Dragan Micic

Langerhans Cell Histiocytosis (LCH): Guidelines for Diagnosis, Clinical Work-Up, and Treatment for Patients Till the Age of 18 Years

These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work‐up, and treatment and long‐term follow‐up of LCH patients are presented. Pediatr Blood Cancer 2013;60:175–184.

Fever of unknown origin in 185 paediatric patients: A single‐centre experience

AIMnWe conducted a prospective study to evaluate the causes and outcome in children with fever of unknown origin (FUO).nnnMETHODSnFrom 1990 to 1999, 185 children with FUO were evaluated. Initial evaluation included routine haematological analysis, Epstein-Barr virus (EBV) serology, urine, stool or blood cultures, chest X-ray and tuberculin probe.nnnRESULTSnIn 131 (70%) patients diagnosis was established, and 70 (37.8%) had infectious disease. EBV infection was the most common infection followed by visceral leishmaniasis (VL), urinary tract infection (UTI) and tuberculosis. Autoimmune disorders were diagnosed in 24 (12.9%), Kawasaki disease in 12 (6.4%), malignant diseases in 12 (6.4%) and miscellaneous conditions in 15 (8.1%) patients. In the remaining 54 (30%) patients, diagnosis was not established and most of them had self-limited disease. During the investigation, 26 (14%) patients developed serious organ dysfunction and five patients (two with virus-associated haemophagocytic syndrome, one with VL and two unknown) died.nnnCONCLUSIONnThe most important infectious causes of FUO in our study were EBV infection and VL. Kawasaki disease represented a significant cause of FUO at the beginning of our study because it was not recognized by primary-care physicians. We report myelodysplastic syndrome as another emerging cause of paediatric FUO. Repeated clinical examination and careful use of specific laboratory examinations, invasive diagnostic procedures or imaging are crucial in approaching paediatric FUO.

Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndrome.

A patient with Wiskott‐Aldrich syndrome who developed Epstein‐Barr virus‐associated haemophagocytic lymphohistiocytosis (EBV‐HLH) is described in this study. At 4 mo of age the patient developed fever associated with bicytopenia and splenomegaly. Analysis of a bone marrow specimen revealed extensive haemophagocytosis, and in situ hybridization for EBV of the bone marrow specimen using an EBV‐encoded RNA probe was positive. Diagnosis of EBV‐HLH was established and immunotherapy with HLH‐94 protocol was started. HLH has been described in patients with other well‐defined primary immunodeficiencies such as X‐linked lymphoproliferative syndrome, Chediak‐Higashi syndrome and Griscelli disease. Also, HLH was reported recently in severe combined immunodeficiency and DiGeorge syndrome.

Atypical strain of Toxoplasma gondii causing fatal reactivation after hematopoietic stem cell transplantion in a patient with an underlying immunological deficiency.

ABSTRACT In immunocompromized patients, including hematopoietic stem cell transplant (HSCT) recipients, life-threatening toxoplasmosis may result from reactivation of previous infection. We report a case of severe disseminated toxoplasmosis that developed early after allogeneic HSCT for T-cell lymphoblastic leukemia/lymphoma in a 15-year-old Toxoplasma gondii-seropositive boy with Nijmegen breakage syndrome, a rare genetic DNA repair disorder associated with immunodeficiency. The donor was the patients HLA-identical brother. Prophylaxis with cotrimoxazole was discontinued a day before the HSCT procedure. Signs of lung infection appeared as early as day 14 post-HSCT. The presence of tachyzoite-like structures on Giemsa-stained bronchoalveolar lavage (BAL) fluid smears suggested toxoplasmosis. Real-time PCR targeted at the T. gondii AF146527 gene revealed extremely high parasite burdens in both blood and BAL fluid. Although immediate introduction of specific treatment resulted in a marked reduction of the parasite load and transient clinical improvement, the patient deteriorated and died of multiple organ failure on day 39 post-HSCT. Direct genotyping of T. gondii DNA from blood and BAL fluid with the PCR-restriction fragment length polymorphism method revealed type II alleles with SAG1, SAG2, and GRA6 markers but alleles of both type I and type II with GRA7. Additional analysis with 15 microsatellite markers showed that the T. gondii DNA was atypical and genetically divergent from that of the clonal type I, II, and III strains. This is the first report of increased clinical severity of toxoplasmosis associated with an atypical strain in the setting of immunosuppression, which emphasizes the need to diagnose and monitor toxoplasmosis by quantitative molecular methods in cases of reactivation risk.

Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis: A Single-Center Experience

BACKGROUNDnHemophagocytic lymphohistiocytosis is a rare multisystem disorder characterized by proliferation and diffuse infiltration multiple organs with histiocytes, including the central nervous system.nnnPATIENTS AND METHODSnThirty children diagnosed with hemophagocytic lymphohistiocytosis between 1997 and 2010 were reviewed and analyzed. Central nervous system disease involvement was defined as the presence of neurological symptoms and signs or elevated values of cerebrospinal fluid cells and/or proteins.nnnRESULTSnAmong the 30 patients, 17 (56%) had central nervous system involvement. Fourteen patients (46%) presented with neurological symptoms including seizures, irritability, bulging fontanelle, cranial nerve palsy, or disturbance of consciousness, whereas the remaining three patients developed central nervous system symptoms during the course of the disease. Seventeen patients (56%) had cerebrospinal fluid abnormalities. Neuroradiological studies were performed in nine patients. The most common findings were edema, atrophy, subcortical necrosis, and high signal intensity on T2-weighted magnetic resonance imaging. All patients were treated according to the Hemophagocytic Lymphohistiocytosis-94 and Hemophagocytic Lymphohistiocytosis-2004 protocols. Patients with central nervous system involvement had greater mortality. In prediction of the outcome, the cutoff value for cerebrospinal fluid protein was 470xa0mg/L. The most common neurological sequela was psychomotor delay.nnnCONCLUSIONnCentral nervous system involvement in hemophagocytic lymphohistiocytosis is common and is associated with poor outcome.

Epstein-Barr virus associated hemophagocytic lymphohystiocytosis during maintenance treatment of acute lymphoblastic leukemia.

To the Editor: Hemophagocytic lymphohystiocytosis (HLH) is a hyperinflammatory syndrome caused by ineffective immune response to diverse stimuli, such as infections, metabolic products or tissue damage [1,2]. HLH occurs in patients with genetic background for this condition, in the setting of immunodeficiency, as well as in healthy individuals. Diagnostic criteria includes clinical, laboratory and histological data [3,4]. Our patient was a 9 years old boy who presented with high fever and pancytopenia during maintenance treatment of acute lymphoblastic leukemia (ALL). He is the second child of healthy, unrelated parents, with uneventful personal and family history. Nine months before this admission we made a diagnosis of preB ALL. Treatment according to BFM protocol induced complete hematological remission after a month, and further intensive chemotherapy took an uneventful course. In the second month of maintenance treatment the boy suffered high fever, accompanied with loose stools and pharyngitis. Physical finding, except sore throat, was completely normal. He had severe pancytopenia, and serum biochemistry revealed LDH 1747 U/L, AST 261 U/L, ALT 223 U/L, feritin of 1987 mcg/ L, triglycerides 3.05mmol/L.Also, he had slightly prolonged prothrombin time, but normal activated partial thromboplastin time and elevated level of fibrinogen of 5.45 g/L. Bone marrow aspirate was hypocelullar, without lymphoblasts, and phenomenon of hemophagocytosis was observed. Etiology of HLH was confirmed with the results of serological testing—concentration IgM on EBV was 170 U/ml (upper limit in our laboratory is 13 U/ml). NK cells in peripheral blood was almost absent (1.6%, normal value is 11%), and there was very low cytotoxic NK activity. We introduced treatment with cyclosporin A, dexametason and VP 16, according to HLH 2004 protocol. After starting this regimen fever resolved after 2 days and there was an improvement in complete blood counts and in general condition, as well. After the fourth dose of VP 16 fever reappearead, followed with the finding of distended and painful abdomen. Despite wide spectrum antimicrobials and G-CSF, the boy succumbed due to typhlitis and septicemia caused bymultiresistant Pseudomonas aeruginosa. HLH is a rare cause of fever in children during the treatment of malignant diseases. Although our patient did not fulfill all criteria for HLH (he had no splenomegaly and coagulopathy), persistent fever with unexplained pancyto-peniashould alert for diagnostic work up for HLH [5].

Leukapheresis in management hyperleucocytosis induced complications in two pediatric patients with chronic myelogenous leukemia.

Complications caused by elevated white blood cell count in pediatric patients with CML could be a presenting feature of the disease. Here, we present two adolescents, aged 16 and 17years, who were admitted for investigation of extremely elevated leukocytes and complications of leucostasis. Initial manifestations were priapism and blurred vision, respectively. Diagnosis of chronic phase of chronic myeloid leukemia is established, and conventional measures for leucoreduction began. However, since there were no improvements, a leukapheresis procedure was initiated. After undergoing 3 daily procedures the leukocyte count declined for each patient, with resolution of pripaism and ophtalmological disturbances. Leukapheresis is safe and effective therapeutic option for patients with complications of hyperleucocytosis. If started in a timely manner, permanent organ damage or death could be avoided.

Molecular diagnosis of childhood acute leukemia: Serbian experience.

To the Editor: Genetic markers in leukemic cells represent one of the most important prognostic factors in childhood acute leukemia. Molecular assays have been developed and an accurate diagnosis of disease subtypes is available for the translocations most frequently occurring in acute lymphoblastic leukemia (ALL) and in acute myeloid leukemia (AML) [1]. While in Serbia cytogenetic analysis have been the only standard method for identifying genetic abnormalities, our goal was to establish a diagnostic center for laboratory tests which are sufficient for risk stratification of patients with childhood acute leukemia.

Fever of unknown origin in 185 paediatric patients: A single-centre experience: FUO in 185 paediatric patients

Aim: We conducted a prospective study to evaluate the causes and outcome in children with fever of unknown origin (FUO). Methods: From 1990 to 1999, 185 children with FUO were evaluated. Initial evaluation included routine haematological analysis, Epstein‐Barr virus (EBV) serology, urine, stool or blood cultures, chest X‐ray and tuberculin probe. Results: In 131 (70%) patients diagnosis was established, and 70 (37.8%) had infectious disease. EBV infection was the most common infection followed by visceral leishmaniasis (VL), urinary tract infection (UTI) and tuberculosis. Autoimmune disorders were diagnosed in 24 (12.9%), Kawasaki disease in 12 (6.4%), malignant diseases in 12 (6.4%) and miscellaneous conditions in 15 (8.1%) patients. In the remaining 54 (30%) patients, diagnosis was not established and most of them had self‐limited disease. During the investigation, 26 (14%) patients developed serious organ dysfunction and five patients (two with virus‐associated haemophagocytic syndrome, one with VL and two unknown) died.