Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM(197) among infants with sickle cell disease. Pneumococcal Conjugate Vaccine Study Group.

OBJECTIVES: To determine the immunogenicity and safety of heptavalent pneumococcal polysaccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) conjugated to CRM(197) (7-valent conjugate pneumococcal vaccine [7VPnC]) among infants with sickle cell disease (SCD) and a comparison group of infants without SCD (non-SCD). DESIGN: Two cohorts of infants were enrolled and received open-label doses of 7VPnC vaccine; infants enrolled before 2 months of age received 7VPnC vaccine at 2, 4, and 6 months of age followed by 23-valent pneumococcal polysaccharide vaccine (PS-23) at 24 months of age for those infants with SCD (schedule A), and infants enrolled between 2 and 12 months of age received 7VPnC at 12 months of age followed by PS-23 at 24 months of age for infants with SCD (schedule B). Safety data were collected for 3 days after each dose of vaccine. Antibody concentrations were measured to each of the 7VPnC serotypes by enzyme-linked immunosorbent assay before each vaccine dose and 1 month after the last 7VPnC dose and the PS-23 vaccine dose. RESULTS: Forty-five infants (34 SCD and 11 non-SCD) were vaccinated according to schedule A and 16 infants (13 SCD and 3 non-SCD) according to schedule B. The 7VPnC vaccine was highly immunogenic for all serotypes among infants with and without SCD who received 3 doses of vaccine according to schedule A: depending on serotype, 89% to 100% achieved antibody concentrations above.15 microg/mL and 56% to 100% achieved antibody concentrations above 1.0 microg/mL. Among infants immunized according to schedule B, a single dose of 7VPnC vaccine resulted in antibody concentrations above.15 microg/mL in 53% to 92% by serotype and above 1.0 microg/mL in 31% to 71% by serotype. A single dose of PS-23 resulted in dramatic increases in the antibody concentrations to all serotypes regardless of 1- or 3-dose priming. There was no difference in the reactogenicity of the 7VPnC vaccine between those with and without SCD. There were no serious reactions to the 7VPnC or PS-23 vaccines, even among those with high antibody concentrations before immunization. CONCLUSIONS: Infants with SCD respond to 7VPnC vaccine with antibody concentrations that are at least as high as infants without SCD. Infants immunized with 7VPnC vaccine at 2, 4, and 6 months of age developed antibody concentrations in the same range as those achieved among infants without SCD enrolled in a large trial that demonstrated vaccine efficacy against invasive disease. Significant rises were seen in antibody concentrations to all 7VPnC serotypes after the PS-23 booster in children receiving schedule A or B.

Prospective evaluation of propofol anesthesia in the pediatric intensive care unit for elective oncology procedures in ambulatory and hospitalized children.

OBJECTIVES: To evaluate our experience with propofol anesthesia delivered by pediatric intensivists in the pediatric intensive care unit (PICU) to facilitate elective oncology procedures in children performed by pediatric oncologists. METHODS: Elective oncology procedures performed with propofol anesthesia in our multidisciplinary, university-affiliated PICU were prospectively evaluated over a 7-month period. Ambulatory and hospitalized children were prescheduled for their procedure, underwent a medical evaluation, and met fasting requirements before the start of anesthesia. Continuous cardiorespiratory and neurologic monitoring was performed by a pediatric intensivist and a PICU nurse, while the procedure was performed by a pediatric oncologist. Propofol was delivered in intermittent boluses to achieve the desired level of anesthesia. Information studied included patient demographics, procedures performed, induction and total doses of propofol used, the duration of the different phases of the patient's PICU stay, the occurrence of side effects, the need for therapeutic interventions, and the incidence of recall of the procedure. RESULTS: Fifty procedures in 28 children (mean age: 7.5 +/- 4.3 years) were evaluated. Sixty-one percent of patients had established diagnoses. Fifty-four percent of procedures were lumbar puncture with intrathecal chemotherapy administration and 26% of procedures were bone marrow aspirations with biopsy. Induction propofol doses were 2. 0 +/-.8 mg/kg for ambulatory and hospitalized patients, while total propofol doses were 6.6 +/- 2.3 mg/kg and 7.9 +/- 2.4 mg/kg for ambulatory and hospitalized patients, respectively. Induction time was 1.5 +/-.7 minutes, recovery time was 23.4 +/- 11.5 minutes, and total PICU time was 88.8 +/- 27.7 minutes. Transient decreases in systolic blood pressure less than the fifth percentile for age occurred in 64% of procedures, with a mean decrease of 25% +/- 10%. Intravenous fluids were administered in 31% of these cases. Hypotension was more common in ambulatory patients but was not predicted by propofol dose, anesthesia time, or age. Partial airway obstruction was noted in 12% of procedures while apnea requiring bag-valve-mask ventilation occurred in 2% of procedures. Neither was associated with age, propofol dose, or the duration of anesthesia. All procedures were successfully completed and there were no incidences of recall of the procedure. CONCLUSIONS: Propofol anesthesia is effective in achieving patient comfort and amnesia, while optimizing conditions for elective oncology procedures in children. Although transient hypotension and respiratory depression may occur, propofol anesthesia seems to be safe to use for these procedures in the PICU setting. Recovery from anesthesia was rapid and total stay was brief. Under the proper conditions, propofol anesthesia delivered by pediatric intensivists in the PICU is a reasonable option available to facilitate invasive oncology procedures in children.

Posttherapy surveillance of B-cell precursor acute lymphoblastic leukemia. Value of polymerase chain reaction and limitations of flow cytometry.

Flow cytometric immunophenotypic analysis is critical in diagnosis and classification of acute leukemia and has been used after therapy to monitor for minimal residual disease. However, the presence of normal B-cell precursors, hematogones, particularly in the context of treated pediatric B-cell precursor acute lymphoblastic leukemia (BP-ALL), may confound such evaluation. In this study, the value of more specific genotypic markers (polymerase chain reaction evaluation of 2 antigen receptor genes) was assessed to resolve this issue. Flow cytometric analysis of enriched mononuclear cells revealed 1% to 20% precursor B cells (PBCs), based on expression of 1 or more pan-B cell antigens in addition to CD10, CD34, and terminal deoxynucleotidyl transferase in all 14 patients studied. Inasmuch as this mimicked the immunophenotype of the original leukemic clone, PBCs, in isolation, were considered suspicious for minimal residual disease. However, 11 of the 14 posttherapy specimens (79%) revealed no monoclonally rearranged antigen receptor genes, and 7 of these 11 patients had trackable genotypic markers at presentation. Accordingly, by PCR these 7 patients had complete molecular remission, supported by clinical follow up of 16 to 73 months. Among the remaining 4 patients with PCR-negative disease, 3 continue in remission, confirming the interpretation of false-positive flow cytometric analysis. In conclusion, flow cytometric monitoring of posttherapy bone marrow specimens from patients with BP-ALL may be misleading, if considered in isolation, in falsely suggesting the presence of minimal residual disease. Rather, PCR for antigen receptor gene rearrangements is a valuable and specific tool, helpful in differentiating hematogones from minimal residual disease in patients with treated BP-ALL whose bone marrow harbors increased PBCs.

Successful prevention of post-transfusion Rh alloimmunization by intravenous Rho (D) immune globulin (WinRho SD).

Alloimmunization to the D blood group antigen following the transfusion of D-positive red blood cells to a D-negative recipient may be prevented in most persons by a prompt and adequate dose of Rho (D) immune globulin (RhIG). Until recently, the only RhIG approved by the US Food and Drug Administration (FDA) for this indication required intramuscular injection, an inconvenient and painful route for the relatively large volume that may be required. We describe the successful prevention of Rh alloimmunization following the unintentional transfusion of D-positive red blood cells to a D-negative infant by the intravenous infusion of WinRho SD, a new RhIG that is FDA-approved for prevention of post-transfusion Rh alloimmunization by intravenous administration. We believe that this more convenient and less painful approach should be the treatment of choice for preventing Rh alloimmunization following the transfusion of D-positive red cells to a D-negative recipient.

Factor concentrates for the treatment of factor XIII deficiency.

Factor XIII deficiency is a severe autosomal recessive bleeding disorder associated with a characteristic pattern of neonatal hemorrhage and a lifelong bleeding diathesis. Even relatively minor trauma can be followed by prolonged and recurrent bleeding. Intracranial hemorrhage is a frequent complication. With the development of safe and effective factor XIII concentrates, reliable prophylactic treatment is possible. Two plasma-derived, virus-inactivated factor XIII concentrates are currently in production. The first, Fibrogammin P, (Centeon LLC, King of Prussia, PA, USA; and Centeon Pharma GmbH, Marburg, Germany) is marketed in Europe, South America, South Africa, and Japan. It is distributed in the United States under a Food and Drug Administration Investigational New Drug Application. A second factor XIII concentrate (Bio Products Laboratory, Elstree, UK) is available for use only on a "named patient" compassionate basis in the United Kingdom. Patients with factor XIII deficiency who receive appropriately timed periodic infusions of such factor XIII concentrates are able to live normal lives, free from catastrophic bleeding episodes.

Lack of graft rejection in a renal transplant recipient with AIDS.

A renal transplant recipient developed evidence of human immunodeficiency virus (HIV) infection and severe opportunistic infection 44 months after transplantation. A strikingly reduced dosage of pharmacologic immunosuppression was required to maintain renal graft function. This may be the result of impaired helper T-cell function associated with the acquired immunodeficiency syndrome (AIDS).

Beta-endorphin's modulation of lymphocyte proliferation is dose, donor, and time dependent.

We find that beta-endorphin (Bend) can have, positive, negative, or neutral dose-dependent effects on the mitogen-stimulated proliferation of human peripheral blood lymphocytes. The distribution of positive, negative, or neutral responses was nonrandom. In studies carried out over a year, we show that an individual's mitogen-stimulated lymphocyte proliferative response to Bend can change with time. We show that the inhibition induced by cortisol can be, in part, relieved by Bend. On the basis of our results and those of others in the field, we put forward a model that can qualitatively account for many of the observations we and other investigators have made.

Early onset acute orbital involvement in childhood acute lymphoblastic leukemia.

A 5-year-old girl with acute lymphoblastic leukemia undergoing induction chemotherapy experienced acute proptosis while agranulocytotic and febrile. Orbital biopsy showed leukemic infiltration, and complete resolution was achieved with local irradiation and chemotherapy. Early onset orbital involvement is highly unusual in acute lymphoblastic leukemia. In the setting of agranulocytosis and fever, rapidly enlarging intraorbital masses require urgent ophthalmologic attention. Immediate biopsy is indicated to distinguish between several treatable conditions including opportunistic infection, hemorrhage, and neoplastic infiltration.

Intracranial hemorrhage in congenital deficiency of factor XIII.

We describe a male infant with congenital deficiency of coagulation Factor XIII who presented in the immediate postnatal period with umbilical stump bleeding and suffered a severe intracranial hemorrhage at 2 months of age. Factor XIII, also known as "fibrin-stabilizing factor," is a transpeptidase that produces strong covalent bonds between soluble fibrin monomers formed during coagulation. Presumptive diagnosis of Factor XIII deficiency was made with a clot solubility screening test, and confirmation was accomplished by demonstrating the absence of cross-linked fibrin chains by electrophoresis. This patient had received replacement therapy for 2 years, initially with intravenous fresh frozen plasma, and recently with Fibrogammin (Hoechst-Roussel Pharmaceuticals), a European Factor XIII concentrate soon to be available in the United States. Factor XIII deficiency is associated with a high incidence of life-threatening complications, notably intracranial hemorrhage. In light of the long half-life of this factor and the relatively low risk associated with new Factor XIII concentrates, such as Fibrogammin, prophylactic life-long replacement therapy should be considered for patients with severe Factor XIII deficiency.

Thymic atrophy and regrowth in response to chemotherapy: CT evaluation.

Twenty-nine consecutive patients 2-35 years old underwent serial thoracic CT evaluations for metastatic disease. Thymic volumes were determined for each patient during cycles of chemotherapy and were compared with the patient's clinical status. This group included patients with Hodgkin's disease (13 patients), osteogenic sarcoma (five), testicular neoplasm (four), Wilms' tumor (three), rhabdomyosarcoma (two), malignant fibrous histiocytoma (one), and Ewing's sarcoma (one). Seven patients with mediastinal lymphoma had tumor involvement of the thymus and therefore were excluded. The 22 remaining patients showed cyclic thymic volume changes in response to chemotherapy or its discontinuance. During the first course of chemotherapy the thymic volume decreased by an average of 43% in 20 of 22 patients. Between the first and second course, regrowth was observed in all 20 of these patients. Among the six patients who received a second course of therapy, an average volume decrease of 36% was observed during the second course with regrowth again occurring during recovery from chemotherapy. Thymic rebound (regrowth 50% greater than baseline volume) occurred in five patients, three of whom were in clinical remission. The thymus appears to atrophy during the administration of chemotherapy and regrow during the recovery phase of chemotherapy in 90% of the patients studied. Thymic hyperplasia or rebound is a relatively common phenomenon occurring in 25% of patients. The size of the thymus appears to be extremely sensitive to chemotherapy.

Rapid diagnosis of neutropenic enterocolitis (typhlitis) by ultrasonography.

Neutropenic enterocolitis (also termed typhlitis) is an acute necrotizing process involving segments of the large and small intestine that occurs in the setting of agranulocytosis, most commonly in patients with acute leukemia. Rapid diagnosis and treatment is necessary for survival. We present a patient in whom abdominal ultrasonography revealed evidence of bowel wall thickening and ascites, confirming the diagnosis of neutropenic enterocolitis. Sonography offers a rapid, safe, and noninvasive means of diagnosis for this condition.

Hepatocellular carcinoma in an 11-year-old girl with Fanconi's anemia. Report of a case and review of the literature.

An 11-year-old girl with Fanconi's anemia, who died of Corynebacterium septicemia, was found at autopsy to have a solitary, previously undiagnosed hepatocellular carcinoma (HCC). Although the association between Fanconi's anemia and malignancies such as leukemia and squamous cell carcinoma is well documented, its relationship to HCC remains controversial and obscure. Anabolic steroid therapy for Fanconi's anemia has also been considered a promoter for hepatocellular neoplasms. This report documents the youngest known patient with Fanconi's anemia to develop HCC and discusses the association between these conditions.

A biochemical variant of human T cell growth factor produced by a cutaneous T cell lymphoma cell line.

Three cell lines of mature T cell origin established from patients with cutaneous T cell lymphoma-leukemia (CTCL) have been found to be constitutive producers of TCGF (L-TCGF). Biologically active L-TCGF can also be eluted from the plasma membranes of these cells. We have compared the biologic and biochemical properties of L-TCGF and TCGF derived from normal lymphocytes (N-TCGF). L-TCGF and N-TCGF share similar biologic activity: both support long-term growth of T cells that have undergone prior lectin or antigen stimulation, and have no effect on unstimulated T cells. However, L-TCGF is a more acidic (pI 4.5 vs 6.5 to 8.0) molecule than N-TCGF and elutes from DEAE-Sepharose at higher salt concentration (0.2 M NaCl vs 0.07 to 0.1 M NaCl). In addition, these two factors display differing mobilities on gel filtration. Treatment of L-TCGF with neuraminidase or alkaline phosphatase does not alter its pI, indicating that enzymatically vulnerable sialic acid or phosphate groups are not involved in the variation. The nature and significance of this biochemical variant remain unknown.

Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor.

Three cell lines of mature T cell origin derived from patients with cutaneous T cell lymphoma-leukemias (CTCL) were found to be constitutive producers of T cell growth factor (L-TCGF). These are the first reported human cell lines which constitutively produce TCGF. Biologically active TCGF could also be eluted from the surface of these cells using an acid glycine buffer under conditions that maintained cell viability, and subcellular fractionation showed that almost all the TCGF activity was associated with the plasma membrane. Over 30 other human hematopoietic cell lines derived from other disorders were unable to produce TCGF even after induction, and their acid eluates did not contain TCGF activity. L-TCGF from CTCL lines had the same biological activity as TCGF obtained from normal leukocytes (N-TCGF) in that they both supported the long-term growth of normal T cells only after the cells were previously activated by antigen or lectin. Both L-TCGF and N-TCGF increased the rate of proliferation of TCGF-independent and TCGF-dependent CTCL cell lines. The same three factor-independent cell lines that released TCGF adsorbed TCGF in a cell-concentration, time-, and temperature-dependent manner. Since the CTCL cell lines produce TCGF, adsorb TCGF, and increase their proliferative rate in response to TCGF or a related molecule, it is suggested that this endogenously produced factor plays a role in maintaining the abnormal proliferation of these cells in culture as permanently growing cell lines independent of exogenous TCGF. However, this does not mean that this is an essential aspect of neoplastic transformation. Since it is unusual to develop these cell lines in the absence of the continuous need for added TCGF, "autostimulation" may be one of the many unusual variant phenotypic properties sometimes associated with neoplastic cells that gives them a selective advantage for in vitro growth.