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Background Hemolysis following the administration of intravenous immunoglobulin (IVIG) is an important adverse event (AE). While the monocyte monolayer assay (MMA) has been used to predict in vivo hemolysis when serologically incompatible blood may be transfused, it has also been shown to correlate with IVIG-associated hemolysis. In this study, the MMA was examined for its utility in assessing the risk of hemolysis after IVIG. Study design and methods Forty-two non-blood group O patients receiving high-dose IVIG (≥2 g/kg) were examined using an autologous and allogeneic MMA. Hemolysis was defined by a drop in hemoglobin of ≥1 g/L, a positive direct antiglobulin test (DAT) and eluate, and a decrease in haptoglobin or increase in lactate dehydrogenase and/or reticulocytes. Results Forty-two patients provided 50 assessable postinfusion samples, with hemolysis observed in 20 (40%) of cases. Autologous MMA using post-IVIG red blood cells significantly correlated with clinical outcomes when compared to allogeneic MMA (P = .0320 vs .5806, t test). No significant difference in receiver operating characteristics was observed when comparing autologous MMA testing against DAT for the diagnosis of IVIG-associated hemolysis. However, when using samples collected 5 to 10 days after receipt of high-dose IVIG, the autologous MMA had higher sensitivity than the DAT. Conclusion MMA testing with autologous monocytes collected 5 to 10 days after receipt of high-dose IVIG can be used for the diagnosis of IVIG-associated hemolysis and may be of particular value in cases in which the Day 5 to 10 DAT is negative.

Background Intravenous Immune Globulin (IVIG) is used to treat numerous immune-mediated and inflammatory conditions. There is growing awareness of hemolysis, occasionally severe, as a side-effect of this therapy. While most cases are associated with anti-A and/or anti-B isoagglutinins, the frequency and mechanism of hemolysis remain poorly characterized. Study design and methods A prospective observational study was conducted to determine incidence, natural history and risk factors for IVIG-mediated hemolysis. A total of 99 infusions of high-dose IVIG (2 g/kg or higher) administered to 78 non-group O patients were monitored and graded according to Canadian IVIG Hemolysis Pharmacovigilance Group. Serum ferritin and C3/C4 levels were monitored as indicators of macrophage activation and complement consumption, respectively. Supplementary investigations included assessment for ABO zygosity, Secretor status, FcR polymorphisms, eluate IgG subclass, monocyte monolayer assay, and a panel of cytokines. Results Hemolysis was observed in 32 of 99 (32%) of infusions, with 19 of 99 (19%) grade 2 or higher. Hemolysis was only apparent 5-10 days after a completed IVIG infusion in 84% of cases and was associated with increases in serum ferritin without complement-consumption. In univariate analysis, increased risk was observed in group AB patients, first-time IVIG recipients, those not taking immuosuppressive medications, or patients treated with a specific IVIG brand; however, in multivariate analysis, product association was no longer observed. No other patient- or practice-related risk factors were identified. Conclusion IVIG-mediated hemolysis is common and frequently severe. Monitoring for 5-10 days following an infusion should be considered in non-O patients receiving high-dose IVIG with known risk factors.

TO THE EDITOR: Although frequently effective[1][1],[2][2] and usually benign, high-dose (2 g/kg) intravenous immunoglobulin (IVIG) therapy can result in marked red blood cell (RBC) hemolysis, which in some cases is life threatening in severity.[3][3][⇓][4]-[5][5] The mechanism by which this

Aim To quantify circulating fibroblast activation protein (cFAP) and dipeptidyl peptidase 4 (cDPP4) protease activities in patients with rheumatoid arthritis (RA), systemic sclerosis (SSc), and a control group with mechanical back pain and to correlate plasma levels with disease characteristics. Methods Plasma was collected from patients with RA (n = 73), SSc (n = 37) and control subjects (n = 26). DPP4 and FAP were quantified using specific enzyme activity assays. Results Median cDPP4 was significantly lower in the RA group (P = 0.02), and SSc group (P = 0.002) compared with controls. There were no significant differences in median cFAP between the three groups. DPP4 and FAP demonstrated a negative correlation with inflammatory markers and duration of disease. There were no associations with disease subtypes in RA, including seropositive and erosive disease. Decreased cDPP4 was found in SSc patients with myositis. Plasma FAP was lower in RA patients receiving prednisone (P = 0.001) or leflunomide (P = 0.04), but higher with biologic agents (P = 0.01). RA patients receiving leflunomide also had decreased cDPP4 (P = 0.014). SSc patients receiving prednisone (P = 0.02) had lower cDPP4 but there was no association with cFAP. Conclusions No association was found between cFAP and RA or SSc. Plasma DPP4 was decreased in RA and SSc when compared with controls. cDPP4 and cFAP correlated negatively with inflammatory markers and there were no significant correlations with disease characteristics in this RA cohort.

Hyperleukocytosis in children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) is associated with early morbidity and mortality. The benefit from leukapheresis is controversial, and its complications are not well defined. We analyzed the frequency of early complications in children with ALL and AML presenting with white blood cell (WBC) count >100 × 10(9)/L, and the type and frequency of complications related to leukapheresis. During a 12-year period, 84 of 634 (13%) ALL and 18 of 143 (12.5%) AML patients presented with hyperleukocytosis. Leukapheresis was performed in 18 ALL and 12 AML patients. The median initial WBC was 474 × 10(9)/L in the leukapheresis group compared with 175 × 10(9)/L in the nonleukapheresis group. Neurological leukostasis occurred in 6 ALL (7.1%) and 4 AML (22.2%) patients. Pulmonary leukostasis occurred in 16 ALL (19%) and 4 AML patients (22.2%). Neurological symptoms improved in few patients after leukapheresis, except in patients with very high WBC (>650 × 10(9)/L in ALL and >400 × 10(9)/L in AML). Leukapheresis improved respiratory symptoms in some patients but caused worsening symptoms in others. Early death was associated with neurological complications, AML diagnosis, and coagulopathy. Leukapheresis did not delay initiation of chemotherapy, nor did it impact early response to chemotherapy or long-term survival. Complications included femoral vein thrombosis, electrolyte imbalances, and hemodynamic instability, which were all reversible. The role of leukapheresis as a cytoreductive procedure in childhood hyperleukocytic leukemia remains to be well defined.

Background: The aim of the present paper was to determine whether monthly i.v. immunoglobulin (IVIG) could be safely discontinued in antiretroviral-treated human immunodeficiency virus (HIV)-infected children. Methods: In a double-blind cross-over trial, children ≤18 years with HIV infection, well controlled on antiretroviral therapy, were randomized to alternating courses of 3 consecutive months of IVIG (400 mg/kg once a month) and 3 consecutive months of placebo for 1 year. The primary outcome was days of fever per month. Secondary outcomes were frequency of serious infections, changes in HIV viral load (VL), CD4+ counts and IgG levels. Results: Fifteen children were enrolled. Using the revised pediatric HIV clinical classification system of the Centers for Disease Control and Prevention, eight were severely symptomatic (C), four were moderately symptomatic (B) and three were mildly symptomatic (A). There were no statistically significant outcome measures. The mean number of days of fever per month with IVIG versus placebo was 0.55 days versus 1.48 days (P = 0.11). The difference was 0.9 days (95% confidence interval: +2.05 to −0.25). There were no serious infections in either period. For the IVIG versus placebo periods, mean CD4 counts were 970 cells/μL versus 906 cells/μL (P = 0.12), VL 2.90 log10 copies/mL versus 2.82 log10 copies/mL (P = 0.70) and IgG levels were 17.41 g/L versus 16.6 g/L (P = 0.13). Conclusion: In antiretroviral-treated HIV-infected children short-term withdrawal of monthly IVIG was not associated with a significant increase in incidence of infections or a decline in immunologic function (CD4 count, viral load and IgG levels). These results suggest that monthly IVIG can be safely discontinued in HIV-infected children who are clinically stable and receiving combination antiretroviral therapy.

Summary. Seventy percent of children with acute lymphoblastic leukaemia (ALL) who may benefit from bone marrow transplant (BMT) lack a human leucocyte antigen (HLA)-matched related donor (MRD). For these children, BMT from a matched unrelated donor (MUD) represents a therapeutic option. We reviewed the course of 62 children with ALL who received fully matched marrow allografts at our institution between 1990 and 1998: 36 with MRDs and 26 with MUDs. Clinical characteristics were similar in the two groups. The interval from attainment of pre-BMT complete remission to transplant was significantly longer in the MUD group. Conditioning (etoposide/total body irradiation) and graft-versus-host disease (GVHD) prophylaxis regimens were the same for all patients, and all received T cell-replete bone marrow. There was no significant difference in probability of engraftment, or time to engraftment, in the two groups. MUD BMT recipients had a significantly greater incidence of grade II–IV acute GVHD (58% versus 24% in the MRD group; P= 0·02), and demonstrated a trend towards more chronic GVHD (39% versus 15%; P= 0·06). Three years post BMT, the probabilities of transplant-related mortality were 33 ± 11% and 20 ± 8% in MUD and MRD groups respectively (P = 0·38); the probabilities of relapse were 28 ± 12% and 41 ± 9% respectively (P = 0·19). Lansky or Karnofsky performance scores in event-free survivors were 90–100 in 87% of the MUD group and 83% of the MRD group. With a median follow up of 38 months (range, 3–97), 3-year event-free survival was 49 ± 11% and 47 ± 9% in the MUD and MRD BMT groups respectively (P = 0·71). These results suggest that MUD BMT is a valuable therapy for children with ALL in whom BMT is indicated, and underscore the importance of efforts aimed at expediting unrelated donor searches for patients lacking a MRD.

When selecting an antiarrhythmic agent the clinician needs to be able to accurately predict the probability that a particular drug will serve its intended purpose in a given patient. This is difficult because of the complexity of variables which govern the relationship between drug administration and clinical outcome. The efficacy of a drug may potentially be predicted from its mechanism of action. At least two classifications of antiarrhythmic agents based on mechanism of action have been proposed. The Vaughan Williams classification is based on the predominant electrophysiological effects of a drug on the action potential. In the Sicilian Gambit approach, a number of potential targets ('vulnerable parameters') for drug action are identified and antiarrhythmic drugs or substances that affect cardiac electrophysiology are characterised by their actions on each of these. The usefulness of these classification systems in predicting antiarrhythmic drug efficacy are limited. Furthermore, in the Vaughan Williams classification not all drugs in the same class have identical effects, whereas some drugs in different classes have overlapping actions. The Sicilian Gambit requires in-depth knowledge regarding cellular and molecular targets of antiarrhythmic agents which may make it intimidating or simply impractical for regular clinical use. Surrogate measures such as 24-hour Holter monitoring and programmed electrical stimulation have been used to predict anti-arrhythmic drug efficacy. However, studies such the Cardiac Arrhythmia Suppression Trial (CAST) have shown that suppression of ventricular ectopy on Holter monitoring does not necessarily correlate with improved survival and may in fact be dangerous. Conversely, studies using programmed electrical stimulation to assess drug effect on variables such as tachycardia inducibility, refractory period and ventricular tachycardia cycle length show that suppression of tachycardia inducibility, prolongation of refractory period and prolongation of ventricular tachycardia cycle length, are all associated with reduced recurrence of tachycardia and possibly improved survival. The most practical use of the current classification systems applied to antiarrhythmic agents may be in their ability to predict with reasonable accuracy, the risk and type of proarrhythmia based on the mechanism of action of an agent.

Programmed upper rate pacing occurred in a patient with a rate-adaptive pacemaker when he was connected to a cardiac monitor in an emergency department. The tachycardia was mistakenly interpreted to be ventricular tachycardia and the patient received multiple DC shocks as well as intravenous amiodarone and sotalol, resulting in severe hemodynamic deterioration. It is important that physicians working in the hospital environment be familiar with this pacemaker-monitor interaction as the problem may be easily rectified by disconnecting the monitor or by reprogramming the pacemaker to a nonrate-adaptive pacing mode.

Graft acceptance following pediatric ABO-incompatible heart transplantation has been associated with a deficiency of donor-specific isohemagglutinins (DSI) due to B-cell elimination. Recent observations suggest that some of these patients do produce DSI. The purpose of this study was to examine the pattern of, risk factors for development and clinical impact of DSI. All children who underwent an ABO-incompatible heart transplant (1996–2009) were included. Serial postheart transplantation DSI titers and clinical outcomes were reviewed. DSI were produced in 27% of the patients (n = 11/41). Anti-A production was significantly greater in “at risk” patients than Anti-B (39% vs. 8%; p = 0.04). Risk factors associated with the development of DSI included: older age at transplantation (HR: 1.15/month, p = 0.04), pretransplant Anti-B level ≥ 1:8 (HR: 9.61, p = 0.004) and HLA sensitization (HR: 2.80, p = 0.11). The presence of DSI did increase the risk of cellular rejection but not antibody-mediated rejection, allograft vasculopathy, graft loss or death. Although these antibodies do not result in any significant clinical consequences, their presence suggests that B-cell tolerance is not the sole mechanism of graft acceptance.

Midazolam and fentanyl together produce better sedation, analgesia and amnesia than do either drug alone, but the electrophysiologic effects of the combination are unknown. Twenty patients undergoing electrophysiologic studies for clinical reasons were studied. Blood pressure, heart rate, respiratory rate, oxygen saturation, and standard variables related to atrioventricular and ventriculoatrial conduction, dual pathways, accessory pathway conduction, sinus node function, and the inducibility of tachycardia were examined before and after intravenous injections of midazolam (0.07 +/- 0.03 mg/kg) combined with fentanyl (0.8 +/- 0.4 micrograms/kg). There were no significant changes in the electrophysiologic variables or ease of inducibility of tachycardia. The drugs were well tolerated; they produced minor and clinically unimportant reductions in mean blood pressure (99 +/- 13 to 89 +/- 16 mm Hg; p < 0.001) and respiratory rate (18 +/- 4 to 16 +/- 3 breaths/min; p = 0.05). Excellent sedation was achieved. Major amnesia was reported by 95% of patients. In conclusion, midazolam combined with fentanyl provides safe and effective sedation for electrophysiologic studies without significantly affecting electrophysiologic variables or the inducibility of tachyarrhythmias.

OBJECTIVE. Anecdotal reports have suggested differences in children's tolerance to different intravenous immunoglobulin products; however, there has been little research on this issue. We sought to determine whether different intravenous immunoglobulin products used in the treatment of juvenile dermatomyositis are equally well tolerated by patients and, if not, whether differences in tolerance are linked to immunoglobulin A content. PATIENTS AND METHODS. The intravenous immunoglobulin infusion history (product given and history of adverse events) of patients who were attending the juvenile dermatomyositis clinic at the Hospital for Sick Children from 1986 to 2005 was reviewed. Products with an immunoglobulin A content of >15 μg/mL were classified as “high immunoglobulin A.” Data were analyzed by using logistic regression models adjusted for repeated measures. RESULTS. Thirty-eight patients with juvenile dermatomyositis received 1056 infusions at the Hospital for Sick Children. Adverse events were reported on 92 occasions (9%), affecting 25 patients (66%), a frequency that is higher than that usually reported in adult patients ( CONCLUSIONS.Intravenous immunoglobulin was found to be safe and well tolerated by most children with juvenile dermatomyositis. However, in contrast to adult studies, we found that significant differences existed in tolerance to different intravenous immunoglobulin products, most likely because of immunoglobulin A concentration. This study confirms anecdotal reports that a high level of immunoglobulin A in intravenous immunoglobulin is less well tolerated by children and provides evidence that product choice is important in pediatrics.

Between June 1994 and December 2003, 31 patients with haematological disorders presenting at the Hospital for Sick Children, Toronto, Canada, received a stem cell transplant (SCT) from a mismatched related donor. Diagnoses included ALL (15), AML (10), CML (1), JMML (1), SAA (2), de novo MDS (1) and Fanconi anaemia (1). Patients were aged between 0.9 to 17.8 years (mean 8.5 years). There were 20 males and 11 females. HLA typing included A, B and DRB1 on all patients (Class 1 alleles by low resolution molecular technique and Class 2 by high resolution technique). 22 patients had 1 major mismatch and 9 had 2–3 major mismatches. The source of stem cells was bone marrow in 15 patients (mean total nucleated cell dose 4.44 x 108/kg, range 1.89–6.63), peripheral blood (PBSC) in 15 patients (mean CD34 dose 11.80 x 106/kg, range 3.19–42.18) and one patient received both BM and PBSC. Of those who received PBSC, 9 had CD34 selection, 3 had CD34 selection and T-cell depletion, and 3 received an unmodified product. Conditioning regimens included cyclophosphamide and total body irradiation (TBI) (15), etoposide and TBI (6), busulfan and cyclophosphamide (6), etoposide and cyclophosphamide (1), fludarabine, cyclophosphamide and TBI (1), fludarabine and cyclophosphamide (1) and fludarabine, melphalan and thiotepa (1). Graft versus host disease (GvHD) prophylaxis included combinations of cyclosporine A, methotrexate, anti-thymocyte globulin and methylprednisolone. There was one primary graft failure and 3 secondary graft failures. Mean time to neutrophil engraftment was 17 days (range 9–36). The incidence of acute and chronic GvHD was 48% and 51% respectively. Of the 31 patients, 15 are alive (12 in complete remission (one of these with a secondary brain tumour) and 3 with relapsed disease) and 16 are dead (3 of relapsed progressive disease, 12 from transplant related mortality (TRM - 9 of these were in CR) and in one the cause is not known). Three year actuarial OS and EFS for the entire group were 50±9% and 45±9%, OS and EFS for those matched at 5/6 loci were 56±11% and 44±11% and OS and EFS for 3/6 and 4/6 matched were 38±16% and 36±16%. The mean follow-up time for survivors is 5.6 years (range 11.6 months to 9.7 years). In this series, there was no significant difference in survival when comparing BM vs. PBSC harvests; in one vs. 2–3 mismatch donors; and in the presence vs. absence of acute or chronic GvHD. These results confirm the feasibility and efficacy of using mismatched related donors for paediatric haematological disorders. Steps should be taken to decrease the TRM to achieve a better survival rate.

Transfusion-related acute lung injury (TRALI) is an infrequent but serious complication that occurs within hours following the transfusion of blood products (eg, red blood cells, platelets, plasma, cryoprecipitate) and is characterized by respiratory distress, hypoxemia, pulmonary edema, hypotension and fever. Most cases require oxygen support and mechanical ventilation (1). TRALI was first described as a specific transfusion reaction in 1983 by Popovsky et al (2). According to a United States Food and Drug Administration report on transfusion-related deaths (3), TRALI was the top-ranked cause of reported fatalities (n=127; 48%) from 2005 through 2009. Two pathophysiological mechanisms have been proposed for TRALI. In the first, named the antibody hypothesis, the pathogenesis of TRALI is related to the infusion of donor antibodies that recognize leukocyte antigens in the transfused host (1,4–10). According to the second hypothesis, called the two-hit or two-event model, neutrophils of recipient origin must be primed by a pre-existing clinical condition. These primed neutrophils trigger an inflammatory response in the lung alveoli when exposed to bioactive substances in the transfused product, resulting in pulmonary edema (11–14). Recent studies suggest that the two theories may be linked (15). This has led to the development of a unifying model (the threshold model) by Bux and Sachs (16). According to this model, the level of priming of neutrophils, either directly or through activation of the pulmonary endothelium, by a patient’s clinical condition and by substances (including antibodies) present in the transfused component, is responsible for triggering TRALI in a recipient. The incidence of TRALI is not well known. Estimates in the literature range from one in 432 to one in 725,000 units, depending on the type of product considered, the case definition of TRALI used, and the nature and size of the denominator (17–20). According to data collected by the Quebec Hemovigilance System (QHS), the incidence of TRALI was one per 23,506 units transfused during the period from 2000 to 2005 (21). The incidence of TRALI is unknown in the paediatric population. A major obstacle in estimating the incidence of TRALI has been the absence of a standard case definition. Such a definition was developed at a consensus conference held in Toronto (Ontario) in April 2004 (11,17), which has allowed for better comparisons of incidence data in different settings. To minimize false-positives, the 2004 consensus definition was restricted to acute lung injury (ALI) occurring within 6 h of transfusion and not attributable to other causes of ALI. The Canadian Paediatric Surveillance Program (CPSP) undertook the present study to determine the incidence of TRALI in the paediatric population and to describe patient characteristics, clinical signs and symptoms, and outcomes of TRALI in children.