Abstract Background X-linked hyper IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared to normal individuals. Hematopoietic cell transplant (HCT) has been ...considered a curative therapy, but the procedure has inherent complications, and may 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 in order 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 the Primary Immune Deficiency Treatment Consortium. Data was collected using a REDCap web application. Survival from time of diagnosis or transplant was estimated using the Kaplan-Meier method, compared using log-rank tests, and modeled using proportional hazards regression. Results Twenty-eight clinical sites provided data on 189 patients diagnosed with XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven patients (38%) 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=0.671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly < 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival HR (95% CL): 4.9 (2.2, 10.8), p<0.001. Among survivors, those treated with HCT had higher median Lansky and Karnofsky scores than those treated without HCT (p<0.001). Among patients receiving HCT, 27 (40%) developed graft versus host disease, and most deaths occurred within 1 year of transplant. 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.
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 American Academy of Allergy, Asthma & Immunology (AAAAI) and the American College of Allergy, Asthma & Immunology (ACAAI) have jointly accepted responsibility for establishing the “Practice ...parameter for the diagnosis and management of primary immunodeficiency.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, and the Joint Council of Allergy, Asthma & Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.
Background Crohn disease is an inflammatory bowel disease (IBD) with a complex mode of inheritance. Although nucleotide binding and oligomerization domain containing 2 (NOD2) is the strongest risk ...factor, the cause of Crohn disease remains unknown in the majority of the cases. X-linked inhibitor of apoptosis (XIAP) deficiency causes X-linked lymphoproliferative syndrome type 2. IBD has been reported in some XIAP-deficient patients. Objective We characterize the IBD affecting a large cohort of patients with mutations in XIAP and examine the possible pathophysiologic mechanisms. Methods We performed a phenotypical and histologic analysis of the IBD affecting 17 patients with hemizygous mutations in XIAP , including 3 patients identified by screening 83 patients with pediatric-onset IBD. The X chromosome inactivation was analyzed in female carriers of heterozygous XIAP mutations, including 2 adults with IBD. The functional consequences of XIAP deficiency were analyzed. Results Clinical presentation and histology of IBD in patients with XIAP deficiency overlapped with those of patients with Crohn disease. The age at onset was variable (from 3 months to 41 years), and IBD was severe and difficult to treat. In 2 patients hematopoietic stem cell transplantation fully restored intestinal homeostasis. Monocytes of patients had impaired NOD2-mediated IL-8 and monocyte chemoattractant protein 1 (MCP-1) production, as well as IL-10, in response to NOD2 and Toll-like receptor 2/4 costimulation. Nucleotide binding and oligomerization domain containing 1 (NOD1)–mediated IL-6 and IL-8 production was defective in fibroblasts from XIAP-deficient patients. The 2 heterozygous female carriers of XIAP mutations with IBD displayed abnormal expression of the XIAP mutated allele, resulting in impaired activation of the NOD2 pathway. Conclusion IBD in patients with XIAP deficiency is similar to Crohn disease and is associated with defective NOD2 function in monocytes. Importantly, we report that it is not restricted to male patients because we identified 2 symptomatic female heterozygous carriers of XIAP mutations.
...current data have clearly shown an association between defects in T-cell immunity, granulomas, and RV. A role for vaccine virus in Fuchs' uveitis is also suspected.7,8 Granulomas have been ...reported only once in CRS.9 We hypothesize that the immune deficiency allows persistence of the attenuated virus, polarization of macrophages to M2 occurs, compromising viral clearance, mutations accrue, and complete viral escape occurs upon acquisition of CD8 epitope mutations.\nFin/22.15/PID Epitope Epitope sequence in vaccine virus Substitutions in patients' virus Neutralizing B-cell epitopes E1214-233low * QQSRWGLGSPNCHGPDWASP None E1245-251 LVGATPE None E1260-266 ADDPLLR None E1274-285 VWVTPVIGSQAR I280arrow rightT CD8+ T-cell epitopes C9-22 MEDLQKALETQSRA T18arrow rightA C11-29 DLQKALETQSRALRAELAA T18arrow rightA C264-272 RIETRSARH T267arrow rightI Table E4 Changes in the antigenic structure of RV antigens of RVs/Oulu.FIN/22.15/PID relative to RA27/3 vaccine Antigen Type Vendor Catalog no.
Allergies have long been observed in Inborn Errors of Immunity (IEI) and might even be the first presentation resulting in delayed diagnosis or misdiagnosis in some cases. However, data on the ...prevalence of allergic diseases among IEI patients are limited and contradictory.
To provide a worldwide view of allergic diseases, across a broad spectrum of IEI, and their impact on the timely diagnosis of IEI.
This is a worldwide study, conceived by the World Allergy Organization (WAO) Inborn Errors of Immunity Committee. A questionnaire was developed and pilot-tested and was sent via email to collect data from 61 immunology centers known to treat pediatric and/or adult IEI patients in 41 countries. In addition, a query was submitted to The United States Immunodeficiency Network (USIDNET) at its website.
Thirty centers in 23 countries caring for a total 8450 IEI patients responded. The USIDNET dataset included 2332 patients. Data from responders showed that a median (IQR) of 16.3% (10–28.8%) of patients experienced allergic diseases during the course of their IEI as follows: 3.6% (1.3–11.3%) had bronchial asthma, 3.6% (1.9–9.1%) atopic dermatitis, 3.0% (1.0–7.8%) allergic rhinitis, and 1.3% (0.5–3.3%) food allergy. As per the USIDNET data, the frequency of allergy among IEI patients was 68.8% (bronchial asthma in 46.9%). The percentage of IEI patients who presented initially with allergic disorders was 8% (5–25%) and diagnosis delay was reported in 7.5% (0.9–20.6%). Predominantly antibody deficiencies had the highest frequency of allergic disease followed by combined immunodeficiency with a frequency of 40.3% (19.2–62.5%) and 20.0% (10–32%) respectively. As per the data of centers, anaphylaxis occurred in 25/8450 patients (0.3%) whereas per USIDNET dataset, it occurred in 249/2332 (10.6%); drugs and food allergy were the main causes in both datasets.
This multinational study brings to focus the relation between allergic diseases and IEI. Major allergies do occur in IEI patients but were less frequent than the general population. Initial presentation with allergy could adversely affect the timely diagnosis of IEI. There is a need for policies to raise awareness and educate primary care and other referring specialties on the association of allergic diseases with IEI. This study provides a network among centers for future prospective studies in the field.
The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols ...address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives.
Summary Common variable immunodeficiency is a primary immunodeficiency of unknown etiology characterized by low serum immunoglobulin G, a decreased ability to make specific antibodies, and variable ...T-cell defects. Approximately 10-30% of patients with common variable immunodeficiency develop clinical evidence of a diffuse parenchymal lung disease with a constellation of histopathologic findings termed granulomatous and lymphocytic interstitial lung disease . In this study, we characterized the histologic and immunohistochemical features in a series of 16 cases diagnosed by open lung biopsy. Peribronchiolar and interstitial lymphocytic infiltration, granulomatous inflammation, and organizing pneumonia were consistent features; interstitial fibrosis with architectural remodeling was also found in a subgroup of patients. By immunohistochemistry, a predominance of CD4+ T lymphocytes with variable numbers of CD8+ T cells and B cells was present, with a striking absence of FOXP3-positive T-regulatory cells. This heretofore unrecognized immunohistochemical finding needs further investigation for a potential role in the pathogenesis of the condition. The presence of interstitial fibrosis with or without architectural remodeling in a subset of patients also needs additional study, for effect on prognosis.
Background Severe combined immunodeficiency (SCID) is characterized by the absence of functional T cells and B cells. Without early diagnosis and treatment, infants with SCID die from severe ...infections within the first year of life. Objective To determined the feasibility of detecting SCID in newborns by quantitating T-cell receptor excision circles (TRECs) from dried blood spots (DBSs) on newborn screening (NBS) cards. Methods DNA was extracted from DBSs on deidentified NBS cards, and real-time quantitative PCR (RT-qPCR) was used to determine the number of TRECs. Positive controls consisted of DBS from a 1-week-old T− B− NK+ patient with SCID and whole blood specimens selectively depleted of naive T cells. Results The mean and median numbers of TRECs from 5766 deidentified DBSs were 827 and 708, respectively, per 3.2-mm punch (∼3 μL whole blood). Ten samples failed to amplify TRECs on initial analysis; all but 1 demonstrated normal TRECs and β-actin amplification on retesting. No TRECs were detected in either the SCID or naive T-cell–depleted samples, despite the presence of normal levels of β-actin. Conclusions The use of RT-qPCR to quantitate TRECs from DNA extracted from newborn DBSs is a highly sensitive and specific screening test for SCID. This assay is currently being used in Wisconsin for routine screening infants for SCID.
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