During the last decades, the growing population of immunocompromised patients has taken part in modern tourism. They visit areas endemic to leishmaniasis such as southern parts of Europe where they may be exposed to VL. Physicians in non-endemic areas of Northern Europe may not be familiar with VL, the potential risk of infection, or the presence of VL in popular tourist destinations along the Mediterranean. Therefore, we expect an increase in VL-cases in areas non-endemic to Leishmania because of the travel activity of immunosuppressed patients to VL endemic areas [6]. Furthermore, the incidence of leishmaniasis cases is increasing in popular tourist destinations such as Spain. Lastly, more cases of VL may be detected due to an improvement of available diagnostic tools such as PCR and sequencing, given that medical doctors in non-endemic areas are alert and primed for the possibility of VL [10,11,12].
VL has been associated with immunosuppressive disorders like HIV infection, myeloproliferative disorders and cancers, but also with immunosuppressive therapy for autoimmune diseases and after solid-organ transplantation [13, 14]. It is possible that autoimmune diseases per se represent a risk factor for developing VL. But to our knowledge, no systematic studies have addressed the risk of VL in patients with rheumatic or other autoimmune diseases not on treatment with immunosuppressive drugs. In our material, all patients with rheumatic disease (four) received immunosuppressive therapy. VL has been demonstrated in case reports of rheumatic patients treated with tumor necrosis factor alpha (TNF-α) antagonists [15,16,17] or methotrexate [18,19,20] and in three non-rheumatic patients on corticosteroids [21]. Patient 7 with ulcerative colitis developed VL while on TNF-α antagonist treatment. In literature, we have only found one single case of VL in a patient with inflammatory bowel disease (Crohn’s disease) on TNF-α antagonists [22].
TNF-α monoclonal antibodies have become a cornerstone in modern treatment of many chronic inflammatory disorders and have received an increased attention as a risk factor for VL than other immunosuppressive drugs [17, 23]. TNF-α has pro-inflammatory effects but also plays an important role in the defense against intracellular infections, such as leishmaniasis. Inhibition or lack of TNF-α activity seem to induce an increased risk of leishmaniasis as demonstrated in mouse models [24].
The risk of VL if treated with methotrexate is only scarcely documented [18,19,20]. The patients with rheumatic diseases in our report were all treated with methotrexate. Methotrexate has been used in treatment of rheumatoid arthritis (RA) since the 1960’s and is often combined with other drugs. Notably, in a literature search, Chen, et al., described eight patients with RA developing VL while treated with the combination of adalimumab and methotrexate [23]. Methotrexate is a competitive inhibitor of folic acid-dependent enzymes, leading to impaired purine and pyrimidine synthesis which inhibits proliferation of lymphocytes [25]. As the cellular immune system is important against intracellular infections, it is plausible that this renders patients on methotrexate at risk of VL.
Corticosteroids are also widely used in the treatment of autoimmune diseases and, like methotrexate, are often used in combination with other drugs. We have not identified any publications on VL in rheumatic patients on prednisolone alone, although several of the reported cases on anti- TNF-α and methotrexate therapy had received corticosteroids as well [18, 23]. In a large controlled study on 25,139 solid organ transplanted patients in Spain and Brazil, 36 cases of VL was identified [26]. A multivariate logistic regression analysis was performed, and the use of corticosteroids – not mycophenolate, cyclosporine or tacrolimus - was the only risk factor associated with VL. It has also been shown that prolonged use of corticosteroids in Leishmania-infected mice, led to decreasing levels of TNF-α and other cytokines, along with increasing numbers of amastigotes in the spleen [27].
L-AmB is the treatment of choice against infections caused by Leishmania infantum [28]. Recent guidelines recommend an increased dose of L-AmB in immunocompromised patients: 4 mg/kg/day iv on days 1–5, 10, 17, 24, 31 and 38 (total dose of 40 mg/kg) [28]. Secondary prophylaxis is only recommended to HIV infected individuals as long as CD4 T lymphocytes counts are < 200 cells/mm3. Assessment of Leishmania PCR to avoid post-treatment relapse is recommended for at least one-year post-treatment [28]. Our patients received total doses of L-AmB in the range of 20-37 mg/kg (Table), i.e. lower than current guidelines. Patient 2 was diagnosed with VL and had treatment initiated in Thailand with non-liposomal amphotericin, before completing therapy in Norway with L-AmB. As we observed two relapses among seven patients after receiving standard doses of L-AmB, it appears reasonable from our limited experience to provide immunocompromised patients with a higher cumulative dose of L-AmB.
Four of the patients had traveled to various destinations endemic to VL, such as Eastern and Western Mediterranean Basin, East Africa, Pakistan and Thailand. It is possible that some of these patients got infected with leishmaniasis years ago, remained asymptomatic, and presented with VL once given immunosuppressive therapy. However, Spain seems like the most probable place of transmission, due to the timing, lengths and/or frequencies of stay in this region, with a possible exception of patient 2 whose place of transmission remains unknown.
All our seven patients underwent a rather extensive diagnostic work-up before a final diagnosis was made. Malignancies and haematological diseases were invariably high on the list of the differential diagnoses. PCR was performed only to confirm the diagnosis after positive microscopy, serology or histology, and for species identification in most cases. This could reflect that PCR as a readily available test modality for leishmaniasis is yet to become known to Norwegian medical doctors. Our laboratory at OUS now offers PCR and sequencing (the only in Norway, population 5.25 million people). As a result of this, the awareness of leishmaniasis seems to have increased. During the last three years a total of 32 cases were diagnosed, among whom eight had VL (including one of the present patients) [29].
