• View in gallery

    Sample selection flowchart. This figure appears in color at www.ajtmh.org.

  • View in gallery

    Length of individual patient treatment. (A) Group 1: multiple-drug therapy for multibacillary leprosy patients recommended by the WHO (MDT/MB/WHO); (B) Group 2: MDT/MB/WHO and itraconazole; and (C) Group 3: controls. This figure appears in color at www.ajtmh.org.

  • View in gallery

    Results from the treatment (multiple drug therapy for multibacillary leprosy patients recommended by the WHO [MDT/MB/WHO] and itraconazole) of lobomycosis of the ear. (A) Forest resident in the municipality of Sena Madureira, state of Acre, with a history of a trauma involving an Amazonian plant. He had previously undergone treatment with itraconazole + surgery without improvement. (B) Total remission and cure after discharge (June 30, 2009). Source: Acre Dermatology Service. This figure appears in color at www.ajtmh.org.

  • 1.

    Francesconi VA, Klein AP, Santos AP, Ramasawmy R, Francesconi F, 2014. Lomomycosis: epidemiology, clinical presentation, and management options. Ther Clin Risk Manag 10: 851860.

    • Search Google Scholar
    • Export Citation
  • 2.

    Brito AC, Quaresma JA, 2007. Lacaziose (doença de Jorge Lobo): revisão e atualização Lacaziosis (Jorge Lobo’s disease): review and update. An Bras Dermatol 82: 461474.

    • Search Google Scholar
    • Export Citation
  • 3.

    WHO Department of Control of Neglected Tropical Diseases, 2013. Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases: Second WHO Report on Neglected Tropical Diseases. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 4.

    Murdoch ME, Reif JS, Mazzoil M, McCulloch SD, Fair PA, Bossart GD, 2008. Lobomycosis in bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon, Florida: estimation of prevalence, temporal trends, and spatial distribution. Ecohealth 5: 289297.

    • Search Google Scholar
    • Export Citation
  • 5.

    Trabulsi LR, Alterthum F, Gompertz OF, Candeias JAN, 2002. Micoses subcutâneas. Trabulsi LR, ed. Microbiologia, 3rd edition. São Paulo, Brazil: Atheneu.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ramos-E-Silva M, Aguiar-Santos-Vilela F, Cardoso-de-Brito A, Coelho-Carneiro S, 2009. Lobomycosis. Literature review and future perspectives. Actas Dermosifiliogr 100 (Suppl 1): 92100.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lupi O, Tyring SK, McGinnis MR, 2005. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol 53: 931951.

  • 8.

    Gonçalves FG, Belone AFF, Rosa PS, Laporta GZ, 2019. Underlying mechanisms of leprosy recurrence in the Western Amazon: a retrospective cohort study. BMC Infect Dis 19: 460.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bustamante B, Seas C, Saloman M, Bravo F, 2013. Lobomycosis successfully treated with posaconazole. Am J Trop Med Hyg 88: 12071208.

  • 10.

    Araújo MG, Santos SNMB, Guedes ACM, 2018. Lobomycosis: a therapeutic challenge. An Bras Dermatol 93: 279281.

  • 11.

    Arenas CM, Rodriguez-Toro G, Ortiz-Florez A, Serrato I, 2019. Lobomycosis in soldiers, Colombia. Emerg Infect Dis 25: 654660.

  • 12.

    Queiroz-Telles F, Nucci M, Colombo AL, Tobón A, Restrepo A, 2011. Mycoses of implantation in Latin America: an overview of epidemiology, clinical manifestations, diagnosis and treatment. Med Mycol 49: 225236.

    • Search Google Scholar
    • Export Citation
  • 13.

    Woods WJ, Belone AFF, Carneiro LB, Rosa PS, 2010. Ten years experience with Jorge Lobo’s disease in the state of Acre, Amazon region, Brazil. Rev Inst Med Trop 52: 273278.

    • Search Google Scholar
    • Export Citation
  • 14.

    Opromolla DVA, Vilani-Moreno FR, Belone AFF, 1999. A doença de Jorge Lobo e a coloração pela prata metenamina. An Bras Dermatol 74: 345349.

    • Search Google Scholar
    • Export Citation
  • 15.

    Opromolla DVA, Belone AFF, Taborda PRO, 2000. Clinic-pathological correlation in 40 cases of lobomycosis. An Bras Dermatol 75: 425434.

  • 16.

    Vilani-Moreno FR, Opromolla DVA, 1997. Determinação da viabilidade do Paracoccidioides loboi em biópsias de pacientes portadores de doença de Jorge Lobo. An Bras Dermatol 72: 433437.

    • Search Google Scholar
    • Export Citation
  • 17.

    Sesso A, Baruzzi RG, 1988. Interaction between macrophage and parasite cells in lobomycosis. The thickened cell wall of Paracoccidioides loboi exhibits apertures to the extracellular milieu. J Submicrosc Cytol Pathol 20: 537548.

    • Search Google Scholar
    • Export Citation
  • 18.

    Opromolla DVA, Taborda PRO, Taborda VBA, Viana S, Furtado JF, 1999. Lobomycosis - reports of 40 new cases. An Bras Dermatol 74: 135141.

  • 19.

    Huang L, Crothers K, Atzori C, Benfield T, Miller R, Rabodonirina M, Helweg-Larsen J, 2004. Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. Emerg Infect Dis 10: 17211728.

    • Search Google Scholar
    • Export Citation
  • 20.

    Frey-Klett P, Burlinson P, Deveau A, Barret M, Tarkka M, Sarniguet A, 2011. Bacterial-fungal interactions: hyphens between agricultural, clinical, environmental, and food microbiologists. Microbiol Mol Biol Rev 75: 583609.

    • Search Google Scholar
    • Export Citation
  • 21.

    Kluge M, 2002. A fungus eats a cyanobacterium: the story of the Geosiphon pyriformis endocyanosis. Proc R Irish Acad 102B: 1114.

 

 

 

 

 

Multidrug Therapy for Leprosy Can Cure Patients with Lobomycosis in Acre State, Brazil: A Proof of Therapy Study

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  • 1 Setor de Pós-graduação, Pesquisa e Inovação, Centro Universitário Saúde ABC, Fundação ABC, Santo André, Brazil;
  • 2 Laboratório Pesquisa do Centro Universitário Uninorte (UNINORTE), Rio Branco, Brazil;
  • 3 Serviço Estadual de Dermatologia do Acre, Programa Estadual de Dermatologia do Acre, Programa Estadual de Controle da Hanseníase (SESACRE), Rio Branco, Brazil;
  • 4 Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, Bauru, Brazil;
  • 5 Universidade Federal do Acre, Rio Branco, Brazil;
  • 6 Division of Infectious Diseases and Global Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, Florida

ABSTRACT

Lobomycosis, also referred to as lacaziosis, is an endemic cutaneous and subcutaneous fungal disease that mainly affects Amazonian forest dwellers in Brazil. There is no disease control program in place in Brazil, and antifungal therapy failures are common, and the therapy is inaccessible to most patients. We performed a randomized, unblinded clinical trial testing the cure rate of multiple drug therapy (MDT) for leprosy with surgical excision, with or without itraconazole. A control arm consisted of patients who did not adhere to either therapeutic regimens but continued to be followed up. Multiple drug therapy consisted of monthly supervised doses of 600 mg rifampicin, 300 mg clofazimine, and 100 mg dapsone, in addition to daily doses of 50 mg clofazimine and 100 mg dapsone. The patients in the MDT plus itraconazole arm also received itraconazole 100 mg twice daily. We followed up 54 patients from the MDT group and 26 patients from the MDT plus itraconazole group for an average of 4 years and 9 months. The 23 controls were followed up for 6 months on average. The following endpoints were observed: 1) unchanged (no apparent improvement), 2) improved (reduction in lesion size and/or pruritus), and 3) cured (complete remission of the lesions, no viable fungi, and no relapse for 2 years after the end of the drug treatment). The results indicated a significantly greater likelihood of cure associated with the use of multidrug therapy for leprosy with or without itraconazole when compared with the control group. The addition of itraconazole to MDT was not associated with improved outcomes, suggesting that MDT alone is effective.

INTRODUCTION

Lobomycosis is a cutaneous and subcutaneous mycoses that affect the population residing in the Brazilian Amazon region. Workers in the forest interior, such as rubber tappers, are especially at risk for this infection.1 The disease is caused by the fungus Lacazia loboi, a dimorphic fungus found in tropical waters throughout Latin America. Infection results from trauma to the skin and is associated with severe disfiguration characterized by keloid-like nodular lesions of the head, legs, and/or arms.1,2 In addition, the disease is also prevalent among other vertebrates. For instance, offshore bottlenose dolphins from the Indian River Lagoon in Florida can be affected as well.3 Lobomycosis is among the most neglected tropical endemic diseases and generally affects people with the lowest incomes living in rural areas of forested regions in Latin America.4,5

Lobomycosis has been detected in numerous Latin American countries, including Colombia, Suriname, French Guiana, Guyana, Venezuela, Panama, Costa Rica, Peru, Ecuador, Bolivia, Honduras, and Mexico. However, Brazil has the highest proportion (70%) of cases (∼500 cases reported to date).2,6,7 The Acre Dermatology Service8 in the western Amazon has recorded 317 cases of the disease in mostly male patients living in the forest, with an average age of 52.7 years. Case reports have shown successful outcomes following surgical excision and antifungal and/or antitubercular drug use (e.g., itraconazole, posaconazole, and clofazimine).911 However, the Acre Dermatology Service noted a high disease recurrence risk with this approach, especially in disseminated disease.12,13 Furthermore, completion of therapy may be hampered by the high cost of antifungals.

One of the conditions managed by the Acre Dermatology Service is leprosy. This group noted that patients who had both leprosy and lobomycosis and were being treated with multiple drug therapy (MDT) for leprosy demonstrated the best outcomes for lobomycosis compared with patients receiving various antifungals (amphotericin, ketoconazole, and itraconazole).13 The main goal of this study was to test the hypothesis that the probability of cure (total remission) is greater in the intervention groups than in the controls, and that itraconazole does not provide additional benefits over MDT alone. This clinical trial was conducted over the course of 22 years by the Acre Dermatology Service under its full responsibility and mission to provide a better quality of life and dignity for people from the Amazon basin.

METHODS

Patients were enrolled in the study on presentation to the Acre Dermatology Service with lobomycosis. The eligibility criteria were being a carrier of the disease, willing to participate in the clinical trial, and living in Acre state. Eligible patients were evaluated at multiple time points: before starting treatment and every 6 months thereafter for a total of 6 years (4 years while on treatment, and 2 years of follow-up after completion of treatment). At each time point, the lesions were photographed, and two skin biopsies were performed: one fresh to count fungi and determine viability, and the other fixed in 10% buffered formalin for histopathological examination.14,15 The technique to determine viability consisted of staining with ethidium bromide and fluorescein diacetate, according to the method described by Vilani-Moreno and Opromolla.16 All patients gave their written informed consent when they agreed to participate in this study. This project was approved by the Ethical Research Committee of the Acre State Health Department (No. 448/2010).

Treatments.

The patients were randomly allocated by order of arrival to the different treatment groups. All patients were initially submitted to the allocated therapeutic protocol. Throughout the study, patients who did not adhere to treatment were reclassified as controls. They continued to be evaluated, unless they were lost to follow-up. The three study arms are as follows:

Group 1: Patients received the MDT for multibacillary (MB) leprosy patients recommended by the WHO (MDT/MB/WHO): clofazimine (50 mg daily) and dapsone (100 mg daily), in addition to single monthly doses of clofazimine (300 mg), rifampicin (600 mg), and dapsone (100 mg). Some patients had one or more surgeries performed to remove the lesions. The total number of patients treated with MDT/MB/WHO was 54.

Group 2: Patients received the MDT/MB/WHO regimen in addition to itraconazole (tablets of 100 mg by mouth twice daily). Patients had one or more surgeries performed to remove the lesions as indicated. The total number of patients treated with MDT/MB/WHO and itraconazole was 26.

Group 3: Patients who did not adhere to either treatment groups were reclassified as controls and continued to be evaluated periodically. The total number of patients in this group was 23.

Surgical excision varied according to the location of the lesions. For example, cauterization was preferred to remove lesions in the auricular pavilion. Small and localized lesions were completely removed using a scalpel as far as the subcutaneous tissue and the wound was sutured. Large lesions, such as plaques, were removed over several surgical procedures, with skin grafts being performed when necessary.

Follow-up and outcomes.

Initially, the expectation was to have 120 eligible patients randomized across Groups 1 (= 60) and 2 (= 60). Randomization was based on a systematic allocation sampling strategy considering the order of entry into the dermatology service. For instance, the first eligible patient was allocated to Group 1, whereas the second was allocated to Group 2, and so on, until the 120th patient could be allocated to Group 2. However, there were patients who did not adhere to treatment (Figure 1). Some of these patients could be periodically evaluated and were used as controls. Blinding was not possible under the circumstances of this trial.

Figure 1.
Figure 1.

Sample selection flowchart. This figure appears in color at www.ajtmh.org.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0090

The following criteria were considered improvements in the evaluation of the therapeutic efficacy of the regimens: decrease in or cessation of pruritus, atrophy of lesions with a decrease in the number of fungi or decrease in the viability index, and a cure, characterized as complete remission of the lesions without relapse for 2 years after the end of the drug treatment. To analyze the results, scores were assigned to determine evolution parameters as follows: Score 1, no apparent improvement; Score 2, improvement in a few parameters (reduction in size of lesion and/or pruritus); and Score 3, cure (characterized as complete remission of the lesions, no viable fungi, and no relapse for 2 years after the end of the drug treatment).

Data analysis.

The probability of cure was estimated using a Poisson risk model with 95% CIs among the three groupings, with the controls as a reference level, and adjusted by age and gender. The variable “age” was dichotomized as 1 (above the mean, >50 years) and 0 (below the mean, ≤50 years). Scores 1–3 were considered in the first analysis (global model), whereas scores 1 and 3 were selected for the second analysis (no improvement versus cure).

RESULTS

A total of 103 patients (Groups 1 and 2 = 80, Group 3 = 23) participated in the study until an endpoint (Scores 1–3) could be measured. Nine of the patients were female (8.7%), and 94 were male (93.3%), with ages ranging from 19 to 98 (50.7 ± 15.8) years. Fifty-four patients from Groups 1 and 2 had a localized lesion (67.5%), whereas 26 patients (32.5%) had multifocal or disseminated lesions (Supplemental Appendix—Table S1). None of the patients had lesions in both ears, but three patients had lesions in one ear and in another region of the body. Most of the patients from Groups 1 and 2 (31/80) presented with monomorphic, keloid-like lesions, located mainly in the auricular pavilion, although some other patients presented with polymorphic lesions with keloidiform or warty appearances. The mean duration of lesions was 18 (range: 1–59) years; for patients with disseminated lesions, the mean duration was 23 years, and for patients with localized lesions, it was 16 years.

The length of the average individual treatment varied among groupings as follows: Group 1 (4 years and 9 months ± 1 year and 10 months, n = 54), Group 2 (4 years and 9 months ± 1 year and 2 months, n = 26), and Group 3 (6 months ± 6 months, n = 23). The total duration of the study was 22 years and 8 months; the first patient was enrolled on September 29, 1995, and the last patient stopped treatment on June 17, 2018 (Figure 2). The measurements of endpoints (Score 1–3) for each of these patients were obtained at a variable amount of time after the end of treatment. Some patients demonstrated cure in less than 4 years. On the other hand, other patients remained under treatment for more than 4 years and were not cured. Controls demonstrated erratic treatment, but they participated in the follow-up for a longer period of time than the length of treatment. For instance, one of the controls was diagnosed on April 4, 2011 started treatment in 2015 for a total of 1 year and 10 months, abandoned treatment before the end of the treatment period, and then came back periodically until November 14, 2018, which was the last day this patient visited the dermatology service.

Figure 2.
Figure 2.

Length of individual patient treatment. (A) Group 1: multiple-drug therapy for multibacillary leprosy patients recommended by the WHO (MDT/MB/WHO); (B) Group 2: MDT/MB/WHO and itraconazole; and (C) Group 3: controls. This figure appears in color at www.ajtmh.org.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0090

With either treatment groups, 1 or 2, the lesions of most patients improved. Histologically, the initial picture was of an extensive granulomatous reaction in the dermis, with numerous fungi inside giant cells and discrete lymphoplasmacytic infiltrates with marked fibrosis. The histopathological examination after treatment showed subepithelial histiocytic aggregates with a foamy cytoplasm of vacuolated appearance, moderate fibrosis, rare lymphocytes, and sparse giant cells containing nonviable fungal structures consisting only of empty capsules. Of the 80 patients evaluated in Groups 1 Group 2, 52 (65%) improved, regardless of the therapeutic regimen used, and a further 20 (25%) individuals not only improved but were considered cured. Of these patients, 19 had the localized form of the disease, with one patient having the disseminated form. Only eight (10%) patients showed little or no improvement (Score 1). Most of these non-responders had disseminated lesions (n = 5, 63%). In those treated with MDT/MB/WHO, 49 patients (91%) improved (Score 2 or 3), and in those treated with MDT/MB/WHO plus itraconazole, 23 (89%) improved, indicating no significant difference between the two schemes. Furthermore, more patients with single lesions improved compared with patients with multifocal or disseminated lesions. Although not significantly different, the scores obtained for the localized form were higher than those for the multifocal or disseminated forms, independent of the treatment. Patients receiving treatment who were cured (20 of 80 patients) progressed to no viable fungi in the follow-up biopsy.

Table 1 shows a global analysis with the three possible outcomes (Scores 1–3). The probability of cure was twice as high in individuals who were treated with MDT/MB/WHO compared with that in the control group, adjusted by age and gender, and this was statistically significant (P = 0.006). Full data are available in Supplemental Appendix—Table S1.

Table 1

Poisson global model on the outcome of lobomycosis disease treatment

Treatment (ref: control)Likelihood of cure* (95% CI)P-value (Wald’s test)
Group 1 (MDT/MB/WHO)1.8 (1.2, 2.8)0.006
Group 2 (MDT/MB/WHO and itraconazole)1.9 (1.2, 3)0.006
Age (1, 0) > 50 years = 11 (0.8, 1.4)0.88
Gender (1, 0) male = 11.1 (0.7, 1.8)0.7

MDT/MB/WHO = multiple drug therapy for multibacillary leprosy patients recommended by the WHO.

Considering Score 1 = no change, Score 2 = improvement, and Score 3 = cure.

Table 2 shows the results from a Poisson model with two outcomes (Score 1 and Score 3). The probability of a cure was ×2.5 greater in individuals who were treated with MDT/MB/WHO than that in the control group, adjusted by age and gender, and this was statistically significant (P = 0.002). Full data are available in Supplemental Appendix—Table S1.

Table 2

Poisson partial model on the outcome of treatment of lobomycosis disease

Treatment (ref: control)Likelihood of cure* (95% CI)P-value (Wald’s test)
Group 1 (MDT/MB/WHO)2.5 (1.4, 4.4)0.002
Group 2 (MDT/MB/WHO and itraconazole)2.6 (1.4, 4.6)0.002
Age (1, 0) > 50 years = 11.1 (0.7, 1.8)0.6
Gender (1, 0) male = 11.1 (0.5, 2.6)0.8

MDT/MB/WHO = multiple drug therapy for multibacillary leprosy patients recommended by the WHO.

Score 1 = no change and Score 3 = cure.

According to Tables 1 and 2, MDT/MB/WHO was effective in most lobomycosis cases even leading to cure, whereas no significant difference was observed between MDT/MB/WHO versus MDT/MB/WHO and itraconazole. This further showed that the inclusion of the antifungal drug itraconazole in the proposed therapy did not improve or worsen patient outcomes compared with untreated or irregularly treated patients (controls). In Figure 3, a patient who underwent MDT/MB/WHO and itraconazole is depicted before treatment in 2007 and at cure after discharge (June 30, 2009).

Figure 3.
Figure 3.

Results from the treatment (multiple drug therapy for multibacillary leprosy patients recommended by the WHO [MDT/MB/WHO] and itraconazole) of lobomycosis of the ear. (A) Forest resident in the municipality of Sena Madureira, state of Acre, with a history of a trauma involving an Amazonian plant. He had previously undergone treatment with itraconazole + surgery without improvement. (B) Total remission and cure after discharge (June 30, 2009). Source: Acre Dermatology Service. This figure appears in color at www.ajtmh.org.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0090

DISCUSSION

Lobomycosis is an important public health problem in the Amazon, and in Acre in particular, where 460 cases have been registered in the state to date. Most of the affected individuals reside in riverine towns with limited access to health services. In addition, when lobomycosis is left untreated, it is a chronic and progressive disease, and spontaneous improvement of lesions has not been observed. Moreover, patients tend to present late in the course of disease, usually many years after the onset of initial symptoms.

In our study, patients with solitary lesions were more likely to improve compared with patients with multifocal or disseminated lesions. Solitary lesions on the trunk and limbs can be surgically excised, in contrast to solitary lesions on the ear or disseminated lesions. All patients with solitary trunk or limb lesions had at least one surgical procedure during the treatment period. Lesions of the ear are more challenging to treat because of the inability to achieve wide surgical margins, as well as decreased drug penetration. Drug penetration is thought to be diminished because of fibrosis.17 The anti-inflammatory properties of clofazimine may reduce the development of fibrosis, thereby enhancing blood flow to the tissue. An important observation after treatment with MDT/MB/WHO, with or without itraconazole, was the reduction of pruritus because this improved the patients’ quality of life. We conclude that the treatment time for lobomycosis should be prolonged for the drugs to be effective. In the present study, the 4-year treatment program resulted in 20 patients being cured. Alterations in patient skin pigmentation due to the use of clofazimine was the only treatment adverse effect noted.

Lobomycosis is a neglected endemic disease, and epidemiological data are not readily available.18 The state of Acre is considered a hot spot for lobomycosis,13 and the current numbers are likely underestimated. The number of patients treated by the Acre Dermatology Service,13 however, indicates a need for more attention to this condition. It is a chronic and stigmatizing disease, and despite success of MDT/MB/WHO, there is still a need for additional therapeutic strategies to increase the cure rate. There is also a need for prevention programs. Multiple-drug therapy for multibacillary leprosy patients recommended by the WHO is provided free of charge, but the cost of antifungals tends to be prohibitive. Therefore, our finding that MDT/MB/WHO is as effective as MDT/MB/WHO and itraconazole has important financial implications for the public health system.

Our study has several limitations. Because of the remote study location and limited resources, routine laboratories to monitor drug adverse effects (e.g., liver function tests and complete blood counts) could not be performed. However, no symptoms consistent with medical adverse effects were noted, except that clofazimine could discolor patients’ skin. Relatedly, drug levels could not be obtained to ascertain adequate absorption. This is a known problem for itraconazole, which has poor oral bioavailability. Future studies could explore the addition of newer antifungals that have good oral bioavailability and proven efficacy against dimorphic fungi (e.g., voriconazole and posaconazole) with MDT/MB/WHO. In addition, the pharmacological mechanism of action of the bactericidal drugs against L. loboi is unknown. However, dapsone is known to have efficacy against another fungus, Pneumocystis jirovecii, likely by inhibiting the folate biosynthesis enzyme dihydropteroate synthase.19 Furthermore, we hypothesize that bacterial–fungus interactions could be related to the bactericidal effect of dapsone and/or rifampicin on L. loboi.20 A symbiotic system has been described between a fungal species and a cyanobacterium that lives within the cytoplasm of the fungal species in a symbiotic fashion (endocytobiosis).21 A further test of this hypothesis in a bioassay study is suggested.

CONCLUSION

Our study showed that leprosy treatment (MDT/MB/WHO) led to improvement or cure in patients with lobomycosis. Treatment with MDT/MB/WHO resulted in the cure of 20 of 80 patients treated (25%). Moreover, treatment was associated with a greater likelihood of cure (×2.5) as compared with controls (patients who did not complete therapy). There was no difference in outcomes with the addition of itraconazole. We therefore recommend the use of MDT/MB/WHO for the treatment of lobomycosis.

Supplemental table

REFERENCES

  • 1.

    Francesconi VA, Klein AP, Santos AP, Ramasawmy R, Francesconi F, 2014. Lomomycosis: epidemiology, clinical presentation, and management options. Ther Clin Risk Manag 10: 851860.

    • Search Google Scholar
    • Export Citation
  • 2.

    Brito AC, Quaresma JA, 2007. Lacaziose (doença de Jorge Lobo): revisão e atualização Lacaziosis (Jorge Lobo’s disease): review and update. An Bras Dermatol 82: 461474.

    • Search Google Scholar
    • Export Citation
  • 3.

    WHO Department of Control of Neglected Tropical Diseases, 2013. Sustaining the Drive to Overcome the Global Impact of Neglected Tropical Diseases: Second WHO Report on Neglected Tropical Diseases. Geneva, Switzerland: World Health Organization.

    • Search Google Scholar
    • Export Citation
  • 4.

    Murdoch ME, Reif JS, Mazzoil M, McCulloch SD, Fair PA, Bossart GD, 2008. Lobomycosis in bottlenose dolphins (Tursiops truncatus) from the Indian River Lagoon, Florida: estimation of prevalence, temporal trends, and spatial distribution. Ecohealth 5: 289297.

    • Search Google Scholar
    • Export Citation
  • 5.

    Trabulsi LR, Alterthum F, Gompertz OF, Candeias JAN, 2002. Micoses subcutâneas. Trabulsi LR, ed. Microbiologia, 3rd edition. São Paulo, Brazil: Atheneu.

    • Search Google Scholar
    • Export Citation
  • 6.

    Ramos-E-Silva M, Aguiar-Santos-Vilela F, Cardoso-de-Brito A, Coelho-Carneiro S, 2009. Lobomycosis. Literature review and future perspectives. Actas Dermosifiliogr 100 (Suppl 1): 92100.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lupi O, Tyring SK, McGinnis MR, 2005. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol 53: 931951.

  • 8.

    Gonçalves FG, Belone AFF, Rosa PS, Laporta GZ, 2019. Underlying mechanisms of leprosy recurrence in the Western Amazon: a retrospective cohort study. BMC Infect Dis 19: 460.

    • Search Google Scholar
    • Export Citation
  • 9.

    Bustamante B, Seas C, Saloman M, Bravo F, 2013. Lobomycosis successfully treated with posaconazole. Am J Trop Med Hyg 88: 12071208.

  • 10.

    Araújo MG, Santos SNMB, Guedes ACM, 2018. Lobomycosis: a therapeutic challenge. An Bras Dermatol 93: 279281.

  • 11.

    Arenas CM, Rodriguez-Toro G, Ortiz-Florez A, Serrato I, 2019. Lobomycosis in soldiers, Colombia. Emerg Infect Dis 25: 654660.

  • 12.

    Queiroz-Telles F, Nucci M, Colombo AL, Tobón A, Restrepo A, 2011. Mycoses of implantation in Latin America: an overview of epidemiology, clinical manifestations, diagnosis and treatment. Med Mycol 49: 225236.

    • Search Google Scholar
    • Export Citation
  • 13.

    Woods WJ, Belone AFF, Carneiro LB, Rosa PS, 2010. Ten years experience with Jorge Lobo’s disease in the state of Acre, Amazon region, Brazil. Rev Inst Med Trop 52: 273278.

    • Search Google Scholar
    • Export Citation
  • 14.

    Opromolla DVA, Vilani-Moreno FR, Belone AFF, 1999. A doença de Jorge Lobo e a coloração pela prata metenamina. An Bras Dermatol 74: 345349.

    • Search Google Scholar
    • Export Citation
  • 15.

    Opromolla DVA, Belone AFF, Taborda PRO, 2000. Clinic-pathological correlation in 40 cases of lobomycosis. An Bras Dermatol 75: 425434.

  • 16.

    Vilani-Moreno FR, Opromolla DVA, 1997. Determinação da viabilidade do Paracoccidioides loboi em biópsias de pacientes portadores de doença de Jorge Lobo. An Bras Dermatol 72: 433437.

    • Search Google Scholar
    • Export Citation
  • 17.

    Sesso A, Baruzzi RG, 1988. Interaction between macrophage and parasite cells in lobomycosis. The thickened cell wall of Paracoccidioides loboi exhibits apertures to the extracellular milieu. J Submicrosc Cytol Pathol 20: 537548.

    • Search Google Scholar
    • Export Citation
  • 18.

    Opromolla DVA, Taborda PRO, Taborda VBA, Viana S, Furtado JF, 1999. Lobomycosis - reports of 40 new cases. An Bras Dermatol 74: 135141.

  • 19.

    Huang L, Crothers K, Atzori C, Benfield T, Miller R, Rabodonirina M, Helweg-Larsen J, 2004. Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance. Emerg Infect Dis 10: 17211728.

    • Search Google Scholar
    • Export Citation
  • 20.

    Frey-Klett P, Burlinson P, Deveau A, Barret M, Tarkka M, Sarniguet A, 2011. Bacterial-fungal interactions: hyphens between agricultural, clinical, environmental, and food microbiologists. Microbiol Mol Biol Rev 75: 583609.

    • Search Google Scholar
    • Export Citation
  • 21.

    Kluge M, 2002. A fungus eats a cyanobacterium: the story of the Geosiphon pyriformis endocyanosis. Proc R Irish Acad 102B: 1114.

Author Notes

Address correspondence to Patrícia Sammarco Rosa, Divisão de Pesquisa e Ensino, Instituto Lauro de Souza Lima, Rod. João Ribeiro de Barros, 17034-971 Bauru, Brazil, E-mail: prosa@ilsl.br or Gabriel Zorello Laporta, Setor de Pós-graduação, Pesquisa e Inovação, Centro Universitário Saúde ABC, Fundação ABC, Av. Lauro Gomes, 09060-870 Santo André, Brazil, E-mail: gabriel.laporta@fmabc.br.

Authors’ addresses: Franciely Gomes Gonçalves and Gabriel Zorello Laporta, Faculdade de Medicina do ABC, Setor de Pós-graduação, Pesquisa e Inovação, Santo Andre, Brazil, E-mails: francielygg@hotmail.com and gabriel.laporta@fmabc.br. Patrícia Sammarco Rosa and Andrea de Farias Fernandes Belone, Divisão de Pesquisa e Ensino, Institute Lauro de Souza Lima, Bauru, Brazil, E-mails: prosa@ilsl.br and abelone@ilsl.br. Léia Borges Carneiro, Vânia Lúcia Queiroz de Barros, Rosineide Ferreira Bispo, Yally Alves da Silva Sbardelott, and William John Woods, Serviço Estadual de Dermatologia do Acre, Programa Estadual de Controle da Hanseníase (SESACRE), Rio Branco, Brazil, E-mails: leia.borges@bol.com.br, vannyla_ice@hotmail.com, rosebispo_8@hotmail.com, yallysbardelott@hotmail.com, and william.ac@brturbo.com.br. Sebastião Afonso Viana Macedo Neves, Centro de Ciências da Saúde e do Desporto, Universidade Federal do Acre, Rio Branco, Brazil, E-mail: tiaoviana.sebastiao@gmail.com. Amy Y. Vittor, Emerging Pathogens Institute, University of Florida, Gainesville, FL, E-mail: amy.vittor@medicine.ufl.edu.

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