Israel Medical Association Journal

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.

Background: Immunoglobulin 4 (IgG4) is the least abundant immunoglobulin in the sera of healthy individuals; however, its levels can vary in different diseases such as IgG4-related disease (high) or Sjögren's syndrome (low). While previous studies have suggested the importance of IgG4 in autoimmune diseases, the clinical and biological significance of high or low levels remains unclear.

Objectives: To investigate the association between IgG4 antibody levels and systemic sclerosis (SSc), as well as the clinical features of the disease.

Methods: We measured IgG4 levels in the sera of 74 SSc patients from the years 2000 to 2019 and compared them to IgG4 levels in 80 healthy donors from the Israeli national blood bank. We performed correlation analyses between IgG4 levels and various factors, including age, sex, disease subtype, disease duration, organs involved, and medications taken by the patients.

Results: Our findings revealed significantly lower IgG4 levels in SSc patients compared to healthy participants. SSc patients receiving steroid treatment exhibited prominently lower IgG4 levels. In addition, SSc patients with Raynaud's phenomenon tended to have lower IgG4 levels compared to those without Raynaud's phenomenon.

Conclusions: Our study demonstrates that IgG4 levels are lower in SSc patients. Further research is needed to elucidate whether this observation contributes to the etiology of the disease or if it represents a common manifestation among other autoimmune diseases.

Background: Giant cell arteritis (GCA) is a large vessel vasculitis predominantly affecting patients over 50 years, typically managed with glucocorticoids, with treatment varying on individual patient needs. While effective for GCA, long-term glucocorticoids use poses significant risks, including the development of osteoporosis, a metabolic bone disease common in older individuals. This overlap poses a significant clinical challenge, as the treatment for GCA inadvertently raises the risk of osteoporosis and necessitates careful balance to manage both conditions effectively.

Objectives: To investigate the occurrence of osteoporosis and other co-morbid conditions in patients with GCA treated with glucocorticoids.

Methods: A retrospective cross-sectional analysis of GCA patients examined the correlation between GCA and osteoporosis by searching the Clalit Health Service database for patients over 50 years of age from January 2002 to January 2018. In addition, we conducted a logistic regression analysis stratifying for other co-morbidities to evaluate the independent association between GCA and osteoporosis.

Results: In total, 6607 GCA patients were compared with 36,066 age- and sex-matched controls. The study revealed a higher prevalence of osteoporosis in the GCA group (43%) compared to controls (27%) (odds ratio [OR] 2.06, 95% confidence interval [95%CI] 1.95–2.17). In addition, hypertension, hyperlipidemia, diabetes mellitus, and ischemic heart disease were more prevalent among GCA patients. After stratifying for cardiovascular co-morbidities, GCA remained independently associated with osteoporosis (OR 2.1, 95%CI 1.96–2.26, P < 0.001).

Conclusions: Glucocorticoid-treated GCA is independently associated with osteoporosis. Healthcare providers must consider this added aspect of GCA for the treatment and management of patients.

Background: Management of patients with reported iodinated contrast media (ICM) allergy is not supported by sufficient data. It is assumed that these patients are at risk for severe reactions, and that premedication provides protection.

Objective: To examine current practice and prognosis in hospitalized patients with ICM allergy.

Methods: In this retrospective study, we analyzed data of 17,356 patients who were hospitalized between 2018 and 2022 and referred for imaging. No-allergy and allergy groups were matched by age, sex, co-morbidities, and indications for imaging. Statistical analysis compared demographic, clinical, and imaging-related parameters.

Results: Our study included records of 501 patients with ICM allergy and 16,855 with no allergy. Patients with allergy were older (70.92 ± 16.25 vs. 59.02 ± 23.74 years, P < 0.001), female preponderance (male proportion 42.5% vs. 54%, P < 0.001), and those with increased cardiovascular and metabolic co-morbidities. The rate of ICM injection was similar among patients with ICM allergy (34%) and no allergy (36%). Most patients with ICM allergy did not receive premedication. Allergic patients demonstrated increased mortality (25.9% vs. 16.5%, P < 0.001); however, this result was not associated with the diagnosis of allergy, anaphylactic reactions, or premedication.

Conclusions: ICM allergy is mostly reported in patients with advanced age and multiple co-morbidities. Mortality was not increased when compared to matched non-allergic individuals. Among patients with reported allergy who were injected with ICM, anaphylaxis was not a cause of death, although fewer than half received premedication. Prospective trials are warranted to revise the clinical approach to ICM allergy.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a rare autoimmune demyelinating disorder of the central nervous system. Optic neuritis (ON) is the most common clinical manifestation of MOGAD in adults. In 2023, new MOGAD diagnostic criteria were proposed, highlighting the importance of supplemental criteria when MOG-immunoglobulin G (IgG) titers are unavailable.

Objective: To investigate the applicability of the 2023 MOGAD criteria in patients diagnosed with MOGAD and treated before the availability of MOG-IgG titers.

Methods: We conducted a retrospective chart review of patients classified as MOGAD between 2010 and 2023 at Rabin Medical Center. Patient demographics as well as clinical and imaging data were collected, including visual acuity, expanded disability status score, core demyelinating events, antibody status, and brain and optic nerve magnetic resonance imaging data. Patients fulfilling the 2023 MOGAD criteria were reported as definite MOGAD.

Results: Fifteen patients met the 2023 MOGAD diagnostic criteria despite lack of MOG-IgG titer. The most common supplemental criterion meeting the 2023 MOGAD criteria was optic disc edema (n=12, 80%), followed by longitudinal optic nerve involvement (53%), bilateral ON (40%), and perineural optic sheath enhancement (33%).

Conclusions: All patients with a clinical diagnosis of MOG-ON in our cohort fulfilled the 2023 MOGAD criteria despite the lack of antibody titers. The 2023 MOGAD criteria can be reliably applied to Israeli cohorts, prior to availability of MOGAD IgG titers, with particular attention to additional supplemental criteria. Since the 2023 MOGAD criteria were published, MOGAD IgG titers have been added to routine testing at our facility.

Background: Gram-negative bloodstream infections (GN-BSI) are life threatening. Appropriate antimicrobial therapy and source control when indicated improve survival. Dementia is an independent risk factor for death and is associated with increased risk for infections, especially in advanced stages. Data about the best diagnostic and therapeutic approaches for patients with dementia and GN-BSI are lacking.

Objectives: To evaluate patients with dementia and GN-BSI and determine whether diagnostic imaging improves clinical outcomes.

Methods: We performed a retrospective cohort study of adult patients with GN-BSI, during 2019–2022. Patients with or without a diagnosis of dementia were compared. Outcomes were in-hospital mortality and recurrent bacteremia. Demographic, clinical, diagnostic, and therapeutic data were collected and analyzed.

Results: A total of 87 patients with dementia and 130 without were included. Patients with dementia received appropriate empirical antimicrobial therapy in 38% of cases compared to 62% of patients without dementia, P < 0.001. Imaging studies were performed in half of patients in both groups. In the dementia group, 17% had abnormal findings that required source control versus 30% in the control group (P = 0.049). Source control was performed in 15% of patients with dementia versus 28% of patients without dementia (P = 0.032). Mortality was 27.6% in the dementia group versus 22.3% in the control group (P = 0.42).

Conclusions: In patients with dementia and GN-BSI, imaging studies have lower effect on clinical outcomes. Imaging studies should be performed in selected cases only and not conducted routinely.

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving apocrine gland-bearing regions. There is an under-representation of non-Caucasians in epidemiologic studies of HS. The characteristics of HS in Israeli Arabs have not yet been studied.

Objectives: To investigate the demographic and clinical profile of HS in the Israeli Arab population.

Methods: A retrospective analysis was conducted in two cohorts of patients with HS in Israel. The patients were derived from the database of a large health management organization (n=4191, 639 Arabs; population-based) and a major tertiary medical center (n=372, 49 Arabs). Demographic and clinical data were compared between ethnic groups.

Results: The prevalence of HS in Israeli Arabs was found to be 0.5%, fivefold higher than in Jews. Arab patients were younger (35.3 vs. 40.5 years, P < 0.001) and mostly male (52% vs. 35.7%, p < 0.001), with lower rates of co-morbidities, including smoking (40.8% vs. 55.7%, p < 0.001), hyperlipidemia, and depression as well as a higher rate of dissecting cellulitis (10.2% vs. 1.9%, p = 0.008). HS was more severe in Arabs, but of shorter duration, with mainly axillary involvement (79.6% vs. 57.9%, p = 0.004). Treatment with hormones was more common in Jews, and with biologic agents in Arabs.

Conclusions: The findings suggest a different phenotype of HS in Arabs, warranting further study.

Background: Ankylosing spondylitis (AS) and inflammatory bowel disease (IBD) are chronic conditions with overlapping pathogenic mechanisms. The genetic predisposition and inflammatory pathways common to both diseases suggest a syndemic relationship. While some evidence points to a connection between the two conditions, other reports do not support this link.

Objectives: To investigate the association between AS and the subsequent incidence of IBD. To identify potential risk factors and effect modifiers that contribute to this relationship.

Methods: Utilizing the Chronic Disease Registry of Clalit Health Services, we conducted a retrospective cohort study of individuals diagnosed with AS between January 2002 and December 2018. We compared these patients with age- and sex-matched controls, excluding those with a prior diagnosis of IBD. Statistical analyses included chi-square and t-tests for demographic comparisons, and Cox proportional hazards models for evaluating the risk of IBD development, with adjustments for various co-morbidities and demographic factors.

Results: The study included 5825 AS patients and 28,356 controls. AS patients demonstrated a significantly higher incidence of IBD with hazard ratios of 6.09 for Crohn's disease and 2.31 for ulcerative colitis, after multivariate adjustment. The overall incidence of IBD in the AS cohort was significantly higher compared to controls.

Conclusions: AS patients exhibit a markedly increased risk of developing IBD. These findings advocate for heightened clinical vigilance for IBD symptoms in AS patients and suggest the need for a multidisciplinary approach to patient care. Further research into the shared pathogenic pathways is needed to develop personalized treatment strategies and improve patient management.

Background: At the beginning of 2020, the coronavirus disease 2019 (COVID-19) pandemic presented a new burden on healthcare systems.

Objectives: To evaluate the impact of the COVID-19 pandemic on the outcome of non-COVID patients in Israel.

Methods: We conducted a retrospective observational cohort study at a tertiary medical center in Israel. From December 2018 until June 2022, 6796 patients were hospitalized in the internal medicine wards. Patients were grouped based on their admission date: admitted during COVID waves (waves group), admitted between waves (interim group), and admitted during the same months in the previous year (former-year group).

Results: Mortality during hospitalization and 30-day mortality were higher in the waves group compared to the interim and former-year groups (41.4% vs. 30.5% and 24%, 19.4% vs. 17.9% and 12.9%, P < 0.001). In addition, 1-year mortality was higher in the interim group than in the waves and former-year group (39.1 % vs. 32.5% and 33.4%, P = 0.002). There were significant differences in the readmissions, both at 1 year and total number. The waves group had higher rates of mechanical ventilation and noradrenaline administration during hospitalization. Moreover, the waves group exhibited higher troponin levels, lower hemoglobin levels, and more abnormalities in liver and kidney function.

Conclusions: Hospitalized non-COVID patients experienced worse outcomes during the peaks of the pandemic compared to the nadirs and the preceding year, perhaps due to the limited availability of resources. These results underscore the importance of preparing for large-scale threats and implementing effective resource allocation policies.

Background: Data are scarce on the immunogenicity of coronavirus disease 2019 vaccines in patients with autoimmune rheumatic diseases (ARD).

Objectives: To measure the immunoglobulin G (IgG) response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunization and to evaluate clinical characteristics associated with seropositivity.

Methods: Samples were collected after the second and third doses of the three different types of vaccines in ARD patients. Seroconversion rates and IgG antibody S1/S2 titers were measured.

Results: The type of ARD diagnosis and previous treatment had no significant impact on the serum IgG antibody levels measured after the second (P = 0.489 and P = 0.330, respectively) and boost dose (P = 0.441 and P = 0.446, respectively). What made a significant difference regarding serum IgG antibody levels after the second dose was the type of SARS-CoV-2 vaccine. The difference was highly statistically significant for all vaccine types (P = 0.001 with the highest odds ratio for the mRNA vaccine). After the boost with the mRNA vaccine, all patients achieved a high level of serum IgG antibody levels (t = 10.31, P = 0.001). No ARD patients experienced serious post-vaccinal reactions. Eight patients developed COVID-19 before the boost dose.

Conclusions: In ARDs patients, the highest level of serum IgG antibody against S1/S2 proteins was achieved with the mRNA vaccine, irrespective of the therapy applied or the type of the disease. We recommend a booster dose with mRNA vaccine in all ARDs for the highest SARS-CoV-2 protection without serious post-vaccinal reactions observed.

Background: At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, many patients presented with acute hypoxemic respiratory failure, requiring ventilatory support. One treatment method was the addition of a reservoir mask to a high flow nasal cannula (HFNC) (dual oxygenation).

Objectives: To evaluate the clinical outcomes of combining reservoir mask on top of a high-flow nasal cannula.

Methods: A retrospective cohort of adult patients who were admitted due to COVID-19 during the first year of the pandemic to Rambam Health Care Campus. The primary endpoint was 30-day mortality. Secondary endpoints were incidence of invasive positive pressure ventilation initiation and admission to the intensive care unit (ICU). Patients who received positive pressure ventilation for reasons other than hypoxemic respiratory failure or who were transferred to another facility while still on HFNC were excluded.

Results: The final analysis included 333 patients; 166 were treated with dual oxygenation and 167 with HFNC only (controls). No significant differences in baseline characteristics were noted between the groups. The dual oxygenation group was slightly older (69.2 ± 14.8 years vs. 65.6 ± 15.5 years, P = 0.034). The 30-day mortality (24.1% vs. 36.5%, P = 0.013), rates of invasive positive pressure ventilation (47% vs. 59.3%, P = 0.024), and ICU admissions (41.6% vs. 52.7%, P = 0.042) were all significantly lower in the dual oxygenation group.

Conclusions: The addition of reservoir masks to HFNC may improve the oxygenation and overall prognosis in patients with severe hypoxemia due to COVID-19.

Background: Age-related changes in multiparametric magnetic resonance imaging (mpMRI) of the prostate have been reported in the general population but not in screening cohorts.

Objectives: To evaluate age-related changes on prostatic mpMRI in a screening cohort of BRCA1/2 mutation carriers.

Methods: Asymptomatic BRCA1/2 mutation carriers underwent mpMRI as part of a screening program. All included patients were followed for 3 years with no evidence of prostate cancer. mpMRIs were retrospectively evaluated by two abdominal radiologists for peripheral zone (PZ) patterns on T2 (homogenous hyperintensity, wedge-shaped hypointensities, patchy hypointensities, or diffuse hypointensity), and transition zone (TZ) pattern on T2 (homogenous, heterogeneous, nodular). Apparent diffusion coefficient (ADC) values of PZ and TZ were measured. Statistical analysis was performed using a predefined age cutoff of 50 years old.

Results: Overall, 92 patients were included: 38 in the younger age group (40–49 years) and 54 in the older age group (50–69 years). PZ homogenous hyperintensity and wedge-shaped hypointensities were more common in the older patients, whereas diffuse hypointensity was more common in younger patients (P < 0.001 for both readers) with substantial inter-reader agreement between the readers (kappa=0.643). ADC values were lower in young patients in the PZ (P < 0.001) and TZ (P = 0.003).

Conclusions: Age-related differences in mpMRI were validated in BRCA mutation carriers. As some features overlap with prostatic carcinoma, awareness is crucial, specifically to diffuse T2 hypointensities of the PZ and lower ADC values in the PZ and TZ, which are more common in younger patients.

Background: Brucellosis is an endemic infection affecting the Mediterranean Basin, Arabian Peninsula, India, Mexico, and South America. Data on brucellosis infections in children are limited.

Objectives: To review and characterize the clinical presentation of pediatric patients diagnosed with brucellosis in a tertiary medical center.

Methods: Retrospective data analysis was conducted on all pediatric patients from January 2010 to December 2020 admitted to the pediatric department with a diagnosis of brucellosis based on a positive serology test or growth of Brucella bacteria in blood culture.

Results: The study comprised 53 children aged 0–18 years. The mean age at presentation was 11.01 ± 4.91 years; 39 male (73.6%). Pre-infection exposure to unpasteurized milk or unvaccinated livestock was reported in 37 (69.8%). Fever was present in 64.6%, followed by arthralgia (49%), loss of appetite (42.3%), and weight loss (24.6%). Gastrointestinal symptoms were reported in 52.8% and included abdominal pain (34.6%), nausea (28.3%), vomiting (24.5%), and diarrhea (2.6%). Eight patients experienced pancytopenia (15.1%). The median length of intravenous antibiotic treatment was 7 days (range 3–14 days) and for oral antibiotic treatment 6 weeks (range 2–24 weeks). Most patients were initially treated with intravenous gentamycin (90.5%) and long-term oral antibiotics, most commonly doxycycline. Two (3.7%) required admission to the pediatric intensive care unit. No mortality was documented, and all cases of relapses were successfully treated.

Conclusions: Pediatric brucellosis is an acute febrile disease often associated with rheumatologic complaints. Patients 8–18 years of age also presented with headache, weight loss, and night sweats.

Background: Polymyositis (PM) and dermatomyositis (DM) are inflammatory mediated myopathies characterized by progressive symmetric proximal muscle weakness and associated with extra-muscular involvement. Central nervous system complications are rarely reported with these diseases.

Objectives: To investigate the association between dementia and PM/DM.

Methods: A retrospective cohort study was conducted using a database from Clalit Health Care, the largest health maintenance organization in Israel. Patients with a first recorded diagnosis of PM/DM were included and were compared with age- and sex-matched controls by a ratio of 1:5. The prevalence of dementia among PM/DM patients compared to controls was assessed using a univariate and a multivariable model. Binary logistic regression analysis was conducted to assess the association of different factors with dementia within the PM/DM cohort.

Results: The study included 2085 PM/DM cases (17.0%) and 10,193 age- and sex-matched controls (83.0%). During the follow-up time, 36 PM/DM patients were diagnosed with dementia compared to 160 controls, with a univariate hazard ratio (HR) of 1.10 (95% confidence interval [95%CI] 0.77–1.58). Within the PM/DM cohort, significant predictors for the development of dementia included increased age at diagnosis (5 years increment; OR 1.86, 95%CI 1.57–2.21, P < 0.001) and treatment with glucocorticoids (OR 5.40, 95%CI 1.67–17.67, P = 0.005).

Conclusions: In our cohort, inflammatory myopathies were not associated with dementia. Age and treatment with glucocorticoids were associated with dementia. If dementia is diagnosed in patients with inflammatory myopathies, other systemic causes should be investigated.

Background: Depression has been shown to be associated with cervical tumors (CTs), an association mostly demonstrated in studies in which temporality could not have been ascertained.

Objectives: To study the association between depression and CTs and the influence of co-morbidities of this association in a large cohort study.

Methods: A retrospective computer-based cohort study was conducted. The cohort included 357,450 female members of Maccabi Healthcare Services. The cohort was classified as depressed or non-depressed using the International Classification of Diseases 9/10 codes. For each subgroup, demographic characteristics, behavioral characteristics, co-morbidities, and CTs diagnosis were obtained. The burden of co-morbidities was defined as the sum of major co-morbidities. We used zero-inflated negative binomial regression analysis due to over-dispersion to estimate the relative risk (RR) for CTs with 95% confidence interval (95%CI).

Results: Depression was diagnosed in 15,789 women. Among this group, CTs were diagnosed in 1585 (10.0%). Among the 341,661 non-depressed, CTs were diagnosed in 4185 (1.2%). After adjustment to age and socioeconomic status, the association between depression and CTs was RR=9.2 (95%CI 8.7–9.9, P-value < 0.0001). The association between depression and CTs increased as the burden of clinical conditions increased (P-value < 0.0001).

Conclusions: Women with depression are at a higher risk for CTs, especially among those who have several co-morbidities. Tighter gynecology surveillance is crucial among these women.