Primary Immune Deficiency Disorders Research Articles

Inborn error of immunity associated with allergic and allergic like symptoms

Introduction: Inborn error of immunity (IEI) includes variety of genetic disorders that affect both the innate and acquired immune system. The number of primary immune deficiency disorders is increasing due to advanced laboratory testing methods. The patients with IEI are susceptible to multiple infectious and non-infectious diseases، including autoimmune disorders، allergies، and malignancies. Several studies have shown an increasing prevalence of non-infectious disorders in patients in IEI. Among the non-infectious manifestations of primary immunodeficiency، allergic symptoms can play an effective and important role in diagnosis and treatment of these patients.
 Methods: Articles were searched in Google Scholar، PubMed، Web of Science، and Scopus databases. In this review، we have tried to use the latest and most reliable articles related to the subject that have been published in Persian and English language.
 Conclusion: Allergic diseases can be a common part of some primary immunodeficiency diseases. Even in some types of primary immunodeficiency، they are considered the main symptom and important indicator of the disease، which are very decisive factors for the diagnosis of immunodeficiency.

Cord blood transplantation for nonmalignant disorders: early functional immunity and high survival.

There is no consensus on the best donor for children with nonmalignant disorders and immune deficiencies in the absence of a matched related donor (MRD). We evaluated the 2-year overall survival (OS) after umbilical cord blood transplantation (UCBT) in patients with nonmalignant disorders from 2009 to 2020 enrolled in a prospective clinical trial using either 5/6 or 6/6 UCB as the cell source. Patients receive a fully ablative busulfan, cyclophosphamide, and fludarabine without serotherapy. Fifty-five children were enrolled, median age 5 months (range, 1-111 months); primary immune deficiency (45), metabolic (5), hemophagocytic lymphohistiocytosis (1), and hematologic disorders (4). Twenty-six patients had persistent infections before transplant. Nineteen of them (34%) were 6/6 matched, and 36 (66%) were 5/6 human leukocyte antigen-matched. The OS at 2 years was 91% (95% cumulative incidence, 79-96), with a median follow-up of 4.3 years. The median time to neutrophil and platelet recovery were 17 days (range, 5-39 days) and 37 days (range, 20-92 days), respectively. All but one evaluable patient achieved full donor chimerism. The cumulative incidence of acute GVHD grades 2-4 on day 100 was 16% (n= 9). All patients with viral infections at the time of transplant cleared the infection at a median time of 54days (range, 44-91 days). All evaluable patients underwent correction of their immune or metabolic defects. We conclude that in the absence of MRD, UCBT following myeloablative conditioning without serotherapy is an excellent curative option in young children with nonmalignant disorders. This trial has been registered at www.clinicaltrials.gov as NCT00950846.

396 - TCR Alpha Beta and CD19+ Depleted Haploidentical Peripheral Stem Cell Transplantation Using Reduced Toxicity Conditioning Regimen with Pharmacokinetics Guided Busulfan, Fludarabine, Thiotepa and Thymoglobulin Offers Durable Donor Engraftment in Children with Primary Immune Deficiency Disorders

396 - TCR Alpha Beta and CD19+ Depleted Haploidentical Peripheral Stem Cell Transplantation Using Reduced Toxicity Conditioning Regimen with Pharmacokinetics Guided Busulfan, Fludarabine, Thiotepa and Thymoglobulin Offers Durable Donor Engraftment in Children with Primary Immune Deficiency Disorders

Hodgkin Lymphoma in a Girl with Common Variable Immune Deficiency: A Case Report and Review of Literature

Common variable immune deficiency (CVID) is among the most primary immune deficiency disorders with unknown etiology which mostly presents in adulthood; however, some patients might show their symptoms during childhood. CVID usually increases predisposition to malignancies. Lymphoproliferative malignancies such as lymphoma are the most incident malignancies among the patients; however, the prevalence of Hodgkin lymphoma (HL) is low among the patients and just a few cases of the disorder reported in children. A 13 year old girl admitted to our ward with bilateral cervical lymphadenopathy has emerged since 13 months ago without any associated symptoms. She was a known case of CVID diagnosed at 1 year of age and was under regularly treatment of monthly IVIG and prophylactic antibiotic since then. The diagnostic approach to her lymphadenopathy led to HL diagnosis and she has undergone the standard chemotherapy protocol for HL which took about 6 months without any radiotherapy and showed complete remission. After 6 years of standard follow ups, she is still in complete recovery. To our knowledge, this report seems to be the tenth case of HL emergence in patients diagnosed with CVID during their childhood and the second case of HL emergence despite regularly receiving of monthly IVIG. Low stage of her HL (2A) and favorable response to the chemotherapy with prolong remission might be explained by the regularly prescription of IVIG since early stages of life; albeit these conclusions need to be approved with further studies in the future cases.

A CASE OF AUTOSOMAL-DOMINANT HYPER-IGE SYNDROME MASQUERADING AS CYSTIC FIBROSIS

A CASE OF AUTOSOMAL-DOMINANT HYPER-IGE SYNDROME MASQUERADING AS CYSTIC FIBROSIS

Two Successful Bone Marrow Transplantations Improved Lung Functions in Patients With Chronic Granulomatous Disease

Chronic Granulomatous Disease (CGD) is a rare inherited primary immune deficiency disorder with defective respiratory burst activity in phagocytes, resulting in recurrent pyogenic infections. In this study, we described two CGD patients who had done bone marrow transplantation (BMT). As Bone marrow transplantation (BMT) is the definitive treatment of the disease, we evaluated the function of their lungs before and after BMT. In both patients, the BMT was from their siblings. In case 1, the patient’s pulmonary function (PFT) before BMT was: FEV1: 34, FVC: 40, FEV1 / FVC: 72%, and after BMT was: FEV1: 66, FVC: 40 by 49, FEV1 / FVC: 64%. In case 2, the patient’s PFT before BMT was: FEV1: 22, FVC: 36, FEV1 / FVC: 41%, and after BMT was: FEV1: 47, FVC: 33, FEV1/FVC: 43%. BMT significantly improved their Pulmonary Problems and Preclinical (PFT). In addition, after BMT, both patients’ well-tolerated clinical signs and the infection rate, and the number of hospitalizations in both patients decreased.

Primary Immune Deficiency: Patients' Preferences for Replacement Immunoglobulin Therapy.

PurposeImmunoglobulin (Ig) replacement therapy is an important life-saving treatment modality for patients with primary antibody immune deficiency disorders (PAD). IVIG and SCIg are suitable alternatives to treat patients with PAD but vary in key ways. Existing evidence on patient preferences for Ig treatments given the complexities associated with IVIG and SCIg treatment is limited and fails to account for variations in preferences across patients. For this reason, we sought to evaluate PAD patient preferences for features of IVIG and SCIg across different patient characteristics.Materials and Methods119 PAD patients completed a discrete-choice experiment (DCE) survey. The DCE asked respondents to make choices between carefully constructed treatment alternatives described in terms of generic treatment features. Choices from the DCE were analyzed to determine the relative influence of attribute changes on treatment preferences. We used subgroup analysis to evaluate systematic variations in preferences by patients’ age, gender, time since diagnosis, and treatment experience.ResultsPatients were primarily concerned about the duration of treatment side effects, but preferences were heterogeneous. This was particularly true around administration features. Time since diagnosis was associated with an increase in patients’ concerns with the number of needles required per infusion. Also, patients appear to prefer the kind of therapy they are currently using which could be the result of properly aligned patient preferences or evidence of patient adaptive behavior.ConclusionsHeterogeneity in preferences for Ig replacement treatments suggests that a formal shared decision making process could have an important role in improving patient care.

Common variable immunodeficiency disorders: What generalists should know.

Primary immune deficiency disorders (PIDDs) are common and underdiagnosed. Predominant antibody deficiencies (PADs) are the most common type of immune deficiency and comprise 55% of the immune deficiencies diagnosed.[1] Although immunoglobulin A (IgA) deficiency remains the most common type of PID, common variable immunodeficiency disorders remain the most common symptomatic PID for which medical therapy is sought.

X-linked Agammaglobulinemia (XLA) Associated with Progressive Neurodegenerative Syndrome: A Case Report

Primary immune deficiency disorders (PIDs) are not an uncommon entity, but the diagnosis is often delayed or even missed due to lack of awareness. Central nervous system involvements due to various reasons are documented in patients with PIDs. This case report describes a 10- year old boy, diagnosed as X-linked agammaglobulinemia (XLA) who developed progressive encephalopathy. He had severe cognitive impairment along with cerebellar and pyramidal dysfunction. MRI of the brain showed generalized cerebral and cerebellar atrophy. Therefore, this boy was diagnosed as a case of XLA with progressive neurodegenerative syndrome.
 BANGLADESH J CHILD HEALTH 2021; VOL 45 (1) : 55-58

Multicenter Outcome of Hematopoietic Stem Cell Transplantation for Primary Immune Deficiency Disorders in India.

BackgroundHematopoietic stem cell transplantation (HSCT) is the curative option for many primary immune deficiency disorders (PID). In the last 5 years, increased awareness, availability of diagnostics based on flow cytometry, genetic testing, improved supportive care, use of reduced toxicity conditioning, and success of haploidentical donor HSCT have improved access to HSCT for children with PID in India. We present results on children with PID who underwent HSCT across India and the factors that influenced outcome.Patients and MethodsWe collected retrospective data on the outcome of HSCT for PID from seven centers. We analyzed the impact of the type of PID, conditioning regimen, time period of HSCT- before or after January 2016, graft versus host disease prophylaxis, cause of mortality and overall survival.ResultsA total of 228 children underwent HSCT for PID at a median age of 12 months (range, 1 to 220 months) with a median follow up of 14.4 months. Infants accounted for 51.3% of the cohort and the male female ratio was 3:1. SCID (25%) and HLH (25%) were the more frequent diagnoses. Matched family donor was available in 36.4% and 44.3% children had a haploidentical HSCT. Reduced and myeloablative conditioning regimens were used with 64% children receiving a treosulfan based conditioning regimen. Peripheral blood stem cells were the predominant graft source at 69.3%. The survival in infants (60.2%) was inferior to children aged over 1 year (75.7% p value = 0.01). Children with Wiskott Aldrich syndrome (74.3%) and chronic granulomatous disease (82.6%) had the best outcomes. The survival was superior in children receiving HSCT from a matched sibling (78%) versus an alternate donor HSCT (61% p value = 0.04). In the cohort transplanted after January 2016 survival improved from 26.8% to 77.5% (p value = 0.00). Infection remains the main cause of mortality at in over 50% children. The 5-year overall survival rate was 68%.ConclusionSurvival of children with PID undergoing HSCT in India has improved dramatically in last 5 years. Alternate donor HSCT is now feasible and has made a therapeutic option accessible to all children with PID.

Non-neutralizing antibodies and limitations of serologic testing for severe acute respiratory syndrome coronavirus 2 in patients receiving immunoglobulin replacement products

With the growing surges in coronavirus disease 2019 (COVID-19) cases caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the globe, there has been a growing concern regarding its implications among patients with primary immune deficiency disorders (PIDs). Common variable immunodeficiency is a common PID characterized by a failure in B cell differentiation with defective immunoglobulin production, making the patients uniquely susceptible to recurrent infections.1 Although current evidence suggests a higher risk for more severe disease in patients with both primary and secondary immune deficiency states, the exact burden of COVID-19 in these disease states is unknown.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

PurposeAllogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS).MethodsWe report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months–21 years).ResultsWith a median follow-up of 26 months (range 7 months–9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III–IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%.ConclusionThis alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS.Trial registrationClinicalTrials.gov Identifier: NCT04232085

Chronic Mucocutaneous Candidiasis in Early Life: Insights Into Immune Mechanisms and Novel Targeted Therapies.

Children with chronic mucocutaneous candidiasis (CMC) experience recurrent infections with Candida spp. Moreover, immune dysregulation in the early life of these patients induces various autoimmune diseases and affects normal growth and development. The adaptive and innate immune system components play a significant role in anti-fungal response. This response is mediated through IL-17 production by T helper cells. Inborn errors in IL-17-mediated pathways or Candida spp. sensing molecules are known to cause CMC. In this review, we describe underlying immune mechanisms of monogenic primary immune deficiency disorders known to cause CMC. We will explore insights into current management of these patients and novel available therapies.

Primary immune regulatory disorders: a growing universe of immune dysregulation.

Primary immune regulatory disorders (PIRD) are a growing subset of diseases referred to as inborn errors of immunity. Unlike classical primary immune deficiency disorders that typically present with severe, recurrent, or unusual infections, the clinical manifestations of PIRD are dominated by immune-mediated diseases (autoimmunity, autoinflammation/hyperinflammation, lymphoproliferation, malignancy, and severe atopy). This review introduces the concept of PIRD including clinical phenotypes, treatments, and new PIRD-associated gene defects. The number of genetic defects associated with PIRD is rapidly growing. The identified genes often encode proteins that play critical roles in regulating the immune response to various triggers. Understanding the molecular mechanisms underlying PIRD has shed light on the clinical phenotypes and has helped to identify targeted therapies. In some cases, hematopoietic cell transplant (HCT) has been successfully employed as a cure. It is important to recognize the broad clinical manifestations of PIRD as patients may have symptoms atypical of classical 'immunodeficiency'. Because of their diverse immune dysregulation problems, they are often primarily managed by other subspecialists. Immunologists can help connect the diverse immune-mediated pathologies to a gene defect. This, in turn, can play a significant role in directing clinical management, selecting effective therapy, and deciding on appropriateness of HCT.

Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID).

Common variable immunodeficiency (CVID) is a primary immune deficiency disorder characterized by a failure in B cell differentiation, impaired immunoglobulin production,and defect in response to vaccines. As a result of defective B cell maturation and differentiation in CVID, the affected patients commonly present with reduced numbers of memory B cell and antibody-secreting plasma cells. B-cell lymphoma 6 protein (BCL6) and B lymphocyte induced maturation protein 1 (BLIMP1) molecules are two important transcription factors that have key roles in the maturation of B cells to plasma cells. Hence, in the current survey, we aimed to evaluate the mRNA and protein expression levels of BCL6 and BLIMP1 in B lymphocytes isolated from peripheral blood in CVID patients. We collected blood samples from 12 CVID patients and 12 healthy controls. We isolated peripheral blood mononuclear cells (PBMCs) using Ficoll density gradient separation. Then, CD19+ B cells were purified using MACS. The protein expression and transcriptional level of BCL6 and BLIMP1 were respectively measured using flow cytometry and real-time PCR. Our results showed that the BLIMP1 mRNA expression, as well as BLIMP1 protein expression, were significantly higher in CVID patients compared to control subjects (p=0.009 and p=0.007, respectively). However, we found no significant difference in mRNA and protein expression of BCL6 between patients and healthy controls. According to our findings, increased mRNA and protein expression levels of BLIMP1 could be involved in defective maturation of B cells in patients with CVID and elucidate mechanistic insights into the pathogenesis of this disorder.

A Review of Primary Immune Deficiency Disorders

This scenario-based review of primary immunodeficiency diseases (PIDD) discusses the differential diagnosis, usual presentations, work-up, and treatment of children with the most commonly encountered immune disorders. Newborn screening (NBS) for severe combined immunodeficiency (SCID) is covered, as are later presenting disorders caused by B cell defects and disorders of the innate immune system.

TREC and KREC profiling as a representative of thymus and bone marrow output in patients with various inborn errors of immunity.

Primary immune deficiency (PID) disorders are clinically and molecularly heterogeneous diseases. T cell receptor excision circles (TRECs) and κ (kappa)-deleting excision circles (KRECs) are markers of T and B cell development, respectively. They are useful tools to assess T and B cell function and immune reconstitution and have been used for newborn screening for severe combined immunodeficiency disease (SCID) and agammaglobulinemia, respectively. Their profiles in several genetically confirmed PIDs are still lacking. The objective of this study was to determine TREC and KREC genomic profiling among various molecularly confirmed PIDs. We used real-time-quantitative polymerase chain reaction (RT-qPCR)-based triplex analysis of TRECs, KRECs and β-actin (ACTB) in whole blood genomic DNA isolated from 108 patients with molecularly confirmed PIDs. All agammaglobulinemia patients had low KREC counts. All SCIDs and Omenn syndrome patients secondary to mutations in RAG1, RAG2, DCLRE1C and NHEJ1 had low TREC and KREC counts. JAK3-deficient patients had normal KREC and the TREC count was influenced by the type of mutation. Early-onset ADA patients had low TREC and KREC counts. Four patients with zeta-chain-associated protein kinase 70 (ZAP70) had low TREC. All purine nucleoside phosphorylase (PNP) patients had low TREC. Combined immunodeficiency (CID) patients secondary to AK2, PTPRC, CD247, DCLREC1 and STAT1 had normal TREC and KREC counts. Most patients with ataxia-telangiectasia (AT) patients had low TREC and KREC, while most DOCK8-deficient patients had low TRECs only. Two of five patients with Wiskott-Aldrich syndrome (WAS) had low TREC counts as well as one patient each with bare lymphocyte syndrome (BLS) and chronic granulomatous disease. All patients with Griscelli disease, Chediak-Higashi syndrome, hyper-immunoglobulin (Ig)M syndrome and IFNGR2 had normal TREC and KREC counts. These data suggest that, in addition to classical SCID and agammaglobulinemia, TREC/KREC assay may identify ZAP70 patients and secondary target PIDs, including dedicator of cytokinesis 8 (DOCK8) deficiency, AT and some individuals with WAS and BLS.

Clinical and Laboratory Profiles of 17 Cases of Chronic Granulomatous Disease in North India.

A primary immune deficiency disorder is often suspected in children with recurrent deep seated and fungal infections and those admitted to pediatricintensive care units. Chronic granulomatous disease (CGD) is inherited disorder leading to infections caused due to defective superoxide production. Cases referred for testing for a primary immunodeficiency disorder were tested for Dihydrorhodamine 123 (DHR) assay by flow cytometry and nitroblue tetrazolium dye (NBT) slide test. The unstimulated and stimulated samples were tested for oxidative burst activity which gives bright fluorescence due to formation of Rhodamine 123 on flow cytometry and blue formazan pigment in NBT slide test. The test results were reported in real time. From a total of 330 patients screened for chronicgranulomatous disease using DHR and NBT slide test, 17 patients (5.1%) were found to have CGD. These included 12 boys and 5 girls. They presented with deep seated infections, recurrent and multiple abscess, recurrent pneumonia and granulomatous lymphadenitis. The causative organisms were Mycobacteriae, Staphylococcus, Burkholderia cepacia, Pseudomonas, Aspergillus and Cytomegalovirus. In 6 out of 17 positive cases family studies were carried out. On follow up five children succumbed to disease, two patients underwent allogeneic bone marrow transplant, the chimerism status was demonstrated by repeat DHR assay at day 50 post-transplant. Rest are in follow up under prophylactic antibiotics and supportive care. As facilities for molecular testing are not easily available for primary immuno deficiency disorders, flow cytometry based clinical laboratories canhelp to screen for some of the frequently suspected disorders like chronic granulomatous disease. This has aided in paediatric care in our centre.

Delivery of subcutaneous immunoglobulin by rapid \u201cpush\u201d infusion for primary immunodeficiency patients in Manitoba: a retrospective review

BackgroundBoth intravenous and subcutaneous human immune globin G (IgG) replacement (IVIG and SCIG, respectively) reduce severe infection and increase serum IgG levels in primary immune deficiency disorder (PIDD) patients who require replacement. SCIG can be administered either with the aid of an infusion pump, or by patients or caregivers themselves, using butterfly needles and a syringe (“SCIG push”). SCIG offers advantages over IVIG, including higher steady state IgG levels, improved patient quality of life indicators, and decreased cost to the healthcare system, and for these reasons, SCIG has been increasingly used in Manitoba starting in 2007. We sought to determine the effectiveness of SCIG push in our local adult PIDD population.MethodsWe conducted a retrospective chart review of all adult patients enrolled in the SCIG push program in Manitoba, Canada from its inception in November 2007 through September 2018. We included patients who were naïve to IgG replacement prior to SCIG, and those who had received IVIG immediately prior. We collected data regarding serum IgG levels, antibiotic prescriptions, hospital admissions, and adverse events during a pre-defined period prior to and following SCIG initiation. Statistical significance was determined via two-tailed t-test.Results62 patients met inclusion criteria, of whom 35 were on IVIG prior and 27 were IgG replacement naïve. SCIG push resulted in an increase in serum IgG levels in those naïve to IgG replacement, as well as in those who received IVIG prior. SCIG push also resulted in a statistically significant reduction in number of antibiotic prescriptions filled in the naïve subgroup, and no significant change in antibiotics filled in the IVIG prior group. 8/62 PIDD patients (12.9%) left the SCIG program during our review period for varying reasons, including side-effects.ConclusionsIn a real-life setting, in the Manitoba adult PIDD population, SCIG push is an effective method of preventing severe infections, with most patients preferring to continue this therapy once initiated.

Incidence Trends, Comorbidities, and Outcomes of Pyogenic Liver Abscess Among Children: A Nationwide Population-based Analysis.

Population-based analysis of incidence, comorbid conditions, microbiological characteristics, and outcomes of pyogenic liver abscess (PLA) in children. Retrospective analysis of National Inpatient Sample (NIS) and Kids Inpatient database (KID) database from 2003 to 2014 and included patients between 1 and 20 years of age. Using ICD-9 codes, we identified all hospitalizations with PLA and compared them with 1 : 10 age- and gender-matched controls. Amebic liver abscess and Candida infections were excluded. Total number of PLA admissions is 4075. The overall incidence of PLA is 13.5 per 100,000 hospitalizations, which increased by 60% between 2003 and 2014. The mean age of patients was 13.03 ± 6.1 years and were predominantly boys-61%. Of the comorbid conditions, hepatobiliary malignancy had the highest odds ratio (OR 71.8) followed by liver transplant (OR 38.4), biliary disease (OR 29.9), inflammatory bowel disease (IBD) (OR 5.35), other GI malignancies (OR 4.74), primary immune deficiency disorder (OR 4.13). Patients with PLA had 12 times increased odds of having associated severe sepsis. Infective endocarditis (IE) (OR 4.5), appendicitis (OR 1.8), and diverticulitis (OR 8.1) were significantly associated with PLA. Almost 39% (1575) of the PLA patients had positive culture, whereas Streptococcus (10.8%) and Staphylococcus spp (9.2%) were the most common pathogens. About 45% of PLA patients underwent percutaneous liver abscess aspiration whereas 4.1% had hepatic resection for PLA. The mortality rate of PLA was 0.8% (n = 32). The incidence of PLA is steadily increasing over the last decade among pediatric population in the United States. Hepatobiliary malignancy and liver transplant are the most common comorbid conditions associated with PLA.