Elena Crestani

Exhaled air temperature in asthma: methods and relationship with markers of disease.

Background Exhaled breath temperature has been proposed as a surrogate marker for the evaluation of airway inflammation in asthmatic patients.

Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

In two complementary papers, Casanova, Malissen, and collaborators report the discovery of human RLTPR deficiency, the first primary immunodeficiency of the human CD28 pathway in T cells. Together, the two studies highlight the important and largely (but not completely) overlapping roles of RLTPR in T and B cells of humans and mice.

RAG1 Deficiency May Present Clinically as Selective IgA Deficiency

BackgroundRecombination-activating gene (RAG) 1 and 2 deficiency is seen in patients with severe combined immunodeficiency (SCID) and Omenn syndrome. However, the spectrum of the disease has recently expanded to include a milder phenotype.ObjectiveWe analyzed a 4-year-old boy who was initially given the diagnosis of selective immunoglobulin A deficiency (SIgAD) based on immunoglobulin serum levels without any opportunistic infections, rashes, hepatosplenomegaly, autoimmunity or granulomas. The patient was found to be infected with varicella zoster; however, the clinical course was not serious. He produced antiviral antibodies.MethodsWe performed lymphocyte phenotyping, quantification of T cell receptor excision circles (TRECs) and kappa deleting recombination excision circles (KRECs), an analysis of target sequences of RAG1 and 2, a whole-genome SNP array, an in vitro V(D)J recombination assay, a spectratype analysis of the CDR3 region and a flow cytometric analysis of the bone marrow.ResultsLymphocyte phenotyping demonstrated that the ratio of CD4+ to CD8+ T cells was inverted and the majority of CD4+T cells expressed CD45RO antigens in addition to the almost complete lack of B cells. Furthermore, both TRECs and KRECs were absent. Targeted DNA sequencing and SNP array revealed that the patient carried a deletion of RAG1 and RAG2 genes on the paternally-derived chromosome 11, and two maternally-derived novel RAG1 missense mutations (E455K, R764H). In vitro analysis of recombination activity showed that both RAG1 mutant proteins had low, but residual function.ConclusionsThe current case further expands the phenotypic spectrum of mild presentations of RAG deficiency, and suggests that TRECs and KRECs are useful markers for detecting hidden severe, as well as mild, cases.

Efficacy and Safety of AR101 in Oral Immunotherapy for Peanut Allergy: Results of ARC001, a Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Trial

BACKGROUND Peanut oral immunotherapy, using a variety of approaches, has been previously shown to induce desensitization in peanut-allergic subjects, but no products have been approved for clinical use by regulatory agencies. OBJECTIVE We performed the first phase 2 multicentered study to assess the safety and efficacy of AR101, a novel oral biologic drug product. METHODS A randomized, double-blind, placebo-controlled trial was conducted at 8 US centers. Eligible subjects were 4 to 26 years old, sensitized to peanut, and had dose-limiting symptoms to ≤143 mg of peanut protein in a screening double-blind, placebo-controlled food challenge (DBPCFC). Subjects were randomized 1:1 to daily AR101 or placebo and gradually up-dosed from 0.5 to 300 mg/day. The primary endpoint was the proportion of subjects in each arm able to tolerate ≥443 mg (cumulative peanut protein) at exit DBPCFC with no or mild symptoms. RESULTS Fifty-five subjects (29 AR101, 26 placebo) were enrolled. In the intention-to-treat analysis, 23 of 29 (79%) and 18 of 29 (62%) AR101 subjects tolerated ≥443 mg and 1043 mg at exit DBPCFC, respectively, versus 5 of 26 (19%) and 0 of 26 (0%) placebo subjects (both P < .0001). Compared with placebo, AR101 significantly reduced symptom severity during exit DBPCFCs and modulated peanut-specific cellular and humoral immune responses. Gastrointestinal (GI) symptoms were the most common treatment-related adverse events (AEs) in both groups, with 6 AR101 subjects (21%) withdrawing, 4 of those due primarily to recurrent GI AEs. CONCLUSIONS In this study, AR101 demonstrated an acceptable safety profile and demonstrated clinical activity as a potential immunomodulatory treatment option in peanut-allergic children over the age of 4, adolescents, and young adults.

Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly

To the Editor: The extrinsic pathway of lymphocyte apoptosis, mediated by the binding of Fas ligand (FasL) to its receptor Fas, limits the expansion of immune cells after clearance of pathogens. Fas and FasL belong to the TNF and TNF-receptor superfamilies, respectively, and preassemble as homotrimers. Upon activation, T cells express on their surface FasL, which binds to and causes the multimerization of Fas on target cells. This causes the association of the intracellular death domain of Fas with the Fas-associated death domain protein, which then recruits caspases-8 and -10 to mediate apoptosis. Defects that impair Fas signaling lead to autoimmune lymphoproliferative syndrome (ALPS), characterized by chronic nonmalignant noninfectious lymphadenopathy, hepatosplenomegaly, expansion

RAG1 Reversion Mosaicism in a Patient with Omenn Syndrome

PurposeTo identify mechanisms of disease in a child born to consanguineous parents, who presented with Omenn syndrome (OS) and was found to carry a heterozygous RAG1 mutation in peripheral blood DNA.MethodsMutation analysis was performed on whole blood and buccal swab DNA. Recombination activity of the mutant RAG1 protein and diversity of T cell repertoire were tested.ResultsApparent heterozygosity for a novel, functionally null RAG1 mutation in peripheral blood DNA from a patient with OS was shown to be secondary to true somatic reversion. Analysis of T cell repertoire demonstrated expression of various TCRBV families, but an overall restricted pattern.ConclusionsThis is the first case of true somatic reversion of a RAG1 mutation in a patient with OS. The reversion event likely occurred at a stage where only a limited pool of T cell progenitors capable of performing V(D)J recombination could be generated. This work emphasizes the importance of performing functional studies to investigate the significance of novel genetic variants, and to consider somatic reversion as a possible disease modifier in SCID.

IgE-mediated hypersensitivity reaction and desensitization to glatiramer acetate in a pediatric patient

To the Editor: Glatiramer acetate (Copaxone) is a polymer of four amino acids, and it closely resembles myelin basic protein. It is widely used as a disease-modifying agent with established efficacy in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) (1). Glatiramer acetate is usually dosed as a 1 ml subcutaneous daily injection. Immediate cutaneous reactions at the site of injection are very common, occurring in up to 60% of patients, often presenting as erythema, edema, and pruritus (2). These reactions are thought to be due to direct mast cell activation at the site of injection causing the release of histamine and other mediators. Other reactions localized to the skin have also been described and thought to be caused by either direct drug toxicity (skin necrosis, lobular panniculitis) or immunomodulation (erythema nodosum, urticarial vasculitis) (3). About 10% of patients are reported to experience an immediate postinjection systemic reaction (IPISR) characterized by flushing, chest pain, anxiety, subjective sensation of dyspnea, and throat constriction. Most of these reactions resolve spontaneously within several minutes (2); however, few of them require immediate medical treatment. Systemic reactions to glatiramer acetate usually result in discontinuation of this effective treatment option with an otherwise relatively benign side effect profile. This can be detrimental, especially for those patients who may not be candidates for other treatments. Some of these reactions may represent IgE-mediated anaphylaxis (4), while others may be due to alternative immunologic mechanisms (2, 5, 6). Reliable testing for evaluation of IgE-mediated reaction has not been established. Furthermore, there are no reports of glatiramer acetate allergy or desensitization in the pediatric population. We report the first case of severe, IgE-mediated reaction followed by successful desensitization to glatiramer acetate in a pediatric patient using novel skin test and desensitization protocols. A 14-year-old adolescent female was referred to our allergy clinic for evaluation of hypersensitivity to glatiramer acetate. The patient had been diagnosed with MS at 11 yr of age, following an episode of severe bilateral optic neuritis, leftsided weakness and ataxia. She was initially treated with intravenous and oral corticosteroids, intravenous immunoglobulin infusions, and plasma exchange. The patient was then transitioned to subcutaneous glatiramer acetate (20 mg daily) for long-term disease control. She experienced pain, itching, mild swelling, and erythema at the injection sites after each dose. She also developed dizziness, shortness of breath, and a sensation of her heart racing for up to 60 min following glatiramer acetate administration. However, symptoms seemed to decrease with continued use and were felt to be consistent with non-specific, immediate reactions reported to occur in association with glatiramer acetate administration (2). Approximately 18 months into her treatment course of daily injections, the patient suddenly developed severe shortness of breath, dizziness with shivering, and tachycardia immediately after the injection of glatiramer acetate. She appeared flushed, diaphoretic with perioral cyanosis and experienced brief loss of consciousness. Emergency personnel were alerted, but by the time of their arrival the symptoms subsided and no treatment was needed. Tryptase level was not measured at the time of the reaction. The severity of this reaction prompted the discontinuation of glatiramer acetate injections and the patient was then started on an alternative disease-modifying agent, namely Interferon beta. However, she soon developed significant liver toxicity from this latter treatment leading to its discontinuation. The patient was then referred to our clinic for further evaluation and possible reintroduction of glatiramer acetate. Apart from MS, the patient had well-controlled mild intermittent asthma and allergic rhinitis with positive skin prick test reactions to dust mite, cat, ash tree, and ragweed. She had no known allergies to other medications or to foods. As glatiramer acetate solution contains 20 mg/ml of active ingredient and 40 mg/ml of mannitol, the patient underwent skin testing to both ingredients (Table 1). Skin prick testing was negative to both glatiramer acetate and mannitol. Intradermal testing to glatiramer acetate resulted in a 7 mm wheal and 20 mm flare at the concentration of 0.0002 mg/ml which was the maximum non-irritating concentration in a control subject. The patient had a negative intradermal reaction to mannitol at the concentration of 0.0004 mg/ml which also was the maximum non-irritating concentration in a control subject. Based on these results and the patient’s history, the presence of an IgE-mediated allergy to glatiramer acetate was deemed likely. As there were no alternative MS treatments available that were felt to provide a favorable risk-benefit profile for her, she was admitted to the step-down ICU unit in order to undergo desensitization to glatiramer acetate. A subcutaneous

Systemic Reactions in Pediatric Patients Receiving Standardized Allergen Subcutaneous Immunotherapy with and without Seasonal Dose Adjustment

BACKGROUND The 2003 Joint Task Force on Practice Parameters recommended standardizing allergen subcutaneous immunotherapy (SCIT). Data from longitudinal surveillance survey in North America reported a systemic reaction (SR) rate of 0.1% to 0.2% of injection visits. The rate of SR to standardized SCIT in pediatric patients has not been well evaluated. OBJECTIVE The objective of this study was to evaluate the rate of SRs to standardized SCIT in pediatric patients aged 5 to 18 years in a single tertiary care center in the United States. METHODS A retrospective chart review was conducted in 2 groups: group 1 started SCIT within a period extending from January 2009 to June 2012, whereas group 2 started SCIT within a period extending from January 2013 to June 2016. The protocol was modified in group 2 such that updosing and maintenance doses were adjusted in the spring for tree and grass pollen and in the fall for weed pollen. RESULTS There were a total of 128 patients in group 1 and 118 patients in group 2. The rate of SR was 0.429% in group 1 and 0.364% in group 2, which was not significant. There was no difference in the severity of SR in the 2 groups with no-fatal or near-fatal SR noted. Asthma was a significant risk factor in the younger age subgroup aged 5 to 11 years. CONCLUSIONS Standardized SCIT appears to be associated with an SR rate of 0.429% to 0.364% of visits in pediatric patients. Protocol modification did not lead to a significant drop in SR. Larger multicenter studies are required to further evaluate the rate of SRs from standardized SCIT.