Israel Medical Association Journal

Background: Deficiency of adenosine deaminase 2 (DADA2) is a rare autosomal recessive disorder caused by loss-of-function mutations in the ADA2 gene, with a broad phenotype spanning systemic vasculitis, hematologic, immune deficiency, and autoinflammatory manifestations.

Objectives: To describe a decade of DADA2 management within a uniquely diverse population.

Methods: We conducted a single-center retrospective cohort study of genetically confirmed DADA2 patients (2014–2024). Demographics, clinical manifestations, laboratory findings, treatments, and long-term outcomes were reviewed.

Results: Seventeen pediatric patients were included from two ethnic groups: Arab Muslim (12/17, 70%) and Georgian Jewish (5/17, 29%). The median age at symptom onset was 3.5 months and at diagnosis 4 years. Phenotypes were purely vasculitic/inflammatory (5/17), purely hematologic (3/17), mixed hematologic-inflammatory (6/17), or mixed hematologic-immunodeficiency (3/17). None had isolated immune deficiency. The purely vasculitic/inflammatory phenotype was confined to Georgian Jewish patients, all homozygous for p.Gly47Arg, presenting with cutaneous and ischemic manifestations. Twelve patients received TNF-α inhibitors: 9 achieved complete response, 1 partial, and 2 none, with no subsequent strokes. Arab patients more often presented with fever, red cell aplasia, cytopenias, and immunodeficiency at younger ages. Three patients underwent hematopoietic stem cell transplantation (HSCT). Two responded favorably, one died of infection-related complications after engraftment.

Conclusions: We observed a distinct, ethnicity-driven genotype–phenotype correlation: Georgian Jewish patients with homozygous p.Gly47Arg had a pure vasculitic/inflammatory phenotype responsive to TNF-α inhibitors, whereas Arab patients harbored heterogeneous variants with hematologic/ immune deficiency phenotype potentially benefiting from HSCT. Early, genetically informed diagnosis and phenotype-driven, multidisciplinary management are essential to improve outcomes.

Background: Although the epidemiology of Creutzfeldt-Jakob disease (CJD) in Israel has been studied extensively, it is unknown whether its incidence is mainly a result of vertical transmission due to the high penetrance of the E200K mutation in patients with familial CJD (f-CJD) compared to sporadic CJD (s-CJD), or whether there are other yet undiscovered contributing factors.

Objectives: To conduct an age-period-cohort (APC) analysis of Creutzfeldt-Jakob disease in Israel.

Methods: In this APC analysis, we used a web-based statistical tool to identify whether patient age, period of birth, and cohort had any effect on incidence trends of s-CJD and f-CJD.

Results: APC analysis demonstrated no significant shifts in net drift, indicating the absence of any overall trend of changes over time. Cohort analysis revealed that individuals affected by either s-CJD or f-CJD who were mostly born in Israel in the second half of the 20th century exhibited the same risk as those born mainly in Libya at the beginning of 20th century. There were no changes in risk of s-CJD and f-CJD between 1985 and 2019.

Conclusions: The incidence rates of s-CJD and f-CJD in Israel have remained unchanged, indicating that the probability of a future increase in the incidence is negligible.

STING-associated vasculopathy with onset in infancy (SAVI) is a rare monogenic type I interferonopathy that may present with heterogeneous clinical manifestations and mimic common inflammatory disorders of childhood. We report the first familial case of SAVI in Israel, affecting a father and daughter carrying an identical pathogenic gain-of-function TMEM173 variant. The daughter initially presented with features fulfilling criteria for rheumatoid factor-positive juvenile idiopathic arthritis (JIA), later developing growth failure and progressive interstitial lung disease. In contrast, the father developed adolescent-onset inflammatory arthritis, subsequently lung disease, and a severe infectious neurological complication during treatment. This case highlights marked intrafamilial phenotypic variability, the diagnostic challenges posed by atypical inflammatory arthritis and the importance of genetic testing in treatment-refractory or systemic disease. Our findings underscore both the benefits and limitations of JAK inhibition in SAVI, particularly with respect to pulmonary disease and growth outcomes.

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: 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.

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: Inflammatory bowel disease (IBD) is a chronic relapsing condition affecting millions worldwide, often diagnosed during young adulthood and associated with significant functional impairment. The Israel Defense Forces (IDF) allows citizens with IBD and other chronic medical conditions to volunteer for military service through a special medical volunteer program. No comprehensive study has examined the impact of military service on disease progression or military performance.

Objectives: To evaluate the association between IBD and military service-related outcomes, including service completion and occupational stability, among IDF medical volunteers.

Methods: In this retrospective study, we examined 734 volunteer soldiers with IBD who served in the IDF between 2019 and 2024. Data were collected from computerized medical records and included demographic, occupational, and medical information.

Results: Among 734 IBD volunteers, 96.7% successfully completed their military service. Male sex (odds ratio 3.73) and lower sick leave utilization (odds ratio 3.13) were key predictors of service completion in multivariable analysis.

Conclusions: The findings suggest that the vast majority of IBD volunteers successfully completed military service, with male sex and lower sick leave utilization as predictors of completion. Given these outcomes, consideration should be given to including carefully selected IBD patients within the standard medical classification system, based on individualized assessment of disease stability and functional capacity, with a non-combat profile, rather than through the volunteer program.

Background: Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract. Biological therapy has transformed disease management; however, its association with postoperative outcomes remains debated.

Objectives: To evaluate the association between preoperative biological therapy and postoperative outcomes following ileocolic resection for Crohn’s disease, and to identify additional factors associated with postoperative complications.

Methods: We conducted a single-center retrospective observational study of Crohn’s disease patients who underwent ileocolic resection between 2021 and 2023. Patients were stratified according to preoperative exposure to biological therapy.

Results: Of 208 screened patients, 150 met inclusion criteria. Postoperative complications were more common in patients receiving biological therapy compared with controls (56% vs. 36.4%, P = 0.017), which was primarily driven by minor complications (48% vs. 30%, P = 0.022). Rates of major complications and length of hospital stay did not differ between the groups. Patients who developed major complications had significantly lower preoperative serum albumin levels (3.08 vs. 3.7 g/dl, P = 0.021).

Conclusions: Preoperative biological therapy was associated with a higher rate of postoperative complications, predominantly minor in severity. Low preoperative serum albumin was associated with major postoperative complications, highlighting the importance of preoperative nutritional assessment and optimization.

Uremic cardiomyopathy (U-CMP), also known as chronic kidney disease cardiomyopathy (CKD-CMP), is a phenotype of non-ischemic cardiomyopathy frequently seen among patients with chronic kidney disease. Left ventricular (LV) systolic dysfunction is seen in approximately 13% of patients, and LV ejection fraction (LVEF) below 40% has been reported in 5.8% of patients [1]. Severe LV dysfunction may be considered a relative contraindication to renal transplantation. We present a case of complete recovery of ventricular function following renal transplantation in a patient with severe U-CMP.

It is 3:00 in the morning at an Israeli medical center. The rhythmic beeping of monitors pierces the silence as an on-call team gathers around a patient's bed. The team includes a Jewish doctor, a Muslim nurse, and a Christian physician. In these critical moments, the only language spoken is the language of medicine–a seamless blend of physiology, pharmacology, and an ancient medical oath.

For us in Israel, this reality is natural and common. Yet, viewed through a historical lens, particularly against the backdrop of World War II when medicine itself was weaponized and conscripted into an extermination machine, this collaboration was nothing short of a monumental triumph of the human spirit. In this editorial, I invite you on a historical journey to revisit two profound narratives where physicians from diverse backgrounds transformed their clinical knowledge and authority into instruments of life and resistance.

Background: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by fibrosis of the skin and internal organs. Its expression can vary across ethnic groups.

Objectives: To compare clinical and serological manifestations of SSc between Jewish and Arab patients in Israel.

Methods: We conducted a retrospective single-center study included 100 patients with SSc selected from our rheumatology clinic at Meir Medical Center, comprising 50 Jewish and 50 Arab patients with available complete clinical and laboratory data. Demographic characteristics, disease features, autoantibody profiles, organ involvement, and treatment patterns were collected.

Results: Most clinical, laboratory, and treatment variables did not differ significantly between Jewish and Arab patients. Significant difference was the higher prevalence of skin telangiectasia in Jewish patients (86%) compared to Arab patients (38%) (P < 0.001) as well as Raynaud phenomenon and pulmonary hypertension. Other manifestations, including organ involvement and autoantibody prevalence, were similar across the groups.

Conclusions: This study reveals significant similarities in the clinical and serological expression of SSc between Jewish and Arab patients in Israel. The higher prevalence of telangiectasia in Jewish patients suggests a possible ethnic or environmental influence on vascular manifestations. Further research is needed to explore the potential genetic or environmental factors contributing to this difference and to assess if this impacts disease progression or treatment outcomes.

A 55-year-old male with a history of Dubin-Johnson syndrome (DJS), obesity, and smoking presented to the emergency department with generalized weakness and jaundice. On admission, he was hypotensive (blood pressure 87/56 mmHg), and profound jaundice was noted. Laboratory investigations revealed severe acute kidney injury with a creatinine level of 5.53 mg/dl and blood urea nitrogen of 92 mg/dl. Liver function tests were mildly elevated, and his lipid profile was within normal limits. Total bilirubin was markedly elevated at 52.5 mg/dl, predominantly direct (40.9 mg/dl). The patient was anuric at the time of catheter insertion.

A non-contrast abdominal computed tomography scan showed normal kidney size and appearance without hydronephrosis. The liver was normal size with sharp borders. The patient was treated with intravenous fluids, inotropic support, and intravenous antibiotics. Despite these interventions, he remained anuric with worsening hyperkalemia, necessitating urgent hemodialysis.

Within 10 minutes of initiating hemodialysis, a yellowish discoloration appeared in the effluent tubing of the dialysate. Simultaneously, the dialyzer fibers, which are typically pinkish in color, began to develop a yellowish tint. By the end of the session, the dialyzer appeared distinctly yellow, likely due to bilirubin deposition [Figure 1A–1C].

Sinus of Valsalva aneurysms (SVA) are uncommon cardiac anomalies. They represent only 0.1–3.5% of congenital heart defects. While rupture of an SVA can lead to acute left-to-right shunting and heart failure, its association with chromosome 22q11.2 deletion (DiGeorge syndrome) has rarely been documented.

Transthoracic echocardiography (TTE) revealed a continuous systolic-diastolic jet suggestive of aortic-to-right-atrial communication. TEE and contrast-enhanced computed tomography (CT) confirmed rupture of a right-coronary-cusp SVA into the right atrium. The patient underwent urgent surgical repair. Initial direct-suture closure was unsuccessful because of persistent flow and was converted to definitive pericardial-patch repair. Postoperative TTE demonstrated complete closure and preserved biventricular function. To the best of our knowledge, this case represents only the third known example of ruptured SVA in a patient with DiGeorge syndrome. It underscores the expanding cardiovascular phenotype of 22q11.2 deletion and highlights the role of multimodality imaging and timely surgical intervention.

Celiac disease (CD) is diagnosed by demonstrating gluten-induced villous atrophy on duodenal biopsy in patients with positive serology. Duodenal histology remains the gold standard, although pediatric guidelines allow a no-biopsy approach in highly seropositive children. Video capsule endoscopy (VCE) can visualize mucosal changes typical of active CD, such as flattening of mucosal folds, fissuring, scalloping, ulcerations, throughout the small bowel, overcoming the regular endoscopy capability of reaching the proximal duodenum and missing distal and patchy lesions. In this review, I discussed whether VCE can replace duodenal biopsy for diagnosing celiac disease. I summarized diagnostic yield, sensitivity/specificity, and clinical contexts favoring VCE as well as its limitations and potential future role (including artificial intelligence enhancement). I found that video capsule endoscopy is a valuable adjunctive tool to diagnose CD, but currently it complements, rather than outright replaces, duodenal biopsy.

Background: The coronavirus disease 2019 (COVID-19) pandemic has disrupted healthcare systems globally, affecting chronic disease management like osteoporosis and the prevention of fragility hip fractures. We hypothesized that it led to suboptimal prevention of secondary femoral neck fractures, reduced treatment frequency, and delayed treatment initiation.

Objectives: To evaluate the treatment initiation rate for secondary prevention of femoral neck fractures, comparing pre-COVID-19, COVID-19, and post-COVID periods, considering patient demographics.

Methods: This retrospective diagnostic cohort study used automated electronic medical records database from Clalit Health Services. Data regarding patients with hip fractures from January 2017 through September 2021 were extracted from the database. Treatment for osteoporosis included one of the following treatments: alendronate, risedronate, zoledronate, abaloparatide, denosumab, romosozumab, and teriparatide. The primary outcome variable in the study is the time taken to initiate appropriate therapy for the secondary prevention of femoral neck fractures.

Results: Treatment frequency decreased over time, with rates declining from 40.4% in 2019 to 33.5% in 2021 (P-value < 0.05). However, the percentage of prompt care management (within 3 months) increased between 2020 and 2021 (47.3%–62.5%) and between 2019 and 2021 (48.7%–62.5%), P < 0.05.

Conclusions: The COVID-19 pandemic reduced the rate of appropriate treatment initiation following hip fractures. However, adherence to timely treatment within 3 months of the fracture has improved. The findings highlight the effectiveness of the health system response in managing crises and ensuring the timely delivery of critical treatment.