Israel Medical Association Journal

Inborn errors of immunity (IEI) result from pathogenic germline variants. These disorders are clinically characterized by increased susceptibility to infections and immune dysregulation, often leading to reduced survival [1]. By linking specific monogenic defects to immune phenotypes, IEI serve as experiments of nature that provide powerful models for dissecting human immunology [2]. The International Union of Immunological Societies (IUIS) currently classifies IEI into 10 major categories with overlapping phenotypes [3]: combined T- and B-cell immunodeficiencies, combined immunodeficiencies with syndromic features, predominantly antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory diseases, complement deficiencies, bone marrow failure, and phenocopies of IEIs. The recent 2024 IUIS update was designed to serve clinicians and researchers and to inform the design of targeted sequencing panels that facilitate the genetic diagnosis of IEI. It lists 508 genes underlying 559 conditions [3]. Of note, molecular, cellular, and clinical investigations of IEI have transformed our understanding of disease pathogenesis and enabled effective targeted therapies.

The field of inborn errors of immunity (IEI), previously known as primary immune deficiencies, includes susceptibility to infections, autoimmunity, uncontrolled inflammation and malignancy is rapidly expanding. Novel scientific discoveries together with artificial intelligence and machine learning are transformed into advances in the diagnosis and treatment of affected patients. These changes require adjustments in the knowledge, skills and attitudes of health care providers, and particularly expert clinicians managing patients with IEI. In this perspective, we highlighted some of the educational needs that should be adapted to ensure that the next generation of physicians provide best care for those affected by IEI.

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].

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.

Peripheral facial nerve palsy is an infrequent but well-recognized clinical presentation encountered by primary care and emergency department physicians. Risk factors include diabetes mellitus (DM) and hypertension, both of which are also associated with an increased risk of cerebrovascular accident, which is a critical consideration in the differential diagnosis [1]. Prompt and accurate differentiation between central and peripheral etiologies is crucial in the initial evaluation of facial palsy. Notably, approximately 5% of cases may be secondary to neoplastic processes, whether benign or malignant [1].

Small cell carcinoma of cervix (SCCC) is a rare and aggressive high-grade neuroendocrine tumor [2]. Neurologic manifestations due to brain metastases from neuroendocrine cancers of the cervix are extremely rare, with no prior reports involving the facial nerve [3].

We report a unique case in which peripheral facial nerve palsy was the initial clinical manifestation of SCCC. This case highlights the importance of maintaining a broad differential diagnosis and underscores the pivotal role of a comprehensive history and physical examination as part of a systematic and holistic approach when evaluating patients presenting with facial nerve palsy.

Background: The rapid evolution of large language models warrants updated benchmarking in ophthalmology to determine whether newer versions offer clinically meaningful improvements over earlier models and human comparators.

Objectives: To evaluate the diagnostic accuracy of ChatGPT-4o and ChatGPT-5 in ophthalmic cases and to compare it with previously reported results of ChatGPT-3.5, residents, and specialists.

Methods: This retrospective cohort study was conducted in one academic tertiary medical center. We reviewed data of patients admitted to the ophthalmology department from June 2022 to January 2023. We then created two clinical cases for each patient. The first was according to medical history alone (Hx). The second added the clinical examination (Hx and Ex). For each case, we asked for the three most likely diagnoses from ChatGPT-4o and ChatGPT-5. We then compared the accuracy rates (at least one correct diagnosis) with previous results of ChatGPT-3.5, residents, and specialists.

Results: A total of 63 cases were analyzed, first using history alone and then with examination findings. Based on history alone, GPT-5 and GPT-4o correctly identified 73% and 70% of cases, respectively, outperforming GPT-3.5 (54%, P < 0.05) and approaching the accuracy of residents (75%) and attending physicians (71%, P < 0.05). When physical examination was included, diagnostic accuracy rose to 94% for GPT-5 and 89% for GPT-4o, surpassing GPT-3.5 (68%, P < 0.05) and closely matching or exceeding human performance (residents 94%, attendings 87%).

Conclusions: ChatGPT-4o and ChatGPT-5 significantly outperformed GPT-3.5 and achieved diagnostic accuracy similar or even higher to clinicians in diagnosing ophthalmology cases.

Polymicrobial endocarditis is a rare clinical entity associated with high rate of morbidity and mortality. We present a case of prosthetic valve endocarditis caused by Enterococcus faecalis and Proteus mirabilis, emphasizing the clinical course, microbiological findings, and potential microbial synergy contributing to disease persistence.

E. faecalis is a gram-positive, facultatively anaerobic bacterium that can cause significant morbidity and mortality. It commonly presents as bacteremia and endocarditis and is a major contributor to nosocomial infections. This bacterium produces biofilms on native and artificial tissues, allowing it to establish resistance to antimicrobial agents. Many infections caused by E. faecalis are polymicrobial, as its biofilm creates an environment that supports the colonization of other microorganisms, leading to mixed-species biofilms on endogenous tissues or medical devices.

Background: Rising rates of antibiotic resistance pose a major challenge in the treatment of Helicobacter pylori (H. pylori) infection. Current treatment guidelines emphasize the importance of acquiring local resistance data to select an effective empirical regimen.

Objectives: To analyze trends in H. pylori antibiotic resistance over two decades in Israel.

Methods: Data from Clalit Health Services for H. pylori isolates cultured from gastric biopsies between January 2007 and December 2023 were included. Susceptibility to clarithromycin, amoxicillin, metronidazole, tetracycline, and levofloxacin was determined using E-tests. Demographic and clinical variables were retrieved to identify predictors of resistance.

Results: We identified 2521 H. pylori isolates (71.6% females, mean age 44.4 ± 15.8 years). Most individuals were residents of central Israel (84.6%) and of Jewish ethnicity (87.8%). Antibiotic resistance was observed in 71.6% of isolates for clarithromycin, 64.3% for metronidazole, and 19.4% for levofloxacin. Resistance to tetracycline and amoxicillin was minimal (0.2% and 1.2%, respectively). Dual clarithromycin-metronidazole resistance occurred in 50.4%, and triple resistance (clarithromycin-metronidazole-levofloxacin) was found in 12.0%. Between 2007 and 2012, clarithromycin resistance increased 5.3% annually, then tapered (odds ratio [OR] 1.05, 95% confidence interval [95%CI] 3.84–6.85, P < 0.001). Age and prior antibiotic use were predictors of resistance for all antibiotics, with the greatest effect observed for drugs in the same class. Female sex was associated with higher resistance to levofloxacin (OR 1.62, 95%CI, 1.28–2.05, P < 0.001).

Conclusions: Antibiotic resistance to H. pylori is high in our geographical region. Nevertheless, resistance rates have remained steady over recent years.

Background: Solid organ transplant (SOT) recipients represent a particularly vulnerable group due to their reliance on immunosuppressive therapies. Previous studies indicated a mortality rate of 20%-30% among SOT recipients with coronavirus disease 2019 (COVID-19). With the advent of the Omicron variant in November 2021, characterized by milder symptoms and lower mortality rates in the general population, safety measures relaxed, potentially impacting vulnerable populations like SOT recipients.

Objectives: To investigate mortality and morbidity among hospitalized SOT recipients with COVID-19 infection during the Omicron wave.

Methods: A retrospective, propensity-matched cohort study conducted at the Rabin Medical Center, Israel, spanned from November 2021 to June 2023. Adult SOT recipients hospitalized with COVID-19 were compared to matched controls.

Results: Among 139 hospitalized SOT recipients and 209 controls, SOT recipients hospitalized with COVID-19 displayed higher in-hospital mortality (19% vs. 11%) and 90-day all-cause mortality (30% vs. 17%). In addition, the 90-day readmission rate was significantly higher among SOT recipients (43% vs. 31%). Multivariable analysis confirmed these trends, with SOT recipients exhibiting increased risk for mortality, readmission, invasive ventilation, and intensive care unit admission.

Conclusions: The heightened vulnerability of hospitalized SOT recipients during the Omicron wave was characterized by higher mortality and readmission rates compared to matched controls. Despite the perceived milder nature of the Omicron variant, SOT recipients remain disproportionately affected. Continued vigilance and targeted interventions are necessary for this population including vaccinations and adherence to preventive measures. Investigating this population’s outcomes through the changing COVID-19 variants is still warranted.

Inborn errors of immunity (IEI), formerly known as primary immunodeficiencies (PID), comprise a diverse group of genetic disorders characterized by increased susceptibility to infections, autoimmunity, autoinflammatory conditions, allergies, and malignancies. These disorders exhibit a broad spectrum of clinical manifestations, including extra-hematopoietic manifestations, which may also present later in life. IEI diagnosis has significantly advanced, in line with the common use of next-generation sequencing-based genetic platforms, such as whole-exome and whole-genome sequencing. Treatment approaches have evolved beyond infection management to include curative therapies such as hematopoietic stem cell transplantation, gene therapy, and targeted pharmacologic treatments. In this review, we explore recent advancements in the understanding, diagnosis, and treatment of IEI, emphasizing the rapid progress in this expanding field.

Background: Burnout is prevalent among healthcare providers and characterized by emotional exhaustion, depersonalization, and reduced personal accomplishment. The coronavirus disease 2019 (COVID-19) pandemic exacerbated burnout due to increased workloads, emotional strain, and heightened risk. Complementary medicine (CAM) interventions like shiatsu massage and reflexology have been explored as potential to mitigate burnout, particularly pandemic-related stress.

Objectives: To assess the efficacy of CAM interventions for alleviating burnout in healthcare providers treating COVID-19 patients during 2022, when the Delta variant was prevalent.

Methods: This prospective observational study included 86 healthcare providers at Rabin Medical Center, Beilinson Campus. Workers were divided into two groups: an intervention group participating in CAM activities and a control group. Participant burnout and post-traumatic stress disorder (PTSD) symptoms were evaluated using the Maslach Burnout Inventory and General Anxiety Disorder 7 at baseline and at one day and one week post-intervention.

Results: The CAM group demonstrated significant reduction in burnout scores, primarily due to an enhanced sense of accomplishment (P = 0.023), with enduring effects observed after one week, although not reaching statistical significance (P = 0.078). There was no observed difference in PTSD scores between the groups (P = 0.28).

Conclusions: The study reveals potential benefits of CAM interventions in reducing burnout symptoms among healthcare providers during the COVID-19 pandemic. The findings underscore the importance of integrating such interventions to address the mental well-being of healthcare providers, especially in high-stress environments. Further randomized controlled trials with diverse samples and extended follow-up are recommended to validate and explore these initial findings.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by an inadequate attenuation of the cytotoxic and innate immune system resulting in uncontrolled inflammation in multiple organ systems. Predominant clinical findings include fever, cytopenia, and hepatosplenomegaly [1].

Infectious diseases are a well-documented trigger of HLH, with viral infection being the most common cause. Less commonly, HLH has also been reported in the setting of bacterial infections, with rare cases described secondary to rickettsial diseases [1]. In this report, we present a case of HLH in the setting of bacterial infection with Rickettsia typhi, murine typhus.

A 38-year-old immunocompetent male with a history of Hodgkin's lymphoma in remission presented to the emergency department at Rambam Hospital with infectious mononucleosis due to an acute cytomegalovirus (CMV) infection. He was also diagnosed with portal vein thrombosis (PVT). After a thorough laboratory and radiological investigation, these two diagnoses were found to be related. No other explanation was identified except for transiently detected antiphospholipid antibodies, which were assumed to be provoked by the CMV infection. In this review, we investigated the relationship between CMV infection and a hypercoagulable state. We searched the PubMed database for case reports, clinical reviews, and meta-analyses that reviewed the relationship between CMV infection and deep vein thrombosis. The incidence of thromboembolism in patients with acute CMV infection was reported to be as high as 6.4%. In addition, anti-cardiolipin antibodies were more commonly present at the time of PVT diagnosis among CMV-positive patients compared to CMV-negative patients, although these antibodies disappeared in most cases. To the best of our knowledge, there is no evidence of added benefit from antiviral therapy in patients with CMV-associated thrombosis. CMV infection may serve as a trigger for a transient hypercoagulable state.