Israel Medical Association Journal

Background: Wilson disease (WD) is an autosomal recessive disease characterized by a defect in hepatocellular copper transport with a wide spectrum of clinical manifestations and reported prevalence.

Objectives: To study the epidemiology and clinical manifestations of WD between two ethnic groups, Jewish and Bedouins, with different marriage patterns, in southern Israel.

Methods: We conducted a retrospective study investigating the clinical course and laboratory characteristics of children diagnosed with WD who were treated at Soroka University Medical Center.

Results: Sixteen patients were diagnosed between 2000 and 2021 (8 males, 50%), 14 were of Bedouins origin. The total cohort prevalence was 1:19,258 while the prevalence of the disease was significantly higher among Bedouins compared to Jews (1:10,828 vs.1:78,270, P-value = 0.004). The median age at diagnosis was 10.2 years, without a significant difference between the groups. The most common presenting symptom was hepatic manifestations: 81.2% had elevated transaminases, 12.5% had jaundice, 25% had neurological symptoms, one had a Kayser-Fleischer ring, and one had psychosis. The mean ceruloplasmin level was 3.0 mg/dl. During follow-up, nine patients normalized transaminases with treatment, while three required liver transplantation. There was no significant difference in the clinical presentation and disease course between the two ethnic groups.

Conclusions: Our cohort showed a high prevalence of WD compared to previous studies, especially among the Bedouin population, which has a high consanguinity rate. The prognosis of WD in our population is similar to other studies and depends mainly on treatment compliance.

Background: Acute bronchiolitis, primarily caused by respiratory syncytial virus (RSV), is the leading cause of hospitalization in young children. Despite international guidelines supporting clinical diagnosis, laboratory evaluations are often conducted with limited validity.

Objectives: To evaluate the association between C-reactive protein (CRP) serum levels on admission and disease severity in children hospitalized due to RSV bronchiolitis.

Methods: This retrospective cohort study included children (0–24 months old) who were hospitalized due to RSV bronchiolitis (2018–2022), CRP levels taken at admission.

Results: We included 1874 children (mean age of 6.7 months, 59% males); median CRP level 1.92 mg/dl. Children with elevated CRP (> 1.92 mg/dl) were significantly older (5.1 vs. 3.8 months, P < 0.001) and had higher rates of pneumonia (9.4% vs. 4.3%, P < 0.001), urinary tract infection (UTI), (2.2% vs. 0.2%, P < 0.001), acute otitis media (AOM) (1.7% vs. 0.2%, P < 0.001), admissions to the pediatric intensive care unit (PICU) (7.4% vs. 3.7%, P < 0.001), antibiotic treatment (49.8% vs. 37.2%, P < 0.001), and longer hospitalizations (3.83 vs. 3.31 days, P < 0.001). Multivariable analysis predicted increased risk for UTI, PICU admission, pneumonia, and longer hospitalization (relative risk 11.6, 2.25, 1.98, 1.44, respectively, P < 0.001). CRP thresholds of 3.51, 1.9, and 2.81 mg/dl for PICU admission, UTI, and pneumonia, were calculated using Youden's index with AUC 0.72, 0.62, and 0.61, respectively.

Conclusions: Elevated CRP levels at admission are associated with increased disease severity and higher complication rates in children hospitalized with RSV bronchiolitis.

Gaucher disease (GD) is an inherited autosomal recessive genetic disorder caused by mutations in the glucocerebroside (GBA1) gene [1]. These variants result in decreased activity of the lysosomal enzyme β-glucocerebrosidase (GCase), which is essential for breaking down glucocerebroside into glucose and ceramide. Consequently, activated macrophages, known as Gaucher cells, accumulate undegraded glucocerebroside. The phagocytic role and naturally high-level GCase activity of macrophages may partly explain why these cells are particularly affected in GD. The accumulation of glucocerebroside in macrophages causes an expansion in the population of these cells, leading to symptoms like hepatosplenomegaly, thrombocytopenia, anemia, bleeding tendency, growth retardation, and bone issues. Bone marrow infiltration may result in bone infarction, episodes of bone crises, and osteonecrosis, mainly of large joints and less commonly as pathological fractures. These latter skeletal complications are the most critical irreversible consequence of untreated GD, significantly impacting the quality of life of patients, and hence should be avoided by early administration of specific therapy. The accumulation of glucocerebroside in lysosomes has been linked to a pro-inflammatory state [2]. In addition, the misfolding and retention of mutant GCase within the endoplasmic reticulum (ER) has been associated with ER stress and activation of the unfolded protein response, contributing to GD phenotypic heterogeneity, inflammation, and immune dysregulation [3].

Background: Coronavirus disease 2019 (COVID-19) is a respiratory illness with broad spectrum of clinical manifestations ranging from asymptomatic cases to severe complications such as acute respiratory failure, multi-organ dysfunction, and death.

Objectives: To evaluate the platelet-lymphocyte ratio (PLR) as a marker of disease severity and mortality in COVID-19 patients. To explore the relationship between PLR and other inflammatory indicators, specifically C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR).

Methods: The cohort included 400 patients (206 males, 194 females; mean age: 64.5 ± 17.1 years [range 20–100 years]) who were hospitalized between April 2020 and December 2021. Data were collected on demographic and clinical characteristics, including ward and critical care details. CRP, NLR, and PLR values were recorded on the first and last days of hospitalization. Patients were categorized based on their hospitalization outcomes.

Results: PLR statistically increased during hospitalization, from 245 ± 160 at admission to 341 ± 747 at discharge (P < 0.001). A significant association was found between PLR and both the length of hospital stay and mortality. The mean PLR in the deceased group was 445 ± 590, compared to 304 ± 795 in the survivors, P = 0.007. This finding showed a correlation between higher PLR and increased severity and mortality.

Conclusion: PLR has been identified as a relevant marker for assessing the severity of COVID-19. Elevated PLR levels are associated with cytokine storm, length of hospital stay, and mortality. The results highlight the relationship between elevated PLR and poor outcome in COVID‐19 patients, suggesting its use in monitoring disease progression and prognosis.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease pathway is heavily influenced by different inflammatory cytokines. There is ample evidence of cannabidiol (CBD) immunomodulation effects.

Objectives: To investigate the effect of CBD on patients with SARS-CoV-2 and to measure the impact on inflammatory cytokines.

Methods: A double blind, placebo-controlled study to compare the clinical outcomes and selected serum cytokine levels in patients with SARS-CoV-2 that received sublingual CBD extraction. Seven patients were randomized to the treatment arm and three to the placebo group.

Results: Clinical outcomes were better in the patient group that received sublingual CBD vs. patients receiving placebo treatment. Serum cytokine mean concentration levels showed differences between the two groups but of mixed trends.

Conclusions: Patients presenting with SARS-CoV-2 and receiving CBD sublingually had better outcomes than those receiving a placebo, although these results did not reflect in selected serum cytokines. Further study is needed.

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.

Background: Cardiovascular disease (CVD) events are rare in premenopausal women. Nevertheless, women with depression have a higher prevalence of CVD. Patients with depression present with endothelial dysfunction and impaired ability to regenerate endothelial progenitor cells (EPCs).

Objectives: To understand the association between depression and CVD, especially in young women.

Methods: We collected peripheral blood samples from 30 premenopausal women diagnosed with major depression and 28 aged-matched healthy women. From these blood samples, we extracted RNA and conducted RNA sequencing to obtain comprehensive gene expression profiles. Gene expression analysis was performed to identify differences between the two groups.

Results: We detected 6540 differentially expressed genes between the two groups, of which 5577 were downregulated and 963 up regulated. Of these genes, we detected a significant decrease of CD144 (VE-Cadherin) (P = 0.0001), CD146 (MCAM) (P = 0.0001) and CD133 (PROM1) (P = 0.00009), all known to enhance EPCs and regeneration of damaged blood vessels. A significant increase was found in the expression of CD31 (PECAM1) (P = 0.0003) and CD45 (PTPRC) (P = 0.00001), both known to promote atherogenesis and thrombogenesis with platelet and T lymphocyte activation.

Conclusions: Young premenopausal women with depression had an impaired ability to grow colony forming units of endothelial progenitor cells (CFU-EPCs). Young women with depression are more vulnerable genetically to develop CVD because of the downregulated genes of the stem cells endothelial vascular regeneration and upregulation of genes coding for platelet and T lymphocyte activation, thus accelerating the atherosclerotic and atherothrombotic pathway.

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.

Background: The coronavirus disease 2019 (COVID-19) pandemic showed the need to evaluate disease severity promptly at the time of hospital admission. 

Objectives: To establish an admission protocol, which included clinical and laboratory findings. 

Methods: We conducted a retrospective study at Wolfson Medical Center, Israel, for a period of 19 months (2020–2021). We established a protocol for patients who were admitted with COVID-19 infection. The protocol parameters included demographic data, co-morbidities, immune status, oxygen level at room air on admission, oxygen demand, lymphopenia, C-reactive protein (CRP) level, lactate dehydrogenase, D-DIMER, creatinine, aspartate transferase, alanine aminotransferase, and ferritin. Based on this protocol, we defined the severity of COVID-19 at the beginning of hospitalization and started treatment without delay. This protocol included ferritin levels as a guide to severity and outcome of patients. A database was established for all the parameters of the patients included in the study. 

Results: The study included 407 patients; 207 males (50.9%), 200 females (49.1%). The age range was 18–101 years. Hyperferritinemia (> 1000 ng/dl) was one of the strongest and most significant predictors for severe disease in these patients (P < 0.001). Lymphopenia, high levels of CRP, alanine aminotransferase, aspartate transferase, lactate dehydrogenase, and creatinine also correlated with severe disease, complications, and death. 

Conclusions: Abnormal ferritin levels were a very significant and clear indicator of the development of severe COVID-19. The addition of ferritin levels to our protocol aided in finding which patients were at increased risk for morbidity and mortality.

Background: Prognostication is complex in patients critically ill with coronavirus disease 2019 (COVID-19).

Objectives: To describe the natural history of ventilated critical COVID-19 patients.

Methods: Due to our legal milieu, active withdrawal of care is not permitted, providing an opportunity to examine the natural history of ventilated critical COVID-19 patients. This retrospective cohort included COVID-19 ICU patients who required mechanical ventilation. Respiratory and laboratory parameters were followed from initiation of mechanical ventilation for 14 days or until extubation, death or tracheostomy.

Results: A total of 112 patients were included in the analysis. Surviving patients were younger than non-survivors (62 years [range 54–69] vs. 66 years [range 62–71], P = 0.01). Survivors had a shorter time to intubation, shorter ventilation duration, and longer hospital stay. Respiratory parameters at intubation were not predictive of mortality. Nevertheless, on ventilation day 10, many of the ventilatory parameters were significantly better in survivors. Regarding laboratory parameters, neutrophil counts were significantly higher in non-survivors on day 1 and C-reactive protein levels were significantly lower in survivors on day 10. Modeling using a generalized estimating equation showed small dynamic differences in ventilatory parameters predictive of survival.

Conclusions: In ventilated COVID-19 patients when there is no active care withdrawal, prognostication may be possible after a week; however, differences between survivors and non-survivors remain small.

Background: The impact of the coronavirus disease 2019 (COVID-19) pandemic on patient populations can be divided to direct consequences of the disease and indirect implications of changes imposed on the national healthcare systems. The impact of the later survival of chronic hemodialysis patients is still unknown.

Objectives: To examine the impact of quarantine on health outcomes of dialysis patients.

Methods: In a retrospective case-controlled study, we compared chronic hemodialysis patients from two separate timeframes: during a quarantine period and a parallel time without quarantine.

Results: The study included 344 hemodialysis patients. Baseline characteristics were compared between those enrolled in 2015 and those enrolled in 2020. Despite comparable clinical parameters, a statistically significant increase in the 6-month mortality rate was observed in 2020 (1.2% vs. 6.7%, P = 0.01), primarily attributed to sepsis. Notably, no deaths were attributed to COVID-19 in 2020. Interdialytic weight gain and dialysis quality remained similar between the two groups, with a mild trend toward excessive weight gain in 2020. Secondary outcomes after 6 months did not significantly differ, except for lower sodium values in 2015 compared to 2020.

Conclusions: Dialysis patients experienced disproportionate effects from the COVID-19 pandemic, even with continuous care and no direct virus-related fatalities. The findings showed unintended consequences of quarantine measures, highlighting adverse impact on both physical and mental health. Recognizing and addressing these consequences are imperative for minimizing their impact in future pandemics, emphasizing the importance of proactive measures in healthcare planning.

Background: The lifestyle of the Arab population in Israel has changed in the last few decades, and modernization and urbanization have impacted the prevalence of chronic diseases.

Objectives: To investigate the prevalence of chronic diseases in the Arab population compared to the Jewish population in Israel.

Methods: This retrospective study included Arab and Jewish people insured by Israel’s largest health maintenance organization. Demographic data and data regarding chronic diseases were collected. Crude prevalence and age group adjusted prevalence were calculated.

Results: In total, 863,116 Arab and 3,674,863 Jewish people were included in the analysis. We found that 18.3% of the Arab population had a diagnosis of diabetes mellitus and 28.8% had obesity compared to 17.5% and 22.5% in the Jewish population, P < 0.001, respectively. The prevalence of chronic heart failure, chronic ischemic heart disease, cerebrovascular accidents, hypertension, and myocardial infarction among Arabs was higher in all age groups compared to Jewish patients. Arab males had higher frequency rates of obesity and hemodialysis treatment compared to Jewish males. The proportion of women with diabetes mellitus, hemodialysis treatment, iron deficiency anemia, or obesity was greater among Arab females.

Conclusions: Significant differences were found in the prevalence of chronic diseases among Arab and Jewish patients in Israel. Culturally relevant interventions are crucial for disease prevention, early diagnosis, and management of chronic diseases among different ethnic groups.

Background: The Agatston coronary artery calcium (CAC) score is a decision-guiding aid for risk assessment and personalized management in the primary prevention of atherosclerotic cardiovascular disease.

Objectives: To explore the real-life clinical experience of CAC testing by characterizing its indications, significance of scores, and corresponding lipid-lowering treatments.

Methods: A retrospective descriptive study of patients treated at the lipids clinic at Rabin Medical Center (Beilinson Campus), who underwent CAC score evaluation between 2017 and 2022 was conducted. The data collected from electronic medical files included demographics, co-morbidities, indications for the test, CAC score levels, and the recommended therapeutic regimen.

Results: The study cohort included 88 patients. The main indication was assessment of the existence of atherosclerosis in cases where there was no clear indication for lipid lowering treatment (65, 74%). In most patients, there was no evidence of atherosclerosis (CAC = 0 AU, n=30) or only mild disease (CAC=1–99 AU, n=35). As the CAC score increased, more patients were prescribed lipid lowering treatments, from very few prescriptions in those with a CAC score of 0 AU and almost 100% among those with score of ≥ 400 AU. The factors that predicted CAC > 0 AU were male sex and older age.

Conclusions: CAC scores should be used more often to determine risk assessment. Further analysis of the implications of scores between 0–400 AU is needed.

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition. Accumulated research and data since 2003 have increasingly affirmed its classification as a systemic disease. Although IgG4-RD generally presents with involvement of one or several organ systems, it can affect almost any organ. The disease manifests gradually with the development of tumor-like lesions.

Constitutional symptoms, such as systemic fever and elevated inflammatory markers, are generally absent in association with this pathological condition. However, it is common for patients to exhibit allergy characteristics in addition to a slight increase in peripheral blood eosinophilia. The clinical manifestations of the disease exhibit variability on the specific organ system affected. Specific involvement of organs can ultimately result in organ failure. For example, retroperitoneal fibrosis commonly leads to post-renal failure [1]. The 2020 Revised Comprehensive Diagnostic (RCD) criteria for IgG4-RD include three components for diagnosis: clinical and radiological components (1), serological diagnosis (2), and unique pathological diagnosis (3). When all three are present it is a definitive diagnosis. The presence of components 1 + 3 constitutes a probable diagnosis, while the presence of components 1 + 2 indicates possible diagnosis [2].

Testicular involvement of IgG4-RD has been described in a few case reports. However, the uniqueness of our case is the manifestation of a testicular mass as a different target organ of relapse in a patient in remission from retroperitoneal fibrosis.

Background: The coronavirus disease 2019 (COVID-19) pandemic posed significant challenges to healthcare systems worldwide, including a surge in the use of extracorporeal membrane oxygenation (ECMO).

Objectives: To compare outcomes and costs of COVID-19 and non-COVID-19 adult patients treated with ECMO in the intensive care unit (ICU) at Tel Aviv Sourasky Medical Center.

Methods: We conducted a retrospective study. Clinical outcomes, ECMO duration, ICU and hospital length of stay (LOS), and healthcare costs were examined and compared between the two groups.

Results: A total of 119 patients were treated with ECMO between 2016 and 2023; 56 (47.1%) diagnosed with COVID-19. The study found no significant difference in mortality rates between COVID-19 and non-COVID-19 patients. However, COVID-19 patients experienced significantly longer ECMO durations and ICU LOS. Hospitalization and ECMO operation costs were notably higher for COVID-19 patients, but overall admission costs were lower compared to non-COVID-19 patients, with cost of surgical interventions, consultations and imaging contributing to the price gap.

Conclusions: Despite longer durations of ECMO and LOS, the economic burden of ECMO in COVID-19 patients was significantly lower than non-COVID-19 patients. Strict patient selection should be utilized, a fortiori during times of surge-capacity.