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Background No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. Methods We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Results Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

To evaluate the relationship between knowledge of genetic diagnosis before HSCT and outcome, we reviewed all HSCTs for primary immune deficiencies (PID) performed at UCSF from 2007 through 2018. SCID, a distinct entity identified since 2010 in California by newborn screening and treated early, was considered separately. The underlying genetic condition was known at the time of HSCT in 85% of cases. Graft failure was less frequent in patients with a genetic diagnosis (19% with a genetic diagnosis versus 47% without, p = 0.020). Furthermore, event-free survival and overall survival (OS) at 5 years were better for those with a genetic diagnosis (78% with versus 44% without, p = 0.006; and 93% versus 60% without, p = 0.0002, respectively). OS at 5 years was superior for known-genotype patients with both SCID (p = 0.010) and non-SCID PID (p = 0.010). There was no difference in OS between HSCT done in 2007–2010 compared to more recently (p = 0.19). These data suggest that outcomes of HSCT for PID with known genotype may reflect specific experience and literature, or that a substantial proportion of patients with PID of undetermined genotype may have had underlying conditions for which HSCT may carry greater risk. The higher rate of graft failure in PID with unknown genotype may be in part explained by insufficient conditioning, which in turn could be dictated by compromised organ function in patients undergoing HSCT late in the course. Widespread availability of PID gene sequencing as standard care can provide genetic diagnoses for most patients with PID prior to HSCT, permitting optimization of transplant approach.

Purpose Metabolic detoxification with enzyme replacement therapy (ERT) promotes immune recovery in patients with adenosine deaminase (ADA)–deficient severe combined immunodeficiency (ADA-SCID). Elapegademase is a PEGylated recombinant bovine ADA ERT developed to replace the now-discontinued bovine-derived pegademase. This study was a 1-way crossover from pegademase to elapegademase in 7 patients with ADA-SCID to assess efficacy and safety outcomes for elapegademase. Methods After once-weekly pegademase dosage was adjusted to achieve therapeutic metabolic detoxification and trough ADA activity, patients transitioned to a bioequivalent dose of elapegademase. Maintenance of metabolic detoxification and adequate ADA activity were evaluated periodically. Results One patient withdrew after 2 doses of an early elapegademase formulation due to injection-site pain caused by EDTA. The 6 remaining patients completed 71−216 weeks of elapegademase therapy with a formulation that did not contain EDTA. In these patients, elapegademase improved ADA activity compared with pegademase and maintained metabolic detoxification. Total lymphocyte counts increased for all completer patients from between 1.2- and 2.1-fold at the end of study compared with baseline. Elapegademase had a comparable safety profile to pegademase; no patient developed a severe infectious complication. Three patients had transient, non-neutralizing antibodies to pegademase, elapegademase, and/or polyethylene glycol ≤ 47 weeks of treatment without effect on trough plasma ADA activity or trough erythrocyte deoxyadenosine nucleotide levels. Conclusion Elapegademase was safe, well tolerated, achieved stable trough plasma ADA activity with weekly dosing, was effective in maintaining metabolic detoxification, and was associated with maintenance or improvements in lymphocyte counts compared with pegademase therapy in patients with ADA-SCID.

Newborn screening efforts focusing on the quantification of T cell receptor excision circles (TRECs), as a biomarker for abnormal thymic production of T cells, have allowed for the identification and definitive treatment of severe combined immunodeficiency (SCID) in asymptomatic neonates. With the adoption of TREC quantification in Guthrie cards across the USA and abroad, typical, and atypical SCID constitutes only ~ 10% of cases identified with abnormal TRECs associated with T cell lymphopenia. Several other non-SCID-related conditions may be identified by newborn screening in a term infant. Thus, it is important for physicians to recognize that other factors, such as prematurity, are often associated with low TRECs initially, but often improve with age. This paper focuses on a challenge that immunologists face: the diagnostic evaluation and management of cases in which abnormal TRECs are associated with variants of T cell lymphopenia in the absence of a genetically defined form of typical or atypical SCID. Various syndromes associated with T cell impairment, secondary forms of T cell lymphopenia, and idiopathic T cell lymphopenia are identified using this screening approach. Yet there is no consensus or guidelines to assist in the evaluation and management of these newborns, despite representing 90% of the patients identified, resulting in significant work for the clinical teams until a diagnosis is made. Using a case-based approach, we review pearls relevant to the evaluation of these newborns, as well as the management dilemmas for the families and team related to the resolution of genetic ambiguities.

DOCK8 immunodeficiency syndrome (DIDS) represents a rare primary immunodeficiency associated with cutaneous viral infections, allergy, and increased risk of malignancy. We report a case of folliculotropic mycosis fungoides with spontaneous resolution occurring in a patient with DIDS.

To evaluate the relationship between knowledge of genetic diagnosis before HSCT and outcome, we reviewed all HSCTs for primary immune deficiencies (PID) performed at UCSF from 2007 through 2018. SCID, a distinct entity identified since 2010 in California by newborn screening and treated early, was considered separately. The underlying genetic condition was known at the time of HSCT in 85% of cases. Graft failure was less frequent in patients with a genetic diagnosis (19% with a genetic diagnosis versus 47% without, p = 0.020). Furthermore, event-free survival and overall survival (OS) at 5 years were better for those with a genetic diagnosis (78% with versus 44% without, p = 0.006; and 93% versus 60% without, p = 0.0002, respectively). OS at 5 years was superior for known-genotype patients with both SCID (p = 0.010) and non-SCID PID (p = 0.010). There was no difference in OS between HSCT done in 2007-2010 compared to more recently (p = 0.19). These data suggest that outcomes of HSCT for PID with known genotype may reflect specific experience and literature, or that a substantial proportion of patients with PID of undetermined genotype may have had underlying conditions for which HSCT may carry greater risk. The higher rate of graft failure in PID with unknown genotype may be in part explained by insufficient conditioning, which in turn could be dictated by compromised organ function in patients undergoing HSCT late in the course. Widespread availability of PID gene sequencing as standard care can provide genetic diagnoses for most patients with PID prior to HSCT, permitting optimization of transplant approach.

Adenosine deaminase (ADA) deficiency causes ∼13% of cases of severe combined immune deficiency (SCID). Treatments include enzyme replacement therapy (ERT), hematopoietic cell transplant (HCT), and gene therapy (GT). We evaluated 131 patients with ADA-SCID diagnosed between 1982 and 2017 who were enrolled in the Primary Immune Deficiency Treatment Consortium SCID studies. Baseline clinical, immunologic, genetic characteristics, and treatment outcomes were analyzed. First definitive cellular therapy (FDCT) included 56 receiving HCT without preceding ERT (HCT); 31 HCT preceded by ERT (ERT-HCT); and 33 GT preceded by ERT (ERT-GT). Five-year event-free survival (EFS, alive, no need for further ERT or cellular therapy) was 49.5% (HCT), 73% (ERT-HCT), and 75.3% (ERT-GT; P < .01). Overall survival (OS) at 5 years after FDCT was 72.5% (HCT), 79.6% (ERT-HCT), and 100% (ERT-GT; P = .01). Five-year OS was superior for patients undergoing HCT at

Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases.

Allergy and immunology practitioners are often consulted to evaluate patients with primary immune deficiency disorders (PIDD), in part because of improved awareness and diagnostic evaluation of these once considered rare diseases. This Yardstick provides information regarding state-of-the-art genetic testing to assist in the evaluation of patients with suspected or confirmed immunodeficiencies. Advances in gene sequencing technology has led to increased accessibility to genetic testing, which is essential for diagnosis, treatment, prognosis, and reproductive/family counseling. Methods that allow simultaneous sequence of several genes, known as targeted gene. sequencing (TGS), whole exome sequencing (WES), and whole genome sequencing (WGS), are currently being offered by clinical laboratories. Fluorescent in situ hybridization (FISH) and chromosomal microarray (CMA) are used to detect duplications or deletions of chromosomal regions. Each of these methods has advantages and disadvantages in the diagnostic workup of PIDD. Counseling on genetic implications to patients and their families is necessary before and after test results are available. Interpretation of results requires understanding of both genetic and immunological mechanisms of disease, especially when a newly described gene variant is reported and its association with disease has not been previously demonstrated.

Background Caregivers of children with primary immunodeficiency disorders (PIDs) experience significant psychological distress during their child's hematopoietic cell transplantation (HCT) process. Objectives This study aims to understand caregiver challenges and identify areas for health care system-level improvements to enhance caregiver well-being. Methods In this mixed-methods study caregivers of children with PIDs were contacted in August to November 2017 through online and electronic mailing lists of rare disease consortiums and foundations. Caregivers were invited to participate in an online survey assessing sociodemographic variables, the child's medical characteristics, psychosocial support use, and the World Health Organization–5 Well-Being Index. Open-ended questions about health care system improvements were included. Descriptive statistics and linear multivariate regression analyses were conducted. A modified content analysis method was used to code responses and identify emergent themes. Results Among the 80 caregiver respondents, caregivers had a median age of 34 years (range, 23-62 years) and were predominantly female, white, and married with male children given a diagnosis of severe combined immune deficiency. In the adjusted regression model lower caregiver well-being was significantly associated with lower household income and medical complications. Challenges during HCT include maintaining relationships with partners and the child's healthy sibling or siblings, managing self-care, and coping with feelings of uncertainty. Caregivers suggested several organizational-level solutions to enhance psychosocial support, including respite services, online connections to other PID caregivers, and bedside mental health services. Conclusions Certain high-risk subpopulations of caregivers might need more targeted psychosocial support to reduce the long-term effect of the HCT experience on their well-being. Caregivers suggested several organizational-level solutions for provision of this support.

In the United States, significant improvement in diagnosis and outcomes for children affected with severe combined immunodeficiency has followed institution of newborn screening using an assay to measure T-cell receptor excision circles in newborn dried blood spot specimens. Key to this outcome is the avoidance of infectious complications in infants with severe combined immunodeficiency.

BackgroundCytomegalovirus (CMV) serostatus of recipient (R) and donor (D) influences hematopoietic stem cell transplant (HSCT) outcome. However, it is not a reliable indicator of CMV infection in primary immunodeficiency disorder (PIDD) recipients who are unable to make adequate antigen-specific immunoglobulin (Ig) or who receive intravenous Ig (IVIg) prior to testing.ObjectiveSince no data exist on PIDD with unknown CMV serostatus, we aimed to evaluate the relationship between pre-HSCT recipient and donor serostatus and incidence of CMV infection in recipients with unknown serostatus.MethodsA retrospective analysis of all pediatric PIDD HSCTs (2007-2018) was performed at University of California San Francisco. Recipients were separated into categories based on pre-transplant serostatus: 1) seropositive (R(+)), 2) seronegative (R(-)), and 3) unknown serostatus (R(x)). Patients with pre-HSCT active CMV viremia were excluded.ResultsA total of 90 patients were included, 69% male. The overall incidence of CMV infection was 20%, but varied in R(+), R(-), and R(x) at 80%, 0%, and 14%, (P-value=.0001). Similarly, 5-year survival differed among groups, 60% R(+), 100% R(-), and 90% of R(x) (P-value=.0045). There was no difference in CMV reactivation by donor serostatus (P-value=.29), however, faster time to clearance of CMV was observed for R(x)/D(+) group (median 9.5days (IQR 2.5-18), P-value=.024).ConclusionWe identify a novel group of recipients, R(x), with an intermediate level of survival and CMV incidence post-HSCT, when compared to seropositive and seronegative recipients. No evidence of CMV transmission from D(+) in R(-) and R(x) was observed. We believe R(x) should be considered as a separate category in future studies to better delineate recipient risk status.

PURPOSE: The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention. METHODS: We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management. RESULTS: Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (p = 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively; p = 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented. CONCLUSION: Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS. TRIAL REGISTRATION: NCT01186913

Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytic cells1,2. We report the initial results of nine severely affected X-linked CGD (X-CGD) patients who received ex vivo autologous CD34+ hematopoietic stem and progenitor cell-based lentiviral gene therapy following myeloablative conditioning in first-in-human studies (trial registry nos. NCT02234934 and NCT01855685). The primary objectives were to assess the safety and evaluate the efficacy and stability of biochemical and functional reconstitution in the progeny of engrafted cells at 12 months. The secondary objectives included the evaluation of augmented immunity against bacterial and fungal infection, as well as assessment of hematopoietic stem cell transduction and engraftment. Two enrolled patients died within 3 months of treatment from pre-existing comorbidities. At 12 months, six of the seven surviving patients demonstrated stable vector copy numbers (0.4–1.8 copies per neutrophil) and the persistence of 16–46% oxidase-positive neutrophils. There was no molecular evidence of either clonal dysregulation or transgene silencing. Surviving patients have had no new CGD-related infections, and six have been able to discontinue CGD-related antibiotic prophylaxis. The primary objective was met in six of the nine patients at 12 months follow-up, suggesting that autologous gene therapy is a promising approach for CGD patients. Initial results from phase I/II lentiviral gene therapy trials provide early evidence supporting its safety and efficacy in treating patients with X-linked chronic granulomatous disease.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; PCONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

TO THE EDITOR: Severe combined immunodeficiency (SCID) may be diagnosed via newborn screening (NBS) by measuring T-cell receptor excision circles.[1][1],[2][2] The incidence of SCID has risen, and this is rise attributed to the identification of patients who would have previously died of infections

Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies., Author summary Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas (abnormal collections (nodules) of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014–2016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity.

Background Threonine Aspartase 1 (Taspase 1) is a highly conserved site‐specific protease whose substrates are broad‐acting nuclear transcription factors that govern diverse biological programs, such as organogenesis, oncogenesis, and tumor progression. To date, no single base pair mutations in Taspase 1 have been implicated in human disease. Methods A female infant with a new pattern of diagnostic abnormalities was identified, including severe craniofacial anomalies, anterior and posterior segment dysgenesis, immunodeficiency, and macrocytic anemia. Trio‐based whole exome sequencing was performed to identify disease‐causing variants. Results Whole exome sequencing revealed a normal female karyotype (46,XX) without increased regions of homozygosity. The proband was heterozygous for a de novo missense variant, c.1027G>A predicting p.(Val343Met), in the TASP1 gene (NM_017714.2). This variant has not been observed in population databases and is predicted to be deleterious. Conclusion One human patient has been reported previously with a large TASP1 deletion and substantial evidence exists regarding the role of several known Taspase 1 substrates in human craniofacial and hematopoietic disorders. Moreover, Taspase 1 deficiency in mice results in craniofacial, ophthalmological and structural brain defects. Taken together, there exists substantial evidence to conclude that the TASP1 variant, p.(Val343Met), is pathogenic in this patient.

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000–1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

Background The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. Objective ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. Methods Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non–daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. Results Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non–daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non–daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. Conclusions Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

ObjectiveTo review currently available data on the transfer of monoclonal antibodies (mAbs) in the breastmilk of women receiving treatment for neurologic and non-neurologic diseases.MethodsWe systematically searched the medical literature for studies referring to 19 selected mAb therapies frequently used in neurologic conditions and “breastmilk,” “breast milk,” “breastfeeding,” or “lactation.” From an initial list of 288 unique references, 29 distinct full-text studies met the eligibility criteria. One additional study was added after the literature search based on expert knowledge of an additional article. These 30 studies were reviewed. These assessed the presence of our selected mAbs in human breastmilk in samples collected from a total of 155 individual women.ResultsDrug concentrations were typically low in breastmilk and tended to peak within 48 hours, although maximum levels could occur up to 14 days from infusion. Most studies did not evaluate the breastmilk to maternal serum drug concentration ratio, but in those evaluating this, the highest ratio was 1:20 for infliximab. Relative infant dose, a metric comparing the infant with maternal drug dose (ConclusionsThe current data are reassuring for low mAb drug transfer to breastmilk, but further studies are needed, including of longer-term effects on infant immunity and childhood development.

PURPOSE: Nitazoxanide was recently reported as having in vitro effectiveness against the rubella virus. Immunodeficiency-related vaccine-derived rubella occurs in some patients who have an inherited immunodeficiency and who received the MMR vaccine. This study investigated the in vivo effectiveness of nitazoxanide therapy. METHODS: This is a retrospective analysis of seven patients treated with nitazoxanide as salvage therapy for immunodeficiency-related vaccine-derived rubella infection. The patients were recruited from an ongoing rubella detection surveillance project. RESULTS: Seven patients with persistent rubella were treated with nitazoxanide and one demonstrated significant clinical improvement. Two additional patients exhibited diminished viral capsid production with one patient having transient slowing of progression. The cohort overall generally had low T cell counts and had a high burden of co-morbidities. There were three deaths. Two deaths were from PML and one was related to hematopoietic stem cell transplantation. CONCLUSIONS: Nitazoxanide has limited in vivo anti-viral effects for immunodeficiency-related vaccine-derived rubella. Most patients did not exhibit clinical improvement.

Hyper IgE syndrome (HIES) should be considered when a patient presents with elevated IgE levels, eczema, recurrent skin abscesses and pneumonia DOCK8 deficiency should be considered in any patient with immunodeficiency and a history of atopy (i.e. allergic rhinitis, food allergies, asthma) and elevated IgE Patients with DOCK8 deficiency are at increased risk of malignancy secondary to cutaneous viral infections. This is due to susceptibility of DOCK8-deficient T and NK cells to cytothripsis during migration through collagen-dense tissues Definitive cure is hematopoietic stem cell transplantation which leads to immune reconstitution and reversal of clinical phenotypes

In the United States, significant improvement in diagnosis and outcomes for children affected with severe combined immunodeficiency has followed institution of newborn screening using an assay to measure T-cell receptor excision circles in newborn dried blood spot specimens. Key to this outcome is the avoidance of infectious complications in infants with severe combined immunodeficiency.

Background Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. Objective We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. Methods A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. Results Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB–dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB–driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20 , intercellular adhesion molecule 1 (ICAM1) , and vascular cell adhesion molecule 1 (VCAM1) , which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin β receptor–stimulated fibroblasts from patients with point mutations compared with those with truncations. Conclusions IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.

Summary Multiple subcutaneous immunoglobulin (SCIG) products are available to treat primary antibody deficiency (PAD). The efficacy and tolerability of 16% SCIG (Vivaglobin®) was compared with 20% SCIG (Hizentra®) in PAD subjects. The study was a prospective, single-centre, open-label study of PAD subjects transitioning Vivaglobin to equivalent Hizentra doses, rounded to the nearest vial size. Comparisons included immunoglobulin (Ig)G levels; tetanus, varicella and Streptococcus pneumoniae titres; adverse events (AEs), annual infection rate and quality of life during 8 weeks of Vivaglobin and 24 weeks of Hizentra. Thirty-two subjects (aged 2–75 years) participated. Rounding to the nearest Hizentra vial size resulted in a 12·8% (± 2·9%) increase in SCIG dose. Median immunoglobulin (Ig)G level following 8 weeks of Vivaglobin was similar to 24 weeks of Hizentra (1050 versus 1035 mg/dl, respectively; P = 0·77). Both products had similar protective titres to tetanus, varicella and serotypes of S. pneumoniae, which were variable but well above protective levels. After 12 weeks of Hizentra, subjects reported fewer local site reactions compared with Vivaglobin. Switching products resulted in increased systemic AEs in some subjects but, overall, not significantly higher than during Vivaglobin treatment. Average infusion time decreased from 104·7 min (3·3 sites) with Vivaglobin to 70·7 min (2·2 sites) with Hizentra (P = 0·0005). Acute serious bacterial infections were similar. Treatment satisfaction was superior with Hizentra. Hizentra and Vivaglobin have similar pharmacokinetics and efficacy. Although transition to a different SCIG product initially increased AEs, Hizentra is well tolerated and can be infused more rapidly and with fewer sites compared to Vivaglobin.

T cells play the central role in adaptive immunity and deficiencies affecting this key component of the immune system result in the most severe forms of primary immunodeficiency. The classic example within this group of immunodeficiencies is severe combined immunodeficiency (SCID). The infectious complications include a wide spectrum of organisms, but viral infections and opportunistic infections are commonly found in infants with SCID who are not identified by newborn screening (NBS). With NBS for SCID through quantification of T cell receptor excision circles (TRECs), the prognosis associated with this condition has improved considerably, with the vast majority of these infants in the USA found early and often without infectious complications. Conditions of T cell immunity not as severe as SCID are broad, and, in addition to infection, noninfectious complications can develop including lymphoproliferation, inflammation, and autoimmunity, notably inflammatory bowel disease. The relatively poor prognosis of T cell immune deficiencies requires those affected to initiate extensive antimicrobial prophylaxis often combined with immunosuppressive treatments to control inflammatory complications. Definitive therapy often includes hematopoietic cell transplant. There are nearly 90 primary immunodeficiency conditions that are considered predominantly T cell and combined T cell and B cell conditions, not all of which can be covered in the scope of this chapter (Picard et al., J Clin Immunol. 35(8):696–726, 2015). Instead we will focus on severe combined immunodeficiency (SCID) in its various forms as well as highlight specific immune defects that illustrate unique aspects of aberrant T cell immunity and resultant clinical manifestations.

Unconditioned unrelated donor bone marrow transplantation for IL7Rα- and Artemis-deficient SCID

Severe combined immunodeficiency (SCID) is characterized by severely impaired T-cell development and is fatal without treatment. Newborn screening (NBS) for SCID permits identification of affected infants before development of opportunistic infections and other complications. Substantial variation exists between treatment centers with regard to pretransplantation care, and transplantation protocols for NBS identified infants with SCID, as well as infants with other T-lymphopenic disorders detected by using NBS. We developed approaches to management based on the study of infants identified by means of NBS for SCID who received care at the University of California, San Francisco (UCSF). From August 2010 through October 2016, 32 patients with NBS-identified SCID and leaky SCID from California and other states were treated, and 42 patients with NBS-identified non-SCID T-cell lymphopenia were followed. Our center's approach supports successful outcomes; systematic review of our practice provides a framework for diagnosis and management, recognizing that more data will continue to shape best practices.

Purpose This retrospective study evaluated the effectiveness and tolerability in clinical practice of an L-proline–stabilized 10 % intravenous immunoglobulin (IVIG; Privigen®) in patients with primary (PID) or secondary immunodeficiency (SID). Methods Patients from 6 centers in Europe and the US were treated with individually determined regimens of Privigen® for ≥3 months. Serum immunoglobulin G (IgG) trough levels, annualized rates of infection, hospitalization and antibiotics use, and the incidence of adverse events (AEs) were analyzed. Results Of 72 patients, three infants with severe combined immunodeficiency (SCID) were analyzed separately. The remaining 69 patients (52.2 % male; median age 38 years [range: 0.1–90.0]) with PID (82.6 %) or SID (17.4 %) received a mean (±standard deviation) Privigen® dose of 532 ± 250 mg/kg/month resulting in trough serum IgG levels of 407–1,581 mg/dL (median: 954 mg/dL). Ten patients (14.5 %) experienced 11 serious bacterial infections over 22.0 ± 15.0 months of treatment (0.087 events/patient/year, upper one-sided 99 % confidence interval: 0.170), the most common being pneumonia (11.6 %). The rates for any infection and hospitalization were 1.082 events/patient/year and 3.63 days/patient/year, respectively. Two patients with severe disease accounted for 303 of 460 hospital days. Across all 72 patients, 13 (18.1 %) patients experienced AEs, including 10 (13.9 %) patients with AEs at least possibly related to Privigen®, including headache (8.3 %), fever, and chills (2.8 % each). No related serious AEs were reported. One infant with SCID died due to severe viral infection. Conclusions Despite the heterogeneous population, effectiveness and tolerability of Privigen® in clinical practice closely matched those reported in clinical studies.

WOS: 000398771800023, PubMed ID: 27697500, 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., Jeffrey Modell Foundation; National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease [U54 AI 082973, R13AI094943], Supported by a grant from Jeffrey Modell Foundation (to M.d.l.M.). The Primary Immune Deficiency Treatment Consortium (PIDTC) is supported by the National Institutes of Health Office of Rare Diseases, National Center for Advancing Translational Sciences and National, Institute of Allergy and Infectious Disease grants U54 AI 082973 and R13AI094943.

X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.

The objective of this study is to determine if immune reconstitution of FOXP3+ T regulatory cells correlates with clinical improvement of IPEX syndrome following allogeneic hematopoietic stem cell transplant. An 8-months-old male infant with a mutation in the polyadenylation site of FOXP3 gene, absence of FOXP3 protein expression and clinical manifestations of IPEX syndrome, including eczema, colitis, failure to thrive, TPN requirement, and elevated serum IgE, underwent matched unrelated hematopoietic stem cell transplant. After reduced-intensity conditioning with alemtuzumab followed by fludarabine and melphalan the patient's neutrophils engrafted day +15 and platelets day +29. Patient was a full donor chimera day +28 and +60. Intracellular FOXP3 protein expression in CD4+ T cells was absent pre-HSCT. After transplantation, percentage CD4+ T cells expressing FOXP3+CD25 bright phenotype quickly increased from 4.5 (day +29) to 23% (day +90) and continued in this trend. Foxp3 mRNA expression confirmed flow cytometry data. Serum IgE levels decreased from 5,000 IU/ml pre-transplant to 6 IU/ml on day +90, eczema resolved, and secretory diarrhea and feeding intolerance improved. T regulatory cell reconstitution is evident soon after HSCT following reduced-intensity conditioning correlating with development of full donor chimerism. Increased FOXP3 expression correlates with correction of clinical and laboratory manifestations of IPEX syndrome providing direct evidence that HSCT is a curative procedure for this disorder.

Human immunoglobulin preparations for intravenous or subcutaneous administration are the cornerstone of treatment in patients with primary immunodeficiency diseases affecting the humoral immune system. Intravenous preparations have a number of important uses in the treatment of other diseases in humans as well, some for which acceptable treatment alternatives do not exist. We provide an update of the evidence-based guideline on immunoglobulin therapy, last published in 2006. Given the potential risks and inherent scarcity of human immunoglobulin, careful consideration of its indications and administration is warranted.

Background Transient hypogammaglobulinemia of infancy (THI) is a heterogeneous disorder with poorly understood pathophysiology. Objectives To better characterize THI and improve understanding of its pathophysiology. Methods Twenty-four children with hypogammaglobulinemia defined by an IgG level less than 2 SDs below the mean on 2 occasions, who did not have other immunologic diagnoses, were followed and retrospectively reviewed. Results The average z-score for IgG level at presentation was −2.4 (mean age, 12 months; median age, 8 months), with a mean level of 254 mg/dL. Thirteen of 24 patients had IgA levels less than 2 SDs below the mean, 5 had IgM levels less than 2 SDs below the mean, and 7 of 23 had elevated IgE levels. Eighteen were followed up until their IgG levels normalized (mean age, 27 months; median age, 23 months), with 12 of 18 normalizing by 24 months and the remainder by 59 months. There was a significant association between presenting IgG z-score and duration of disease ( P = .05). Five of the 18 patients had absolute CD19 + B-cell counts greater than the 95% percentile for age ( P + B-cell count across all patients were greater than those of the age-matched controls ( P = .02). Most patients had nonprotective titers to Haemophilus influenzae type b vaccine, and one third had nonprotective titers to tetanus vaccine. Twenty patients carried at least one atopic diagnosis, and 13 of those had recurrent wheezing. Conclusions THI is associated with a number of immunologic abnormalities beyond just hypogammaglobulinemia. These abnormalities include impaired specific antibody responses and increased proportions of CD19 + B cells and may be suggestive of particular immunologic mechanisms that result in hypogammaglobulinemia.

Background Inhaled corticosteroids (ICs) are considered first-line therapy for persistent asthma. At medium to high doses, ICs can suppress the hypothalamic-pituitary-adrenal (HPA) axis. Various provocative stimuli have been used to evaluate HPA axis function, but they are labor intensive and time-consuming. Dehydroepiandrosterone sulfate (DHEA-S) is a corticotropin-dependent adrenal androgen precursor that is suppressible in patients treated with ICs. Objectives To evaluate DHEA-S as a possible marker for HPA axis dysfunction in children treated with ICs. Methods Children with moderate-to-severe persistent asthma and a history of medium- to high-dose IC exposure for at least 6 months were evaluated using low-dose and standard high-dose cosyntropin stimulation testing to assess adrenal function, and DHEA-S levels were compared with the results. Results Thirteen (59%) of 22 patients exhibited an abnormal cortisol response to cosyntropin. Age- and sex-specific mean DHEA-S z scores were significantly lower in cosyntropin abnormal responders (−1.2822) compared with normal responders (0.2964) ( P = .008). The receiver operating characteristic curve for DHEA-S z scores had an area of 0.786 (95% confidence interval, 0.584–0.989), reaching 100% sensitivity with a DHEA-S z score of −1.5966 or less and 100% specificity with a DHEA-S z score greater than 0.0225. Conclusions Most children develop biochemical evidence of adrenal suppression after treatment with medium to high doses of ICs. The presence of low DHEA-S levels can be used as a screening test to identify the child who needs more formal testing of the HPA axis.

In the US, the assay of T cell receptor excision circles (TRECs) in newborn dried blood spot specimens to detect severe combined immunodeficiency (SCID) was first piloted in 2008 in the state of Wisconsin. It has been rapidly adopted with 49 states and Puerto Rico now either routinely screening all newborns or planning to do so in 2017. Advances in SCID NBS over the last 9 years have revolutionized the ability to detect SCID and has led to profound improvement in outcomes of affected children.

Ferrochelatase (FECH; EC 4.99.1.1) catalyzes the terminal step of the heme biosynthetic pathway. Defects in the human FECHgene may lead to erythropoietic protoporphyria (EPP), a rare inherited disorder characterized by diminished FECH activity with protoporphyrin overproduction and subsequent skin photosensitivity and in rare cases liver failure. Inheritance of EPP appeared to be autosomal dominant with possible modulation by low expression of the wild-type FECH allele. Animal FECHs have been demonstrated to be [2Fe-2S] cluster-containing proteins. Although enzymatic activity and stability of the protein appear to be dependent on the presence of the [2Fe-2S] cluster, the physiologic role of the iron-sulfur center remains to be unequivocally established. Three of the 4 [2Fe-2S] cluster-coordinating cysteines (ie, C403, C406, and C411 in the human enzyme) are located within the C-terminal domain. In this study 5 new mutations are identified in patients with EPP. Three of the point mutations, in 3 patients, resulted in FECH variants with 2 of the [2Fe-2S] cluster cysteines substituted with tyrosine, serine, and glycine (ie, C406Y, C406S, and C411G) and with undetectable enzymatic activity. Further, one of the patients exhibited a triple point mutation (T1224→A, C1225→T, and T1231→G) leading to the N408K/P409S/C411G variant. This finding is entirely novel and has not been reported in EPP. The mutations of the codons for 2 of the [2Fe-2S] cluster ligands in patients with EPP supports the importance of the iron-sulfur center for the proper functioning of mammalian FECH and, in at least humans, its absence has a direct clinical impact.

In the United States, newborn screening (NBS) is currently recommended for identification of 31 debilitating and potentially fatal conditions. However, individual states determine which of the recommended conditions are screened. The addition of severe combined immunodeficiency (SCID) screening to the recommended NBS panel has been fully instituted by 18 states, with another 11 states piloting programs or planning to begin screening in 2014. Untreated, SCID is uniformly fatal by 2 years of age. Hematopoietic stem cell transplantation usually is curative, but the success rate depends on the age at which the procedure is performed. Short-term implementation costs may be a barrier to adding SCID to states' NBS panels. A retrospective economic analysis was performed to determine the cost-effectiveness of NBS for early (5 times higher ($350,252 vs $66,379), and operating room-anesthesia charges were approximately 4 times higher ($57,105 vs $15,885). The cost-effectiveness of early treatment for SCID provides a strong economic rationale for the addition of SCID screening to NBS programs of other states.