555788
letter2014
MSJ0010.1177/1352458514555788Multiple Sclerosis JournalAK Artemiadis, G Nikolaou et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Letter
Visceral leishmaniasis infection in a fingolimod-treated multiple sclerosis patient AK Artemiadis, G Nikolaou, D Kolokythopoulos, N Tegos, A Terentiou, N Triantafyllou and I Papanastasiou
Multiple Sclerosis Journal 1–2 DOI: 10.1177/ 1352458514555788 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Keywords: Visceral, leishmaniasis, fingolimod, multiple sclerosis, side-effect, infection Date received: 15 August 2014; revised: 25 August 2014; 8 September 2014; accepted: 5 April 2014
Dear Editor, Fingolimod, the first oral immunomodulatory treatment for relapsing multiple sclerosis (MS), acts by blocking lymph-node egress of T cells expressing the CCR7-receptor, such as CD4+ or CD8+ naive (TN), central memory (TCM) and Th17 and Th17/Th1-helper cells, all of which contribute to MS pathogenesis.1 So far, two serious herpetic infections both in the fingolimod 1.25 mg arm have been reported.2 We report a patient who was treated with fingolimod for 29 months. This 37-year-old woman presented with an evening fever of 37–39°C, night sweats, fatigue and mild pain in the left hypochondriac region. Physical examination revealed darkening of the skin, hepatomegaly and splenomegaly. The patient was living in a province of Attica, which has many stray dogs. During fingolimod treatment regular blood tests had showed acceptable lymphocytopenia (over 300 Κ/μl). Blood tests revealed normocytic, normochromic anaemia (Hb: 9.7g/dl, Hct: 28.8%), increased reticulocytes (90.5K/μl), leukocytopenia (2.600/μl), neutropenia (1.8K/μl), lymphocytopenia (0.5K/μL), thrombocytopenia (PLT: 116.000/μl), elevated CRP (11.73 mg/dl) and ESR (74 mm), increased GGT (105 U/l), slightly elevated liver function tests (AST: 46 IU/l, ALT: 58 IU/l), positive direct Coombs test with increased haptoglobins (1450 mg/l), increased IgG antibodies (3170 mg/dl) and elevated serum gammaglobulins. Abdominal ultrasound and computerized tomography revealed marked hepatosplenomegaly. Bone marrow biopsy revealed increased erythroblasts, expansion of both polyclonal plasmatocytes and mature B-cells, with no evidence of haematologic
disease. There was no hypo-globulinaemia and no evidence of neoplasia, HIV, herpetic, hepatitis and other microbial infections. Antibodies to the recombinant-kinesin 39 (rK39) antigen were positive and serum PCR disclosed a Leishmania infantum infection. The patient was treated with intravenous liposomal amphotericin B and made a full recovery with normalization of blood tests. Visceral leishmaniasis is a disseminated disease caused by Leishmania donovani and Leishmania infantum (L. chagasi), transmitted between vertebrate hosts (e.g. dogs) by the bite of phlebotomine sandflies.3 In Greece the mean annual incidence of leishmaniasis is 0.36/100,000, with a cumulative incidence of 8–12/100,000 in the prefecture of Attica during a 13-year period.3 Fingolimod was instituted in Greece 3 years ago and there are now 2100 actively treated patients (about 1260 in Attica; personal communication with the sponsor). Since this is the first case of leishmaniasis in fingolimod-treated patients, a crude assessment of the cumulative incidence would be 1/1260 or 79.37/100,000 in Attica, much higher than the expected one despite the different length of the surveillance time periods (13 vs. 3 years). In individuals with impaired cellular immunity, visceral leishmaniasis is characterized by increased humoral immune responses.4 More importantly, there is evidence attesting that both CD4+ and CD8+ TCM cells provide immunity to Leishmania spp acting as a reservoir of effector memory T-cells (TEM cells) upon TEM cells upon secondary infection.4 In extended periods of antigen presentation (i.e. chronic infections or reinfections) the TEM cells inevitably decline, thus
Correspondence to: Artemiadis K. Artemios 1st Department of Neurology, Aeginition Hospital, School of Medicine, Kapodistrian University of Athens. Department of Neurology, NIMTS Hospital, Athens, Monis Petraki Str., 10-12, GR-115-21, Greece. [email protected] AK Artemiadis N Triantafyllou 1st Department of Neurology, Aeginition Hospital, School of Medicine, Kapodistrian University of Athens, Athens, Greece G Nikolaou A Terentiou I Papanastasiou Department of Neurology, NIMTS Hospital, Athens, Greece D Kolokythopoulos Department of Hematology, NIMTS Hospital, Athens, Greece N Tegos Hellenic Centre for Diseases Control and Prevention, Ministry of Health, Athens, Greece
http://msj.sagepub.com 1
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Multiple Sclerosis Journal their contribution to peripheral immunity eventually wanes.5 It is in these situations where the integrity of TCM cells is a prerequisite for the replenishment of the TEM cells reservoir and the successful immune response to foreign antigens. It is thus evident that Th1 cells and TCM, which are mainly affected by fingolimod, are integral parts of an effective immune response to leishmaniasis infection. In patients with MS living in regions where leishmaniasis is endemic the administration of fingolimod should be done with caution. Conflicts of Interest None declared.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008; 71: 1261–1267. 2. Cohen JA, Barkhof F, Comi G, et al.; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415. 3. Gkolfinopoulou K, Bitsolas N, Patrinos S, et al. Epidemiology of human leishmaniasis in Greece, 1981–2011. Euro Surveill 2013; 18: 20532. 4. Wilson ME, Jeronimo SM and Pearson RD. Immunopathogenesis of infection with the visceralizing Leishmania species. Microb Pathog 2005; 38: 147–160. 5. M Opata M and Stephens R. Early decision: Effector and effector memory T cell differentiation in chronic infection. Curr Immunol Rev 2013; 9: 190–206.
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at Eindhoven Univ of Technology on January 13, 2015
letter2014
MSJ0010.1177/1352458514555788Multiple Sclerosis JournalAK Artemiadis, G Nikolaou et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Letter
Visceral leishmaniasis infection in a fingolimod-treated multiple sclerosis patient AK Artemiadis, G Nikolaou, D Kolokythopoulos, N Tegos, A Terentiou, N Triantafyllou and I Papanastasiou
Multiple Sclerosis Journal 1–2 DOI: 10.1177/ 1352458514555788 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Keywords: Visceral, leishmaniasis, fingolimod, multiple sclerosis, side-effect, infection Date received: 15 August 2014; revised: 25 August 2014; 8 September 2014; accepted: 5 April 2014
Dear Editor, Fingolimod, the first oral immunomodulatory treatment for relapsing multiple sclerosis (MS), acts by blocking lymph-node egress of T cells expressing the CCR7-receptor, such as CD4+ or CD8+ naive (TN), central memory (TCM) and Th17 and Th17/Th1-helper cells, all of which contribute to MS pathogenesis.1 So far, two serious herpetic infections both in the fingolimod 1.25 mg arm have been reported.2 We report a patient who was treated with fingolimod for 29 months. This 37-year-old woman presented with an evening fever of 37–39°C, night sweats, fatigue and mild pain in the left hypochondriac region. Physical examination revealed darkening of the skin, hepatomegaly and splenomegaly. The patient was living in a province of Attica, which has many stray dogs. During fingolimod treatment regular blood tests had showed acceptable lymphocytopenia (over 300 Κ/μl). Blood tests revealed normocytic, normochromic anaemia (Hb: 9.7g/dl, Hct: 28.8%), increased reticulocytes (90.5K/μl), leukocytopenia (2.600/μl), neutropenia (1.8K/μl), lymphocytopenia (0.5K/μL), thrombocytopenia (PLT: 116.000/μl), elevated CRP (11.73 mg/dl) and ESR (74 mm), increased GGT (105 U/l), slightly elevated liver function tests (AST: 46 IU/l, ALT: 58 IU/l), positive direct Coombs test with increased haptoglobins (1450 mg/l), increased IgG antibodies (3170 mg/dl) and elevated serum gammaglobulins. Abdominal ultrasound and computerized tomography revealed marked hepatosplenomegaly. Bone marrow biopsy revealed increased erythroblasts, expansion of both polyclonal plasmatocytes and mature B-cells, with no evidence of haematologic
disease. There was no hypo-globulinaemia and no evidence of neoplasia, HIV, herpetic, hepatitis and other microbial infections. Antibodies to the recombinant-kinesin 39 (rK39) antigen were positive and serum PCR disclosed a Leishmania infantum infection. The patient was treated with intravenous liposomal amphotericin B and made a full recovery with normalization of blood tests. Visceral leishmaniasis is a disseminated disease caused by Leishmania donovani and Leishmania infantum (L. chagasi), transmitted between vertebrate hosts (e.g. dogs) by the bite of phlebotomine sandflies.3 In Greece the mean annual incidence of leishmaniasis is 0.36/100,000, with a cumulative incidence of 8–12/100,000 in the prefecture of Attica during a 13-year period.3 Fingolimod was instituted in Greece 3 years ago and there are now 2100 actively treated patients (about 1260 in Attica; personal communication with the sponsor). Since this is the first case of leishmaniasis in fingolimod-treated patients, a crude assessment of the cumulative incidence would be 1/1260 or 79.37/100,000 in Attica, much higher than the expected one despite the different length of the surveillance time periods (13 vs. 3 years). In individuals with impaired cellular immunity, visceral leishmaniasis is characterized by increased humoral immune responses.4 More importantly, there is evidence attesting that both CD4+ and CD8+ TCM cells provide immunity to Leishmania spp acting as a reservoir of effector memory T-cells (TEM cells) upon TEM cells upon secondary infection.4 In extended periods of antigen presentation (i.e. chronic infections or reinfections) the TEM cells inevitably decline, thus
Correspondence to: Artemiadis K. Artemios 1st Department of Neurology, Aeginition Hospital, School of Medicine, Kapodistrian University of Athens. Department of Neurology, NIMTS Hospital, Athens, Monis Petraki Str., 10-12, GR-115-21, Greece. [email protected] AK Artemiadis N Triantafyllou 1st Department of Neurology, Aeginition Hospital, School of Medicine, Kapodistrian University of Athens, Athens, Greece G Nikolaou A Terentiou I Papanastasiou Department of Neurology, NIMTS Hospital, Athens, Greece D Kolokythopoulos Department of Hematology, NIMTS Hospital, Athens, Greece N Tegos Hellenic Centre for Diseases Control and Prevention, Ministry of Health, Athens, Greece
http://msj.sagepub.com 1
Downloaded from msj.sagepub.com at Eindhoven Univ of Technology on January 13, 2015
Multiple Sclerosis Journal their contribution to peripheral immunity eventually wanes.5 It is in these situations where the integrity of TCM cells is a prerequisite for the replenishment of the TEM cells reservoir and the successful immune response to foreign antigens. It is thus evident that Th1 cells and TCM, which are mainly affected by fingolimod, are integral parts of an effective immune response to leishmaniasis infection. In patients with MS living in regions where leishmaniasis is endemic the administration of fingolimod should be done with caution. Conflicts of Interest None declared.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008; 71: 1261–1267. 2. Cohen JA, Barkhof F, Comi G, et al.; TRANSFORMS Study Group. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402–415. 3. Gkolfinopoulou K, Bitsolas N, Patrinos S, et al. Epidemiology of human leishmaniasis in Greece, 1981–2011. Euro Surveill 2013; 18: 20532. 4. Wilson ME, Jeronimo SM and Pearson RD. Immunopathogenesis of infection with the visceralizing Leishmania species. Microb Pathog 2005; 38: 147–160. 5. M Opata M and Stephens R. Early decision: Effector and effector memory T cell differentiation in chronic infection. Curr Immunol Rev 2013; 9: 190–206.
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at Eindhoven Univ of Technology on January 13, 2015
