Allergic-like disorders and asthma in patients with common variable immunodeficiency: a multi-center experience.

OBJECTIVE: Common variable immune deficiency (CVID) encompasses a variety of diseases characterized by disturbed immunoglobulin (Ig) production and various immune dysregulations. Scarce data are available regarding relationships between CVID and allergic diseases. Here we examined possible associations between allergies and CVID. METHODS: For this multicenter study, we prospectively enrolled 79 adult CVID patients (≥18 years) who were diagnosed and treated between 2002-2017 at the Hadassah-Hebrew University and Shaare Zedek Medical Centers, Jerusalem, Israel. These patients were examined for allergic manifestations. Patient evaluation comprised medical history, physical examination, skin allergen testing, complete blood count, serum immunoglobulins, IgE levels, and pulmonary function tests. RESULTS: After implementing exclusion criteria, 29 patients were included in the final analysis. Allergic-like disorders were diagnosed in 65% of CVID patients with non-elevated serum IgE levels. Moreover, allergic CVID patients exhibited a higher prevalence of bronchiectasis on chest CT. Autoimmunity was diagnosed in 41.3% of CVID subjects. The type I allergy detected in our study was non-IgE mediated. CONCLUSIONS: Timely diagnosis and stratification of allergy in CVID patients is expected to improve their outcome and quality of life, as well as promote appropriate treatment and better management of pulmonary exacerbations.

Genetic workup as a complementary tool for the diagnosis of primary complement component deficiencies: a multicenter experience.

Diagnosis of primary complement deficiencies requires a high index of suspicion. Thus, susceptible patients are often underdiagnosed and untreated. Here, we present a multicenter experience with two novel inborn errors of the classical complement system. This is a retrospective multicenter analysis of computerized medical records of children (<18 years) admitted in the period between 2012 and 2018 at Shaare Zedek Medical Center in Jerusalem and Edmond and Lily Safra Children's Hospital, Tel-Hashomer Medical Center, in Ramat Gan, Israel. Patients were genetically diagnosed by a complementary immune workup. We identified 5 patients (3 males) from four different families harboring two novel mutations in the complement components C6-C8. Genetic mutations were identified by whole-exome sequencing or by sequencing of the coding exons of a single gene based on the findings in the immune workup. Clinical manifestations consisted of meningitis with or without meningococcemia. The immune workup demonstrated nearly absent levels of CH50, compatible with a complement pathway defect. Diagnosis delay ranged between 0 and 30 years. CONCLUSION: Awareness of risk factors for primary complement deficiencies, even at the first infectious episode, should facilitate prompt immune and genetic workup, commencing diagnosis and proper treatment for the patient and family. WHAT IS KNOWN: • Deficiencies in the classical terminal complement components increase susceptibility to invasive meningococcal infections. • Recurrent meningococcal infections mandate a diagnostic workup of the complement system. WHAT IS NEW: • Genetic workup can be utilized for prompt diagnosis of complement deficiencies. • High rates of consanguinity, even in the presence of a single meningococcal infection, should promote immune and genetic workups.

Chronic demodicosis in patients with immune dysregulation: An unexpected infectious manifestation of Signal transducer and activator of transcription (STAT)1 gain-of-function.

Signal transducer and activator of transcription (STAT)1 heterozygous gain-of-function (GOF) mutations are known to induce immune dysregulation and chronic mucocutaneous candidiasis (CMCC). Previous reports suggest an association between demodicosis and STAT1 GOF. However, immune characterization of these patients is lacking. Here, we present a retrospective analysis of patients with immune dysregulation and STAT1 GOF who presented with facial and ocular demodicosis. In-depth immune phenotyping and functional studies were used to characterize the patients. We identified five patients (three males) from two non-consanguineous Jewish families. The mean age at presentation was 11.11 (range = 0.58-24) years. Clinical presentation included CMCC, chronic demodicosis and immune dysregulation in all patients. Whole-exome and Sanger sequencing revealed a novel heterozygous c.1386C>A; p.S462R STAT1 GOF mutation in four of the five patients. Immunophenotyping demonstrated increased phosphorylated signal transducer and activator of transcription in response to interferon-α stimuli in all patients. The patients also exhibited decreased T cell proliferation capacity and low counts of interleukin-17-producing T cells, as well as low forkhead box protein 3+ regulatory T cells. Specific antibody deficiency was noted in one patient. Treatment for demodicosis included topical ivermectin and metronidazole. Demodicosis may indicate an underlying primary immune deficiency and can be found in patients with STAT1 GOF. Thus, the management of patients with chronic demodicosis should include an immunogenetic evaluation.

Celiac Disease and Celiac Antibodies in DM1 Patients: When Are Screening and Biopsy Recommended?

INTRODUCTION: The prevalence of celiac disease (CD) is increased in diabetes mellitus type 1 (DM1) patients. In most cases, CD is diagnosed in asymptomatic patients and hence periodic screening tests are recommended, but the timing, frequency of tests and indication for duodenal biopsy is unclear. The purpose of this study was to investigate the dynamics of CD serology in DM1 and identify risk factors for CD. METHODS: Celiac serology and duodenal biopsy results from 1990 until 2015 were collected from patients with DM1. The outcome of positive celiac serology, the incidence and risk factors for CD in DM1 patients were investigated. RESULTS: A total of 314 DM1 patients who had celiac serology were identified, with follow-up period up to 23 years. Of 31 patients (9.9%) with positive celiac serology, 11(35.4%) had spontaneous normalization after various time periods. Eighteen patients were diagnosed with CD (58.1% of positive celiac serology, 5.73% of the study cohort). Age under 4.5 years was a risk factor for CD, but not family background of autoimmune diseases or gender. All patients with CD diagnosis were diagnosed during the first 6 years following DM1 diagnosis. CONCLUSION: Screening asymptomatic DM1 patients for CD beyond 6 years after diagnosis is not recommended. Spontaneous normalization of CD serology occurs, and hence, serologic follow-up may be performed. In children with DM1 diagnosis under the age of 4.5 years or with positive CD serology at DM1 diagnosis, there is an increased risk for CD and therefore positive serology should lead to biopsy.

Hypernatremic Dehydration in Young Children: Is There a Solution?

BACKGROUND: Hypernatremic dehydration is a common and potentially life-threatening condition in children. There is currently no consensus as to the optimal strategy for fluid management. OBJECTIVES: To describe the relationship between the type, route and rate of fluids administered and the rate of decline in serum sodium (Na+) concentration. METHODS: We reviewed the medical records of all children under the age of 2 years who were hospitalized with hypernatremic dehydration (serum Na+ ≥ 155 mEq/L) in Shaare Zedek Medical Center during the period 2001-2010. Collected data of 62 subjects included initial and subsequent serum Na+ levels, and rate and Na+ concentration of all intravenous and oral fluids administered until the serum Na+ reached ≤ 150 mEq/L. RESULTS: Median initial serum Na+ was 159.5 mEq/L (IQR 157-163, maximal value 170). The median rate of decline in serum Na+ until serum Na+ reached 150 mEq/L was 0.65 mEq/L/hr (IQR 0.45-0.95). Forty-two children received hypotonic oral fluids which accounted for approximately one-quarter of all fluids they received. There was no significant difference in the rate of decline in serum Na+ between those who consumed oral fluids and those who did not. Neither was there a correlation between the rate of IV fluids, receipt of oral fluids or the degree of dehydration, with the rate of decline in serum Na+. No child experienced an apparent short-term adverse outcome. CONCLUSIONS: A cumulative rate of 5.9 mI/kg/hr of IV fluid administration may reduce the serum Na+ by an acceptable rate (0.65 mEq/L/hr). Fluid therapy comprising up to 25% hypotonic oral fluids and 75% IV fluids high in Na+ concentration was not associated with any short-term adverse outcome in our patient population.

[HOW TO APPROACH A PATIENT WITH SUSPECTED IMMUNODEFICIENCY].

Our immune system protects us from various pathogens, autoimmune processes and malignancy. Primary immunodeficiency disorders are rare, however in contrast to the conventional perception, primary immunodeficiency diseases are more common than expected and may occur at any age. An insult to the immune system, primary or secondary, may lead to an increased incidence of infectious diseases, autoimmune diseases and malignancies. Primary care physicians, frequently encounter children and adults who suffer from recurrent infections, emphasizing the need for a structured approach for the evaluation of patients with suspected immunodeficiency. The growing knowledge of the fundamental mechanisms and function of the immune system together with recent developments in the field of clinical immunodeficiency enables us to use advanced diagnostic tools for the early diagnosis and treatment of these patients. In this review, we summarize the main aspects and updates of primary and secondary immune deficiency diseases, outline the "red flags" of immunodeficiency states and offer a stepwise workup approach for primary physicians and clinical immunology specialists. Some of the immunodeficiency "red flags" include recurrent infections, invasive infections, atypical pathogens, partial response to antibiotic treatment and frequent use of antibiotics, failure to thrive, chronic diarrhea and fungal infections, unexplained skin rash and a family history.

Valproic acid hypersensitivity and desensitization.

Rash, a hypersensitivity reaction, is a common cause of withdrawal from an effective antiepileptic drug (AED) in patients with epilepsy. We present a case of successful desensitization to valproic acid in a 12-year-old male with childhood absence epilepsy and a hypersensitivity reaction, whose epilepsy did not respond to other AEDs. Desensitization is a practical therapeutic solution for patients who develop a non-life-threatening hypersensitivity reaction to an AED for which there may be no substitute.

A pleiotropic recurrent dominant ITPR3 variant causes a complex multisystemic disease.

Inositol 1,4,5-trisphosphate (IP3) receptor type 1 (ITPR1), 2 (ITPR2), and 3 (ITPR3) encode the IP3 receptor (IP3R), a key player in intracellular calcium release. In four unrelated patients, we report that an identical ITPR3 de novo variant-NM_002224.3:c.7570C>T, p.Arg2524Cys-causes, through a dominant-negative effect, a complex multisystemic disorder with immunodeficiency. This leads to defective calcium homeostasis, mitochondrial malfunction, CD4+ lymphopenia, a quasi-absence of naïve CD4+ and CD8+ cells, an increase in memory cells, and a distinct TCR repertoire. The calcium defect was recapitulated in Jurkat knock-in. Site-directed mutagenesis displayed the exquisite sensitivity of Arg2524 to any amino acid change. Despite the fact that all patients had severe immunodeficiency, they also displayed variable multisystemic involvements, including ectodermal dysplasia, Charcot-Marie-Tooth disease, short stature, and bone marrow failure. In conclusion, unlike previously reported ITPR1-3 deficiencies leading to narrow, mainly neurological phenotypes, a recurrent dominant ITPR3 variant leads to a multisystemic disease, defining a unique role for IP3R3 in the tetrameric IP3R complex.

SARS-CoV-2 spike antibody concentration in gamma globulin products from high-prevalence COVID-19 countries are transmitted to X-linked agammaglobulinemia patients.

Purpose: Patients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient. Methods: A single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly. Results: Five XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (>50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population. Conclusion: As the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

B cell repertoire in patients with a novel BTK mutation: expanding the spectrum of atypical X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton tyrosine kinase) BTK) gene. Affected patients have severely reduced amounts of circulating B cells. Patients with atypical XLA may have residual circulating B cells, and there are few studies exploring these cells' repertoire. We aimed to study the B cell repertoire of a novel hypomorphic mutation in the BTK gene, using the next generation sequencing (NGS) technology. Clinical data was collected from our clinical records. Real-time PCR was used to determine KREC copies, and NGS was used to determine the immunoglobulin (Ig) heavy chain (IgH) repertoire diversity. Both patients had a relatively mild clinical and laboratory phenotype, residual BTK protein expression, and the same novel mutation in the BTK gene, c.1841 T > C, p. L614P. Signal-joint kappa-deleting recombination excision circles (sj-KREC) for both patients were completely absent reflecting lack of naïve B cells. The intron RSS-Kde coding joints (cj) were significantly reduced, reflecting residual replicating B cells. NGS displayed restricted IgH repertoire with highly uneven distribution of clones, especially for Pt2. We report a novel BTK mutation, c.1841 T > C (p. L614P) that is associated with a relatively mild phenotype. We conclude that the IgH repertoire in atypical XLA is restricted with highly uneven distribution of clones. This phenomenon may be explained by extremely reduced to non-existent levels of BTK in B cells. This report sheds further light on atypical cases of XLA.

The risk of serious bacterial infections among young ex-premature infants with fever.

Background and Objectives: To determine the rate of serious-bacterial-infections (SBI) in young ex-premature infants with fever, and to develop a risk-stratification algorithm for these patients. Methods: A retrospective cohort study including all infants who presented to the pediatric emergency department (ED) of a tertiary-care university-hospital between 2010 and 2020 with fever (≥38°C), were born prematurely (<37-weeks), had post-conception age of <52-weeks, and had available blood, urine, or CSF cultures. The rates of SBI by age-of-birth and age-at-visit were calculated and compared to a cohort of matched full-term controls. Results: The study included a total of 290 ex-premature cases and 290 full-term controls. There were 11 cases (3.8%) with an invasive bacterial infection (IBI) of either bacteremia, meningitis or both and only six controls (2.1%) with IBI (p = 0.32). Over 28-days chronologic-age, there were 10 (3.6%) IBIs among cases and no IBIs among the controls (p = 0.02). There were eight (3%) cases and three (1%) controls with IBI who were well-appearing on physical examination (p = 0.19). All eight well-appearing ex-premature infants were under 60-days adjusted-age, seven of whom (88%) were also under 28-days adjusted-age. There were 28 (10.6%) cases and 34 (12%) controls with urinary tract infection (UTI) (p = 0.5). Among cases under 60-days adjusted-age, urinalysis was not reliable to exclude UTI (50% negative). Conclusions: Well-appearing ex-preterm infants have a significant risk for IBI until the adjusted age of 28-days and for UTI until the adjusted age of 60-days. Further studies are needed to evaluate the approach to fever in this unique population.

GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis.

The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

Lessons Learned From Five Years of Newborn Screening for Severe Combined Immunodeficiency in Israel.

BACKGROUND: Implementation of newborn screening (NBS) programs for severe combined immunodeficiency (SCID) have advanced the diagnosis and management of affected infants and undoubtedly improved their outcomes. Reporting long-term follow-up of such programs is of great importance. OBJECTIVE: We report a 5-year summary of the NBS program for SCID in Israel. METHODS: Immunologic and genetic assessments, clinical analyses, and outcome data from all infants who screened positive were evaluated and summarized. RESULTS: A total of 937,953 Guthrie cards were screened for SCID. A second Guthrie card was requested on 1,169 occasions (0.12%), which resulted in 142 referrals (0.015%) for further validation tests. Flow cytometry immune-phenotyping, T cell receptor excision circle measurement in peripheral blood, and expression of TCRVß repertoire for the validation of positive cases revealed a specificity and sensitivity of 93.7% and 75.9%, respectively, in detecting true cases of SCID. Altogether, 32 SCID and 110 non-SCID newborns were diagnosed, making the incidence of SCID in Israel as high as 1:29,000 births. The most common genetic defects in this group were associated with mutations in DNA cross-link repair protein 1C and IL-7 receptor α (IL-7Rα) genes. No infant with SCID was missed during the study time. Twenty-two SCID patients underwent hematopoietic stem cell transplantation, which resulted in a 91% survival rate. CONCLUSIONS: Newborn screening for SCID should ultimately be applied globally, specifically to areas with high rates of consanguineous marriages. Accumulating data from follow-up studies on NBS for SCID will improve diagnosis and treatment and enrich our understanding of immune development in health and disease.

Unilateral lung intubation for pulmonary air leak syndrome in neonates: a case series and a review of the literature.

Air leak syndrome represents a common set of complications of ventilated premature neonates and includes pneumothorax, pneumomediastinum, pulmonary interstitial emphysema, and pneumatocele. Unilateral intubation is an infrequently utilized treatment option. We report our experience of three cases of air leak syndrome in neonates, each treated with unilateral intubation, including two cases of recalcitrant pneumothorax. A review of the literature of similar neonatal cases is presented. In view of our experience and the review of the literature, we suggest that unilateral intubation is an efficient and relatively safe therapy in cases of neonatal air leak syndrome. It is also suggested that appropriate treatment duration should be at least 48 hours.

A costly covenant: ritual circumcision and urinary tract infection.

BACKGROUND: Ritual circumcision in neonates may cause a urinary tract infection within 2 weeks of the procedure. OBJECTIVES: To evaluate the prevalence of urinary tract infection among Jewish male circumcised neonates < or = 28 days old) evaluated for fever in the emergency room. METHODS: All available medical records of neonates presenting to the pediatric emergency room for evaluation of fever over a 10 year period were reviewed. Data included gender, ethnic background, age (in days) on presentation to the emergency room, age (in days) when circumcision was performed (in males > or = 8 days of age), and results of urine, blood and cerebrospinal fluid cultures. Families of males older than 8 days of age who had a UTI were contacted by telephone to verify the circumcision status when the infant presented to the ER, to ascertain whether the circumcision had been performed ritually by a mohel* or by a physician, and, if not recorded in the chart, to verify the day of life on which circumcision was performed. RESULTS: Among neonates older than 8 days of age, 60 (24.7%) of the 243 febrile Jewish males had a UTI, as compared to 12 (8.4%) of 143 females (P < 0.0001). In 39 of 54 male neonates (72%) for whom circumcision was performed ritually on the eighth day of life, UTI occurred within 9 days of the circumcision. For females, there was no such clustering of UTI cases in the second week of life, nor during any other time period. CONCLUSIONS: Febrile male neonates who have undergone ritual circumcision have a high prevalence of UTI and must be evaluated and treated accordingly.

Systemic hypoxia inhibits T cell response by limiting mitobiogenesis via matrix substrate-level phosphorylation arrest.

Systemic oxygen restriction (SOR) is prevalent in numerous clinical conditions, including chronic obstructive pulmonary disease (COPD), and is associated with increased susceptibility to viral infections. However, the influence of SOR on T cell immunity remains uncharacterized. Here we show the detrimental effect of hypoxia on mitochondrial-biogenesis in activated mouse CD8+ T cells. We find that low oxygen level diminishes CD8+ T cell anti-viral response in vivo. We reveal that respiratory restriction inhibits ATP-dependent matrix processes that are critical for mitochondrial-biogenesis. This respiratory restriction-mediated effect could be rescued by TCA cycle re-stimulation, which yielded increased mitochondrial matrix-localized ATP via substrate-level phosphorylation. Finally, we demonstrate that the hypoxia-arrested CD8+ T cell anti-viral response could be rescued in vivo through brief exposure to atmospheric oxygen pressure. Overall, these findings elucidate the detrimental effect of hypoxia on mitochondrial-biogenesis in activated CD8+ T cells, and suggest a new approach for reducing viral infections in COPD.