Rubén Berrueco

Pandemic influenza A (2009 H1N1) in children with acute lymphoblastic leukaemia.

Pandemic influenza A (2009‐H1N1) usually results in mild clinical illness, but in some individuals it can be life‐threatening. There are no reports of this disease among paediatric patients with acute lymphoblastic leukaemia (ALL). We report ten consecutive patients with ALL and pandemic influenza treated in a single institution. Median age was 7 years (range: 3–12). All were treated with oseltamivir. There were no deaths. Two patients under intensive chemotherapy developed pneumonia and one required ventilatory support. ALL patients under maintenance treatment had mild disease. In conclusion, in our series only patients under intensive treatment developed a moderate to severe disease.

Prospective surveillance study of blood stream infections associated with central venous access devices (port-type) in children with acute leukemia: an intervention program.

The use of intensive chemotherapy and central devices has improved patients survival, but it is associated with catheter-related blood-stream infections (CRBSI). An educational program was instituted for preventing CRBSI occurrence in acute leukemia pediatric patients having totally implanted central devices. The Centers of Disease Control and Prevention criteria were used as definition for CRBSI. Data collected were age, sex, diagnosis, chemotherapy, inpatient versus outpatient, microbiological data, risk factors, social risk score, and treatment performed. CRBSI rate decreased from 6.7 to 3.7/1000 catheter-days with preventive measures (P=0.05). A further decrease to 1.5/1000 catheter-days was reached after the intensification of the educational program (P=0.01). Severe neutropenia at the time of catheter insertion was related to CRBSI and to infection recurrence (P<0.05). Most of the episodes occurred during induction chemotherapy. Thirty-six CRBSI episodes occurred in 25 of 73 patients. The most frequent microorganism isolated was Staphylococcus spp. Antibiotherapy was successful in 83.3% of episodes. Six patients needed a central venous access device replacement. Our intervention program was successful to decrease the CRBSI rates and its intensification allowed a further decrease, approaching reported rates in this setting. Severe neutropenia at the time of central venous access device insertion was related to CRBSI occurrence and recurrence.

National registry of hemoglobinopathies in Spain (REPHem)

Although highly prevalent throughout the world, the accurate prevalence of hemoglobinopathies in Spain is unknown.

Multiplex real-time PCR for prompt diagnosis of an outbreak of human parainfluenza 3 virus in children with acute leukemia.

IntroductionHuman parainfluenza virus type 3 (HPIV-3) causes significant morbimortality in immunocompromised patients. Outbreaks of severe pneumonitis have been previously described in this setting.Materials and methodsRetrospective observational study in children diagnosed with acute leukemia and a documented HPIV-3 infection in the context of a nosocomial outbreak occurred in a single center.ResultDuring summer 2012, an HPIV-3 infection was detected in six hospitalized children with acute leukemia. All the patients had respiratory symptoms and one of them suffered from parotitis.ConclusionEarly diagnoses using multiplex real-time polymerase chain reaction (PCR) let us control this outbreak. A phylogenetic analysis confirmed person-to-person transmission of a single HPIV-3 variant.

Very high Hypertriglyceridemia Induced: Is Plasmapheresis Needed?

To the Editor: A 15-year-old male diagnosed with T-acute lymphoblastic leukemia (ALL) began induction chemotherapy according to the Spanish Society of Hemato-Oncology. On day 14, he was started on 10 doses of intramuscular E. coli L-asparaginase (Kidrolase) 10,000 IU/m, every other day. On day 33, 2 days after L-asparaginase was completed, the patient’s serum triglyceride was of 1,347 mg/dl and peaked at 5,298 mg/dl on day 37. Total cholesterol was also high (793 mg/dl). Family history was negative for lipid disorders. He remained asymptomatic (no lethargy or abdominal pain) and serum lipase and amylase were normal in serial blood samples. A conservative management (lowfat diet) was decided and chemotherapy was continued as per protocol. The patient did not receive triglyceride-lowering medication and plasmapheresis was not performed. Serum triglyceride normalized 7 days later. Five days after finishing intensification chemotherapy (in which L-asparaginase and glucocorticosteroids were given again), serum triglyceride peaked at 1,439 mg/dl. The patient remained asymptomatic and serum triglyceride fell rapidly in a few days with conservative management (low-fat diet). L-asparaginase depletes serum asparagine, an essential aminoacid for lymphoblasts. This treatment has been associated with lipid metabolism disturbances, increasing endogenous synthesis of very low-density lipoprotein and blocking removal of triglyceride from the plasma due to a decrease in lipoprotein lipase activity [1]. The use of other agents as glucocorticosteroids as well as ALL per se, had been associated with this type of alteration [2]. Hypertriglyceridemia is frequently observed after L-asparaginase treatment but it is transient and benign [2,3]. Its association with pancreatitis has not been proven in this setting [4] and chemotherapy discontinuation is not warranted. Only in cases where symptomatic pancreatitis is present should treatment be discontinued. Plasmapheresis aimed at lowering triglycerids has been reported in patients with very high hypertriglyceridemia: Kfoury-Baz et al. reported a 34-year-old man with ALL who developed severe hypertriglyceridemia (5,620 mg/dl) during Lasparaginase treatment. He had severe abdominal pain and mild increase of lipase. Treatment with L-asparaginase was discontinued and a plasmapheresis performed. They recommended stopping asparaginase for serum triglyceride levels higher than 2,000 mg/dl or in case of pancreatitis [5]. Jain et al. [6] reported a pediatric patient with ALL who developed a very high hypertriglyceridemia (5,250 mg/dl) and an acute pancreatitis who underwent a plasma exchange. However, in a study in children with ALL, hypertriglyceridemia was frequent after L-asparaginase (67% of the patients) but was not associated with pancreatitis [2]. Patients with very high hypertriglyceridemia (e.g., 4,520 mg/ dl) did not develop pancreatitis, as was the case in our patient. The need of plasmapheresis in this setting is, therefore, not clear. Treatment with L-asparaginase was likely responsible for the very high hypertriglyceridemia in our patient, but these high levels were transient and had no immediate deleterious effects, including no evidence of pancreatitis or need for plasmapheresis and/or discontinuation of chemotherapy. In cases where concurrent severe hypertriglyceridemia and symptomatic pancreatitis develop, plasmapheresis could be a treatment option, although it is not clearly always indicated.

Outcome and toxicities associated to chemotherapy in children with acute lymphoblastic leukemia and Gilbert syndrome. Usefulness of UGT1A1 mutational screening.

Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood. Although intensive chemotherapy has improved survival in those patients, important side effects, including hyperbilirubinemia, are frequent. Gilbert syndrome (GS) is a frequent condition that causes a reduction in glucuronidation and intermittent hyperbilirubinemia episodes. This could provoke a greater exposure to some cytotoxic agents used in ALL, increasing the risk of toxicity. On the other hand, unexplained hyperbilirubinemia could lead to unnecessary modifications or even treatment withdrawals, which could increase the risk of relapse, but data regarding this in ALL pediatric population are scarce.

Syndromic albinism and haemophagocytosis.

A 3-year-old boy (4th child of consanguineous parents) was admitted because of the suspicion of a haemophagocytic syndrome (2-week history of fever, hepatosplenomegaly and pancytopenia). Blood analysis showed haemoglobin 80 g/l, leucocyte count 4AE5 · 10/l, platelet count 115 · 10/l, fibrinogen 1AE4 g/l, triglycerides 2AE78 mmol/l and ferritin 1849 lg/l. Bone marrow aspiration showed haemophagocytosis (Fig A and B), and polymerase chain reaction was positive for Epstein–Barr virus (EBV) (119AE801 copies/ml). On examination, his silver-grey hair colour was remarkable. On direct light microscopic examination, the hair had melanin aggregates and clumps of pigment distributed along the medulla (Fig I), as opposed to the smooth distribution of this pigment in a normal hair (Fig II). A syndromic albinism [Griscelli syndrome (GS) type 2] was suspected and confirmed by molecular studies (homozygotic deletion in RAB27A). The child was treated with antibiotics, corticosteroids, ciclosporin and etoposide with a good outcome. He is now going to receive a haemopoietic stem cell transplant from an unrelated donor. A 34-week gestational age girl (6th child of consanguineous parents) was admitted to the neonatal care unit because of her prematurity. Giant cytoplasmic granules were seen in peripheral blood leucocytes (Fig C) as well as in bone marrow haematopoietic progenitors (Fig D). On examination, grey hair and skin hypopigmentation were found. Microscopic examination of her hair showed small granular aggregates of melanin in the hair shaft (Fig III). These findings led to the diagnosis of Chediak-Higashi syndrome (CHS). During the first 3 years of life she had otomastoiditis complicated by a cerebral venous sinus thrombosis, easy bruising, deafness and psychomotor delay. At the age of 3 years she developed a haemophagocytic syndrome triggered by EBV infection. Treatment with corticosteroids, ciclosporin and etoposide was unsuccessful and the patient died from progressive disease and systemic candidiasis. Albinism syndromes have been associated with systemic diseases. Of note, direct microscopic examination of hair and a blood film are simple and useful diagnostic tools in these cases. In GS the diagnosis can be suspected from the characteristic silver-grey hair colour, especially when associated with a haemophagocytic syndrome (accelerated phase). In CHS the diagnosis can be made when a patient has grey hair albinism and giant granules in leucocytes. (A)

Controversias en el tratamiento de la trombocitopenia inmune pediátrica

Immune thrombocytopenia (ITP) is a relatively common disorder in childhood. Although it usually achieves spontaneous remission at this age, the management of persistent or chronic ITP in children is still controversial. The aim of this article is to address current controversies related to the treatment of persistent, chronic, and refractory ITP in children, including the role of rituximab and splenectomy, as well as focusing on a new approach with thrombopoietin receptor agonists (TPO-RAs). Eltrombopag and romiplostim are safe and useful drugs for paediatric ITP. These two TPO-RAs might delay surgery and other treatments such as rituximab. However, the potential side effects described in adult patients should be considered. Paediatric patients with refractory ITP, undergoing new treatments, should be supervised in specialised centres.

Spuriously low pulse oximetry saturation associated with hemoglobin Sydney in a child and relatives: Identification of this unstable hemoglobin may avoid unnecessary testing and hospital admissions

To the Editor: Pulse oximetry is a noninvasive method to measure hemoglobin oxygen saturation (SpO2) widely used in different medical settings. In some cases, low SpO2 is accidentally found in otherwise asymptomatic patients, and cardiopulmonary testing is performed in order to establish the cause of their apparent hypoxemia.1 In some of these individuals, there is a discrepancy between low SpO2 measured by pulse oximetry and normal arterial blood oxygen measurement (SaO2). In these cases, low SpO2 readings are considered to be an artifact due to the presence of a hemoglobin variant, instead of being related to cardiopulmonarydisease.2,3 Therefore, hemoglobinopathies must be included in the diagnostic approach in otherwise asymptomatic patients who have unexpected low SpO2. 1 The identification of these rare hemoglobinopathies may help to avoid unneeded testing, treatments, or even hospital admissions.1 Most of the 1,200 hemoglobin variants described so far are not associated with abnormal SpO2 readings. 3 However, this finding can occasionally result in the identification of a hemoglobin variant.4 Among them, somehave lowSpO2 and concordant lowSaO2, for example, certain inherited low oxygen affinity variant forms of hemoglobin. Although rarely reported, in a subset of patients such as in our case, spurious low SpO2 measurement associated with normal SaO2 can be caused by a hemoglobin variant. Discrepancy between SpO2 and SaO2 can be explained because there is variance in light absorption by the hemoglobin at two wavelengths measured by the pulse oximeter.2 In this report, we describe a family with the unstable hemoglobin Sydney associated with an apparent low SpO2, which has not been reported before as a cause of this phenomenon. A 19-month-old Spanish male child presented to the emergency department of our pediatric hospital with fever, cough, and breathing difficulty. Physical examination was remarkable for the heart rate of 144 beats per minute and the respiratory rate of 40 breaths per minute, pulse oximeter estimated a SpO2 of 90% on room air, there was wheezing on auscultation, and the chest radiograph was normal. Albuterol nebulization, oral corticosteroids, and oxygenwere administeredwith no improvement. Despite subsequent clinical improvement, low SpO2 persisted. Cardiopulmonary causes of hypoxemiawere ruled out. Family history revealed six relatives (Fig. 1A)with chronic hemolysis; the father had been diagnosed with unstable hemoglobin, which is not further characterized. Moreover, he also presented low SpO2. The grandfather had been splenectomized. The patient’s blood analysis revealed mild compensated hemolysis (Supplementary Table S1). Peripheral blood smear showed nonspeF IGURE 1 (A) Pedigree of the family: Symbols with a dot represent affected patients. (B) High-performance liquid chromatography (HPLC) from patient (1) and his father (2). Arrows show anomalous hemoglobin

Aplastic Crisis Secondary to Parvovirus B19 Infection as the First Manifestation of an Undiagnosed Hereditary Spherocytosis: Report of a Pediatric Series of Spanish Patients.

To the Editor: Human Parvovirus-B19 (HPV-B19) infection is a well-known cause of aplastic crisis in patients with chronic hemolytic anemia, such as hereditary spherocytosis (HS).1–5 In the pediatric population HS may have not been diagnosed when HPV-B19 infection occurs; therefore, it might be difficult to suspect hemolysis when the presenting symptom is a severe aregenerative anemia.6 We describe 8 pediatric patients in whom the first manifestation of an undiagnosed HS was an aplastic crisis due to HPV-B19. We performed a retrospective study between January 2008 and June 2015 in a Pediatric University Hospital in Barcelona. Table 1 shows patients characteristics. In brief, there were 5 women. The median age at diagnosis was 9.5 years (range, 4 to 12y). Presenting symptoms in most cases were fever, abdominal pain, and vomiting. Only 1 patient developed an exanthema. All patients presented moderate to severe microcytic/normocytic anemia (median hemoglobin, 58g/L; range, 31 to 86) with low reticulocyte count in 7 of them. One patient had leukopenia. Direct antiglobulin test was negative in all cases. Although corrected reticulocyte count was low, other signs of hemolysis, such as mild unconjugated hyperbilirubinemia, increased lactate dehydrogenase, or decreased haptoglobin were present. Serologic assay (anti-HPV-B19 IgM) was positive in all cases. HPV-B19 is the cause of erythema infectiosum, which is a common and self-limited exanthematous illness of childhood. The prodromal phase consists of fever, headache, and flu-like symptoms. The hallmark is a characteristic rash that appears after this phase. In healthy children, this virus is frequently associated to mild aregenerative anemia and in some cases to leukopenia and/or thrombocytopenia.4 Patients with hematologic diseases may not present the characteristic typical course. As described in pediatric patients with HS7 the characteristic rash was not observed in our series of pediatric patients except for 1 case.8 All patients presented with fever and most of them had abdominal pain and severe aregenerative anemia.1,7 In mild forms of HS, hemolysis is compensated and some children may not be diagnosed until a viral infection may trigger an aplastic crisis and uncover the underlying defect.1 Thus, in a patient presenting with unexplained acute moderate to severe aregenerative anemia, the possibility of an aplastic crisis secondary to HPV-B19 infection in an undiagnosed mild HS has to be considered, even in patients without a known family history. To confirm this diagnosis, other clinical and laboratory signs of hemolysis should be sought and an expert should evaluate a blood smear. As not always a hematopathologist is available, it is important to keep a blood smear for further evaluation, before transfusion. In our series, spherocytes could be observed in all cases. In addition, should these patients require hospital admission, the suspicion of HPV-B19 infection is important, as it will prompt to avoid their admission in a hemato-oncology ward to prevent an infectious outbreak in susceptible patients. Special precaution should be taken to avoid contact of the patient with pregnant women because HPV-B19 can cause severe intrauterine infections. In conclusion, severe aregenerative anemia by HPV-B19 infection may be the presenting symptom of HS in children. Anna Alonso-Saladrigues, MD* Albert Català, MD* Rubén Berrueco, MD, PhD* Mireia Camós, MD, PhDw Montserrat Torrebadell, MDw Susana Rives, MD, PhD* *Department of Pediatric Hematology and Oncology wLaboratory Department, Molecular Genetics, Hospital Sant Joan de Déu de Barcelona, University of Barcelona Barcelona, Spain