in South and Central America ^{[1][2][3][4][5][6][7]}[12,13,14,15,16,17,18]. Intriguingly, lobomycosis also occurs in dolphins ^[8][6]. While it would be reasonable to suppose that sylvatic animals such as the sloth, new world monkeys, or the puma might be susceptible to the disease, this has not been borne out.

Of the 490 lobomycosis cases reported worldwide by 2006 ^[9][1], the distribution was as follows: 318 cases (65%) in Brazil, 50 (10%) in Colombia, 34 (7%) in Suriname, 23 (5%) in Venezuela, 21 (4%) in Costa Rica, 16 (3%) in French Guiana, 13 (3%) in Panama, 4 (0.5%) in Peru, 3 (0.5%) in Bolivia, 2 (0.5%) in Ecuador and in Guyana, and one (0.25%) in Mexico, Europe, the United States, and Canada ^[9][1]. While the Amazon basin was the probable source of infection for nearly all cases, at least two cases, reported from South Africa, may have been acquired outside of the Amazon basin ^[10][23]. The first case was of a 65-year-old man with keloidal skin lesions of the feet, arms, and face, with a travel history to Mexico. The second case was of a 20-year-old swimmer and diver who frequently visited Palestine and the United Kingdom ^[10][23]. In the former case, it can be interpreted that the actual distribution of L. loboi may be greater than expected, expanding beyond the Amazon basin towards North America. In the latter case, it could be speculated that L. loboi-contaminated water may confer risk of infection to swimmers or divers.

While the pathogenesis of lobomycosis is poorly understood, the natural history of the disease in humans is characterized by a long incubation period and a slowly progressive, chronic infection. This is likely the result of the subversion of the local immune response ^[9][1]. The lengthy incubation period makes it difficult to pinpoint the exact time and location of exposure. Nonetheless, cases of lobomycosis in ecotourists show that transmission can be caused by an acute event (e.g., trauma involving forest debris) dating back years. For example, a 55-year-old Italian man showed infiltrative nodular lesions on the left tibia in August 2016 ^[11][19]. The likely origin of this infection was attributed to an exposure to Lacazia fungi several years before during a five-day trek in the forests of the Canaima National Park, Bolivar state, Venezuela ^[11][19].

The absolute case numbers of Lobomycosis have risen over the years, adding more information, but also more puzzles with regards to its mode of transmission. For instance, a case reported five years ago had the probable location of transmission noted as unknown ^[12][34]. The case was of a 36-year-old male farmer who presented with keloid lesions of the left ear. He lived as a farmer in Brazil’s Minas Gerais state, which is located no less than 300 km from the Amazon Basin. He had received visits from Amazonian people at his farm prior to the onset of lobomycosis, raising the question of whether an infected human could have been the source of transmission. Additionally, six new cases of lobomycosis were reported in the Colombian National Army ^[13][35]. The disease was probably acquired while in the service in the eastern Colombian Amazon ^[13][35]. The duration of illness was between two and 15 years, which suggests that these soldiers were exposed at different times in the same jungle area ^[13][35]. Although this jungle area was identified as an infection site for the case series ^[13][35], the unknown is where in the environment Lacazia fungi reside over the years. Furthermore, a second case of lobomycosis with Mexico as the probable site of infection was reported recently ^[14][36], building on the initial case in a South African who had travelled to Mexico ^[10][23]. This second individual was a farmer and beekeeper living in southwestern Mexico presenting with multiple nodular lesions in the right ear ^[14][36]. In Greece, a histologically confirmed case was reported in a 64-year-old woman without any travel history to Central or South America, marking the first such case from Europe ^[15][37]. On the contrary, lobomycosis cases declined amongst the Kaiabi Indians, dropping to only three new cases in the last 20 years ^[16][38].

An important outcome from the follow up of lobomycosis cases amongst the Kaiabi Indians between 1965 and 2019 is that a spontaneous cure has not been observed ^[16][38]. This means that every new case becomes a prevalent case over time ^[17][39]. This, combined with probable high numbers of undiagnosed cases, leads to a mounting burden of disease. The known prevalence today totals 907 cases of lobomycosis in the world ^[18][40]. Out of this (N = 907), 496 cases (55%) were reported in Acre state, Brazil ^[18][40]. In this state, 207 new cases of lobomycosis were reported between 2009–2021. Of these 207 cases, 19 cases occurred in women (9%), the youngest of which involved a 10-year-old child, while the oldest case was of a 106-year-old, and the majority of the individuals affected lived in forested areas ^[18][40]. In addition to the known 907 reported cases globally so far ^[18][40], it is expected that a larger number remain undiagnosed, contributing to a “hidden prevalence” of lobomycosis.

It had long been believed that lobomycosis was a human disease of Latin American origin until the disease was reported in bottlenose dolphins (Tursiops truncates) off the coast of Florida in 1971 ^[19][20][21][41,42,43]. Due to human interaction with this geographically widespread dolphin species, lobomycosis cases resulting from dolphin-to-human transmission have been reported ^[21][22][23][43,44,45]. At least two cases were confirmed as zoonotic transmission of lobomycosis. Both cases involved work-related contact with a sick dolphin in which the human patients presented with lesions on their hands months after contact ^[21][22][23][43,44,45]. Additionally, the possibility of animal-to-human transmission was further implicated when one of the reseco-archeuthors here (PSR) acquired the disease upon handling experimental mice inoculated with live yeast-like cells from a lobomycosis patient ^[24][46]. However, reports of zoonotic transmission are rare and may be more likely in immunocompromised individuals.

Lobomycosis in the bottlenose dolphin is as widespread as the geographical range of the bottlenose dolphin itself, with a prevalence as high as 16% ^{[25][26][27][28][29][30][31][32][33][34][35][36]}[47,48,49,50,51,52,53,54,55,56,57,58]. Reports showed lobomycosis in bottlenose dolphins off the coasts of Florida, North Carolina (Atlantic Ocean) and Texas (Gulf of Mexico) in the United States, the coasts of Spain and France (Bay of Biscay), and the Brazilian Atlantic coast of Rio Grande do Sul state (Tramandi River) ^{[25][26][27][28][29][30][31][32][33][34][35][36]}[47,48,49,50,51,52,53,54,55,56,57,58]. The disease has also been reported in the Guiana dolphin (Sotalia guianensis) ^[22][44]. Interestingly, while the disease occurs readily among dolphins in regions that are not endemic to humans, there is a complete absence of the disease in freshwater dolphins in human-endemic regions, including the Orinoco River in Venezuela and the Amazon River in Brazil ^[26][27][48,49].

The diagnosis of lobomycosis is challenging, as the lesions are often mistaken for cutaneous leishmaniasis, nontuberculous mycobacterial infections including leprosy, sporotrichosis, or other dermatological mycoses ^[17][39]. Distinguishing clinical features of lobomycosis include slowly progressing keloidal nodules, which may ulcerate or develop a verrucous appearance over time. Other presentations include hypo- or hyperpigmented macules and papules. Lesions may be pruritic or cause a burning sensation, and they can be isolated or disseminated, and are usually localized in the lower limbs, followed by the ears, upper limbs, and head ^[37][38][59,60]. In the disseminated form, body deformities, an intense pruritus, and ulcerations are commonly observed ^[39][61].

Biopsy for histological analysis is considered the gold standard ^{[6][9][11][37][40][41]}[1,10,17,19,32,59]. Lacazia fungal cells are identified by staining with haematoxylin-eosin and Gomori-Grocott methenamine silver stains ^[41][32]. Analysis of haematoxylin-eosin dyed papillary dermis by light microscopy at 100× magnification reveals hyperkeratosis, collagen fibroplasia, vascular neoformation, and diffuse inflammatory infiltrate with lymphocytes, epithelioid cells, giant cells, and hemosiderin-laden histiocytes ^[17][39]. Reticular dermis dyed by Gomori-Grocott methenamine silver and analysed at 200–400× magnification shows round thick-double-walls yeasts occurring singly or in interconnected chains ^[17][39]. These histopathological features can be used for the diagnosis of lobomycosis ^[41][42][32,62].

Vinyl adhesive tape (also known as the Scotch test) can also be used for diagnosis after observation of ulcerated lesions ^[43][63]. This test is based on the transepidermal elimination of L. loboi, in which fungus is eliminated through the horny layer of the epidermis ^[42][62]. This technique consists of the application of vinyl adhesive tape to the scale-encrusted aspect of the lesion, followed by the application of this tape to a glass side present with potassium hydroxide (KOH) and dimethyl sulfoxide (DMSO), and subsequent examination by light microscopy. While the diagnostic accuracy has not been well studied, Miranda et al. confirmed lobomycosis via this technique in five of five patients, and were able to distinguish it from other tropical neglected mycoses (chromoblastomycosis and paracoccidiodomycosis) ^[43][63]. Different from lobomycosis, paracoccidioidomycosis and chromoblastomycosis can be cultured in the laboratory ^[43][63].

Molecular testing has also been successfully employed for the diagnosis of lobomycosis ^[11][38][39][19,60,61]. Amplification and direct sequencing of fungal ribosomal RNA genes yielded the diagnosis of lobomycosis in a European man who had travelled to the Amazon region of Venezuela ^[11][19]. Another approach has been to amplify the gp43-like gene ^[38][60]. However, as molecular testing may not always be available in endemic regions, clinical and microscopic diagnosis remain the most used approaches to identify cases ^[38][39][60,61].

Over the years, numerous antifungal and antibiotic regimens have been attempted with generally unsatisfactory outcomes, falling short of total remission. One studies used sulfadimethoxine 1000 mg/day for an 80-year-old patient in Venezuela in 1961 ^[44][64] or sulfamethoxypyridazine 500 mg/day for two cases of 50-year-olds in French Guyana in 1962 ^[45][65]. The former study showed partial remission of skin infiltrations and nodules ^[44][64], while the latter showed no clear resolution of skin lesions ^[45][65]. An experimental approach using ketoconazole 400 mg/day showed a decrease in the number of Lacazia fungi and mild to moderate remission of skin lesions ^[46][66]. In another study (1980), ketoconazole 200 mg/day for six months given to a 45-year-old farmer in Brazil resulted in an unsatisfactory outcome with no cure ^[47][67].

After therapeutic studies undertaken by Opromolla et al. in the 1990s ^[41][43][32,63], clofazimine and itraconazole were considered for lobomycosis treatment. Treatment with clofazimine and itraconazole for one year in a 46-year-old Brazilian male was reported to result in the total remission of skin lesions ^[48][68]. The success of this treatment regimen may be attributed to this patient’s localized facial lesion ^[48][68], which is less complex than treating the disseminated forms of the disease ^[40][49][10,69]. In another case involving a localized skin lesion of the left ear, a 29-year-old male forest ranger in Peru was treated with posaconazole 400 mg twice a day for 27 months ^[50][70]. Although it resulted in the remission of skin lesions, Lacazia fungi were still viable after treatment ^[50][70]. However, even after four years of follow up of this case, the disease had not recurred ^[50][70]. In another successful case, a patient was initially treated with itraconazole 200 mg/day and cryotherapy for seven months ^[12][34]. As lobomycosis re-appeared, he had further surgery along with clofazimine (100 mg/day), itraconazole (200 mg/day) and cryotherapy with liquid nitrogen for two years ^[12][34]. At the time of the study’s end, the complete remission of skin lesions and the absence of fungi in a biopsy were seen ^[12][34].

Notably, combination therapy with itraconazole clofazimine, rifampin, dapsone, and surgical excision resulted in a clinical cure in both localized and disseminated forms of the disease ^[24][43][51][46,63,71]. To date, the most promising approach to lobomycosis was found by chance while treating leprosy patients co-infected with lobomycosis in the Leprosy Elimination Program carried out by SDPA in Acre state, Brazil. Ten co-infected patients were treated with the standard protocol for multibacillary (MB) leprosy with multiple drug therapy (MDT; rifampin, clofazimine, and dapsone) as recommend by the World Health Organization (WHO) ^[40][10]. Patients reported reduced itching and softening of the skin lesions. Patients were periodically evaluated, and followed up with biopsy and fungal viability assessments ^[40][10]. All lesions showing atrophy were then surgically excised, with no further disease recurrence, resulting in 10 of 10 patients cured ^[40][10]. Recently, SDPA reported a randomized clinical trial with multibacillary multidrug therapy (MDT/MB/WHO) and surgery resulting in a likelihood ratio of 2.5 (CI 95% 1.4–4.4) of cure compared with untreated or incompletely treated patients (controls) ^[51][71]. In this trial, out of 80 patients treated with MDT/MB/WHO, 72 (90%) showed improvement, and 20 (25%) were considered cured ^[51][71]. MDT/MB/WHO alone is effective in most lobomycosis cases. MDT/MB/WHO associated with surgery can even lead to cure in the disease’s disseminated forms.