• 1.

    Kaye P, Scott P, 2011. Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9: 604615.

  • 2.

    Conceição-Silva F, Leite-Silva J, Morgado FN, 2018. The binomial parasite-host immunity in the healing process and in reactivation of human tegumentary leishmaniasis. Front Microbiol 9: 1308.

    • Search Google Scholar
    • Export Citation
  • 3.

    van Griensven J, Carrillo E, López-Vélez R, Lynen L, Moreno J, 2014. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 20: 286299.

    • Search Google Scholar
    • Export Citation
  • 4.

    Tuon FF, Gomes-Silva A, Da-Cruz AM, Duarte MI, Neto VA, Amato VS, 2008. Local immunological factors associated with recurrence of mucosal leishmaniasis. Clin Immunol 128: 442446.

    • Search Google Scholar
    • Export Citation
  • 5.

    de Camargo RA, Nicodemo AC, Sumi DV, Gebrim EM, Tuon FF, de Camargo LM, Imamura R, Amato VS, 2014. Facial structure alterations and abnormalities of the paranasal sinuses on multidetector computed tomography scans of patients with treated mucosal leishmaniasis. PLoS Negl Trop Dis 8: e3001.

    • Search Google Scholar
    • Export Citation
  • 6.

    Amato VS, Andrade HF, Amato Neto V, Duarte MI, 2003. Short report: persistence of tumor necrosis factor-alpha in situ after lesion healing in mucosal leishmaniasis. Am J Trop Med Hyg 68: 527528.

    • Search Google Scholar
    • Export Citation
  • 7.

    Amato VS, Tuon FF, Camargo RA, Souza RM, Santos CR, Nicodemo AC, 2011. Can we use a lower dose of liposomal amphotericin B for the treatment of mucosal American leishmaniasis? Am J Trop Med Hyg 85: 818819.

    • Search Google Scholar
    • Export Citation
  • 8.

    Murray HW, 2012. Leishmaniasis in the United States: treatment in 2012. Am J Trop Med Hyg 86: 434440.

  • 9.

    Rocio C, Amato VS, Camargo RA, Tuon FF, Nicodemo AC, 2014. Liposomal formulation of amphotericin B for the treatment of mucosal leishmaniasis in HIV-negative patients. Trans R Soc Trop Med Hyg 108: 176178.

    • Search Google Scholar
    • Export Citation
  • 10.

    Darcis G, Van der Auwera G, Giot JB, Hayette MP, Tassin F, Arrese Estrada J, Cnops L, Moutschen M, de Leval L, Leonard P, 2017. Recurrence of visceral and muco-cutaneous leishmaniasis in a patient under immunosuppressive therapy. BMC Infect Dis 17: 478.

    • Search Google Scholar
    • Export Citation
  • 11.

    Souza RM, Andrade HF Jr., Duarte MI, Braz LM, Schubach AO, Silva FC, Amato VS, 2017. Reactivation of cutaneous and mucocutaneous tegumentary leishmaniasis in rheumatoid arthritis patients: an emerging problem? Rev Inst Med Trop Sao Paulo 59: e6.

    • Search Google Scholar
    • Export Citation
  • 12.

    Mandell MA, Beverley SM, 2017. Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. Proc Natl Acad Sci U S A Jan 31;114(5).

    • Search Google Scholar
    • Export Citation
  • 13.

    Nicodemo AC, Duailibi DF, Feriani D, Duarte MIS, Amato VS, 2017. Mucosal leishmaniasis mimicking T-cell lymphoma in a patient receiving monoclonal antibody against TNFα. PLoS Negl Trop Dis Sep 21;11(9).

    • Search Google Scholar
    • Export Citation
  • 14.

    Bogdan C, Röllinghoff M, 1998. The immune response to Leishmania: mechanisms of parasite control and evasion. Int J Parasitol 28: 121134.

    • Search Google Scholar
    • Export Citation
  • 15.

    Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet JP, Gradoni L, Ter Horst R, López-Vélez R, Moreno J, 2008. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 21: 334359 , table of contents.

    • Search Google Scholar
    • Export Citation
  • 16.

    Monge-Maillo B, Norman FF, Cruz I, Alvar J, López-Vélez R, 2014. Visceral leishmaniasis and HIV coinfection in the Mediterranean region. PLoS Negl Trop Dis 8: e3021.

    • Search Google Scholar
    • Export Citation
  • 17.

    Amato VS, de Andrade HF, Duarte MI, 2003. Mucosal leishmaniasis: in situ characterization of the host inflammatory response, before and after treatment. Acta Trop 85: 3949.

    • Search Google Scholar
    • Export Citation
Past two years Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 508 128 8
PDF Downloads 79 48 4
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

 

 

Secondary Prophylaxis with Liposomal Amphotericin B in a Patient with Mucosal Leishmaniasis Undergoing Immunobiological Therapy for Active Ankylosing Spondylitis

View More View Less
  • 1 Department of Infectious Diseases, University of São Paulo Medical School, Sao Paulo, Brazil;
  • | 2 Department of Pathology, University of São Paulo Medical School, Sao Paulo, Brazil;
  • | 3 Department of Infectious and Parasitic Diseases, Clinical Hospital, University of São Paulo Medical School, Sao Paulo, Brazil

Immunosuppressive treatments for rheumatic diseases present special problems in areas endemic for chronic infectious diseases because of the possibility of reactivation. Leishmaniasis is a significant neglected tropical disease caused by different species of protozoan parasites within the genus Leishmania. Amastigotes live as intracellular parasites in a variety of mammalian cells, most notably within phagocytes such as macrophages, and residual parasites can persist even after treatment and healing of the lesions. We herein report a case of relapsing mucosal leishmaniasis after aggressive immunotherapy for ankylosing spondylitis, with requirement for secondary prophylaxis with amphotericin B to prevent reactivation. This approach can be necessary for patients from endemic areas of tegumentary leishmaniasis, who will undergo aggressive immunotherapy.

INTRODUCTION

Leishmaniasis is an anthropozoonosis caused by different flagellated protozoan species of the genus Leishmania transmitted by the bite of phlebotomine insects. The clinical manifestation of the disease depends not only on the Leishmania species involved but also on the patient’s immune status.1

In humans, disease can manifest as tegumentary leishmaniasis (TL), affecting both cutaneous (cutaneous leishmaniasis) and mucosal tissue (mucosal leishmaniasis), or as visceral leishmaniasis, affecting visceral organs. Tegumentary leishmaniasis is a granulomatous disease of the skin and/or mucosa, most commonly manifesting as localized or disseminated cutaneous ulcers, diffusely scattered papules, mucosal lesions, or even atypical lesions.2 Visceral leishmaniasis is the most severe form of the disease, which can be fatal if untreated.3 However, subclinical infection without progression to disease also occurs.

The host’s pattern of immune response plays an important role and can determine the evolution of leishmaniasis, leading to either disease or control. Even in the presence of immune control, residual parasites can cause chronic reactivation of disease. The pathogenesis of mucosal tissue has been associated with a hyperactive T-cell–mediated immune response, often resulting in progressive granulomatous inflammatory response with extensive destruction of the mucosal tissue.4,5 These patterns show different profiles of preferential cytokine production as well as other cell products involved in the final activation of effector cells and tissue lesion, especially tumor necrosis factor (TNF) alpha.6

Liposomal amphotericin B is an efficient drug in the treatment of all forms of leishmaniasis.79 Although some patients achieve clinical cure of leishmaniasis, the need for longer duration of treatment in addition to the risk of reactivation and relapse makes the clinical form of mucosal tissue difficult to treat and control. This situation becomes critical in the presence of comorbidities such as HIV infection, immunosuppressive therapy for cancer and autoimmune disorders, and immunosuppression following organ transplantation that alter the patient’s immune response, thereby compromising therapeutic response and evolution of mucosal tissue.10,11

Tumor necrosis factor inhibitors have revolutionized the treatment of ankylosing spondylitis (AS), and five of them have been shown to be useful in the control of AS, namely, infliximab, etanercept, adalimumab, certolizumab, and golimumab. All these TNF inhibitors can significantly improve function, spinal mobility, peripheral synovitis, enthesitis, and quality of life scores. Despite their efficacy, their use can increase the risk of severe infections, mainly by opportunistic intracellular agents, such as Leishmania.12 Thus, leishmaniasis in patients treated with anti–TNF-alpha therapy should be added to the list of opportunistic infections associated with biological treatments.

The main objective of this work was to draw clinicians’ attention to the risk of reactivation of latent infections in patients undergoing immunosuppressive anti-TNF therapy and raise awareness of secondary prophylaxis in cases of mucosal tissue to prevent relapses and destructive lesions.

Case report.

A 38-year-old man living in the Brazilian states of Minas Gerais and Roraima, both endemic for leishmaniasis, was diagnosed with AS in 2005 and had undergone several therapeutic approaches since then without effective response. In 2015, adalimumab was initiated, but the treatment was interrupted after 5 months because of a crusted lesion in the nasal septum. The lesion was biopsied and immunohistochemical analysis initially suggested the presence of NK/T lymphoma. However, further investigation confirmed a diagnosis of leishmaniasis based on strongly positive serological tests (indirect immunofluorescence 1:80 and ELISA 1:1,280) and a positive polymerase chain reaction (PCR) of mucosal biopsy. The PCR method was according to previous publication.13 Nasal endoscopy revealed granulomatous tissue after crust removal, suggesting active disease. The patient was treated with liposomal amphotericin B at a total dose of 35 mg/kg,79 with clinical improvement.

In December 2015, adalimumab treatment was resumed because of AS activity, but the nasal lesion relapsed and adalimumab was interrupted again. The patient was hospitalized for retreatment with liposomal amphotericin B at the same dose. Afterward, adalimumab treatment was resumed. Since September 2016, this patient has been receiving secondary prophylaxis with liposomal amphotericin B at 3 mg/kg every 3 weeks without mucosal tissue relapses.

DISCUSSION

Some infectious agents are capable of residual survival within the host following clinical cure—a phenomenon called parasite persistence.14 This latency can be maintained for long periods, sometimes persisting for the host’s entire life. In our clinical case, the patient lived in endemic regions for leishmaniasis and had no previous history of cutaneous or mucosal lesions, thus suggesting that he had latent Leishmania infection, which became manifest after immunosuppression by adalimumab. The role played by the parasite–host interaction in the phenomenon of parasite persistence is not completely clarified,1,14 but there are some reports demonstrating that Leishmania species are capable of modulating the host’s immune response, hence allowing them to survive within the host without causing significant harm.

We use liposomal amphotericin B at a total dose of 35 mg/kg in our clinic based on previous reports of good clinical response and healing of the lesion.79 Secondary prophylaxis with amphotericin B has already been described for cases of Leishmania infantum/HIV coinfection,15,16 but the prophylactic use of this drug in mucosal tissue is not common and requires additional assessment in controlled studies, including large numbers of patients with long-term follow-up.

Evolutionary control of leishmaniasis has been directly related to the presence of type 1 immune response, with production of cytokines such as IFN-gamma and TNF-alpha.17 Physiologically, TNF-alpha plays an important role in the host’s defense regarding formation and maintenance of granuloma and control of the disease. Anti-TNF monoclonal antibodies can reactivate chronic granulomatous diseases; therefore, timely screening for latent infections and prophylactic treatment for positive cases is necessary. Current recommendations do not include screening and prophylaxis for leishmaniasis before or during anti-TNF-alpha therapy.

In the present article, we described the case of a patient who lived in endemic regions for leishmaniasis in whom anti-TNF therapy for AS led to a relapse of mucosal tissue, which was clinically cured after specific treatment. Afterward, we successfully managed to prevent mucosal tissue relapse after initiating secondary prophylaxis with liposomal amphotericin B at a dosage of 3 mg/kg every 3 weeks, whereas AS remission was maintained by adalimumab therapy. Therefore, we emphasize the need to include TL in the investigation and differential diagnosis of mucocutaneous lesions in patients undergoing immunosuppressive therapy by monoclonal antibodies, mainly in individuals living in endemic areas. The present case report suggests that secondary prophylaxis with liposomal amphotericin B can be useful for the prevention of leishmaniasis relapse in patients undergoing immunobiological therapy with anti-TNF-alpha antibodies for the control of AS.

REFERENCES

  • 1.

    Kaye P, Scott P, 2011. Leishmaniasis: complexity at the host-pathogen interface. Nat Rev Microbiol 9: 604615.

  • 2.

    Conceição-Silva F, Leite-Silva J, Morgado FN, 2018. The binomial parasite-host immunity in the healing process and in reactivation of human tegumentary leishmaniasis. Front Microbiol 9: 1308.

    • Search Google Scholar
    • Export Citation
  • 3.

    van Griensven J, Carrillo E, López-Vélez R, Lynen L, Moreno J, 2014. Leishmaniasis in immunosuppressed individuals. Clin Microbiol Infect 20: 286299.

    • Search Google Scholar
    • Export Citation
  • 4.

    Tuon FF, Gomes-Silva A, Da-Cruz AM, Duarte MI, Neto VA, Amato VS, 2008. Local immunological factors associated with recurrence of mucosal leishmaniasis. Clin Immunol 128: 442446.

    • Search Google Scholar
    • Export Citation
  • 5.

    de Camargo RA, Nicodemo AC, Sumi DV, Gebrim EM, Tuon FF, de Camargo LM, Imamura R, Amato VS, 2014. Facial structure alterations and abnormalities of the paranasal sinuses on multidetector computed tomography scans of patients with treated mucosal leishmaniasis. PLoS Negl Trop Dis 8: e3001.

    • Search Google Scholar
    • Export Citation
  • 6.

    Amato VS, Andrade HF, Amato Neto V, Duarte MI, 2003. Short report: persistence of tumor necrosis factor-alpha in situ after lesion healing in mucosal leishmaniasis. Am J Trop Med Hyg 68: 527528.

    • Search Google Scholar
    • Export Citation
  • 7.

    Amato VS, Tuon FF, Camargo RA, Souza RM, Santos CR, Nicodemo AC, 2011. Can we use a lower dose of liposomal amphotericin B for the treatment of mucosal American leishmaniasis? Am J Trop Med Hyg 85: 818819.

    • Search Google Scholar
    • Export Citation
  • 8.

    Murray HW, 2012. Leishmaniasis in the United States: treatment in 2012. Am J Trop Med Hyg 86: 434440.

  • 9.

    Rocio C, Amato VS, Camargo RA, Tuon FF, Nicodemo AC, 2014. Liposomal formulation of amphotericin B for the treatment of mucosal leishmaniasis in HIV-negative patients. Trans R Soc Trop Med Hyg 108: 176178.

    • Search Google Scholar
    • Export Citation
  • 10.

    Darcis G, Van der Auwera G, Giot JB, Hayette MP, Tassin F, Arrese Estrada J, Cnops L, Moutschen M, de Leval L, Leonard P, 2017. Recurrence of visceral and muco-cutaneous leishmaniasis in a patient under immunosuppressive therapy. BMC Infect Dis 17: 478.

    • Search Google Scholar
    • Export Citation
  • 11.

    Souza RM, Andrade HF Jr., Duarte MI, Braz LM, Schubach AO, Silva FC, Amato VS, 2017. Reactivation of cutaneous and mucocutaneous tegumentary leishmaniasis in rheumatoid arthritis patients: an emerging problem? Rev Inst Med Trop Sao Paulo 59: e6.

    • Search Google Scholar
    • Export Citation
  • 12.

    Mandell MA, Beverley SM, 2017. Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. Proc Natl Acad Sci U S A Jan 31;114(5).

    • Search Google Scholar
    • Export Citation
  • 13.

    Nicodemo AC, Duailibi DF, Feriani D, Duarte MIS, Amato VS, 2017. Mucosal leishmaniasis mimicking T-cell lymphoma in a patient receiving monoclonal antibody against TNFα. PLoS Negl Trop Dis Sep 21;11(9).

    • Search Google Scholar
    • Export Citation
  • 14.

    Bogdan C, Röllinghoff M, 1998. The immune response to Leishmania: mechanisms of parasite control and evasion. Int J Parasitol 28: 121134.

    • Search Google Scholar
    • Export Citation
  • 15.

    Alvar J, Aparicio P, Aseffa A, Den Boer M, Cañavate C, Dedet JP, Gradoni L, Ter Horst R, López-Vélez R, Moreno J, 2008. The relationship between leishmaniasis and AIDS: the second 10 years. Clin Microbiol Rev 21: 334359 , table of contents.

    • Search Google Scholar
    • Export Citation
  • 16.

    Monge-Maillo B, Norman FF, Cruz I, Alvar J, López-Vélez R, 2014. Visceral leishmaniasis and HIV coinfection in the Mediterranean region. PLoS Negl Trop Dis 8: e3021.

    • Search Google Scholar
    • Export Citation
  • 17.

    Amato VS, de Andrade HF, Duarte MI, 2003. Mucosal leishmaniasis: in situ characterization of the host inflammatory response, before and after treatment. Acta Trop 85: 3949.

    • Search Google Scholar
    • Export Citation

Author Notes

Address correspondence to Antonio Carlos Nicodemo, Department of Infectious Diseases, University of São Paulo Medical School, Sao Paulo 01308000, Brazil. E-mail: ac_nicodemo@uol.com.br

Authors’ addresses: Antonio Carlos Nicodemo and Valdir Sabbaga Amato, Department of Infectious Diseases, University of São Paulo Medical School, Sao Paulo, Brazil, E-mails: ac_nicodemo@uol.com.br and valdirsa@netpoint.com.br. Heitor Franco de Andrade Jr., Department of Pathology, University of São Paulo Medical School, Sao Paulo, Brazil, E-mail: hfandrad@usp.br. Pablo Muñoz Torres, Department of Infectious and Parasitic Diseases, Clinical Hospital, University of São Paulo Medical School, Sao Paulo, Brazil, E-mail: pamt90.nap@gmail.com.

Save