Atypical presentation of acute myeloblastic leukemia in two pediatric patients

Acute myeloblastic leukemia (MLA) is an uncommon disease in childhood and its prognosis is worse than that of lymphoblastic leukemia. Severe hemorrhage, infections and perfusion disorders secondary to leukostasis are the main complications leading to its high mortality rate. Two pediatric patients with MLA (M5a and M2) are presented. Both patients were admitted to the pediatric intensive care unit with acute respiratory distress syndrome and intracranial hemorrhage respectively, secondary to leukostasis. The first patient showed favorable clinical course and underwent bone marrow transplantation four months later; in contrast, the second patient died a few hours after admission. The physiopathology of each case, the therapeutic approach and the use of leukopheresis as a therapeutic alternative in patients with hyperleukocytosis and leukostasis are discussed. A high degree of suspicion is required to make a diagnosis as early as possible in order to avoid the death of a large percentage of patients before cytostatic treatment begins.     

The therapy of hyperammonemia due to ornithine transcarbamylase defiency in a male neonate.

Ornithine transcarbamylase deficiency in the male neonate has been considered to be invariably fatal because of the severity of the hyperammonemia. An extreme degree of hyperammonemia in a male neonate was brought under control by a series of exchange transfusions, prolonged peritoneal dialysis, adequate caloric intake, and a mixture of essential amino acids with an excess of aspartic acid and arginine. After the initial phase, it was possible to maintain the plasma ammonia level with dietary therapy alone, in spite of a number of complications that might be expected to cause tissue damage and increase the hyperammonemia.     

Current results of cooperative AML therapy studies in children: BFM-78 and 83

271 children with AML entered the cooperative studies BFM-78 (151 pat.) and BFM-83 (120 pat.) since Dec. 1, 1978. In the second study BFM-83 the 8-10 week intensive induction/consolidation therapy of study BFM-78 was preceded by an 8-day intensive therapy consisting of cytosine arabinoside, daunorubicin and VP-16. 10 children died prior to starting the protocol therapy from hemorrhage and/or leukostasis. 80% of the 261 protocol patients achieved a complete remission. 7% were early deaths by hemorrhage and/or leukostasis 3% died of other complications. 10% were partial or nonresponders. 54 relapses, 11 with CNS involvement have occurred in study BFM-78 after a follow up of 2.10-6.7 years (median 4.10 yrs.). The life table probabilities for event free survival (EFS) and event free interval (EFI) after 6.7 years are 37% (SD 4%) and 47% (SD 5%) respectively. The results of study BFM-83 after a follow up of 0.3-2.8 years (median 1.8 yrs.) are: 23 relapses, EFS 40% (SD 10%) and EFI 48% (SD 12%). So far, the overall results of both studies are nearly identical. The analyses of the prognostic factors show that initial hyperleukocytosis (greater than or equal to 100 X 10(3)/mm3) represents a high risk for early fatal hemorrhage and/or leukostasis, for nonresponse and for the incidence of relapses. Initial deaths caused by hemorrhage and/or leukostasis occur also significantly more often in patients with M5-subtype and extramedullary organ involvement. Additional strategies for achieving a better prognosis in high risk patients are necessary.     

Blood component transfusion in the intensive care nursery. Indications and special problems

Increasingly, transfusions of component blood products are used in the setting of the neonatal intensive care unit. There is a need to analyze the indications and potential complications of this therapy critically. We review here the problems primarily unique to the neonatal population and suggest an approach to the transfusion requirements of this group. Specifically, we discuss the rationale, indications and complications of red cell, granulocyte, and platelet transfusions in these patients. Discussion of exchange transfusion and the particular blood banking requirements of these patients will be reviewed in subsequent articles.     

Postoperative complications in cirrhotic pediatric deceased donor liver transplantation: Focus on transfusion therapy

Intraoperative transfusions seem associated with patient death and graft failure after PLTx. A retrospective analysis of recipients’ and donors’ characteristics and transplantation data in a cohort of patients undergoing PLTx from 2002 to 2013 at the Bergamo General Hospital was performed. A two‐stage hierarchical Cox proportional hazard regression with forward stepwise selection was used to identify the main risk factors for major complications. In addition, propensity score analysis was used to adjust risk estimates for possible selection biases in the use of blood products. Over the 12‐year period, 232 pediatric cirrhotic patients underwent PLTx. One‐year patient and graft survival rates were 92.3% and 83.7%, respectively. The Kaplan‐Meier shows that the main decrease in both graft and patient survival occurs during the first months post‐transplantation. At the same time, it appears that most of the complications occur during the first month post‐transplantation. One‐month and 1‐year patient complication‐free survival rates were 24.8% and 12.1%, respectively. Our study shows that intraoperative red blood cells and platelet transfusions are independent risk factors for developing one or more major complications in the first year after PLTx. Decreasing major complications will improve the health status and overall long‐term patient survival after pediatric PLTx.     

Prevention of infection and bleeding in leukemic patients receiving intensive remission maintenance therapy

Leukemic patients were treated with intensive chemotherapy to reduce the number of leukemic cells remaining after complete remission was induced. This therapy resulted in periods of severe granulocytopenia and thrombocytopenia. Considering 13 patients who did not receive antibacterial prophylaxis, documented infection was quite common including four episodes of bacteremia and three urinary tract infections. By contrast, patients who received co-trimoxazole as antibacterial prophylaxis experienced one half as many febrile episodes and no serious infections. Prophylactic co-trimoxazole is beneficial for patients with marrow remission in this study. Similar benefit in patients with leukemic marrows remains to be established. All patients received prophylactic platelet transfusions three times a week when their platelet counts were < 20,000/μl. There were no episodes of bleeding other than petechiae.     

Biology and pathogenesis of CNS leukemia

Despite routine preventive central-nervous-system (CNS) therapy, 5-10% of children with acute lymphoblastic leukemia continue to suffer CNS relapse. In a majority of these patients, bone marrow relapse ensues and is usually fatal. A better understanding of the biology and pathogenesis of CNS leukemia is needed to develop more effective methods of prevention and treatment of this adverse complication of acute leukemia. Concepts of the origin and proliferation of leukemic cells in the CNS are reviewed, as well postulated mechanisms of their ingress into and egress out of the CNS.     

Characterizing complication risk from multisite,intermittent transfusions for the treatment of sickle cell disease

Blood transfusions are indicated for some acute complications of sickle cell disease (SCD). To characterize the SCD population at increased risk of transfusion‐associated complications, Georgia hospital discharge data were used to estimate the frequency of intermittent transfusions and the proportion of patients receiving them at multiple institutions. Ten years of data (2007‐2016) showed almost 19% of patients with SCD (1585/8529) received transfusions at more than one hospital. The likelihood of multisite transfusions increased from ages 18 through 40 and with the number of transfusions received. The results support the need to track and share transfusion histories in order to reduce complication risks.     

A quality improvement initiative standardizing premedication for blood product transfusions

For children with cancer, blood product transfusions are crucial, but can be complicated by transfusion reactions. To prevent these complications, premedication is often given, although not always evidence-based. Herein, we describe a significant decrease in the use of premedication (72%–28%) at our institution after the implementation of standardized guidelines, without an increase in transfusion reactions (3.2% prior vs. 1.5% after standardization). Importantly, there were no severe transfusion reactions leading to hospitalization or death. Our results provide evidence in favor of more judicious use of premedication prior to transfusions in patients 21 years and younger being treated for cancer.     

Management of sickle cell disease: progress during the past 10 years

Despite the lack of successful drug development during the last 10 years, significant advances have been made in the management of a number of the complications of sickle cell disease. Identification of the vascular changes in the retina has led to the use of argon or zenon laser therapy to prevent progression of these changes to retinal hemorrhage and loss of visual acuity. Aseptic necrosis of the head of the femur or humerus is now successfully managed with the insertion of a bone graft or prosthesis. Exchange transfusions are believed to have prevented recurrent cerebrovascular accidents. The use of prophylactic penicillin and pneumococcal vaccine may have reduced the incidence of sepsis, pneumonia, and meningitis due to susceptible organisms in young children. While this progress can be said to have improved the quality of life of many patients, other complications of sickle cell disease remain as therapeutic dilemmas. The ability to prevent complications is hampered both by a lack of specific therapeutic measures and ignorance as to which patients are likely to develop complications.     

Minor elective surgical procedures using general anesthesia in children with sickle cell anemia without pre-operative blood transfusion

BACKGROUND: Pre-operative red blood cell (RBC) transfusions are often recommended for patients with sickle cell disease (SCD) who require elective surgery under general anesthesia. However, definitive randomized studies demonstrating the benefit of transfusions in this setting have not been conducted. In particular, the merits of transfusion prior to minor or low-risk surgical procedures in children with SCD have not been demonstrated. PROCEDURE: We hypothesized that children with sickle cell anemia (Hb SS) who have minor elective surgical procedures develop few complications even without pre-operative transfusion. We accessed our Comprehensive Sickle Cell Program's Database to identify all such procedures performed during a 13-year period. Medical records were reviewed to characterize the surgical procedure, the use of transfusions, and perioperative complications. RESULTS: Twenty-eight children with Hb SS had a total of 38 minor surgical procedures. No perioperative transfusions were given in 34 of the cases (85%). Five of these 34 surgeries (15%) were associated with minor post-operative complications (fever or transient pain). No post-operative acute chest syndrome was encountered. CONCLUSIONS: Minor or low-risk elective surgical procedures in children with Hb SS may not routinely require pre-operative transfusion. A randomized clinical trial to compare transfusion with no transfusion for minor surgical procedures is needed.     

Cytoreductive procedures in the early management in cases of leukemia and hyperleukocytosis in children

Cytoreduction for hyperleukocytosis before the initiation of primary therapy may reduce morbidity and mortality from blast cell lysis in children with acute lymphoblastic leukemia (ALL) and from leukostasis in children with acute nonlymphoblastic leukemia (ANLL) or chronic myelogenous leukemia (CML). The clinical features of 35 children (23 with ALL, 5 with ANLL, and 7 with CML) who underwent cytoreduction before the institution of definitive therapy were studied. Twelve children had exchange transfusions and 23 underwent leukaphereses. The cytoreductive procedures were equally effective in removing peripheral leukocytes (median decrease, 60%) and produced no complications. Ten children required additional cytoreduction because of further leukocyte increase before chemotherapy became effective. Three children with ALL who had renal insufficiency and metabolic derangement prior to leukapheresis subsequently required additional therapeutic measures. Three children with respiratory symptoms attributable to leukostasis improved after cytoreduction, and there were no episodes of intracerebral hemorrhage. These observations demonstrate the safety and efficiency of exchange transfusion and leukapheresis, and provide support for the role of cytoreduction in the early management of cases of hyperleukostasis and leukemia in children.     

Splenectomy after angiographic embolization of the splenic artery in patients with massive splenomegaly and severe thrombocytopenia, in juvenile subacute myelomonocytic leukemia

Splenectomy for massive splenomegaly in thrombocytopenic patients refractory to platelet transfusions carries increased surgical risks. Blocking of the splenic artery may reduce the size of the organ, prolong the survival of transfused platelets, and reduce the surgical complications. We describe four cases of extreme splenomegaly and thrombocytopenia where successful splenectomy was carried out after angiographic embolization of the splenic artery in children with juvenile chronic myelogenous leukemia. Significant improvement was observed in platelet counts and in the survival of platelets after transfusions in three of the patients. There was a concomitant decrease in transfusion requirements. Isoimmunization prevented prolonged platelet survival in the fourth case. We recommend earlier splenectomy in these patients to reduce transfusion requirements and delay the onset of poor platelet survival after transfusions.     

Fulminant and fatal course of acute lymphoblastic leukemia due to lactic acidosis and suspected abdominal compartment syndrome

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and its prognosis has considerably improved over the past 2 decades due to new therapeutic approaches. In some cases, however, it can develop very rapidly and cause possibly fatal complications. We report on the case of an 11-year-old boy with ALL, who rapidly developed severe lactic acidosis and abdominal compartment syndrome. He died of multiorgan failure only 5 days after diagnosis of ALL had been established. Autopsy revealed systemic leukemic infiltrations. We suppose that the mass of tumor cells induced a cascade of metabolic and endocrine reactions, which not only triggered the rapid progression of the disease but were also accountable for the lack of response to treatment. The pathophysiology of abdominal compartment syndrome as a rare and in our case ultimately fatal complication of ALL is described.     

Reasoning, clinical aspects, and results of a guarded platelet substitution therapy in children with acute lymphoblastic and myeloblastic leukemia treated according to the BFM therapy studies

In this retrospective study of 62 children with ALL and 10 children with AML, data are compiled on the special aspects of a guarded indication for platelet transfusions; in Tubingen this indication is usually based solely on clinical signs of incipient or manifest bleeding at platelet counts below 11,000/mm³. This is in contrast to the practice most often used to transfuse platelets at counts below 20,000/mm³ for prophylactic reasons irrespective of therapeutic need. The guarded indication aims at keeping the rate of allosensitization by platelet transfusions as low as possible. Of all patients in remission induction of ALL and of AML, platelet transfusions were needed by 53% and 80% respectively; the mean platelet support was 2.9 units in ALL and 19.0 units in AML. In relapse, the need increased considerably. Of all patients with ALL, 11% were sensitized by platelet transfusions; lethal complications related to this guarded indication could not be seen.     

Cytomegalovirus Infection in Early Infancy: Five Atypical Cases

Five cases of neonatal cytomegalovirus infection are described. None of them had the classical picture of neonatal cytomegalic inclusion disease. Two were cases of rhesus isoimmunization and two others were regarded initially as possible cases of ABO incompatibility. They were given intrauterine or postnatal exchange transfusions. Two of these cases were fatal, and one of them was remarkable in that cytomegalic cells were found at necropsy only in the salivary glands.One infant was born apparently well, apart from certain skeletal and corneal developmental anomalies, and probably acquired his cytomegalovirus infection naturally at about the time of birth.The possibility of introduction of cytomegalovirus infection by exchange blood transfusion is discussed, along with some of the resulting diagnostic problems.     

Pediatric intracranial complications of central venous catheter placement

Central venous catheters are essential in the medical management of critically ill pediatric patients. Medical practitioners should be aware of the potential for misplacement of these devices as such complications may result in serious injury and possible death. Catheter malpositioning is not limited to any particular site and may have far-reaching consequences that affect a single or multiple organ systems. We present two cases where central venous catheter positioning led to complications that resulted in intracranial pathology which was fatal in one case.     

Transfusion-associated viral infections

Viral infections are a frequent occurrence following transfusion of blood products. While generally benign, these infections are capable of causing significant morbidity and mortality. Therefore, it is prudent to follow several general approaches diligently to reduce the risks of these infections in patients undergoing transfusions of blood products. These suggested measures include the following: 1. Prescribe and administer blood and blood products only when absolutely needed. 2. Use volunteer blood donors only. 3. Avoid use of pooled blood products when possible. 4. Use only blood and blood products that have been appropriately tested for HBsAg and HIV. 5. Use ALT determinations to screen blood products and eliminate those with high level. 6. Avoid the use of clotting-factor concentrates but, if necessary, use only those which have been heat-treated. 7. Limit use of leukocyte transfusion. 8. Use only CMV seronegative blood and blood products or frozen deglycerolized red cells in patients at high risk for posttransfusion CMV infection.     

Stem cell transplantation for hemoglobinopathies

Hereditary anemias caused by beta-thalassemia and sickle cell disease are the most common genetic diseases worldwide. Supportive therapies such as chronic lifelong transfusions, iron chelation for thalassemia, and transfusions or hydroxyurea for sickle cell anemia have significantly ameliorated clinical manifestations of these diseases but cannot eliminate disease and treatment-related complications that result in end-organ damage. Allogeneic hematopoietic stem cell transplantation is the only cure for patients with hemoglobinopathies. Results of transplants have steadily improved over the last few decades due to effective control of transplant-related complications and development of new preparative regimens. Our understandings of mixed chimerism in patients with hemoglobinopathies provide a rationale for the use of less intensive conditioning regimens and gene therapy in these disorders. Although the role of stem cell transplantation for thalassemia major is well defined, few transplants have been carried out in sickle cell disease, and, in light of recent advances, the role of stem cell transplantation in this disease should be revised. This review summarizes the current status of stem cell transplantation for hemoglobinopathies.     

Dr. Alvin M. Mauer. Early studies in white cell kinetics

Certain serendipidous events shaped the professional career of Dr. Alvin Mauer and made it possible for him to complete research that exerted a powerful influence on our understanding of the kinetics of granulocytes and leukemia cells. The availability of the isotope, P32-tagged diisopropyl fluorophosphate (DFP32), was essential to the successful conduct of his early studies on granulocyte kinetics. Later the availability of tritium-labeled thymidine made it possible to label specific subpopulations of dividing leukemic cells and to precisely determine their proliferative characteristics and other biological features. The establishment of comprehensive centers for management of children with hemophilia was made possible by the discovery of the technique used in the preparation of cryoprecipitate. Comprehensive care of these children for the first time became feasible and cost-effective.