Israel Medical Association Journal

Inborn errors of immunity represent a heterogeneous group of disorders with variable clinical manifestations. Within this group of disorders, severe combined immunodeficiency (SCID) is the most profound disorder, where affected infants present clinically early in life, and have almost uniformly fatal outcome unless hematopoietic stem cell transplantation (HSCT) is performed. Gene therapy or enzyme replacement therapy are options in some specific SCID forms [1]. The estimated incidence of SCID in the United States is 1 in 58,000 live births, while in Israel the incidence is as high as 1 in 29,000 live births. This higher rate is due to a high rate of consanguineous marriages in certain communities [2].

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. In contrast to typical HUS, which is triggered by Shiga toxin–producing bacteria, aHUS results from genetic or acquired dysregulation of the alternative pathway (AP) of the complement system and has an estimated incidence of 1–2 cases per million per year [1]. Early recognition is critical, as terminal complement inhibition with C5 blockers significantly improves renal and overall outcomes [2,3].

Agammaglobulinemia was the first primary immunodeficiency identified in humans. It is characterized by an absent or significantly reduced number of mature B cells, decreased serum immunoglobulins, and recurrent infections beginning in infancy. The entity was first described in 1952 by Colonel Ogden Bruton at the Walter Reed Army Hospital in the United States. Bruton reported on an 8-year-old boy who had experienced 19 episodes of pneumonia over 4 years and was found to have a complete absence of antibody-containing γ-globulins in his serum [1].

Over time, through improvement in the immune and genetic investigations, our understanding of agammaglobulinemia has expanded enabling earlier diagnosis and treatment resulting in a change of the disease course.

Inborn errors of immunity (IEI), formerly referred to as primary immunodeficiencies, is a growing spectrum of over 550 genetically defined disorders of the immune system. As our understanding of the mechanisms of these disorders grows, immune dysregulation syndromes, autoimmunity, malignancy, bone marrow failure with immunodeficiency, and phenocopies are recognized as part of the clinical spectrum of IEI. Early recognition and accurate classification are critical as many IEI conditions have specific therapeutic implications, including targeted immune modulation, immunoglobulin replacement therapy, hematopoietic stem cell transplantation, and gene therapy. In this review, we present recent changes in classification, updated laboratory workup strategies, and therapeutic advances.

Inborn errors of immunity (IEI) are a heterogeneous group of monogenic disorders affecting immune function, associated with a broad clinical spectrum including recurrent infections and immune dysregulation consisting of poly-autoimmunity, multiple allergies, and malignancies. To date, more than 550 causative genes have been identified, with inheritance patterns that may be autosomal dominant, autosomal recessive, or X-linked. Pathogenic variants may result in loss-of-function, dominant-negative, or gain-of-function effects, leading to variable phenotypic presentations and, at times, incomplete penetrance. Despite advances in genomic technologies, a definitive molecular diagnosis is reached in only 30–35% of cases. Early and accurate genetic diagnosis is crucial for guiding targeted therapy and providing effective genetic counseling. This review presents an updated overview of IEI from the geneticist's perspective and offers a practical approach to the genetic evaluation and diagnosis of these conditions.

Neutrophils serve as a cornerstone of innate immunity. Beyond their classical antimicrobial repertoire, these cells are versatile and capable of shaping the adaptive immune response through direct interactions with dendritic cells and lymphocytes in addition to cytokine-mediated effects. Additional functional phenotypes have also been described with regard to cancer and chronic inflammation. The clinical importance of neutrophils in host defense is perhaps best illustrated by the spectrum of inborn neutrophil disorders, ranging from congenital neutropenia to defects of adhesion and phagocytosis. We present a patient with clinical and laboratory features of hemophagocytic lymphohistiocytosis with a bacterial infection. The patient was subsequently found to carry a homozygous variant in the NCF2 gene, establishing a diagnosis of autosomal recessive chronic granulomatous disease (CGD). This presentation, combining cytokine storm with ongoing infection-driven inflammation, exemplifies the multifaceted role of neutrophils in health and disease. In this review, we provide clinical and immunological insights into neutrophil disorders, illustrated through a case of CGD as a paradigm of primary neutrophil dysfunction.

Background: Syndromic inborn errors of immunity (IEIs) are a heterogeneous group of disorders characterized by immune dysfunction associated with congenital anomalies and multisystem involvement. Tricho-hepato-enteric syndrome (THES) is an ultra-rare autosomal recessive syndromic IEI caused by biallelic pathogenic variants in TTC37 or SKIV2L. Delayed recognition is common because of its broad clinical spectrum.

Objectives: To describe the clinical, immunologic, genetic, and histopathologic characteristics of two children with THES and to highlight a structured diagnostic approach for syndromic immunodeficiencies.

Methods: We retrospectively reviewed the clinical presentation, laboratory investigations, immune phenotyping, endoscopic and histopathologic findings, and molecular analyses of two unrelated children diagnosed with THES at a tertiary pediatric immunology center. Molecular confirmation was obtained by whole-exome sequencing.

Results: Both patients presented during early infancy with intractable diarrhea, severe failure to thrive, characteristic dysmorphic features, brittle woolly hair, and inflammatory enteropathy requiring prolonged nutritional support. Immunologic evaluation demonstrated immune dysregulation, including inverted CD4/CD8 ratios, abnormalities of humoral immunity, and impaired vaccine-specific antibody responses. Histopathology revealed chronic active colitis with crypt distortion, inflammatory infiltrates, and crypt abscesses, consistent with very-early-onset inflammatory bowel disease-like enteropathy. Whole-exome sequencing identified homozygous pathogenic variants in SKIV2L in one patient and TTC37 in the other, establishing the diagnosis. Management included nutritional support, immunoglobulin replacement, antimicrobial prophylaxis, and immunomodulatory therapy.

Conclusions: Recognition of syndromic phenotype combined with comprehensive immune evaluation and early genomic testing facilitates prompt diagnosis, multidisciplinary management, genetic counseling, and consideration of emerging targeted therapies.

Background: Bone marrow failure syndromes (BMFs) comprise a heterogeneous group of genetic disorders characterized by impaired hematopoiesis and multisystem involvement. Dyskeratosis congenita (DC) is a telomere biology disorder caused by defects in telomerase or telomere maintenance, leading to progressive BMF and variable extra-hematopoietic manifestations.

Objectives: To describe the clinical, immunologic, genetic, and telomere biology findings in a patient with DC caused by a novel biallelic telomerase reverse transcriptase (TERT) mutation, and to highlight diagnostic and therapeutic considerations in telomere-associated BMFs.

Methods: We assessed cellular and humoral immune functions. Genetic analysis was conducted using whole-exome sequencing (WES) with segregation analysis. Telomere length was assessed by flow-FISH. Functional and radiologic evaluations were performed to define disease extent.

Results: A 2-year old male born to consanguineous parents presented with multisystemic clinical features, and hypocellular bone marrow. WES identified a novel homozygous TERT missense variant (c.3052G>A; p.Ala109Thr) supported by markedly shortened telomeres. Neuroimaging revealed cerebellar hypoplasia consistent with Hoyeraal-Hreidarsson syndrome. Immunologic evaluation demonstrated skewed CD4:CD8 ratios. An incidental heterozygous MEN1 variant was also detected.

Conclusions: We expand the clinical and genetic spectrum of TERT-associated DC and illustrate the critical role of genomic diagnostics and telomere assessment in BMFs. Early molecular diagnosis enables targeted evaluation, informs prognosis, and guides personalized management in telomere biology disorders. In addition, the identification of actionable secondary variants further highlights both the power and complexity of comprehensive genomic testing.

Background: Common variable immunodeficiency (CVID) is the most common clinically significant primary immunodeficiency disorder, typically presenting with hypogammaglobulinemia and recurrent infections. Mechanistically, CVID is caused by abnormal B-cell maturation or function. These abnormalities lead to an impaired ability to generate a normal quantity or diversity of antibodies and an impaired response to neo-antigens. In addition to the resulted immunodeficiency, CVID can also involve immune dysregulation affecting different organ systems, with the lungs being one of the more commonly involved organs. Granulomatous lymphocytic interstitial lung disease (GLILD) is a challenging and well known CVID-related complication. It is associated with high morbidity and increased risk of mortality.

Objectives: To describe the clinical and immunological features of five CVID patients with radiologic and/or pathologic features consistent with granulomatous lymphocytic interstitial lung disease.

Methods: We conducted a review of clinical, laboratory, imaging, and pathology data, as well as B-cell and T-cell immunophenotyping of patient PBMCs, focusing on unique characteristics of CVID GLILD patients.

Results: CVID GLILD patients showed several clinical characteristics, including multiorgan involvement with cytopenias and lymphoproliferation but without significant gastrointestinal involvement. B-cell phenotyping showed abnormal B-cell maturation and development with severely impaired class switching. In addition, unique T-cell phenotype with low to near-absent naive CD4⁺ T cells was observed.

Conclusions: Lung involvement in the form of GLILD is associated with significant co-morbidity and typical B-cell and T-cell immunophenotyping. Patients should be actively screened for the possibility of GLILD, especially when regularly performed lymphocyte immunophenotyping suggests similar patterns.

Modern armed conflicts increasingly expose civilian infrastructure, including hospitals, to direct military threats such as missile attacks. Hospitals provide care for some of the most vulnerable patients, including bedridden individuals and those requiring continuous monitoring that cannot be easily relocated. Protecting these patients during active hostilities presents a major operational challenge. Hospitals must maintain clinical care, prepare for potential infrastructure damage, and remain ready to receive mass casualty victims. Previous disasters and conflict-related evacuations have demonstrated the complexity and risks of relocating hospitalized patients under emergency conditions [1,2].

Background: National crises can significantly impact healthcare utilization patterns yet analyses of different types of crises are limited. While the effects of the coronavirus disease 2019 (COVID-19) pandemic on emergency department (ED) utilization have been well-documented, the healthcare impact of the Israel–Hamas war, which began 7 October 2023, remains unexplored.

Objectives: To compare ED utilization patterns for non-traumatic low back pain (LBP) during two distinct national crises.

Methods: We conducted a retrospective observational study analyzing ED visits for non-traumatic LBP at our medical center. We compared ED utilization patterns, visual analog scale (VAS) pain scores, and surgical rates during 60 days before and after two distinct dates: 7 October 2023 and 19 March 2020 (the start of the COVID-19 lockdown). Statistical analysis included independent t-tests for continuous variables and chi-square tests for categorical variables.

Results: Following 7 October, ED visits decreased by 28.6% (504 to 360). Mean VAS scores and surgery rates showed a non-significant increase from 5.5 ± 2.6 to 5.8 ± 2.4, and from 3.0% to 4.2%, respectively. During the COVID-19 lockdown, ED visits declined by 44.2%, with non-significant changes in pain scores (6.0 ± 3.0 to 5.5 ± 2.9) and surgical rates (3.5% to 2.5%).

Conclusions: Both events led to significant reductions in ED utilization for non-traumatic LBP, despite the heightened risk factors. Surgical rates remained stable, yet many symptomatic patients may have foregone adequate care. These findings underscore the need for resilient, crisis-specific emergency preparedness strategies to ensure continued access to care.

Background: Coronavirus disease 2019 (COVID-19) causes severe complications in 15% of patients, many of whom are pregnant. Most infected women continue their pregnancies until term even though severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in the decidua.

Objectives: To assess the impact of SARS-CoV-2 infection remote from delivery on obstetric outcomes.

Methods: Women diagnosed with SARS-CoV-2 infection confirmed by polymerase chain reaction at least 14 days prior to delivery were enrolled prospectively and followed monthly until delivery. Their obstetric outcomes were compared to those of women who gave birth at our center during the year preceding the pandemic. The primary endpoint was a composite of hypertensive disorders of pregnancy, oligohydramnios, and fetal distress or meconium-stained amniotic fluid during labor. Other demographic and obstetric variables were also recorded.

Results: The obstetric outcomes of 143 patients were compared to those of 3565 patients who gave birth during the year preceding the pandemic. The composite rate of placental complications was significantly higher in the study group (58 [41%] vs. 593 [17%], respectively), with an odds ratio of 3.4 (95% confidence interval 2.4–4.7). There was also an increased rate of labor induction or advancing the elective cesarean date in the study group (37 [26%] vs. 601 [17%]). No significant differences were found in the Apgar score, cord pH or gestational age at infection.

Conclusions: The risk of placental complications remains greater in pregnant women infected with SARS-CoV-2 after acute illness resolution. Those patients should be monitored closely until delivery.

Background: Electrocardiogram (ECG) may detect atrial fibrillation (AF), but the true rate of ECG performance is unknown.

Objectives: To explore the performance rate of ECG testing in patient populations at high risk for AF in a real-world cohort and to explore the incidence of newly diagnosed AF.

Methods: This retrospective observational cohort study included de-identified data of members of Maccabi Health Services older than 65 years, excluding patients with prior AF and other cardiac diseases. Patients were followed between 1 January 2016 and 30 September 2020. The number of ECGs performed in an outpatient setting for each patient was reported.

Results: In total, 211,515 patients (59.8% female) were included. The mean age was 70.3 ± 6.6 years, with a mean CHA₂DS₂-VASc score of 2.6 ± 1.0. During the study period, over half of the patients (n=112,340; 53.1%) did not undergo any ECG tests, 51,644 patients (24.4%) had one ECG, 24,914 patients (11.8%) had two, while 22,617 patients (10.7%) had more than three. Of the patients referred for an ECG, 67,433 (81.1%) underwent ECG testing within 2 months following the referral. The median time from ECG referral to ECG testing was 5 days.

Conclusions: Most patients older than 65 years had no ECG tests within a 5-year period. However, when referred to an ECG test, most patients complied within a median of 5 days.

Background: Differences in socioeconomic status and ethnicity are linked to disparities in health outcomes, which can affect how consistently patients treat abnormal screening results and cause minority groups to be diagnosed at more advanced stages of disease.

Objective: To compare epidemiological and clinical parameters between Jewish and Arab women who were diagnosed with cervical cancer at Ziv Medical Center during a 10-year period.

Methods: We conducted a retrospective study of consecutive women diagnosed with cervical cancer at a single institution between 2014 and 2024.

Results: Overall, 83 women diagnosed with cervical cancer in the last 10 years at Ziv Medical Center were included in the study: 53 Jewish (64.6%), 30 Arab (36.2%). The groups were similar in mean age at diagnosis, body mass index, smoking status, Pap history performance prior to the diagnosis, menopause status at diagnosis, stage at diagnosis, and treatment. Arab women had higher parity (< 0.001). According to the results of our study, the percentage of cervical cancer patients undergoing Pap screening, prior to diagnosis from the Arab and Jewish sectors, were 16.7% and 17%, respectively, compared to the national screening rate of 54%. Most of the women were diagnosed at an advanced stage (≥ IIB): 83.3% and 69.8%, respectively, compared to 25% in developed countries.

Conclusions: Jewish and Arab women diagnosed with cervical cancer in northern Israel do not differ in epidemiological and clinical parameters, including age at diagnosis and stage. These findings may be attributed to the low performance rate of Pap screening tests in both groups.

Background: Postoperative atrial fibrillation (POAF) is well recognized after cardiac surgery; however, its incidence and clinical course following non-cardiac surgery (NCS) remain unclear.

Objectives: To evaluate the association between POAF after NCS, patient co-morbidities, and type of surgery.

Methods: In this retrospective cohort study, patients who underwent NCS at a private hospital network between 2016 and 2023 were included. Patients with a history of atrial fibrillation (AF) were excluded. Patients who developed POAF within 24-48 hours were compared with those who did not. To address baseline differences, propensity score matching (1:10) and inverse probability weighting combined with Firth’s penalized logistic regression were applied. Odds ratios with 95% confidence intervals were calculated.

Results: POAF developed in 174 patients within 24–48 hours postoperatively, compared with 391,329 controls. Older age, ischemic heart disease, diabetes, and prior stroke were associated with increased odds of POAF, although significance diminished after multivariable adjustment. Weighted regression confirmed these findings with narrower confidence intervals. Higher POAF risk was observed after laparoscopic pancreatectomy, hepatectomy, rectopexy, synovectomy, and gastrectomy. Total knee replacement was the most common procedure among POAF cases, representing 22% of cases and a fourfold increased risk.

Conclusions: Advanced age and cardiovascular co-morbidities were associated with increased POAF risk after NCS, although attenuated after adjustment. Consistent findings across statistical models support the robustness of the results. Targeted monitoring in high-risk patients may improve postoperative outcomes.