Adelle Atkinson

Safety of Intravenous Immunoglobulin in the Treatment of Juvenile Dermatomyositis: Adverse Reactions Are Associated With Immunoglobulin A Content

OBJECTIVE. Anecdotal reports have suggested differences in childrens 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 (<1%–5%). Adverse events were reported more often with products that contained high immunoglobulin A (15.0% vs 8.0%). These were accounted for specifically by fever (8.0% vs 1.0%), lethargy or malaise (2.0% vs 0.1%), and nausea or vomiting (5.0% vs 1.0%). Of the possible pharmacologic predictors, including dose, immunoglobulin G concentration, immunoglobulin A level, pH, glycine content, sugar content, sodium content, and osmolality, only immunoglobulin A level was significantly associated with adverse events. 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.

Adenosine deaminase deficiency can present with features of Omenn syndrome

However, FIP1L1-PDGFRA–positive patients with CEL may also respond to anti–IL-5 antibody treatment, perhaps because the FIP1L1-PDGFRA gene fusion alone is not sufficient and may require IL-5 to induce CEL. To understand whether the eosinophil differentiation process can be stopped by neutralizing IL-5, we administrated 4 intravenous injections of an anti–IL-5 antibody (mepolizumab, 750 mg each) with intervals of 2 weeks. The patient did not respond with a detectable decrease of his eosinophil count as a consequence of this treatment (Fig 1, B), suggesting that the neutralization of IL-5 by mepolizumab was not sufficient to stop the eosinophil differentiation process. The antibody treatment had also no influence on the relative distribution of T subpopulations and B cells or the expression of markers indicating their activation. Although single imatinib treatment had no effect (Fig 1, A), we thought a combination of mepolizumab and imatinib mesilate might be able to reduce eosinophil numbers. Therefore, we treated the patient with 400 mg imatinib daily, starting 2 weeks after the last mepolizumab infusion. At this time, mepolizumab still exhibits antieosinophil activity in hypereosinophilic patients. Again, no effect of imatinib on eosinophil numbers or symptoms was seen (Fig 1, B). The patient was subsequently substituted with 25 mg hydrocortisone. He died of heart failure in 2006. Because imatinib resistance might be caused by mutations, we analyzed the primary structure of the entire FIP1L1-PDGFRA fusion gene. To this end, the complete FIP1L1-PDGFRA cDNA was amplified by RT-PCR and sequenced. We identified 2 mutations in PDGFRA sequence (accession no. M22734: T1949C and T2034C), resulting in 2 amino acid changes within the kinase domain: S601P and L629P (Fig 1, C and D). No homologous mutations have been described in the BCR-ABL fusion oncoprotein causing imatinib resistance in chronic myeloid leukemia. Therefore, the exact molecular mechanisms through which these newly identified mutations likely cause imatinib resistance remain to be investigated. It should be noted that no mRNA was available before the patient received the drug for the first time. Therefore, the possibility exists that the imatinib treatment may have influenced the mutation. Nevertheless, mutations within the kinase domain of oncoproteins are common causes of drug resistance. Taken together, patients with CEL with the FIP1L1-PDGFRA gene fusion may be resistant to imatinib mesilate because of mutations within the tyrosine kinase domain of the chimeric protein, and increased IL-5 levels in blood do not predict an antieosinophil response to anti–IL-5 antibody therapy. The identification of novel drug-resistant variants may help to develop the next generation of target-directed compounds for CEL and other leukemias.

Novel RAG1 mutation in a case of severe combined immunodeficiency.

Objective. The recombination activating enzymes RAG1 and RAG2 are essential to the process of V(D)J rearrangement in B and T cells and thus to the development of normal immune function. Mutations in RAG1 or RAG2 can lead to a spectrum of disorders, ranging from typical B−T− severe combined immunodeficiency to Omenns syndrome. We present a unique presentation of RAG1 deficiency. Patient. We report on a 6-month-old girl who presented with severe respiratory distress, which continued to progress despite antibiotic therapy but seemed to respond to treatment with corticosteroids. The patient exhibited no erythroderma or eosinophilia, and her lymphoid organs were not enlarged. Results. Investigation of the immune system showed normal numbers of CD3+ T cells, which expressed either CD4 or CD8. Subsequent analysis of the T-cell receptor demonstrated that nearly all CD3+ T cells were clonal; one clone expressed CD4, whereas the other expressed CD8. The extremely restricted T-cell repertoire and the lack of circulating B cells prompted analysis of the RAG1 gene, which revealed a novel homozygous thymine to cytosine substitution at nucleotide position 2686. Conclusions. This case underscores the importance of more extensive evaluation of the immune system even when widely available, standard, flow cytometric analysis shows normal numbers of T cells that express CD4 or CD8, especially in the absence of circulating B cells.

Low Serum Immunoglobulin G2 Levels in Infancy Can Be Transient

OBJECTIVE. The immunoglobulin G2 subclasses contain predominantly antipolysaccharide antibodies. It was therefore believed intuitively that low immunoglobulin G2 levels could predispose individuals to infections with encapsulated bacteria. Although many reports initially supported this notion, more recent studies challenged it. Regardless of the biological significance, the natural history of low immunoglobulin G2 levels has not been carefully studied. METHODS. We studied the outcome of low serum immunoglobulin G2 subclass levels in children. Thirteen patients who were referred because of recurrent infections were found to have low immunoglobulin G2 levels. Laboratory evaluation at presentation and follow-up visits included total serum immunoglobulins, immunoglobulin subclasses, and specific antibodies to protein antigens and to pneumococcal vaccine. RESULTS. Low immunoglobulin G2 levels resolved completely within 0.6 years to 6 years (median: 1.5 years) in all patients. All 13 patients responded adequately to vaccination with protein antigens such as tetanus toxoid and polio as well as to immunization with pneumococcal vaccine. Four of 13 patients had a previous history of transient hypogammaglobulinemia, raising the possibility that the other cases may simply represent the tail end of this condition. CONCLUSION. We have demonstrated that low immunoglobulin G2 detected in early infancy and childhood is likely to resolve completely within several months and up to 6 years from the time of presentation.

Objective Evaluation of Otoscopy Skills Among Family and Community Medicine, Pediatric, and Otolaryngology Residents

INTRODUCTION The objective of this study is to evaluate and compare the perceived need for otolaryngology training and otoscopy diagnostic skills in primary care (Family and Community Medicine, Pediatric Medicine), and Otolaryngology Head and Neck Surgery (OTO-HNS) postgraduate trainees. Participant otoscopy skills were evaluated using the OtoSim simulator. METHODS Family and Community Medicine, Pediatric, and OTO-HNS residents were recruited. Each resident participated in 3 separate otoscopy training and assessment sessions. The ability to correctly identify middle ear pathology was objectively evaluated using OtoSim™. Pretest, posttest, and 3-month retention test results were compared among residents in a paired comparison paradigm. Survey data assessing exposure to OTO-HNS during undergraduate and postgraduate training were also collected. RESULTS A total of 57 residents participated in the study. All residents reported limited exposure to OTO-HNS during undergraduate medical training. Primary care trainees performed poorly on pretest assessments (30% ± 7.8%; 95% CI). Significant improvement in diagnostic accuracy was demonstrated following a single 1-hour teaching session (30%-62%; p < 0.001). Primary care residents demonstrated a significant decrease in diagnostic accuracy at a 3-month follow-up assessment (62%-52%, p < 0.001). Self-perceived comfort with otology was poorly correlated to pretest performance among primary care trainees (r = 0.26) and showed a stronger positive correlation among OTO-HNS trainees (r = 0.56). CONCLUSIONS A single teaching session with an otoscopy simulator significantly improved diagnostic accuracy in primary care and OTO-HNS trainees. Improved performance is susceptible to deterioration at 3 months if acquired skills are not frequently used. Self-perceived comfort with otology may not be an accurate predictor of otoscopic diagnostic skill.

Dietary exposures and allergy prevention in high-risk infants: a joint position statement of the Canadian Society of Allergy and Clinical Immunology and the Canadian Paediatric Society

Allergic conditions in children are a prevalent health concern in Canada. The burden of disease and the societal costs of proper diagnosis and management are considerable, making the primary prevention of allergic conditions a desirable health care objective. This position statement reviews current evidence on dietary exposures and allergy prevention in infants at high risk of developing allergic conditions. It revisits previous dietary recommendations for pregnancy, breastfeeding and formula-feeding, and provides an approach for introducing solid foods to high-risk infants. While there is no evidence that delaying the introduction of any specific food beyond six months of age helps to prevent allergy, the protective effect of early introduction of potentially allergenic foods (at four to six months) remains under investigation. Recent research appears to suggest that regularly ingesting a new, potentially allergenic food may be as important as when that food is first introduced. This article has already been published (Paediatr Child Health. 2013 Dec;18(10):545–54), and is being re-published with permission from the original publisher, the Canadian Paediatric Society.

No systemic reactions to influenza vaccination in egg-sensitized tertiary-care pediatric patients

BackgroundThere are numerous, disparate guidelines for influenza vaccination in egg-allergic patients. We aimed to describe the outcome of selectively applied guidelines, based on risk-stratification, to our high risk, egg-allergic, tertiary-care pediatric population.MethodsEgg allergy was confirmed with skin testing. The vaccine administered was an adjuvunated 2009 H1N1 influenza A vaccine with < 0.165 mcg/ml ovalbumin. Patients with mild egg allergy were to receive the vaccination in 1 dose, those with severe egg allergy were to receive 2 split doses, and patients with exquisite egg allergy or significant co-morbidities were to be skin tested with the vaccine (prick full strength, intradermal 1:100 of final concentration without adjuvant) and had 5 step desensitization if the testing was positive, or 1-2 step administration if negative. Patients were observed for 60 minutes after the final dose and anaphylaxis treatment was available. We report the frequency of allergic reactions.ResultsNinety-nine patients were referred and 79 had positive egg testing. Asthma was present in 67% and 30% had prior anaphylaxis to egg. We vaccinated 77 of 79 patients: 71 without performing vaccine skin testing. Two refused vaccination. No patient had a systemic reaction or required treatment. Two patients experienced positive testing to the adjuvanated intradermal vaccine, but were negative without adjuvant.ConclusionsOur results suggest that most egg-allergic tertiary care pediatric patients can be vaccinated with a low ovalbumin content influenza vaccine without prior vaccine testing. Vaccine skin testing, if used at all, can be reserved for special circumstances. The squalene adjuvant may cause an irritant reaction with intradermal testing.

Fatal lung fibrosis associated with immunodeficiency and gonadal dysgenesis in 46XX sisters--a new syndrome.

Inherited immune deficiencies are a heterogeneous group of diseases that can be either isolated, with the immune defect being the exclusive manifestation, or associated with other abnormalities. We report on two sisters, born to consanguineous parents of Sri‐Lankan descent, who presented in infancy with immunodeficiency, gonadal dysgenesis, and fatal lung fibrosis. Immune studies demonstrated combined humoral and cellular abnormalities including reduced immunoglobulin production, an absence of lymphoid tissue, markedly reduced T‐lymphocyte numbers and function and reduced newly thymus‐derived T‐cells. Both infants succumbed to rapidly progressive lung fibrosis. Autopsy showed dysgenetic gonads bearing no discernible oocytes. In both, karyotypes were normal female (46,XX). Comparative genome hybridization and analysis of genes known to be associated with severe immune defects in infancy or gonadal dysgenesis showed no abnormality. The distinct findings in these two sisters have not been reported before and thus suggest a hitherto unknown autosomal recessive condition that includes immune dysfunction, gonadal dysgenesis, and pulmonary fibrosis.

Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)

Background Combined immunodeficiency (CID) is a T‐cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. Objective We sought to identify the genetic aberration in 4 related patients with CID, early‐onset asthma, eczema, and food allergies, as well as autoimmunity. Methods We performed whole‐exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. Results A heterozygous novel c.C88T 1‐bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole‐exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild‐type CARD11. The CARD11 defect altered the classical nuclear factor &kgr;B pathway, resulting in poor in vitro T‐cell responses to mitogens and antigens caused by reduced secretion of IFN‐&ggr; and IL‐2. Conclusion Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.

Anti-signal Recognition Particle-positive Juvenile Polymyositis Successfully Treated with Rituximab

To the Editor: Juvenile polymyositis (PM) is a rare form of idiopathic inflammatory myositis (IIM) in children, accounting for 2%–8% of cases1,2. In contrast to juvenile dermatomyositis (DM), the characteristic rashes are absent. Myositis-specific antibodies (MSA) can be used to further classify IIM. Anti-signal recognition particle (SRP) antibody is present almost exclusively in PM, and is usually associated with a necrotizing myopathy with a severe or fulminant course and a poor response to therapy3. A previously healthy 12-year-old girl presented with a 1-month history of increasing proximal muscle weakness, alopecia, dysphagia, and Raynaud’s phenomenon. There was no history of rash or skin changes. On examination, she had visible wasting of her shoulder muscles, manual muscle testing (MMT) of 3/5 in a proximal distribution, and a Childhood Myositis Assessment Scale (CMAS)4 score of 15/52. There were no skin findings associated with juvenile DM. Serum inflammatory markers were normal. Muscle enzymes were elevated (creatine phosphokinase 8826 U/l, lactate dehydrogenase 4305 U/l, aspartate aminotransferase 368 U/l), and electromyography demonstrated an active myopathic process. Magnetic resonance imaging (MRI) of the shoulder and hip girdles revealed symmetrically increased T2 signal in hip adductors and shoulder muscles. Pulmonary function tests demonstrated a mild chest wall restrictive pattern with normal carbon monoxide diffusion capacity. Electrocardiogram … Address correspondence to Dr. B.M. Feldman, Division of Rheumatology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. E-mail: brian.feldman{at}sickkids.ca