Clinical updates in inborn errors of immunity: a focus on the noninfectious clinical manifestations.

PURPOSE OF REVIEW: In the last 5 years, several new inborn errors of immunity (IEI) have been described, especially in the areas of immune dysregulation and autoinflammation. As a result, the clinical presentation of IEIs has broadened. We review the heterogeneous presentation of IEIs and detail several of the recently described IEIs with a focus on the noninfectious manifestations commonly seen. RECENT FINDINGS: IEIs may present with early onset and/or multiple autoimmune manifestations, increased risk for malignancy, lymphoproliferation, severe atopy, autoinflammation and/or hyperinflammation. Because of this, patients can present to a wide array of providers ranging from primary care to various pediatric subspecialists. The International Union of Immunological Societies (IUIS) expert committee has created a phenotypic classification of IEIs in order to help clinicians narrow their evaluation based on the laboratory and clinical findings. SUMMARY: Both primary care pediatricians and pediatric subspecialists need to be aware of the common clinical features associated with IEI and recognize when to refer to allergy-immunology for further evaluation. Early diagnosis can lead to earlier treatment initiation and improve clinical outcomes for our patients.

Clinical and functional spectrum of RAC2-related immunodeficiency.

ABSTRACT: Mutations in the small Rho-family guanosine triphosphate hydrolase RAC2, critical for actin cytoskeleton remodeling and intracellular signal transduction, are associated with neonatal severe combined immunodeficiency (SCID), infantile neutrophilic disorder resembling leukocyte adhesion deficiency (LAD), and later-onset combined immune deficiency (CID). We investigated 54 patients (23 previously reported) from 37 families yielding 15 novel RAC2 missense mutations, including one present only in homozygosity. Data were collected from referring physicians and literature reports with updated clinical information. Patients were grouped by presentation: neonatal SCID (n = 5), infantile LAD-like disease (n = 5), or CID (n = 44). Disease correlated to RAC2 activity: constitutively active RAS-like mutations caused neonatal SCID, dominant-negative mutations caused LAD-like disease, whereas dominant-activating mutations caused CID. Significant T- and B-lymphopenia with low immunoglobulins were seen in most patients; myeloid abnormalities included neutropenia, altered oxidative burst, impaired neutrophil migration, and visible neutrophil macropinosomes. Among 42 patients with CID with clinical data, upper and lower respiratory infections and viral infections were common. Twenty-three distinct RAC2 mutations, including 15 novel variants, were identified. Using heterologous expression systems, we assessed downstream effector functions including superoxide production, p21-activated kinase 1 binding, AKT activation, and protein stability. Confocal microscopy showed altered actin assembly evidenced by membrane ruffling and macropinosomes. Altered protein localization and aggregation were observed. All tested RAC2 mutant proteins exhibited aberrant function; no single assay was sufficient to determine functional consequence. Most mutants produced elevated superoxide; mutations unable to support superoxide formation were associated with bacterial infections. RAC2 mutations cause a spectrum of immune dysfunction, ranging from early onset SCID to later-onset combined immunodeficiencies depending on RAC2 activity. This trial was registered at www.clinicaltrials.gov as #NCT00001355 and #NCT00001467.

Family Responses to Different Types of Clinician Empathy Expression in Pediatric Care Conferences.

Background: Clinician empathy positively impacts patient outcomes. Few studies have assessed the effects of different types of empathic expression. Objective: To describe how families respond when clinicians express empathy in different ways. Design: Prospective, mixed-methods cohort. Setting/Subjects: English and interpreted pediatric inpatient care conferences at a U.S. quaternary hospital between January 1, 2018 and January 1, 2021. Measurements: Directed content analysis of clinician empathic statements and family responses. Results: Of 29 patient-family dyads, 11 (39%) used language interpretation. In response to 80 clinician empathic statements, families expressed agreement or shared more 84% (67/80) of the time. Families shared more about their perspective in response to explore statements 71.4% (10/14) of the time, in response to validate statements 61% (17/28) of the time, and in response to respect/support statements 39% (11/28) of the time. Conclusion: Certain types of empathic statements may be more effective at prompting families to share more about their perspective, a key element of shared decision-making.

Exploring the links between necrotizing enterocolitis and cow's milk protein allergy in preterm infants: a narrative review.

A broad range of allergic disorders and intolerance are associated with cow's milk protein in the infant diet. Allergy and intolerance to cow's milk proteins are commonly recognized in the healthy term infant, and the prevalence cow's milk protein intolerance (CMPI) varies widely but 5 challenge confirmed studies free from selection bias ranged from 1.9%-4.9%. These disorders are classified by the presence of IgE, non-IgE or T-cell-mediated signaling. Additionally, the severity of these adverse food reactions can range from mild gastrointestinal symptoms to severe sepsis-like episodes, as in the case of food protein-induced enterocolitis syndrome (FPIES). Food protein-induced intolerance in the healthy young infant lies in stark contrast to enterocolitis that typically occurs in the preterm neonate. Necrotizing enterocolitis (NEC) is a distinct progressive disease process, usually characterized by a high mortality rate, with a risk of death from 30% to 50%. While its exact etiology is unclear, its main triggers include formula (cow's milk protein), hypoxia, perfusion-related issues, and unregulated inflammation in the premature intestine. The distinction between NEC and cow's milk protein intolerance is difficult to discern in some cases. In the late preterm population, infants with colitis can have both NEC and cow's milk intolerance on the differential. In infants with multiple episodes of mild NEC, cow's milk protein intolerance may be the underlying diagnosis. In this review, we compare the pathophysiological characteristics, diagnosis and treatment of disorders of cow's milk protein intolerance with the entity of preterm NEC. This review highlights similarities in both entities and may inspire future cross-disciplinary research.

The latent tuberculosis infection cascade of care during the COVID-19 pandemic response in a Mid-Sized US city.

Background: The COVID-19 pandemic response may unintentionally disrupt multiple public health services, including tuberculosis control programs. We aimed to assess differences in the cascade of care for latent tuberculosis infection (LTBI) in a Midwest U.S. city during the COVID-19 pandemic response. Methods: We conducted a retrospective cohort study of adult patients who presented for LTBI evaluation at the Hamilton County Public Health Tuberculosis Clinic in Ohio between 2019 and 2020. The pre-COVID-19 response period was defined as 01/2019 to 02/2020, and the COVID-19 pandemic response period (first wave) was defined as 04/2020 to 12/2020. We reviewed electronic medical records to extract sociodemographic information, medical history, follow-up and treatment data to define steps within the LTBI cascade of care. Logistic regressions were used to assess factors associated with LTBI treatment acceptance and completion, adjusted by potential confounders and COVID-19 period. Results: Data from 312 patients were included. There was a significant decrease in the number of monthly LTBI referrals (median, 18 vs. 8, p = 0.02) and LTBI evaluations (median, 17.5 vs. 7, p < 0.01) during the first wave of COVID-19. The proportion for whom immigration was listed as the indication for LTBI testing also declined (30% vs. 9%; p < 0.01) during COVID-19. More LTBI diagnoses were based on interferon-gamma release assay (IGRA; 30% vs. 49%; p < 0.01) during the COVID-19 response period. The proportion of people in the clinic for whom treatment for LTBI was recommended was similar before and during COVID-19 (76% vs. 81%, p = 0.41), as was LTBI treatment acceptance rates (56% vs. 64%, p = 0.28), and completion rates (65% vs. 63%, p = 0.85). In multivariate analysis, LTBI treatment acceptance was associated with Hispanic ethnicity, younger age, male sex, IGRA being used for diagnosis, and non-healthcare occupation, independent of COVID-19 period. LTBI treatment completion was associated with taking a rifamycin-containing regimen, independent of COVID-19 period. Conclusion: We observed a significant decline in the number of monthly LTBI referrals and evaluations during the first wave of COVID-19, revealing an unintended negative impact of the COVID-19 response in our region. However, LTBI treatment acceptance and completion rates were not affected during COVID-19.

Empathy Expression in Interpreted and Noninterpreted Care Conferences of Seriously Ill Children.

BACKGROUND AND OBJECTIVES: Clinician empathy is associated with improved communication and clinical outcomes. We hypothesized that, when clinicians express empathy, families are more likely to deepen discussions, and that clinicians express less empathy in care conferences with language interpretation. METHODS: Prospective, mixed methods cohort study of English and interpreted audio-recorded transcripts of care conferences for pediatric patients with serious illness hospitalized at a single urban, quaternary medical institution between January 2018 and January 2021. Directed content analysis identified empathic opportunities, clinician empathetic statements or missed opportunities, and family responses. Clinician empathic statements were "buried" if immediately followed by more clinician medical talk. Descriptive analyses summarized demographics and codes. χ2 analyses summarized differences among language interpretation and family responses. RESULTS: Twenty-nine patient-family dyads participated. Twenty-two (81%) family members were female. Eleven (39%) used language interpretation (8 Spanish, 2 Vietnamese, 1 Somali). Families created 210 empathic opportunities. Clinicians responded with unburied empathy 80 times (38%, no differences for English versus interpreted care conferences, P = .88). When clinicians buried empathy or missed empathic opportunities, families responded with alliance (agreement, gratitude, or emotional deepening) 14% and 15% of the time, respectively. When clinicians responded with unburied empathy, families responded with alliance 83% of the time (P < .01). CONCLUSIONS: Our study suggests that clinician empathic expression does not differ when language interpretation is used in pediatric care conferences. Clinicians often miss opportunities to express empathy, or they bury it by medical talk. Although unburied empathy created opportunities for relationship-building and family-sharing, buried empathy negatively impacted these domains similarly to no empathic expression.

The use of DXA for early detection of pediatric cystic fibrosis-related bone disease.

BACKGROUND: Cystic fibrosis (CF)-related bone disease (CFBD) is seen in adults and can be associated with respiratory illness and malnutrition. There is limited and conflicting data regarding CFBD in pediatric CF. With longer life expectancy and promotion of disease prevention, pediatric CFBD demands further investigation. METHODS: Our center initiated a quality improvement (QI) project from April 2016 to December 2018 to improve CFBD screening in patients 8 years or older, per current CF Foundation (CFF) guidelines. Our team formulated a dual-energy X-ray absorptiometry (DXA) scan algorithm based upon degree of bone mineral density (BMD); shared CFBD guideline recommendations in our quarterly newsletter; and ordered scans for eligible patients at weekly review meetings. We reviewed DXA results from 141 patients after institutional review board approval and gathered data including comorbidities, genetics, anthropometric measures, medication exposure, and relevant serum studies. RESULTS: Fifty-three percent of our patients had normal BMD (n = 75). Seventeen patients (12%) had a Z score ≤ -2. Patients with lower BMD also had lower mean forced expiratory volume (FEV1 ) percent predicted (FEV1 %) (p < 0.001) as well as lower body mass index % (p = 0.001). Patients with lower BMD were overall older at time of DXA (p = 0.016). During study duration, 13 patients who had abnormal DXA results underwent repeat DXAs after physical therapy; 11 of the 13 showed improvement in DXA results. CONCLUSIONS: A DXA scan is a useful screening tool and can be used to identify pediatric patients who could benefit from further therapy and interventions to preserve adequate bone health and avoid further loss. QI initiatives can lead to improved screening and diagnosis and earlier intervention such as physical therapy. Further studies are needed to better understand the utility of physical therapy in children with CF.

Case report of severe refractory inflammatory dermatoses in a young female diagnosed with hereditary alpha tryptasemia.

Hereditary alpha tryptasemia (HaT), an autosomal dominant condition first described in 2014, has previously been associated with multiple dermatologic, allergic, gastrointestinal, neuropsychiatric, autonomic, and connective tissue abnormalities. We describe a pediatric patient with predominantly mixed cutaneous inflammatory manifestations and atopic manifestations resistant to treatment who was found to have HaT. HaT should be considered in individuals with refractory inflammatory dermatologic disease and signs and/or symptoms concerning for mast cell activation.

Inborn errors of immunity associated with elevated immunoglobulin E.

OBJECTIVE: To review the characteristic clinical and laboratory features of inborn errors of immunity (IEI) that are associated with elevated immunoglobulin (Ig)E levels. DATA SOURCES: Primary peer-reviewed literature. STUDY SELECTIONS: Original research articles reviewed include interventional studies, retrospective studies, case-control studies, cohort studies, and review articles related to the subject matter. RESULTS: An extensive literature review was completed to allow for comprehensive evaluation of several monogenic IEI. This review includes a description of the classic clinical features, common infections, characteristic laboratory findings, specific diagnostic methods (when applicable), and genetic basis of disease of each syndrome. A comprehensive flow diagram was created to assist them in the diagnosis and evaluation of patients with elevated IgE levels who may require evaluation for an IEI. CONCLUSION: IEI should be considered in patients with elevated IgE levels, especially if they have recurrent infections, eczematous dermatitis, malignancy, lymphoproliferation, autoimmunity, or connective tissue abnormalities.

Diagnosis and Management of Pediatric Hypereosinophilic Syndrome.

Hypereosinophilic syndrome (HES) is a diverse group of disorders characterized by peripheral blood eosinophilia of 1.5 × 109/L (1,500/µL) or greater with evidence of end-organ damage attributable to eosinophilia and no other cause of the end-organ damage. The HES is rare, especially in children. This review aims to provide best practices in diagnosis and treatment of HES in children, including how to differentiate between primary and secondary causes of hypereosinophilia; how to distinguish the differences in clinical presentation, treatment, and prognosis of HES in children and adults; and how to identify key steps in the evaluation and management of HES in children.

Teriparatide Therapy in a 4-Month-Old With Severe Hypoparathyroidism.

Teriparatide is a human parathyroid hormone analog approved for the treatment of osteoporosis in adult patients. Its use for hypocalcemia and hypoparathyroidism in the pediatric population is described through case reports and small case series; however, larger studies that demonstrate long-term efficacy and safety are limited. At our institution, a 4-month-old premature (gestational age: 32 weeks) infant with multiple congenital anomalies, functional athymia, and severe hypoparathyroidism and receiving calcitriol, vitamin D, and calcium carbonate supplementation was initiated on subcutaneous injection of teriparatide. During the course of treatment, her calcium carbonate, vitamin D, and calcitriol supplementation requirements substantially decreased. Teriparatide effectively increased serum ionized calcium concentrations and decreased serum phosphorus concentrations in the present case-study over a 6-month period. Teriparatide was well tolerated, and no evidence of hypercalcemia was observed throughout treatment.

App providing psychosocial and educational supports benefits caregivers of children with newly diagnosed food allergies.

Background: Approximately 6 million children in the United States have a diagnosed food allergy, and 32% of caregivers experience significant psychological distress due to the diagnosis. Despite substantial impacts on psychosocial health and quality of life, few interventions aim to help caregivers of newly diagnosed children. There is a clear, unmet need for interventions to address caregiver distress, especially after the initial diagnosis. Objective: We developed a mobile psychosocial health intervention, the Food Allergy Symptom Self-Management with Technology (FASST) app. Primary end points were to determine the app's feasibility and caregiver satisfaction. Methods: This was a phase II, randomized controlled, implementation study (4-week duration) in caregivers (N = 30) of children ≤ 18 years of age who were newly diagnosed with a food allergy (≤90 days after the diagnosis). Caregivers (n = 20) were randomized to use the FASST app (intervention group) with access to individualized, self-help symptom relief interventions and food allergy support, and educational resources; or to use a limited app with a basic FASST interface and links to a few educational resources (control group [n = 10]). Ten participants (intervention group, n = 5; control group, n = 5) participated in semistructured interviews at week 4. Results: Both groups found the app relatively easy to use. The intervention group scores for safety preparedness during social activities increased by 24%, whereas those in the control group experienced a 1% decline. The intervention group participants increased the use of websites to find food allergy information by 17% at week 4 compared with 4% for the control group. Although the intervention group participants showed greater gains than did those in the control group in their confidence to prepare for and prevent allergic reactions, and greater declines in perceived social limitations, more participants in the control group endorsed confidence in their ability to recognize (11% versus 5%, respectively) and treat (10% versus 6%, respectively) allergic reactions. Conclusion: Analysis of our results suggests that the FASST app may provide a feasible means of delivering psychosocial and educational supports to caregivers of children recently diagnosed with a food allergy.Clinical trial NCT04512924, www.clinicaltrials.gov.

Electrochemical Sensing of Neonicotinoids Using Laser-Induced Graphene.

Neonicotinoids are the fastest-growing insecticide accounting for over 25% of the global pesticide market and are capable of controlling a range of pests that damage croplands, home yards/gardens, and golf course greens. However, widespread use has led to nontarget organism decline in pollinators, insects, and birds, while chronic, sublethal effects on humans are still largely unknown. Therefore, there is a need to understand how prevalent neonicotinoids are in the environment as there are currently no commercially available field-deployable sensors capable of measuring neonicotinoid concentrations in surface waters. Herein, we report the first example of a laser-induced graphene (LIG) platform that utilizes electrochemical sensing for neonicotinoid detection. These graphene-based sensors are created through a scalable direct-write laser fabrication process that converts polyimide into LIG, which eliminates the need for chemical synthesis of graphene, ink formulation, masks, stencils, pattern rolls, and postprint annealing commonly associated with other printed graphene sensors. The LIG electrodes were capable of monitoring four major neonicotinoids (CLO, IMD, TMX, and DNT) with low detection limits (CLO, 823 nM; IMD, 384 nM; TMX, 338 nM; and DNT, 682 nM) and a rapid response time (∼10 s) using square-wave voltammetry without chemical/biological functionalization. Interference testing exhibited negligible responses from widely used pesticides including the broad-leaf insecticides parathion, paraoxon, and fipronil, as well as systemic herbicides glyphosate (roundup), atrazine, dicamba, and 2,4-dichlorophenoxyacetic acid. These scalable, graphene-based sensors have the potential for wide-scale mapping of neonicotinoids in watersheds and potential use in numerous electrochemical sensor devices.

Immune Dysregulation in Human ITCH Deficiency Successfully Treated with Hematopoietic Cell Transplantation.

BACKGROUND: Mutations in ITCH, which encodes an E3 ubiquitin-protein ligase, can result in systemic autoimmunity and immunodeficiency. The clinical phenotype and mechanism of disease have not been fully characterized, resulting in a paucity of therapeutic options for this potentially fatal disease. OBJECTIVE: We aimed to (1) expand the understanding about the phenotype of human ITCH deficiency (2) further characterize the associated immune dysregulation, and (3) report the first successful hematopoietic cell transplant (HCT) in a patient with ITCH deficiency. METHODS: Disease profiling was performed in a patient with multisystem immune dysregulation. Whole exome sequencing with trio analysis and functional validation of candidate disease variants were performed, including mRNA and protein expression. Analyses to further delineate the immunophenotype included quantitative evaluation of lymphoid and myeloid subsets with flow cytometry and mass cytometry. RESULTS: A patient with multisystem immune dysregulation presenting with growth failure, very-early-onset inflammatory bowel disease, arthritis, uveitis, psoriasis, and type 1 diabetes mellitus underwent whole exome sequencing, which identified novel compound heterozygous mutations in ITCH. Reduced expression of ITCH mRNA and absent ITCH protein were found. Abnormalities in both lymphoid and myeloid lineages were identified. The patient underwent HCT. He demonstrated excellent immune reconstitution and resolution of many manifestations of his systemic disease. CONCLUSIONS: Here we report ITCH deficiency with unique clinical features of colonic very-early-onset inflammatory bowel disease, arthritis, and uveitis in the setting of immune dysregulation and further characterize the underlying immune dysregulation. We demonstrate that HCT can be an effective, and potentially curative, therapy for ITCH deficiency.

Food Allergy Symptom Self-Management With Technology (FASST) mHealth Intervention to Address Psychosocial Outcomes in Caregivers of Children With Newly Diagnosed Food Allergy: Protocol for a Pilot Randomized Controlled Trial.

BACKGROUND: Approximately 2.4 million children in the United States suffer from food-induced anaphylaxis, a condition that is annually responsible for over 200 deaths and 200,000 emergency room visits. As a result, caregivers of children newly diagnosed with severe and life-threatening food allergic reactions experience clinically significant symptoms of psychological distress, including fatigue, anxiety, depressed mood, social isolation, and substantially reduced quality of life. Despite this recognition, there is a lack of caregiver-centered self-management interventions to address these concerns. OBJECTIVE: In this protocol, we propose to develop and conduct feasibility testing of a technology-enhanced, self-management, mobile health, smartphone app intervention called Food Allergy Symptom Self-Management with Technology for Caregivers (FASST) designed to meet the psychosocial health needs of caregivers of children with a new diagnosis of food allergy. METHODS: This pilot study uses qualitative work (Phase I) to inform a 4-week longitudinal randomized controlled trial (Phase II). In Phase I, 10 caregivers of children (≤18 years old) with established food allergy (≥1 year from diagnosis) will participate in semistructured interviews to inform the development of the FASST app. In Phase II, 30 caregivers of children (≤18 years old) with a newly diagnosed food allergy (≤90 days from diagnosis) will be randomized 2:1 to receive the FASST intervention (n=20) or control condition (basic app with educational resources; n=10). Process measures include feasibility, caregiver acceptability, adherence, and satisfaction. Outcome measures include caregiver fatigue, anxiety, depression, sleep, self-efficacy, and quality of life measured at baseline, week 4, and 3 months post study completion. RESULTS: Phase I study activities have been completed, and Phase II participant enrollment into the randomized controlled trial is expected to commence in 2021. CONCLUSIONS: With limited readily available resources at their disposal, the results from this study have the potential to provide caregivers of children with a newly diagnosed food allergy a tool to help them self-manage and mitigate negative psychosocial factors during a critical time period in the caregiving/condition trajectory. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04512924: https://clinicaltrials.gov/ct2/show/NCT04512924. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25805.

Geographic Variability and Pathogen-Specific Considerations in the Diagnosis and Management of Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare but serious primary immunodeficiency with varying prevalence and rates of X-linked and autosomal recessive disease worldwide. Functional defects in the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex predispose patients to a relatively narrow spectrum of bacterial and fungal infections that are sometimes fastidious and often difficult to identify. When evaluating and treating patients with CGD, it is important to consider their native country of birth, climate, and living situation, which may predispose them to types of infections that are atypical to your routine practice. In addition to recurrent and often severe infections, patients with CGD and X-linked female carriers are also susceptible to developing many non-infectious complications including tissue granuloma formation and autoimmunity. The DHR-123 oxidation assay is the gold standard for making the diagnosis and it along with genetic testing can help predict the severity and prognosis in patients with CGD. Disease management focuses on prophylaxis with antibacterial, antifungal, and immunomodulatory medications, prompt identification and treatment of acute infections, and prevention of secondary granulomatous complications. While hematopoietic stem-cell transplantation is the only widely available curative treatment for patients with CGD, recent advances in gene therapy may provide a safer, more direct alternative.

Viability of Neural Cells on 3D Printed Graphene Bioelectronics.

Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States after Alzheimer's disease (AD). To help understand the electrophysiology of these diseases, N27 neuronal cells have been used as an in vitro model. In this study, a flexible graphene-based biosensor design is presented. Biocompatible graphene was manufactured using a liquid-phase exfoliation method and bovine serum albumin (BSA) for further exfoliation. Raman spectroscopy results indicated that the graphene produced was indeed few-layer graphene (FLG) with ID/IGGraphene= 0.11. Inkjet printing of this few-layer graphene ink onto Kapton polyimide (PI) followed by characterization via scanning electron microscopy (SEM) showed an average width of ≈868 µm with a normal thickness of ≈5.20 µm. Neuronal cells were placed on a thermally annealed 3D printed graphene chip. A live-dead cell assay was performed to prove the biosensor biocompatibility. A cell viability of approximately 80% was observed over 96 h, which indicates that annealed graphene on Kapton PI substrate could be used as a neuronal cell biosensor. This research will help us move forward with the study of N27 cell electrophysiology and electrical signaling.