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BackgroundAutosomal dominant hyper-IgE syndrome (AD-HIES) is a rare condition.ObjectiveData from the USIDNET Registry provide a resource to examine the characteristics of patients with rare immune deficiency diseases.MethodsA query was submitted to the USIDNET requesting deidentified data for patients with physician-diagnosed AD-HIES through July 2016.ResultsData on 85 patients diagnosed with AD-HIES (50 males; 35 females) born between 1950 and 2013, collected by 14 physicians from 25 states and Quebec, were entered into the USIDNET Registry by July 2016. Cumulative follow-up was 2157 years. Of these patients, 45.9% had a family history of HIES. The complications reported included skin abscesses (74.4%), eczema (57.7%), retained primary teeth (41.4%), fractures (39%), scoliosis (34.1%), and cancer (7%). Reported allergic diseases included food (37.8%), environmental (18%), and drugs (42.7%). The mean serum IgE level was 8383.7 kU/mL and was inversely correlated to the patient's age. A total of 49.4% had eosinophilia; 56% were known to be on trimethoprim-sulfamethoxazole, 26.6% on antifungal coverage, and 30.6% on immunoglobulin replacement therapy. Pneumonias were more commonly attributed to Staphylococcus aureus (55.3%) or Aspergillus fumigatus (22.4%); 19.5% had a history of lung abscess; these were most often associated with Pseudomonas aeruginosa (P Fisher's exact test = .029) or A. fumigatus (P Fisher's exact test = .016). Lung abscesses were significantly associated with drug reactions (P χ2 = .01; odds ratio: 4.03 [1.2-12.97]), depression (P Fisher's exact test = .036), and lower Karnofsky index scores (P Mann-Whitney = .007).DiscussionData from the USIDNET Registry summarize the currently reported clinical characteristics of a large cohort of subjects with AD-HIES.

Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient population. There are also nonimmunologic risks associated with HCT for SCID that appear to be dependent upon the genotype of the patient. In this report, we have evaluated the published data on late effects and attempted to summarize the known risks associated with conditioning and alternative donor sources. These data, while informative, are also a clear demonstration that there is still much to be learned from the SCID population in terms of their post-HCT outcomes. This paper will summarize current findings and recommend further research in areas considered high priority. Specific guidelines regarding a recommended approach to long-term follow-up, including laboratory and clinical monitoring, will be forthcoming in a subsequent paper.

BACKGROUND:Hizentra® (IGSC 20%) is a 20% liquid IgG product approved for subcutaneous administration in adults and children 2 years of age and older who have primary immunodeficiency disease (PIDD). There is limited information about the use of IGSC 20 % in very young children including those less than 5 years of age. METHODS:A retrospective chart review involved 88 PIDD infants and children less than 5 years of age who received Hizentra®. RESULTS:The mean age at the start of Hizentra® was 34 months (range 2 to 59 months). IGSC 20 % was administered weekly to 86 infants (two additional infants received twice weekly and three times weekly infusions, respectively) and included an average of 63 infusions (range 6-182) for an observation period up to 45.5 months. Infusion by manual delivery occurred in 15 patients. The mean dose was 674 mg/kg/4 weeks. The mean IgG level was 942 mg/dL while on IGSC 20 %, compared to a mean trough IgG level of 794 mg/dL (p < 0.0001) during intravenous or subcutaneous IgG administration prior to IGSC 20 %. Average infusion time was 47 (range 5-120) minutes, and the median number of infusion sites was 2 (range 1-4). Local reactions were mostly mild and observed in 36/88 (41%) children. No serious adverse events were reported. A significant increase in weight percentile (7 % ± 19.2, p = 0.0012) among subjects was observed during IGSC 20% administration. The rate of serious bacterial infections was 0.067 per patient-year while receiving IGSC 20%, similar to previously reported efficacy studies. CONCLUSIONS:Hizentra® is effective in preventing infections, and is well tolerated in children less than age 5 years.

Flexible dosing of IgPro20 (Hizentra®, CSL Behring, King of Prussia, Pennsylvania) maintains normal serum immunoglobulin G (IgG) levels in patients with primary immunodeficiencies (PID). Until now, clinical trials testing the pharmacokinetic (PK) characteristics of serum IgG of weekly and biweekly subcutaneous IgG therapy were not published. This is the first study assessing PK characteristics following weekly and biweekly IgPro20 in patients with PID. The PK study was conducted in 2 parts: weekly dosing (12 weeks) and biweekly dosing (up to 12 months). Serum IgG concentration‐time data were analyzed using noncompartmental methods to generate PK parameters. Fifteen patients provided PK samples for both dosing regimens. For weekly and biweekly regimens, mean doses per infusion were 109 and 213 mg/kg, respectively, and median tmax was 2.0 and 3.02 days, respectively. The mean Ctrough values were similar in weekly and biweekly regimens (10.21 and 10.13 g/dL, respectively). The geometric mean ratios (GMRs) with 90% confidence intervals of biweekly to weekly Cmax and Ctrough were 1.10 (1.06–1.13) and 0.98 (0.95–1.01), respectively. The GMR of dAUC was 1.07 (1.03–1.10). This PK analysis demonstrated similar systemic IgG exposure after weekly and biweekly IgPro20 dosing with an equivalent monthly dose in patients with PID. [ABSTRACT FROM AUTHOR]

The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome. [ABSTRACT FROM AUTHOR]

Summary: Primary haemophagocytic lymphohistiocytosis (HLH) diseases are a collection of inherited genetic disorders that cause the syndrome of HLH. Great advances have been made in the last 20 years with regard to the discovery of many of the genetic aetiologies of disease. Several advances have also been made on the clinical stage. Accurate screening diagnostics for primary HLH diseases that are superior to traditional Natural Killer cell function testing have been developed and are now available in many countries. There is now grounded clinical experience on which to base routine treatment decisions for patients with HLH. Newer approaches to allogeneic haematopoietic cell transplantation have increased overall patient survival. Despite these advances, however, there is still much work to be done to further improve patient care. This ‘How I Treat’ article will focus on summarizing current diagnostic, treatment and transplant strategies for patients with primary HLH diseases. [ABSTRACT FROM AUTHOR]

The article focuses on newborn screening for severe combined immunodeficiency. It states that severe combined immunodeficiency is a medical emergency that can potentially be cured by hematopoietic stem cell transplantation or gene therapy, and mentions that outcomes for severe combined immunodeficiency are greatly improved by early diagnosis and treatment. It notes that newborn screen evaluates for T-cell lymphopenia using a T-cell receptor excision circle assay.

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies. [ABSTRACT FROM AUTHOR]

Purpose: Severe Combined Immune Deficiency (SCID) is universally fatal unless treated with hematopoietic stem cell transplantation (HSCT). Following the identification of disseminated Bacille Calmette-Guérin (BCG) infections in Canadian First Nations, Métis and Inuit (FNMI) children with unrecognized primary immune deficiencies, a national surveillance study was initiated in order to determine the incidence, diagnosis, treatment and outcome of children with SCID in Canada. Methods: Canadian pediatricians were asked to complete a monthly reporting form if they had seen a suspected SCID case, from 2004 to 2010, through the Canadian Paediatric Surveillance Program (CPSP). If the case met CPSP SCID criteria, more detailed data, including demographics and clinical information about investigations, treatment and outcome was collected. Results: A total of 40 cases of SCID were confirmed for an estimated incidence of SCID in non-FNMI Canadian children of 1.4 per 100,000 live births (95 % CI 1 to 1.9/100,000). The proportion of SCID cases that were FNMI (17.5 %) was almost three times higher than was expected on the basis of proportion of the pediatric population estimated to be FNMI (6.3 %) resulting in an estimated incidence of 4.4 per 100,000 live births (95 % CI 2.1 to 9.2/100,000) in FNMI Canadian children. The mean age at diagnosis for all SCID cases was 4.2 months (range 1–583 days). There were 12 deaths (30 %; 95 % CI 18–46 %); seven died of confirmed or suspected infections before they could receive an HSCT. Conclusions: The frequency of SCID cases in FNMI children is higher than in the general Canadian pediatric population. The high mortality rate, due primarily to infection, suggests that early diagnosis by newborn screening followed by HSCT could significantly benefit children with SCID. [ABSTRACT FROM AUTHOR]

Background Congenital multiple intestinal atresia (MIA) is a severe, fatal neonatal disorder, involving the occurrence of obstructions in the small and large intestines ultimately leading to organ failure. Surgical interventions are palliative but do not provide long-term survival. Severe immunodeficiency may be associated with the phenotype. A genetic basis for MIA is likely. We had previously ascertained a cohort of patients of French-Canadian origin, most of whom were deceased as infants or in utero. The goal of the study was to identify the molecular basis for the disease in the patients of this cohort. Methods We performed whole exome sequencing on samples from five patients of four families. Validation of mutations and familial segregation was performed using standard Sanger sequencing in these and three additional families with deceased cases. Exon skipping was assessed by reverse transcription-PCR and Sanger sequencing. Results Five patients from four different families were each homozygous for a four base intronic deletion in the gene TTC7A, immediately adjacent to a consensus GT splice donor site. The deletion was demonstrated to have deleterious effects on splicing causing the skipping of the attendant upstream coding exon, thereby leading to a predicted severe protein truncation. Parents were heterozygous carriers of the deletion in these families and in two additional families segregating affected cases. In a seventh family, an affected case was compound heterozygous for the same 4bp deletion and a second missense mutation p.L823P, also predicted as pathogenic. No other sequenced genes possessed deleterious variants explanatory for all patients in the cohort. Neither mutation was seen in a large set of control chromosomes. Conclusions Based on our genetic results, TTC7A is the likely causal gene for MIA. [ABSTRACT FROM AUTHOR]

The recommended dose of IgG in primary immunodeficiency (PID) has been increasing since its first use. This study aimed to determine if higher subcutaneous IgG doses resulted in improved patient outcomes by comparing results from two parallel clinical studies with similar design. One patient cohort received subcutaneous IgG doses that were 1.5 times higher than their previous intravenous doses (mean 213 mg/kg/week), whereas the other cohort received doses identical to previous subcutaneous or intravenous doses (mean 120 mg/kg/week). While neither cohort had any serious infections, the cohort maintained on higher mean IgG dose had significantly lower rates of non-serious infections (2.76 vs. 5.18 episodes/year, P < 0.0001), hospitalization (0.20 vs. 3.48 days/year, P < 0.0001), antibiotic use (48.50 vs. 72.75 days/year, P < 0.001), and missed work/school activity (2.10 vs. 8.00 days/year, P < 0.001). The higher-dose cohort had lower health care utilization and improved indices of well being compared to the cohort treated with traditional IgG doses. [ABSTRACT FROM AUTHOR]

With >36 years of data collected, PIDTC prospective (6901) and retrospective (6902) natural history studies provide an unprecedented opportunity to study hematopoietic cell transplantation (HCT) outcomes for SCID over time. Patients in this 6901/6902 analysis met PIDTC diagnostic criteria for SCID and underwent HCT. Categorial variables were analyzed between decades (a) 1982-89 (b) 1990-99 (c) 2000-09 (d) 2010-18 using the chi-square test. Continuous outcomes were compared using the Kruskal-Wallis test. Kaplan-Meier method was used for estimates of overall survival (OS). 896 children with typical (n=742) and atypical (n=154) SCID requiring HCT between 1982-2018 were enrolled. Diagnosis of SCID for reasons other than family history or newborn screening was common (60%) in early cohorts (a-c) dropping to 30% in cohort (d). Distribution of SCID genotypes changed over time (Fig 1), and novel/unknown genotypes also decreased from (a) 53% to (d) 13%, p<0.001. Due to the rise of gene therapy, there were fewer patients with adenosine deaminase deficient SCID receiving HCT in cohort (d) compared to prior decades. Median age at HCT has decreased, from 193 to 112 days of life, p<0.001. While marrow was the most common stem cell source in the 1980's (95%), currently peripheral blood stem cells and cord blood are given to 46% of patients (p<0.001). The increased use of unrelated donors parallels a decrease in mismatched related donors (Fig 2a; p<0.001). In univariate analysis, use of conditioning has increased from 12% in the 1980's to 65% currently (Fig 2b, p<0.001); contributing factors that will be evaluated in upcoming multivariate analyses include genotype, typical vs atypical SCID, and donor type. Day +100 cumulative incidence of grades 3-4 acute graft-versus-host disease (GVHD) has dropped, from 9.6% to 5.9% (p=0.02). OS has markedly improved in the last decade (Fig 3a), with 1- and 5-year OS being 90 and 87%, respectively (p=0.02). In particular, gains have been made in OS when using alternative donors (p=0.02) (Fig 3c,d) while OS for matched sibling HCT remains high (Fig 3b). This longitudinal data set, spanning the implementation of NBS and advancements in diagnostics and supportive care, highlights improved OS after HCT for SCID, including alternative donors. Exploration of decreased toxicity approaches that maintain high OS and engraftment are warranted. [ABSTRACT FROM AUTHOR]