Hyper-IgE Syndrome due to an Elusive Novel Intronic Homozygous Variant in DOCK8.

Rare, biallelic loss-of-function mutations in DOCK8 result in a combined immune deficiency characterized by severe and recurrent cutaneous infections, eczema, allergies, and susceptibility to malignancy, as well as impaired humoral and cellular immunity and hyper-IgE. The advent of next-generation sequencing technologies has enabled the rapid molecular diagnosis of rare monogenic diseases, including inborn errors of immunity. These advances have resulted in the implementation of gene-guided treatments, such as hematopoietic stem cell transplant for DOCK8 deficiency. However, putative disease-causing variants revealed by next-generation sequencing need rigorous validation to demonstrate pathogenicity. Here, we report the eventual diagnosis of DOCK8 deficiency in a consanguineous family due to a novel homozygous intronic deletion variant that caused aberrant exon splicing and subsequent loss of expression of DOCK8 protein. Remarkably, the causative variant was not initially detected by clinical whole-genome sequencing but was subsequently identified and validated by combining advanced genomic analysis, RNA-seq, and flow cytometry. This case highlights the need to adopt multipronged confirmatory approaches to definitively solve complex genetic cases that result from variants outside protein-coding exons and conventional splice sites.

The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

Concerns for anaphylaxis may hamper severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization efforts. We convened a multidisciplinary group of international experts in anaphylaxis composed of allergy, infectious disease, emergency medicine, and front-line clinicians to systematically develop recommendations regarding SARS-CoV-2 vaccine immediate allergic reactions. Medline, EMBASE, Web of Science, the World Health Organizstion (WHO) global coronavirus database, and the gray literature (inception, March 19, 2021) were systematically searched. Paired reviewers independently selected studies addressing anaphylaxis after SARS-CoV-2 vaccination, polyethylene glycol (PEG) and polysorbate allergy, and accuracy of allergy testing for SARS-CoV-2 vaccine allergy. Random effects models synthesized the data to inform recommendations based on the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach, agreed upon using a modified Delphi panel. The incidence of SARS-CoV-2 vaccine anaphylaxis is 7.91 cases per million (n = 41,000,000 vaccinations; 95% confidence interval [95% CI] 4.02-15.59; 26 studies, moderate certainty), the incidence of 0.15 cases per million patient-years (95% CI 0.11-0.2), and the sensitivity for PEG skin testing is poor, although specificity is high (15 studies, very low certainty). We recommend vaccination over either no vaccination or performing SARS-CoV-2 vaccine/excipient screening allergy testing for individuals without history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient, and a shared decision-making paradigm in consultation with an allergy specialist for individuals with a history of a severe allergic reaction to the SARS-CoV-2 vaccine/excipient. We recommend further research to clarify SARS-CoV-2 vaccine/vaccine excipient testing utility in individuals potentially allergic to SARS-CoV2 vaccines or their excipients.

Associations Between Religious/Spiritual Coping and Depression Among Adults with Cystic Fibrosis: A 12-Month Longitudinal Study.

Individuals with cystic fibrosis (CF) face a challenging disease, and depression is a significant concern. Many patients draw on religious/spiritual resources to assist them in managing the demands of chronic illness; however, these coping efforts rarely have been evaluated among adults with CF. This longitudinal study examined relationships between distinct types of positive and negative religious/spiritual coping at baseline (assessed with the RCOPE) and depression screening outcomes 12 month later (assessed with the Hospital Anxiety and Depression Scale). In logistic regression analyses controlling for disease severity (FEV1% predicted), lower likelihood of depression caseness at 12 months was predicted by higher general religiousness at baseline, greater use of benevolent religious reappraisal coping, greater use of spiritual connection coping, and lower spiritual discontent. Results suggest that distinct aspects religious/spiritual coping have differential associations with subsequent depression outcomes. Findings extend prior research to an important, understudied medical population, and address a clinically meaningful outcome.

Analysis of maternal and perinatal determinants of allergic sensitization in childhood.

BACKGROUND: Non-communicable diseases, such as allergies, are influenced by both genetic and epigenetic factors. Perinatal determinants conceivably modify the epigenetic makeup of the developing fetal immune system preventing or predisposing the development of allergies. The aim of this study therefore was to identify independent perinatal factors associated with allergic sensitization in childhood. METHODS: In a single center retrospective case-cohort study electronic obstetric medical records and available skin prick testing results of children were analyzed. For the analysis 286 skin prick test positive (sensitized) children [median (IQR): 3.47 (1.70-7.34) years] were compared with data from all remaining live births in the obstetric cohort (n = 66,583). RESULTS: Sensitized children more frequently had a mother born in Asia (19.1% vs. 10.2%; P < 10-6). Applying backward elimination logistic regression, seven out of 23 initially entered perinatal factors remained in the model. High maternal age (> 35 years; OR: 1.912; P < 0.001), male offspring sex (OR: 1.423; P < 0.01) and assisted conception (OR: 1.771; P < 0.05) increased the risk for allergic sensitization. In contrast, maternal smoking (OR: 0.469; P < 0.005), increasing parity (OR: 0.881; P < 0.05), maternal pre-pregnancy overweight (OR: 0.742; P < 0.005) and preterm birth (OR: 0.484; P < 0.05) decreased the risk for allergic sensitization. CONCLUSIONS: In addition to supporting previous findings, this study is first to report an increased risk of allergic sensitization after assisted conception. Beyond this finding's potential implementation in preventative strategies, exploration of this association could further pathophysiological understanding of allergic disease.

Collagen-An Important Fish Allergen for Improved Diagnosis.

BACKGROUND: Fish collagen is widely used in medicine, cosmetics, and the food industry. However, its clinical relevance as an allergen is not fully appreciated. This is likely due to collagen insolubility in neutral aqueous solutions, leading to low abundance in commercially available in vitro and skin prick tests for fish allergy. OBJECTIVE: To investigate the relevance of fish collagen as an allergen in a large patient population (n = 101). METHODS: Acid-soluble collagen type I was extracted from muscle and skin of Atlantic salmon, barramundi, and yellowfin tuna. IgE binding to collagen was analyzed by ELISA for 101 fish-allergic patients. Collagen-sensitized patients' sera were tested for IgE binding to parvalbumin from the same fish species. IgE cross-linking was analyzed by rat basophil leukemia assay and basophil activation test. Protein identities were confirmed by mass spectrometry. RESULTS: Purified fish collagen contained type I α1 and α2 chains and their multimers. Twenty-one of 101 patients (21%) were sensitized to collagen. Eight collagen-sensitized patients demonstrated absence of parvalbumin-specific IgE to some fish species. Collagen induced functional IgE cross-linking, as shown by rat basophil leukemia assay performed using 6 patients' sera, and basophil activation test using fresh blood from 1 patient. Collagen type I α chains from barramundi and Atlantic salmon were registered at www.allergen.org as Lat c 6 and Sal s 6, respectively. CONCLUSIONS: IgE sensitization and IgE cross-linking capacity of fish collagen were demonstrated in fish-allergic patients. Inclusion of relevant collagen allergens in routine diagnosis is indicated to improve the capacity to accurately diagnose fish allergy.

Longitudinal associations between gratitude and depression 1 year later among adult cystic fibrosis patients.

Individuals with cystic fibrosis (CF) are confronted by a range of difficult physical and psychosocial sequelae. Gratitude has drawn growing attention as a psychosocial resource, but it has yet to be examined among adults with CF. The current investigation evaluated longitudinal associations between trait gratitude and subsequent outcomes from depression screening 12 months later, adjusting for disease severity (FEV1% predicted) and other significant clinical or demographic covariates. Participants were 69 adult CF patients recruited from a regional adult treatment center. They completed a validated measure of gratitude (Gratitude Questionnaire-6) at baseline and a screening measure of depression (Hospital Anxiety and Depression Scale) at 12-month follow-up. In a logistic regression analysis controlling for disease severity, higher levels of baseline gratitude were associated with reduced likelihood of depression caseness at 12 months (OR .83, 95% CI .73-.91, p = .001). Gratitude remained predictive after adjusting for other psychosocial resource variables (i.e., perceived social support and positive reframing coping). Findings offer an initial indication of the potential salutary role of dispositional gratitude in an understudied clinical population.

Hematopoietic stem cell transplant effectively rescues lymphocyte differentiation and function in DOCK8-deficient patients.

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

Persistent Adherence to Airway Clearance Therapy in Adults With Cystic Fibrosis.

BACKGROUND: Airway clearance therapy (ACT) is a core component of daily treatment for cystic fibrosis (CF). However, surprisingly little is known about sustained or persistent use of ACT over time among adults with CF. This longitudinal study examined persistent adherence to ACT over 12 months and its modifiable predictors, drawing on aspects of Social Cognitive Theory and the Theory of Planned Behavior. METHODS: Subjects were drawn from a regional CF center in the southern United States. Predictor variables evaluated at baseline included self-efficacy for ACT (ie, self-confidence in overcoming barriers), outcome expectations (ie, perceived necessity of ACT and concerns about its disruptive effects), and subjective norms (ie, perceptions of being influenced by others). The Cystic Fibrosis Treatment Questionnaire (CFTQ) was used to assess self-reported adherence to ACT at baseline, at 6 months, and at 12 months. RESULTS: The mean age of subjects was 27.2 ± 9.1 y, and mean FEV1% predicted was 65.5 ± 24.8. Forty-six percent of subjects reported persistent use of ACT (classified as adherent at all assessment periods). In bivariate analyses, all social cognitive predictor variables assessed at baseline were significantly related to persistent adherence (all P < .03), except subjective norms. In logistic regression analyses that modeled the effects of these predictors simultaneously while controlling for FEV1%, fewer baseline concerns about ACT (odds ratio = 0.82, 95% CI 0.69-0.99) and greater self-efficacy (odds ratio = 1.09, 95% CI 1.01-1.18) remained significant independent predictors. CONCLUSIONS: This longitudinal study addresses an important gap in the literature regarding adherence to ACT over time (12 mo) in a routine clinical setting. Persistent adherence was problematic. As anticipated, social cognitive variables (self-confidence and perceived concerns) predicted self-reported persistence, and these may represent practical targets for intervention.

Fatal Anaphylaxis: Mortality Rate and Risk Factors.

Up to 5% of the US population has suffered anaphylaxis. Fatal outcome is rare, such that even for people with known venom or food allergy, fatal anaphylaxis constitutes less than 1% of total mortality risk. The incidence of fatal anaphylaxis has not increased in line with hospital admissions for anaphylaxis. Fatal drug anaphylaxis may be increasing, but rates of fatal anaphylaxis to venom and food are stable. Risk factors for fatal anaphylaxis vary according to cause. For fatal drug anaphylaxis, previous cardiovascular morbidity and older age are risk factors, with beta-lactam antibiotics, general anesthetic agents, and radiocontrast injections the commonest triggers. Fatal food anaphylaxis most commonly occurs during the second and third decades. Delayed epinephrine administration is a risk factor; common triggers are nuts, seafood, and in children, milk. For fatal venom anaphylaxis, risk factors include middle age, male sex, white race, cardiovascular disease, and possibly mastocytosis; insect triggers vary by region. Upright posture is a feature of fatal anaphylaxis to both food and venom. The rarity of fatal anaphylaxis and the significant quality of life impact of allergic conditions suggest that quality of life impairment should be a key consideration when making treatment decisions in patients at risk for anaphylaxis.

Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets.

Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rß1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rß1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.

Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies.

BACKGROUND: Follicular helper T (TFH) cells underpin T cell-dependent humoral immunity and the success of most vaccines. TFH cells also contribute to human immune disorders, such as autoimmunity, immunodeficiency, and malignancy. Understanding the molecular requirements for the generation and function of TFH cells will provide strategies for targeting these cells to modulate their behavior in the setting of these immunologic abnormalities. OBJECTIVE: We sought to determine the signaling pathways and cellular interactions required for the development and function of TFH cells in human subjects. METHODS: Human primary immunodeficiencies (PIDs) resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Circulating follicular helper T (cTFH) cell subsets, memory B cells, and serum immunoglobulin levels were quantified and functionally assessed in healthy control subjects, as well as in patients with PIDs resulting from mutations in STAT3, STAT1, TYK2, IL21, IL21R, IL10R, IFNGR1/2, IL12RB1, CD40LG, NEMO, ICOS, or BTK. RESULTS: Loss-of-function (LOF) mutations in STAT3, IL10R, CD40LG, NEMO, ICOS, or BTK reduced cTFH cell frequencies. STAT3 and IL21/R LOF and STAT1 gain-of-function mutations skewed cTFH cell differentiation toward a phenotype characterized by overexpression of IFN-γ and programmed death 1. IFN-γ inhibited cTFH cell function in vitro and in vivo, as corroborated by hypergammaglobulinemia in patients with IFNGR1/2, STAT1, and IL12RB1 LOF mutations. CONCLUSION: Specific mutations affect the quantity and quality of cTFH cells, highlighting the need to assess TFH cells in patients by using multiple criteria, including phenotype and function. Furthermore, IFN-γ functions in vivo to restrain TFH cell-induced B-cell differentiation. These findings shed new light on TFH cell biology and the integrated signaling pathways required for their generation, maintenance, and effector function and explain the compromised humoral immunity seen in patients with some PIDs.

Hormonally mediated disturbance of angiogenesis in the human endometrium after exposure to intrauterine levonorgestrel.

BACKGROUND: The levonorgestrel intrauterine system (LNG-IUS) is a contraceptive device that is used for treatment of menorrhagia. The system induces inter-menstrual bleeding within the first few months after insertion. We hypothesized that this bleeding might be associated with a change in vascular development. METHODS: A randomized, controlled study was undertaken on 48 women. RESULTS: Hysterectomy specimens were obtained and immunocytochemistry was carried out with antibodies to CD31, alpha-smooth muscle actin and myosin. Stereological measurement of blood vessels was also undertaken. Most vessels appeared normal, including the arterioles. Large thin-walled vessels were present in the superficial endometrium of the treated group but were almost completely absent in the controls. The distribution of cytoskeletal markers revealed well-formed basal arterioles with more widespread expression in the superficial stroma than was found in untreated tissue. The volume fraction of blood vessels (P = 0.0001), the number of vessel cross-sections per unit area (P = 0.0003) and the cross-sectional diameters of the largest vascular lumens (P = 0.0001) were significantly increased following treatment with LNG-IUS. However, there was no difference in the median values of vessel diameter or the vascular surface density. CONCLUSION: These findings suggest that the LNG has a localized effect on some vessels within the superficial endometrium.