Cutaneous, mucocutaneous and visceral leishmaniasis in Sweden from 1996–2016: a retrospective study of clinical characteristics, treatments and outcomes

Leishmaniasis, a vector-borne disease caused by the intracellular parasite Leishmania, is defined by the World Health Organization (WHO) as a neglected tropical disease [1]. Leishmania infection has a broad range of clinical manifestations: cutaneous (CL), mucocutaneous (MCL), visceral (VL), post-kala-azar dermal (PKDL), and diffuse cutaneous leishmaniasis, depending on the Leishmania species and the immunological response of the patient [2]. Leishmaniasis is now endemic in at least 102 tropical and subtropical countries and regions [3, 4].

For decades, pentavalent antimonial was the gold standard treatment regardless of the Leishmania species. Due to treatment failure and relapse, possibly caused by resistance among certain subtypes, as well as drug toxicity, new treatments have been introduced. Currently, several alternatives are available and recommended depending on the clinical manifestation, subtype/species, and geographical region [5].

Experience in managing leishmaniasis is often limited in non-endemic regions, which may lead to a delay in diagnosis and unfavourable treatment outcomes [6]. In Sweden, patients are rare and seldom encountered in clinical practice. There is no domestic leishmaniasis in Sweden because the vector is absent; however, the number of imported leishmaniasis cases has increased in recent years [7]. Management of leishmaniasis in Sweden has not previously been described, and there are no Swedish guidelines for treatment. Hence, treatment guidelines published by other European countries and the USA have been used [8, 9].

In this study, we assess patient characteristics, clinical presentation and treatments of leishmaniasis in Sweden from 1996 to 2016, with aim to evaluate the treatment outcomes and optimise the management of leishmaniasis in a non-endemic setting.

In total, 165 cases of leishmaniasis were diagnosed at the National Reference Laboratory from 1996 to 2016, and medical records from 156 patients (95%) were available for review and included in the study. CL was the dominant manifestation (n = 144, 96%). Other manifestations were MCL, VL and PKDL. The most common species were L. tropica, L. major and L. braziliensis/L. braziliensis complex. In seven cases, subtyping analysis was not possible due to the small amount of DNA extracted from the samples or limitations in the analysis over time (Fig. 1).

The annual number of leishmaniasis cases increased during the period 1996–2016, especially from 2013 to 2016 (Fig. 2). The patients were mainly adolescents or young men (Table 1). Migrants were the largest group of patients, followed by tourists and returning workers, including volunteers and military personnel (Table 1). The military personnel came from the Swedish Armed Forces and were infected in Afghanistan in 2010, as previously described [14]. Immunosuppression among the patients was rare (Table 1).

The most common countries of origin of infection were Syria (n = 50, 32%) and Afghanistan (n = 30, 19%), followed by Iran (n = 11, 7%) (Additional file 1: Figure S1).

The time from start of symptoms to first visit at hospital varied between migrants and the other groups. Among non-migrants, 37 patients (51%) sought medical care for symptoms and lesions within the first three months, whereas migrants often reported having had symptoms before arriving in Sweden (Table 1).

Treatment was started within the first three months after the diagnostic sample was collected in 124 (93%) of the patients, and 81 patients (61%) were treated within the first month (Table 1).

This retrospective study describes clinical characteristics, treatment and outcomes of leishmaniasis in Sweden from 1996 to 2016. CL was the dominant manifestation. Other manifestations were mucocutaneous (n = 4, 3%), visceral (n = 2, 1%) and post-kala-azar dermal leishmaniasis (n = 1, 1%). Two cases of MCL due to L. donovani were diagnosed among our patients. Mucocutaneous manifestations are rare for L. donovani and only described a few times in the litterature [15, 16].

The number of leishmaniasis cases increased during the study period, especially between 2013 and 2016, when the number of migrants from highly endemic areas, such as Syria and Afghanistan, increased in Sweden [17]. In previous studies from European countries, the distribution of cases was different; with migrants being a minority, and travellers and those visiting friends and relatives being the majority [18, 19]. We found that many of the migrants had been in Sweden for up to six months before they had their first medical examination. This “patient delay” was not observed in the other groups, which generally sought healthcare within the first three months after the onset of symptoms. Some of the migrants had already received treatment for leishmaniasis, but many had not sought any healthcare for their manifestations before they reached Sweden. This observation highlights the importance of identifying and treating migrants during their migration through Europe and before they reach Sweden. Nonetheless, half of the cases were non-migrants infected during temporary visits in endemic areas. The patients who were Swedish military personnel were all infected in Afghanistan while stationed there in 2010 [14]. During the same period, other countries with military personnel in Afghanistan reported similar findings [20, 21].

Among the different treatments, cryotherapy had the highest cure rate in the patients with CL. Nonetheless, cryotherapy is not recommended for use on larger lesions (more than 5 cm) and/or lesions on the face or hands. This restriction might have influenced the positive outcome of cryotherapy. The use of cryotherapy is mentioned less frequently in European guidelines for the treatment of CL but seems to have had a positive treatment outcome in our study group. However, more studies are needed to evaluate the efficacy of cryotherapy as a treatment or co-treatment for CL.

Local treatment with intralesional SS had a cure rate of 80% in our study. Although Layegh et al. [22] reported that a combination treatment with intralesional SS and cryotherapy had a better outcome than a single treatment, this combination has only been used in three cases in this study, all with a positive result.

The dose and length of treatment with intravenous SS have varied over time in Sweden. Previously, the WHO recommendations were followed, but as a result of new data [23], treatment is now based on weight and given for a shorter time. There have been some problems in obtaining SS in Sweden in some cases. These problems might have delayed the time to start the treatment in some cases; in other cases, LA was chosen instead.

Different treatment recommendations for LA were used during the study period. Solomon et al. recommended giving LA for five consecutive days at a dose of 3 mg/kg, followed by a sixth dose on day ten [24]. In our study, 22 patients with CL followed this regimen. Twelve patients were cured, and ten patients relapsed, of whom eight had L. tropica.

In our study, 15 patients were treated with fluconazole as a first-line treatment; seven (47%) of these patients were cured. Previous studies with fluconazole have shown inconclusive effects on CL caused by L. major; with a positive effect reported in studies from high-endemic areas [25, 26], while the same effect was not observed among returning travellers [27]. Five of our seven patients who were cured with fluconazole had an infection caused by L. major. Since L. major often causes self-healing lesions, it is difficult to evaluate the effect of fluconazole in our study.

The patients with rheumatic diseases and immunosuppressive treatment showed a delay in time to symptoms compared with immunocompetent patients, as described in previous case reports [28, 29]. The patient in this study who was infected with L. tropica and treated with TNF inhibitors showed some improvement during treatment with LA but relapsed after treatment. This relapse may have been due to an early restart of immunosuppressive treatment with TNF inhibitors or due to L. tropica, which is known to frequently cause relapse. Since there are only approximately forty cases of leishmaniasis occurring in combination with immunosuppressive treatment reported in the litterature [28, 29], and these cases have been caused by various subtypes, there are no general recommendations concerning when to restart treatment with TNF inhibitors. The other two patients with TNF inhibitors in this study were cured after first-line treatment, and they had a different leishmaniasis subtype (L. donovani); furthermore, their TNF inhibitor treatments were not restarted. An increasing number of individuals are given immunosuppressive treatments, and when travelling to endemic areas, the number of leishmaniasis cases might increase; therefore, awareness and early identification of leishmaniasis within this group of patients is important.

The number of leishmaniasis cases diagnosed in Sweden increased between 1996 and 2016, mainly in migrants from endemic countries. Although leishmaniasis is rare in Sweden, patients appear to be diagnosed early and treated according to current European guidelines, resulting in an overall high cure rate.