SciELO - Scientific Electronic Library Online

 
vol.52Clinical and epidemiology evaluation of Aids-infected patients hospitalized between 2011 and 2016 in the Santos region of BrazilDifferent susceptibilities of Aedes aegypti and Aedes albopictus larvae to plant-derived products author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

Share


Revista da Sociedade Brasileira de Medicina Tropical

Print version ISSN 0037-8682On-line version ISSN 1678-9849

Rev. Soc. Bras. Med. Trop. vol.52  Uberaba  2019  Epub Apr 11, 2019

http://dx.doi.org/10.1590/0037-8682-0172-2018 

Short Communication

Clinico-immunological spectrum of American tegumentary leishmaniasis and leprosy coinfection: A case series in Southeastern Brazil

Sebastian Vernal1 

Roberto Bueno-Filho1 

Ciro Martins Gomes2 

Ana Maria Roselino1 
http://orcid.org/0000-0002-2709-1825

1Divisão de Dermatologia, Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brasil.

2Departamento de Dermatologia, Universidade de Brasília, Brasília, DF, Brasil.

Abstract

INTRODUCTION:

American tegumentary leishmaniasis (ATL) and leprosy share common areas of prevalence, but reports of coinfection are scarce.

METHODS:

We report a series of 9 ATL-leprosy cases and discuss the association. An integrative diagram to analyze the clinico-immunological features of coinfection with both diseases.

RESULTS:

Nine patients with leishmaniasis (5 cutaneous, 3 mucocutaneous, 1 disseminated case) exhibited concurrent infection with distinct clinical forms of leprosy. Our diagram-based analysis evidenced a divergent clinico-immunological spectrum for each disease in 8 out of 9 cases.

CONCLUSIONS:

The spectrum of ATL-leprosy comorbidity suggests that the host has a specific immune response against each pathogen.

Keywords: Leishmaniasis; leprosy; Coinfection; Cutaneous leishmaniasis; Mucocutaneous leishmaniasis

American tegumentary leishmaniasis (ATL) and leprosy remain the major neglected diseases in some developing countries1,2. Leishmaniasis encompasses a spectrum of vector-borne parasitic infections caused by protozoa belonging to the genus Leishmania, which is represented mainly by the species Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis, in Brazil1. ATL caused by L. (V.) braziliensis initiates as a single skin ulcer or as multiple skin ulcers that can be followed by mucosal involvement months or years later1. Leprosy is a chronic infectious disease caused by the non-cultivable bacillus Mycobacterium leprae that affects the skin and peripheral nerves2. Both diseases have become important public health concerns due to their wide geographic distribution, high incidence rates, and clinical manifestations with subsequent permanent serious injuries and mutilations1,2. ATL and leprosy are endemic to Brazil, where most of the new cases in the Americas emerge1,2.

Although both diseases are prevalent in some countries, reports on comorbidity in the same patient are scarce. In 1978, 8 patients with coinfections of leprosy and cutaneous leishmaniasis (CL) were reported in Ethiopia3, followed by reports of ATL-leprosy concurrence in Venezuela4, India5,6, Northeastern Brazil7, Southeastern Brazil8-12, and Central America13.

ATL and leprosy share some intriguing features, as both are caused by obligate intracellular organisms and characterized by a spectrum of clinico-immunological manifestations that depend on T-cell-mediated immunity14,15. Intracellular pathogens such as M. leprae and Leishmania spp. can be effectively controlled by the Th1 CD4+ subpopulation of the T-cell response. The immune hyperergic pole of both ATL and leprosy is characterized by a strong macrophage activation stimulated mainly by interferon (IFN)-γ and interleukin (IL)-2. Clinically, the Th1 pole of leprosy is represented by the paucibacillary (PB) forms indeterminate (I), tuberculoid (TT), and borderline-tuberculoid (BT) of the Ridley-Jopling classification2, and that of ATL by the mucocutaneous leishmaniasis (ML) form1. These clinical forms typically show a strong reaction in the intradermal lepromin (or Mitsuda) test and the leishmanin (or Montenegro) test, respectively. Furthermore, the anergic pole is characterized by a depressed specific T-cell response with Th2 pole predominance. This pole is represented by the multibacillary (MB) clinical forms of leprosy, borderline-borderline (BB), borderline-lepromatous (BL), and lepromatous leprosy (LL), and by the diffuse anergic cutaneous form of leishmaniasis (CL) caused by L. (L.) amazonensis or the disseminated form (DL) caused by L. (V.) braziliensis infection14,15. Although ATL-leprosy coinfection in an immunocompetent patient is still a rare occurrence, it is a comorbidity of growing concern. The specific immune response to one disease seems to influence the clinical picture of the other, which explains the unpredictable course and difficult management of both infections occurring in the same patient10.

We aimed to report a case series of ATL-leprosy coinfections on the basis of an integrative diagram that emphasizes the clinico-laboratory features to establish a possible Th1/Th2 immunological spectrum relationship between these infectious diseases.

Diagnoses of ATL and leprosy were confirmed on the basis of the World Health Organization recommendations1,2. For ATL diagnosis, exclusive skin involvement was defined as the CL form, whereas lesions affecting the skin and mucosa or just the mucosa were classified as the ML form. Patients with 10 or more pleomorphic lesions in 2 or more body parts were classified as having DL. The Ridley-Joplin classification was used to determine the clinical form of leprosy2. Leishmanin1 and lepromin2 intradermal tests were performed to assess the cellular immune response. Enzyme-linked immunosorbent assay (ELISA) with an anti-phenolic glycolipid 1 (PGL1) antibody was conducted to measure the humoral response associated with leprosy2. Patients were negative for HIV and hepatitis B and C serology, except for case 9 who was positive for hepatitis C. ATL diagnosis was confirmed by polymerase chain reaction (PCR) using primers (forward: based on a minicircle kDNA from the Leishmania sp. 120-bp sequence 5'-(G/C)(G/C)(C/G)CC(A/C)CTAT(A/T)TTACACCCAACCCC-3', reverse: 5'-GGGGAGGGGCGTTCTGCGAA-3') based on the sequence of a minicircle kDNA of Leishmania spp rendering a 120-bp PCR product. The ATL subgenus Viannia was identified by consecutive digestion of the PCR product with the restriction enzymes HaeIII and BsrI. Leprosy was diagnosed by PCR with primers targeting a 336-bp sequence of the M. leprae gene MntH (forward: 5'-CGGCTTCACGTCCAGTTTCTTC-3', reverse: 5'-TAAGTGCCCTCGATGTAAGCGG-3').

Based on the clinico-immunological spectra of ATL and leprosy described in the literature14,15, we generated an integrative figure to identify overlaps between the clinical forms of ATL and leprosy in terms of immunological spectrum and intradermal tests (cellular immune response), serology (humoral response), and histopathology (presence or absence of pathogen)14,15. This diagram served to clarify and compare the association between both diseases in this case report series (Figure 1A).

FIGURE 1 (A) Clinical and immunological spectra of American tegumentary leishmaniasis and leprosy and placement of the reported 9 cases within the proposed spectra. (B) Clinical laboratory features of each patient according to the clinical spectrum for leprosy and American tegumentary leishmaniasis. BB: borderline-borderline, BL: borderline-lepromatous, BT: borderline-tuberculoid, CL: cutaneous leishmaniasis, DL: disseminated leishmaniasis, LL: lepromatous leprosy, ML: mucocutaneous leishmaniasis, N.D.: not determined, PGL: phenolic glycolipid 1, TT: tuberculoid leprosy. 

The 9 cases were also presented based on their clinical, laboratory, and immunological spectra to identify associations between both diseases (Figure 1B). Tables 1 and 2 summarize the demographical, clinical, and laboratory features of each patient.

TABLE 1: Clinical and immunological features of the initially diagnosed disease of 9 patients with American tegumentary leishmaniasis and leprosy in Southeastern Brazil. 

Cases Age Sex Occupation Initial clinical presentation Disease Initial tests Initial Diagnosis
(years) duration (months) Treatment
1 53 M Farmer Malar ulcer 5 LST + MA CL
Amastigotes -
PCR (L. Viannia complex) +
2 68 M Farmer Nasal mucosal infiltration and 6 LST ± MA followed by ML
ulceration Amastigotes + Amphotericin B
3 49 M Truck driver Anesthetic lesions on the trunk, abdomen, and legs - Mitsuda + AFB - Bacilloscopy - MDT BT
4 64 M Farmer LL (treated in primary health - Mitsuda N.D. MDT LL
post). Squeals such as Anti-PGL1 +
atrophy of interosseous hand Bacilloscopy -*
muscles and bilateral ulnar thickening
5 54 M Retired Diffuse infiltrated - Mitsuda N.D. MDT LL
erythematous lesions, bilateral Anti-PGL1 +
ulnar thickening AFB + Bacilloscopy +
6 22 F Student Skin ulcers on the right 36 LST + MA CL
forearm and left malar region Amastigotes -
7 66 M Janitor Sensitivity reduced on the 12 Mitsuda + MDT Neural TT
dorsum of the left foot and Anti-PGL1 +
paresthesia in the left leg Bacilloscopy
8 84 M Farmer Nasal septum ulcer - LST + MA (irregular) ML
Amastigotes -
PCR (L. Viannia complex) +
9 58 M Retired Sensitivity reduced on the 60 LST - MDT (irregular) BB
dorsum Anti-PGL1 -
Bacilloscopy -

AFB: acid-fast bacilli; BB: borderline-borderline; BL: borderline lepromatous; BT: borderline tuberculoid; CL: cutaneous leishmaniasis; DL: disseminated leishmaniasis; F: female; LL: lepromatous leprosy; LST: leishmanin skin test; M: male; MA: meglumine antimoniate; MDT: multidrug therapy; ML: mucocutaneous leishmaniasis; PCR: polymerase chain reaction; PGL1: phenolic glycolipid 1; TT: tuberculoid leprosy; +: positive test result; -: negative test result; ±: weak reaction in the test; *: post-treatment.

TABLE 2: Clinical and immunological features of the secondary disease of 9 patients with American tegumentary leishmaniasis and leprosy in Southeastern Brazil 

Cases Time to secondary clinical manifestation (months) Secondary clinical presentation Secondary test Diagnosis
1 5 Anesthetic lesions in the neck and abdomen Mitsuda + TT
Anti-PGL1 -
AFB -
PCR (M. leprae) +
Bacilloscopy -
2 72 Facial infiltration, cilia loss, generalized Mitsuda N.D. LL
erythematous lesions, and compromised Anti-PGL1 +
peripheral nerve Bacilloscopy +
3 60 Ulcer in the left knee LST + CL
Amastigotes -
PCR (L. Viannia complex) +
4 12 Friable granulomatous vegetative nasal lesion LST+ ML
(Still under MDT for Amastigotes -
leprosy) PCR (L. Viannia complex) +
PCR (M. leprae) +
5 24 Trunk ulcer LST + CL
Amastigotes -
PCR (L. Viannia complex) +
PCR (M. leprae) +
6 12 Red grouped papules on the left malar region Mitsuda N.D. TT
near the leishmaniotic scar Anti-PGL1 N.D.
Bacilloscopy -
PCR (M. leprae) +
7 18 Ulcer on the right forearm LST + CL
Amastigotes -
PCR (L. Viannia complex) +
8 120 Erythematous macule in the right thigh associated Mitsuda - TT
with anesthesia for thermic sensitivity and pain Anti-PGL1 -
Bacilloscopy -
PCR (M. leprae) +
9 120 10 ulcers on the posterior region of the neck, in LST - DL
the left arm, and in the trunk Amastigotes +
PCR (L. Viannia complex) +
PCR (M. leprae) +

AFB: acid-fast bacilli; BB: borderline-borderline; BL: borderline lepromatous; BT: borderline tuberculoid; CL: cutaneous leishmaniasis; DL: disseminated leishmaniasis; LL: lepromatous leprosy; LST: leishmanin skin test; MA: meglumine antimoniate; MDT: multidrug therapy; ML: mucocutaneous leishmaniasis; PCR: polymerase chain reaction; PGL1: phenolic glycolipid 1; TT: tuberculoid leprosy; +: positive test result; -: negative test result; ±: weak reaction in the test; *: post-treatment.

In 3 cases (patients 4, 8, and 9) the subgenera L. Viannia and M. leprae were simultaneously identified by PCR in the same skin or mucosa sample. Three patients (cases 1, 2, and 6) were initially diagnosed with ATL, were treated and cured, and presented again later with clinical features of leprosy. In the remaining 3 patients, the order of disease manifestation was opposite: they first presented with leprosy and later exhibited clinical features of ATL during or after leprosy treatment (cases 3, 5, and 7).

ATL and leprosy share a clinico-immunological spectrum ranging from a strong T-cell response to a predominant B-cell response14,15, but we are the first to compare the spectra of both diseases in a case series.

Concurrent ATL and leprosy have previously been reported3-5,12. Initial MB leprosy manifestation followed by clinical ML several years later has also been described10. Both ML and MB leprosy cause latent infections and sometimes decades elapse before these diseases become clinically recognizable14,15, which complicates determination of the time of infection and concomitant manifestation.

The delay in clinical manifestations may also reflect lack of adhesion to treatment of one or both diseases7. Case 4 was treated with irregular multidrug therapy for leprosy for 1 year following clinical manifestation of ML, making it practically impossible to determine which disease was contracted first due to the long latency of both diseases. A case series in Ethiopia3 identified patients that presented with leprosy for 2 to 7 years before clinical manifestation of CL. Nevertheless, an exact comparison with our study is difficult because L. (L.) tropica was the causative pathogen in these patients. Likewise, comorbidity of leishmaniasis with the BL clinical leprosy form5 and TT leprosy6 has been reported in India. Nevertheless, the anergic pole was attributed to the Leishmania spp. complex.

The subgenus L. Viannia was identified in a patient with LL in Venezuela that also showed CL association 5 years after leprosy was diagnosed4. In 2002, Goulart et al.8 reported the first association between ATL caused by the subgenus L. Viannia and leprosy in Southeastern Brazil. Interestingly, this patient presented with the BL leprosy form with septal obstruction and was diagnosed with ML 3 years later8, a pattern resembling the time-lapse observed in our case 4. Since then, 8 cases have been reported in the state of Maranhão in Northeastern Brazil, 7 of which experienced BB-CL comorbidity and 1 CL associated with indeterminate leprosy7.

Genetic variations have been related to infectivity and pathogenicity of Leishmania. Certain L. (V.) braziliensis strains were proposed as causative pathogens for DL which is an emerging in Brazil but has never been reported as a coinfection with leprosy (patient 9). The concomitant chronic hepatitis C infection of this patient may have increased the susceptibility to ATL and leprosy coinfection.

ML is allocated to the maximum resistance pole of the Th1 immune profile. This exacerbated immune response accounts for local mucous destruction14. The immune response of ML patients did not resemble the immune spectrum of leprosy in this study10 (Figure 1). For example, case 2 presented with the LL form in the anergic pole, and high levels of anti-PGL1 antibodies and presence of bacillus-forming globias in the skin confirmed the Th2 immune pattern and consequently deficient macrophage activity in this patient. Nevertheless, the patient exhibited the ML hyperergic pole representing ATL with granulomatous infiltrate and the amastigote form of Leishmania spp. was still present in the histopathological exam. Case 4 also presented with ML with no evidence of previous cutaneous ulcers but with concurrence of the LL clinical form.

The complex interaction between the parasite and the immune response of the host may complicate the interpretation of the ATL spectrum. ML induces a strong Th1 response resulting in a granulomatous immune response. Nonetheless, ML usually results from previous CL that disseminated to the mucosa via the blood or lymphatic system, a process that is probably attributed to failure in the local cellular immune response10. Thus, it appears that ML should not be placed within the spectral pole of a strong T-cell immune response.

The fact that the immune response of the host to each of the pathogens may alter the course of the other disease may lead to a clinical picture that differs from that expected for each disease alone, and physicians should be aware that the diagnosis of coinfection could be challenging. Azeredo-Coutinho et al.10 reported a case of LL with an IL-10-mediated regulatory response controlling the ML immunopathology, which may explain the opposing spectral Th1/Th2 poles for leprosy and ATL observed in cases 2 and 4. Moreover, the genetic profile of the host should be carefully analyzed to identify specific predispositions for ATL and leprosy that possibly explain the infrequent occurrence of both diseases in the same patient.

To our knowledge, this is the first study proposing a comparison between the clinical and laboratory features of ATL and leprosy based on the Th1/Th2 immunological spectrum. The diagram shown here could prove useful to researchers and physicians working in areas where leprosy and leishmaniasis are prevalent (Figure 1A).

Due to the retrospective character of this case series, the genetic background of the patients and certain other parameters such as the immunological profile (e.g., cytokines) and intercurrences during disease progression were not analyzed. Nonetheless, we described important immunological tests and clinical features, allowing us to conduct a clinico-immunological comparison of both diseases in 9 patients.

The cases described herein included patients that were particularly susceptible to a coinfection with ATL and leprosy because they live in an area where both diseases are endemic. Although epidemiological susceptibility is probably the most important risk factor for contracting both diseases, immunological and genetic conditions that favor a coinfection cannot be excluded.

The present study has shown no correlation between the Th1/Th2 immunological spectra of the clinical forms of ATL and leprosy in this case series, which suggests a specific host immune response against each pathogen. Increasing incidence rates of ATL and leprosy concurrence must be acknowledged to improve diagnostic and therapeutic strategies in regions where both diseases are prevalent.

Acknowledgements

We thank Dr. Margarida Moraes for revision of the histopathological laryngeal biopsy and the staff of the Head and Neck Surgery Department for the laryngoscope exam of case 2. We further thank Dr. Marcela A. Ambiel, Dr. Norma T. Foss, and the clinical staff at the University Hospital for assessing the ATL and leprosy outpatients. We thank the biologists Flavia T. A. Vieira, Natalia A. de Paula, and Sandra Silva Rodrigues Santos for their support in the laboratory.

REFERENCES

1. World Health Organization (WHO). Control of the leishmaniasis. World Health Organ Tech Rep Ser. 2010;949(XII-XIII):1-186. [ Links ]

2. World Health Organization (WHO). WHO Expert Committee on Leprosy. World Health Organ Tech Rep Ser . 2012;968:1-61. [ Links ]

3. Barnetson RSC, Bryceson ADM. Cutaneous leishmaniasis and leprosy. Trans R Soc Trop Med Hyg. 1978;72(2):160-3. [ Links ]

4. Torrealba J, Mendoza I, Ocanto T, Barroeta S, Mejia de Alejos MA, Bonfante-Garrido R. Concomitant cutaneous leishmaniasis and leprosy in Venezuela. Trans R Soc Trop Med Hyg . 1995;89(1):69. [ Links ]

5. Patrao NA, Bhat RM, Dandekeri S, Kambil SM. Diffuse cutaneous leishmaniasis in coexistence with leprosy. Int J Dermatol. 2015;54(12):1402-6. [ Links ]

6. Al-Aboud K, Al-Hawasawi K, Ramesh V, Al-Aboud D, Al-Githami A. Linear cutaneous leishmaniasis occurring on a leg affected by tuberculoid leprosy. Br J Dermatol. 2002;147(5):1022-3. [ Links ]

7. Costa JML, Saldanha ACR, Melo LS, da Silva AR, Ferreira LA, Costa G, et al. Cutaneous Leishmaniasis (CL) associated with leprosy: a new and emerging clinicoepidemiological entity observed in the northeast of Brazil. Gaz Med Bahia. 2009;79(Supl.3):95-102. [ Links ]

8. Goulart IMB, Patrocínio LG, Nishioka SA, Patrocínio JA, Ferreira MS, Fleury RN. Concurrent leprosy and leishmaniasis with mucosal involvement. Lepr Rev. 2002;73(3):283-4. [ Links ]

9. Delobel P, Launois P, Djossou F, Sainte-Marie D, Pradinaud R. American cutaneous leishmaniasis, lepromatous leprosy, and pulmonary tuberculosis coinfection with downregulation of the T-helper 1 cell response. Clin Infect Dis. 2003;37(5):628-33. [ Links ]

10. Azeredo-Coutinho RBG, Matos DCS, Nery JAC, Valete-Rosalino CM, Mendonça SCF. Interleukin-10-dependent down-regulation of interferon-gamma response to Leishmania by Mycobacterium leprae antigens during the clinical course of a coinfection. Braz J Med Biol Res. 2012;45(7):632-6. [ Links ]

11. Di Luca DG, De Andrade PJ, Sales AM, De Menezes VM, Galhardo MC, Pimentel MI, et al. Superposition of leprosy and other neglected tropical diseases in the state of Rio de Janeiro: a case series report. Lepr Rev . 2013;84(4):302-7. [ Links ]

12. Mercadante LM, Santos MAS, Pegas ES, Kadunc BV. Leprosy and American cutaneous leishmaniasis coinfection. An Bras Dermatol. 2018;93(1):123-5. [ Links ]

13. Soto LA, Caballero N, Fuentes LR, Muñoz PT, Gómez-Echevarría JR, López MP, et al. Leprosy Associated with Atypical Cutaneous Leishmaniasis in Nicaragua and Honduras. Am J Trop Med Hyg. 2017;97(4)1103-10. [ Links ]

14. Silveira FT, Lainson R, Corbett CE. Clinical and immunopathological spectrum of American cutaneous leishmaniasis with special reference to the disease in Amazonian Brazil: a review. Mem Inst Oswaldo Cruz. 2004;99(3):239-51. [ Links ]

15. Polycarpou A, Walker SL, Lockwood DN. New findings in the pathogenesis of leprosy and implications for the management of leprosy. Curr Opin Infect Dis. 2013;26(5):413-9. [ Links ]

Financial Support: This research was not funded by any specific grant from a funding agency. SV received a PhD scholarship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior).

Received: May 10, 2018; Accepted: December 05, 2018

Corresponding author: Dra. Ana Maria Roselino. e-mail: amfrosel@fmrp.usp.br

Conflict of Interest: The authors have no conflicts of interest to declare.

Creative Commons License This is an open-access article distributed under the terms of the Creative Commons Attribution License