Indira Warrier

The spectrum of Evans’ syndrome

Eleven patients (10 boys, one girl) with Evans’ syndrome with a median follow up time of 8.0 years were evaluated retrospectively. Six patients had either persistent hepatosplenomegaly or generalised lymphadenopathy, or both. In five patients, an increase in lymph node and/or spleen size was observed during the exacerbations of cytopenias. Seven patients had quantitative serum immunoglobulin abnormalities at the time of presentation. There were associated systemic manifestations in nine patients. Various forms of treatment were used with mixed results. Four patients died from sepsis and haemorrhage; four had complete recovery—two after splenectomy. These findings show that Evans’ syndrome is a heterogeneous disorder with significant morbidity and mortality. High incidence of quantitative serum immunoglobulin abnormalities, lymphoid hyperplasia, and associated systemic manifestations suggest that Evans’ syndrome may represent a stage of a more broad spectrum, generalised immune dysregulation.

The overall effectiveness of prophylaxis in severe haemophilia

Summary.u2002 The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on‐demand treatment of haemophilic patients. Twenty‐five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4u2003years and at start of prophylaxis was 4.5u2003years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one–six) episodes of line sepsis. Haemophilia A patients received an average of 23.8u2003Uu2003kg−1 (20–30u2003Uu2003kg−1) of recombinant factor VIII three times a week while haemophilia B patients received 50u2003Uu2003kg−1 recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long‐term morbidity and a better quality of life despite increased central lines and higher factor usage.

Safety and Efficacy of Low-Dose Intravenous Immune Globulin (IVIG) Treatment for Infants and Children with Immune Thrombocytopenic Purpura

Purpose: This report presents pooled data from two multicenter studies conducted to assess the efficacy, safety, and tolerance of lower-dose intravenous immune globulin (IVIG) regimens of 250 mg/kg/day, 400 mg/kg/day, and 500 mg/kg/day for 2 days, compared to an established higher-dose regimen of 1 g/kg/day for 2 days, in children with immune thrombocytopenic purpura (ITP). Patients and Methods: A total of 24 children received IVIG (Gammar Sr I.V.). In Study 1, 10 centers enrolled 12 children between 5 and 12 years old who received IVIG at either 400 mg/kg/day or 1 g/kg/day for 2 days. In Study 2, five centers enrolled 12 infants and children younger than 5 years old who received IVIG at 250 mg/kg/day or 500 mg/kg/day for 2 days. Both studies were prospective and randomized. Results: IVIG treatment was effective (platelets increased at least 30,000/cu mm over baseline) in 94% (16 of 17) of the evaluable patients in the low-dosage group. Platelet increases occurred rapidly: by 48 hours, total platelet counts ranged from 32,000/cu mm to 256,000/cu mm, and peak platelet counts reached 38,000/cu mm to 551,000/cu mm. Adverse events (AEs) were most often mild, lasted less than 3 hours, and were usually those typically associated with immunoglobulin administration-headache, nausea, vomiting, and fever. There were two serious AEs—an anaphylactoid reaction in one patient in the 400 mg/kg group and aseptic meningitis in one patient in the 1 g/kg high-dosage group. Both patients recovered without sequelae and were responders. Although the incidence of AEs varied by dosage groups, this difference was not significant. However, the incidence of AEs was affected by age. AEs were significantly lower in patients younger than 5 years of age. Conclusions: In this small, randomized trial, low-dose IVIG in 2-day regimens of 250, 400, or 500 mg/kg/day rapidly reversed thrombocytopenia just as effectively as 1 g/kg/day in infants and young children with ITP. Lower-dosage regimens are safe and well-tolerated; the incidence of AEs is lower in children younger than 5 years of age.

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand’s disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety‐nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF‐containing FVIII product, type 3 patients with vWF‐containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Intravenous gamma globulin treatment for chronic idiopathic thrombocytopenic purpura in children

Six children, five to 16 years of age, with the chronic, autoimmune form of idiopathic thrombocytopenic purpura were given intravenous gamma globulin (Gamimune, Cutter Biological, Berkeley, California) in a dose of 400 mg/kg per day for five consecutive days as six-hour infusions. Two of the six children had undergone splenectomy but the other four had not. Three of six children had a good or excellent response to the first five-day course of intravenous gamma globulin. The peak platelet count occurred within 12 days of the start of therapy in all. All three have required booster doses of intravenous gamma globulin to maintain platelet counts at a safe level. All children had marked increases in serum IgG following intravenous gamma globulin, except one who had undergone splenectomy and who had chronic idiopathic thrombocytopenic purpura with high baseline levels of immunoglobulin G (IgG). The significance of the observed increase in platelet-associated IgG during treatment is not clear. No untoward reactions necessitating cessation of therapy were encountered during this study. Our short-term observations in six children with chronic idiopathic thrombocytopenic purpura indicate that high-dose intravenous gamma globulin is an effective form of treatment for certain children with this condition.

Sirolimus rescue for tacrolimus-associated post-transplant autoimmune hemolytic anemia.

Abstract: Autoimmune hemolytic anemia (AIHA) has been reported to occur after renal transplantation, and typically does so in the first few weeks post‐transplant. We report on a 3‐yr‐old child who developed cold AIHA nearly 1 yr after an ABO identical, living donor renal transplant from his mother. Numerous transfusions, pulse steroids, repeat plasma exchange treatments, and IVIG were unsuccessful. Nearly 3 wk into his illness, tacrolimus was changed to cyclosporine, and then to sirolimus, and resulted in a prompt response. He currently has a normal renal function and a normal hemoglobin level on sirolimus monotherapy.

Use of intravenous gamma globulin in children and adolescents with idiopathic thrombocytopenic purpura and other immune thrombocytopenias

Approximately 85 to 90 percent of cases of idiopathic thrombocytopenic purpura (ITP) in children are of the acute, self-limited variety that generally occurs after a viral infection. The remaining 10 to 15 percent of children with this disorder have the chronic (autoimmune) type of ITP. For these patients, splenectomy is often the recommended treatment if severe bleeding occurs and platelet counts remain below 40,000/mm3. However, splenectomy has associated risks and the response to this surgery cannot always be predicted. Intravenous gamma globulin (IVIG) has proven useful as an alternative to splenectomy, especially in children who are considered too young for splenectomy or in those in whom there is no response to splenectomy. It should be noted that booster shots are frequently required and the patients ITP may become refractory. IVIG may also be useful in preparing a child with ITP for splenectomy and in treating children or adolescents with ITP who have central nervous system or other serious hemorrhages. Although IVIG is not always effective in raising the platelet count, it does provide a very useful alternative method of treating this disorder.

Evidence for a shift from a type I lymphocyte pattern with HIV disease progression

Whether a shift from a type I (cell mediated) immune profile occurs with progressive HIV-related immune dysfunction is a matter of heated debate. We analyzed data for 333 HIV antibody-positive (HIV+) and -negative (HIV-) hemophilic children/adolescents, to examine whether the relationships among immunologic parameters and vaccine-related serology supported a shift with advancing HIV infection. In stepwise logistic regression analysis of HIV+ childrens data, anergy to a panel of delayed hypersensitivity skin test antigens was positively associated with serum immunoglobulin A (IgA) levels (p = 0.012) and CD8+ cell counts (p = 0.021) and negatively associated with CD4+ cell counts (p = 0.002). Modeling supported anergy as a positive correlate of log IgA level (p = 0.046) and CD4+ lymphocyte count as a negative correlate, for HIV+ participants only (p < 0.0001). For mumps, the proportion of vaccinated HIV+ participants with protective IgG antibody titers was higher among those with CD4+ lymphocyte counts < 200 cells/mm3 (p = 0.058). For HIV+ participants < 14 years of age, this same trend was seen for measles and rubella, but was not seen in any age group for bacterial vaccine antigens. The intercorrelations among skin test anergy, CD4+ lymphocyte counts, serum IgA levels, and viral vaccine antigen-related serologic titers for HIV+ participants are consistent with an association between progressive HIV-related immune dysfunction and a predominance of type II (humoral immunity) or Type 0 (mixed immunity), relative to type I, lymphocyte profiles.

Retrovir therapy in hemophilic children with symptomatic human immunodeficiency virus infection: efficacy and toxicity.

In desperation, we have used retrovir in five hemophilic children (10–16 years old) over the past 22 months. All had presented with various clinical manifestations of acquired-immune-deficiency-syndrome (AIDS)-related complex or AIDS. Our decision to treat with retrovir was based on clinical manifestations and very low numbers of CD4 cells (<200). The most common clinical presentation was recurrent oral moniliasis. Other significant findings included recurrent herpes zoster, thrombocytopenia, growth failure, and biliary tract infection. Initially, all five children received the full adult dosage of retrovir (200 mg q 4 h x 6 doses/day). This dosage had to be reduced in four children because of toxicity. The most commonly observed toxic side effects were anemia and neutropenia. Alanine aminotransferase (ALT) levels rose to 4–10 times the upper limit of normal in four of five children. One was on concomitant ketokonazole prior to the rise in ALT level. Myalgia and headache were reported by two patients. Improvement in clinical and immunological status was observed in all children initially. After 12–18 months of retrovir therapy, infectious complications secondary to prolonged neutropenia were seen in these immunocom-promized children. However, compared to historic controls, these children have had fairly stable disease. We feel that all hemophilic children with symptomatic human immunodeficiency virus infection should be offered this drug, even though the optimal dosage for children is not yet established.

818 SIGNIFICANCE OF ELEVATED B2 MICROGLOBULIN (B2m) IN THE CEREBROSPINAL FLUID (CSF) OF CHILDREN WITH ACUTE LEUKEMIA (AL)

Recent reports have indicated that elevated CSF levels of B2m in AL patients may precede the cytologic diagnosis of central nervous system (CNS) involvement. This prompted us to reevaluate the CSF B2m levels obtained on 42 AL patients at CHM during the years 1974-1975. All but 3 had acute lymphoblastic leukemia (ALL) 36 ALL children were receiving CNS prophylaxis consisting of intrathecal (IT) Methotrexate (MTX) and fractional radiation to the CNS (IMFRA) given at 10 wks. intervals. CSF was obtained at the time of administration of IT MTX either for prophylaxis or for overt CNS relapse. The level of B2m in the CNS prophylaxis group (36) varied from 0.4 to 3.65 mg/I (x 1.55 mg ± .79). 4 had elevated levels of B2m (>3 mg/l,x +2SD) at a time when CSF was free of leukemic cells. Three eventually developed CNS leukemia 2 mos., 8 mos., and 4 yrs. later. The CSF B2m level at the time of overt CNS relapse in 6 AL children varied from 0.93 - 5 mg/1 (x 3.18 ± 1.78). This differed significantly (p: <.001) from the CNS prophylaxis group. B2m level was > 3 mg/1 in 5/6. These data confirm the prior observations of others that CSF B2m levels are elevated during CNS relapse. Thus elevated levels may indicate impending relapse. Prophylactic IT MTX in itself does not appear to significantly alter the normal CSF B2m levels.