Hemophagocytic Lymphohistiocytosis in Children With Visceral Leishmaniasis.

Abstract

To the Editor: In the July 2015 issue of The Pediatric of Infectious Disease Journal, Blázquez-Gamero et al1 reported a study analyzing the relationship between visceral leishmaniasis (VL) in children and acquired hemophagocytic lymphohistiocytosis (HLH) syndrome. Twenty-four children with VL were studied and 10 (41%) developed HLH syndrome. In HLH, there is a disorder of the activation and proliferation of T-cells and macrophages, with subsequent cytokine production, leading to uncontrolled inflammation. Acquired HLH is associated with several infections, particularly Epstein-Barr virus and other herpesvirus infections, and less frequently with Leishmania infections.1,2 We conducted a retrospective study of VL in children who were cared for in 3 hospitals in the Alicante province of Spain, on the Mediterranean coast, from July 1993 to June 2015. The diagnostic criteria for HLH are those proposed in 2004 by the Hemophagocytic Lymphohistiocytosis Study Group.3 Soluble interleukin-2 receptor (sCD25) in plasma and natural killer cell activity were not measured. Quantitative variables were analyzed by Student t test and qualitative variables by the Fisher exact test. Thirty-eight children were diagnosed with VL during the study period. Twenty-five children were studied. Data for the presence of fever or splenomegaly and complete blood count and serum triglyceride were recorded during 96 hours after diagnosis. Eight children (32%; 95% confidence interval: 17.2%–51.9%) met criteria for HLH syndrome. Table 1 shows HLH criteria and other clinical and epidemiologic characteristics of the patients analyzed. Patients with HLH had significantly lower hemoglobin (P = 0.004) and platelets (P = 0.01) and higher ferritin (P = 0.001) and serum triglycerides (P = 0.005). Bone marrow aspirates were performed in 17 children, and none had findings of hemophagocytosis. No specific treatment for HLH was given. All of our patients, whether or not they had HLH, had favorable outcomes with either liposomal amphotericin B or sodium stibogluconate treatment.TABLE 1: Differences of Children With and Without HLH SyndromeIn the study of Bode et al,2 VL-associated HLH represented 2.1% (15 of 710) of all HLH cases included in a national reference center database. In the study by Blázquez-Gamero et al,1 41% of children met HLH criteria. In our study, the percentage of VL-associated HLH in children was lower than that reported in the study by Blázquez-Gamero et al3 and higher than that reported in the study by Bode et al.2 HLH has a varied presentation with nonspecific signs and symptoms. In secondary forms of HLH, remission may be achieved by treating the underlying disease. Recently, tocilizumab, a humanized monoclonal antibody against the interleukin-6 receptor, has been shown to regulate the immune response for VL with HLH.4 In our study, favorable outcome was achieved only by treating the underlying VL. Although we did not find any signs of hemophagocytosis in our bone marrow samples, Hussein et al5 stress importance of a careful examination of bone marrow for this. In our retrospective study, we found results similar to those who demonstrated that secondary HLH can occur with VL as part of the natural history of this disease and that it does not imply a worse prognosis if the infection is treated properly. ACKNOWLEDGMENTS The authors thank the entire staff of the Pediatric Services of the Hospital Marina Baixa, Villajoyosa (Spain), the Hospital Clínico Universitario de Sant Joan d’Alacant (Spain), and the Hospital General Universitario de Alicante (Spain) for making this study possible. Agustin Clavijo, MD Tatiana Salvador, MD, PhD Department of Pediatrics Hospital Marina Baixa Villajoyosa, Alicante, Spain Luis Moral, PhD, MD Department of Pediatrics Hospital General Universitario de Alicante Alicante, Spain Cesar Gavilan, MD Department of Pediatrics Hospital Clinico Universitario de Sant Joan d’Alacant San Juan de Alicante, Spain Christian Squittieri, MD, FAAP Department of Pediatrics Hospital Marina Baixa Villajoyosa, Alicante, Spain Jose M. Ramos, PhD, MD, DTM&H1 Department of Internal Medicine Hospital General Universitario de Alicante Alicante, Spain