Visceral leishmaniasis triggering an adult‐onset Still's disease: a unique case

Key Clinical Message Adult‐onset Still's disease (AOSD) due to visceral leishmaniasis (VL) has not been previously reported. This case report analyzes a single episode of AOSD probably due to a visceral leishmaniasis successfully treated with pentamidine isethionate and prednisone.


Introduction
Fever of unknown origin (FUO) is a persistent febrile illness without an established etiology despite intensive diagnostic evaluation. Visceral leishmaniasis (VL) and adult-onset Still's disease (AOSD) are both causes of FUO. We describe a case of AOSD probably due to a visceral leishmaniasis.

Case Report
A 30-year-old woman was admitted to our Internal Medicine Department because of a continuous remittent fever (up to 40°C) present for a month, profuse sweating, pelvic girdle arthralgia and myalgia, and sore throat with dry cough. The patient always lived in Trapani and did not travel recently. She had been in her usual health until a month before admission in Trapani Hospital, where laboratory tests showed neutrophilic leukocytosis, normochromic normocytic anemia, erythrocyte sedimentation rate (ESR) of 120 mm/h, C-reactive protein (CRP) of 193 mg/L; negative results for ANA, ANCA, anti-dsDNA antibodies, AMA and rheumatoid factor (RF) 0; CA 125 of 44 u/mL; absence of IgM anti-EBV and anti-CMV; and negative Widal and Wright test and of oval, vivax, falciparum plasmodium serodiagnosis. Whole-body computed tomography (CT) showed modest liver and spleen volume increase and paraaortic and common iliac artery lymphadenopathy (max 2 cm), while sternal bone marrow aspiration showed reactive hyperplasia. Esophagogastroduodenoscopy (EGDS) revealed an enlarged ampulla of Vater with mild plasmacytic infiltrate and rare lamina propria eosinophilic granulocytic infiltrate in histologic examination. The empirical antibiotic therapy with amoxicillin-clavulanate, ceftriaxone, levofloxacin, teicoplanin, and gentamicin was ineffective. Her medical history includes surgical treatment of left femoral hernia when she was 10 years.
On admission, blood pressure was 110/70 mmHg, heart rate 80 beats per minute, respiratory rate 16 breaths per minute, body temperature 38.5°C, and oxygen saturation 92%, while the patient was breathing ambient air. She was pale with nonpruritic, evanescent, macular, erythematous (salmon-pink) rash ( Fig. 1) alert and oriented, pharyngeal erythema. Cardiac examination revealed 2/6 ejection murmur on aortic area. Abdomen was treatable with the lower liver and spleen borders of the 2 cm below the costal margin. Severe pelvic girdle pain with stiffness, functional limitation, and myalgia was present as wellthe overall level of disease activity on a visual analog scale (VAS) was 3.
ECG highlighted nonspecific anterolateral repolarization disorders. Echocardiogram (Fig. 2) showed diffuse transmural hyperechoic aspect of myocardium and small circumferential pericardial detachment with hyperechoic aspect of the pericardium, more evident on right sections.
Head, chest, abdomen and pelvis contrast-enhanced CT was similar to the previous.
Adult-onset Still's disease is an exclusion diagnosis among infectious, neoplastic, and rheumatic diseases [5]; the last two were excluded by CT, EGDS, tumor markers, and negative autoimmune pattern.
During the workup of FUO with severe anemia, assuming AOSD, in a patient living in a leishmaniasis endemic area, we performed revaluation of sternal bone marrow aspiration searching and detecting amastigotes ( Figure 3). Therefore, an anti-Leishmania antibody titer (indirect immunofluorescence assay method) was requested showing 1:160, while polymerase chain reaction (PCR) with specific primers confirmed the presence of Leishmania spp. [6].
Leishmania infantum, responsible for visceral disease in the Mediterranean region with a reservoir in the domestic dog, could be the causative agent of patient's disease. In fact, patient lived near a cemetery frequented by stray dogs. Therefore, the patient was treated with intravenous liposomal amphotericin B (3 mg/kg IV once daily), replaced by pentamidine isethionate (4 mg/kg IV every other day), dexamethasone (6 mg IV), and promethazine prophylaxis for angioedema and wheezing appearance. A promptly clinical improvement followed this latter treatment.
The following gradual corticosteroid anaphylactic prophylaxis reduction led to a relapse of remittent fever (peak 40°C), sweating, arthralgia, myalgia, evanescent, macular, erythematous (salmon-pink) rash, dry cough, and persistent elevation of inflammatory markers. This symptom relapse excludes reactive arthritis [7] and led to an AOSD diagnosis, according to Yamaguchi's criteria [5]. Therefore, prednisone (1 mg/kg PO) was associated, following the diagnosis of secondary AOSD. The patient was treated with twenty pentamidine isethionate doses and a month of steroid therapy with slow taper off. Peripheral blood anti-Leishmania antibodies and PCR and sternal bone marrow aspiration resulted negative at the end of specific therapy. Her overall condition and laboratory results significantly improved, ESR and CRP normalized (Table 1), and myocardial hyperechogenicity and pericardial effusion reduced. The final clinical and pathological diagnosis was as follows: adult-onset Still's disease caused by visceral leishmaniasis.
At one-year follow-up, the patient was in healthy condition.

Discussion
Only two Leishmania species are endemic in European countries. L. infantum has a reservoir in the dogs and is  [8]. Visceral leishmaniasis has an annual incidence of 400,000 cases, with about 20,000-40,000 associated deaths and high degree of underreporting cases [9].
Leishmaniases are divided into three medical conditions that involve cutaneous, mucocutaneous, or visceral pathology.
Visceral leishmaniasis has a variable asymptomatic incubation period with intermittent fever, malaise, and shivering for early symptoms and anemia, leucopenia, and hepatosplenomegaly for overt disease [9].
Liposomal amphotericin B has the best safety profile and has been approved by the Food and Drug Administration (FDA) for the treatment of VL [10]. Therefore, it is the most used drug in leishmaniasis species-directed therapy in travelers [11].
Adult-onset Still's disease is a rare systemic inflammatory disorder of unknown etiology and pathogenesis, characterized by quotidian or double-quotidian spiking fevers with evanescent rash, arthritis, and multiorgan involvement. The disease is responsible for a significant proportion of FUO cases and affects mainly younger people between 16 and 35 years of age (three quarters of the patients) [12][13][14].
The AOSD diagnosis according to Yamaguchi's criteria [5] foresees the presence of five criteria (at least two major) with sensitivity of 96.2% and specificity of 92.1% [12][13][14][15][16][17][18]. The major criteria include arthralgia or arthritis ≥2 weeks with swelling or limited range of motion; warmth, pain, stiffness in one or more joints, in the absence of other reason of arthralgia; persistent, remittent fever ≥39°C ≥ 1 week; typical rash (evanescent, macular, erythematous salmon-pink rash usually associated with fever); and elevated leukocyte count (>10,000/mm 3 with >80% granulocytes). Minor criteria comprehend sore throat; lymphadenopathy and/or spleen involvement (recent significant lymph node swelling and splenomegaly confirmed on palpitation or by echography); elevated liver function tests (transaminases and/or lactate dehydrogenase) not attributable to drug, toxicity or allergy; and negative tests for antinuclear antibodies and RF. Exclusion criteria comprehend infections, malignancies, and other rheumatic diseases.
The clinical course can develop into three distinct patterns (self-limited or monocyclic, intermittent or polycyclic systemic, chronic articular) with significant prognostic implications; each of them affects about one-third of AOSD patients [12].
Elevated ferritin levels are a nonspecific but common feature for AOSD diagnosis [20]. In this case report, only moderate ferritin increase was due to concomitant anemia with very low hemoglobin levels and severe iron deficiency. Furthermore, normal serum ferritin levels should not be used to rule out the diagnosis, although the glycosylated fraction of ferritin is a more specific marker of AOSD [12][13][14][15][16][17][18][19][20].
In conclusion, leishmaniasis is a systemic infectious disease with important public health implications concerning people living or visiting endemic areas such as Sicily or Italy.
Therefore, clinicians should be considered VL in the differential diagnosis of patients with fever, anemia, and hepatosplenomegaly.
The inadequate response to standard anti-Leishmania therapy alone (pentamidine) and the clinical improvement secondary to corticosteroid addition confirm the hypothesis that AOSD was due to VL.
Single-episode AOSD presentation is generally due to or triggered by infectious agents.
Diagnosis of AOSD requires exclusion of infectious; however, viruses and microbial have been implicated as triggers in AOSD pathogenesis.
To the author's knowledge, no previous AOSD cases secondary to Leishmania infection have been reported in the literature.

Authorship
SS, SC, SA, MC, and GD: wrote and revised the manuscript. SS, SC, EV, and EC: performed the analysis of case data; all authors: contributed to data analysis, drafting, and clinical revision of the manuscript and agreed to be responsible for any aspect of the manuscript.