Ramsay L. Fuleihan

Transplantation Outcomes for Severe Combined Immunodeficiency, 2000–2009

BACKGROUND The Primary Immune Deficiency Treatment Consortium was formed to analyze the results of hematopoietic-cell transplantation in children with severe combined immunodeficiency (SCID) and other primary immunodeficiencies. Factors associated with a good transplantation outcome need to be identified in order to design safer and more effective curative therapy, particularly for children with SCID diagnosed at birth. METHODS We collected data retrospectively from 240 infants with SCID who had received transplants at 25 centers during a 10-year period (2000 through 2009). RESULTS Survival at 5 years, freedom from immunoglobulin substitution, and CD3+ T-cell and IgA recovery were more likely among recipients of grafts from matched sibling donors than among recipients of grafts from alternative donors. However, the survival rate was high regardless of donor type among infants who received transplants at 3.5 months of age or younger (94%) and among older infants without prior infection (90%) or with infection that had resolved (82%). Among actively infected infants without a matched sibling donor, survival was best among recipients of haploidentical T-cell-depleted transplants in the absence of any pretransplantation conditioning. Among survivors, reduced-intensity or myeloablative pretransplantation conditioning was associated with an increased likelihood of a CD3+ T-cell count of more than 1000 per cubic millimeter, freedom from immunoglobulin substitution, and IgA recovery but did not significantly affect CD4+ T-cell recovery or recovery of phytohemagglutinin-induced T-cell proliferation. The genetic subtype of SCID affected the quality of CD3+ T-cell recovery but not survival. CONCLUSIONS Transplants from donors other than matched siblings were associated with excellent survival among infants with SCID identified before the onset of infection. All available graft sources are expected to lead to excellent survival among asymptomatic infants. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Genome-wide association study identifies peanut allergy-specific loci and evidence of epigenetic mediation in US children

Food allergy (FA) affects 2–10% of U.S. children and is a growing clinical and public health problem. Here we conduct the first genome-wide association study of well-defined FA, including specific subtypes (peanut, milk, and egg) in 2,759 U.S. participants (1,315 children; 1,444 parents) from the Chicago Food Allergy Study; and identify peanut allergy (PA)-specific loci in the HLA-DR and -DQ gene region at 6p21.32, tagged by rs7192 (p=5.5×10−8) and rs9275596 (p=6.8×10−10), in 2,197 participants of European ancestry. We replicate these associations in an independent sample of European ancestry. These associations are further supported by meta-analyses across the discovery and replication samples. Both single-nucleotide polymorphisms (SNPs) are associated with differential DNA methylation levels at multiple CpG sites (p<5×10−8); and differential DNA methylation of the HLA-DQB1 and HLA-DRB1 genes partially mediate the identified SNP-PA associations. This study suggests that the HLA-DR and -DQ gene region likely poses significant genetic risk for PA.

Use of intravenous immunoglobulin and adjunctive therapies in the treatment of primary immunodeficiencies: A working group report of and study by the Primary Immunodeficiency Committee of the American Academy of Allergy Asthma and Immunology.

There are an expanding number of primary immunodeficiency diseases (PIDDs), each associated with unique diagnostic and therapeutic complexities. Limited data, however, exist supporting specific therapeutic interventions. Thus, a survey of PIDD management was administered to allergists/immunologists in the United States to identify current perspectives and practices. Among 405 respondents, the majority of key management practices identified were consistent with existing data and guidelines, including the provision of immunoglobulin therapy, immunoglobulin dosing and selective avoidance of live viral vaccines. Practices for which there are little specific data or evidence-based guidance were also examined, including evaluation of IgG trough levels for patients receiving immunoglobulin, use of prophylactic antibiotics and recommendations for complementary/alternative medicine. Here, variability applied to PIDD patients was identified. Differences between practitioners clinically focused upon PIDD and general allergists/immunologists were also identified. Thus, a need for expanded clinical research in PIDD to optimize management and potentially improve outcomes was defined.

Food allergy is associated with an increased risk of asthma.

Background The atopic march is well documented, but the interrelationship of food allergy (FA) and asthma is not well understood.

The Hyper IgM Syndromes

The hyper IgM syndromes are a group of rare inherited immune deficiency disorders characterized by impairment of immunoglobulin isotype switching resulting from defects in the CD40 ligand/CD40 signaling pathway. X-linked forms of hyper IgM are caused by defects in the CD40 ligand gene or NF-κB essential modulator, while autosomal recessive forms of hyper IgM are caused by defects in CD40 or downstream signaling molecules including activation-induced cytidine deaminase, uracil N glycosylase or postmeiotic segregation increased 2. The loss of interaction between CD40 and its ligand results in an impairment of T cell function, of B cell differentiation and of monocyte function while only B cell differentiation appears to be affected in defects of sinaling molecules downstream of CD40 with the exception of defects of the NF-κB complex, which mediates signaling via multiple receptor pathways. With many genetic defects in the hyper IgM syndrome identified, it is possible to diagnose patients definitively, to perform genetic screening, and to delineate the clinical manifestations of the different diseases in this syndrome. Stem cell transplantation is an available therapeutic option for defects that result in a combined immunodeficiency while antibody replacement appears sufficient for the strictly humoral immunodeficiencies.

Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts

The present uncertainty of which live viral or bacterial vaccines can be given to immunodeficient patients and the growing neglect of societal adherence to routine immunizations has prompted the Medical Advisory Committee of the Immune Deficiency Foundation to issue recommendations based on published literature and the collective experience of the committee members. These recommendations address the concern for immunodeficient patients acquiring infections from healthy subjects who have not been immunized or who are shedding live vaccine-derived viral or bacterial organisms. Such transmission of infectious agents can occur within the hospital, clinic, or home or at any public gathering. Collectively, we define this type of transmission as close-contact spread of infectious disease that is particularly relevant in patients with impaired immunity who might have an infection when exposed to subjects carrying vaccine-preventable infectious diseases or who have recently received a live vaccine. Immunodeficient patients who have received therapeutic hematopoietic stem transplantation are also at risk during the time when immune reconstitution is incomplete or while they are receiving immunosuppressive agents to prevent or treat graft-versus-host disease. This review recommends the general education of what is known about vaccine-preventable or vaccine-derived diseases being spread to immunodeficient patients at risk for close-contact spread of infection and describes the relative risks for a child with severe immunodeficiency. The review also recommends a balance between the need to protect vulnerable subjects and their social needs to integrate into society, attend school, and benefit from peer education.

The hygiene hypothesis revisited: does exposure to infectious agents protect us from allergy?

Purpose of review The increase in incidence and prevalence of allergic disease remains a mystery and cannot be explained solely by genetic factors. The hygiene hypothesis provides the strongest epidemiological explanation for the rise in allergic disease. This review evaluates the recent epidemiological and mechanistic research in the role of infectious agents in the pathogenesis of or protection from allergic disease. Recent findings Recent literature has extended the epidemiological findings of the protective effect of being born and reared in a farm environment and associates an increased diversity of organisms in house-dust samples with protection from allergic disease. Furthermore, human and animal studies provide increasing evidence for the role of both the innate and adaptive immune systems, including regulatory cells, as mediators of this protective effect. Summary There is evidence that exposure to some infectious organisms can protect from atopy, whereas other infections appear to promote allergic diseases. The timing of exposure to infection and the properties of the infectious agent, in addition to the genetic susceptibility of the host, play an important role in the future development of allergic disease.

Impaired B cell development and function in mice with a targeted disruption of the homeobox gene Hex

Hex is a homeobox gene that is expressed in all stages of B cell development except plasma cells. We studied lymphocyte development in the absence of Hex by using the RAG1-deficient blastocyst complementation system because homozygous disruption of Hex is embryonic lethal. Hex−/−;RAG1−/− chimeric mice had severely reduced numbers of mature B cells, pre-B cells, and CD5+ B cells with a striking 15-fold increase in the percentage of B220−CD19+ cells in the bone marrow. Hex−/−;RAG1−/− chimeric mice failed to generate IgG antibodies to T cell-independent antigens, although their serum IgM levels and antibody responses to T cell-dependent antigens were intact. Therefore, Hex is necessary for B cell development and function and its absence results in a dramatic increase in B220−CD19+ cells.

Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation

Background: X‐linked hyper‐IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. Objectives: We sought to collect data on the clinical presentation, treatment, and follow‐up of a large sample of patients with XHIGM to (1) compare long‐term overall survival and general well‐being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan‐Meier method compared with log‐rank tests and modeled by using proportional hazards regression. Results: Twenty‐eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow‐up and vital status information. Sixty‐seven (38%) patients received HCT. The average follow‐up time was 8.5 ± 7.2 years (range, 0.1‐36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987‐1995; the hazard ratio was significantly less than 1 for diagnosis years 1995‐1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2‐10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft‐versus‐host disease, and most deaths occurred within 1 year of transplantation. Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964‐2013). However, survivors treated with HCT experienced somewhat greater well‐being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

Naturally occurring tolerance acquisition to foods in previously allergic children is characterized by antigen specificity and associated with increased subsets of regulatory T cells.

Food allergy affects approximately 6–8% of children, and increasing in prevalence. Some children naturally outgrow their food allergy without intervention, but the mechanisms by which this occurs remain poorly understood. We sought to investigate the role of regulatory T cells in the development of naturally acquired tolerance.