Israel Medical Association Journal

Fever of unknown origin (FUO) is defined as the repeated occurrence of elevated body temperature above 38.3°C (101°F) lasting for at least 3 weeks with no clear diagnosis despite a thorough investigation of more than one-week duration. FUO cases could be categorized into three major etiologies: infectious, neoplastic, and systemic inflammatory. Despite novel diagnostic modalities, clinicians still encounter a significant number of unresolved FUO cases, accounting for as many as 50% of cases [1]. Prolonged futile FUO investigations may be a source of frustration for many clinicians [2]. We described a unique cause for FUO that shares the complexity of the diagnostic workup and emphasizes the importance of ¹⁸F-fluorodeoxyglucose positron-emission tomography/computed tomography (PET/CT) modality in the process of investigating FUO.

Background: Up to half the patients diagnosed with acute coronavirus disease 2019 (COVID-19) presented with gastrointestinal symptoms. Gastric mucosal cells, enterocytes, and colonocytes express the viral entry receptor angiotensin-converting enzyme 2 (ACE2) and coreceptor transmembrane protease serine 2 (TMPRSS2) and are prone to infection. Direct infection of gastrointestinal epithelial cells has been demonstrated. COVID-19 disease was first diagnosed in Israel at the end of February 2020 with 842,536 confirmed cases and 6428 deaths by the end of June 2021. In our multicenter, retrospective cohort study, we looked for gastrointestinal signs and symptoms in two periods and correlated them with mortality. Period 1 included the first and second waves and the original virus. Period 2 represented the third wave and the alpha variant.

Objectives: To reveal gastrointestinal signs and symptoms in two periods and correlate them with mortality.

Methods: From 22,302 patients hospitalized in general medical centers, we randomly selected 3582 from Period 1 and 1106 from Period 2. The study was performed before vaccinations were available.

Results: Gastrointestinal signs and symptoms, diarrhea, vomiting, abdominal pain, and taste/smell loss were significantly more prevalent during Period 1. Thirty-day mortality and in-hospital mortality were significantly higher in Period 2 than in Period 1, 25.20% vs. 13.68%, and 21.17% vs. 12.87%, respectively (P < 0.001).

Conclusions: Thirty-day mortality and in-hospital mortality rates were 1.84 and 1.64 times higher from 6 November 2020 to 15 January 2021, the alpha variant, and in negative correlation with gastrointestinal symptoms.

Background: Morbidly adherent placentation (MAP) increases the risk for obstetric hemorrhage. Cesarean hysterectomy is the prevalent perioperative approach. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive and relatively simple endovascular procedure to temporarily occlude the aorta and control below diaphragm bleeding in trauma. It has been effectively used to reduce obstetric hemorrhage.

Objectives: To evaluate whether REBOA during cesarean delivery (CD) in women with morbidly adherent placentation is a safe and effective treatment modality.

Methods: We introduced REBOA for CD with antepartum diagnosis of MAP in 2019 and compared these patients (RG) to a standard approach group (SAG) treated in our center over the preceding year, as a control. All relevant data were collected from patient electronic files.

Results: Estimated blood loss and transfusion rates were significantly higher in SAG; 54.5% of SAG patients received four RBC units or more vs. one administered in RG. No fresh frozen plasma, cryoprecipitate, or platelets were administered in RG vs. mean 3.63, 6, and 3.62 units, respectively in SAG. Ten SAG patients (90.9%) underwent hysterectomy vs. 3 RG patients (30%). Five SAG patients (45%) required post-surgical intensive care unit (ICU) admission vs. no RG patients. Bladder injury occurred in five SAG cases (45%) vs. 2 RG (20%). One RG patient had a thromboembolic event. Perioperative lactate levels were significantly higher in SAG patients.

Conclusions: Use of REBOA during CD in women with MAP is safe and effective in preventing massive bleeding, reducing the rate of hysterectomy, and improving patient outcome.

Background: Small left atria (LA) is associated with an increased risk of mortality.

Objectives: To determine whether the attributed risk of mortality is influenced by the underlying etiologies leading to decreased volumes.

Methods: We retrospectively evaluated patients with an available LA volume index (LAVI) as measured by echocardiography who came to our institution between 2011 and 2016. Individuals with small LA (LAVI < 16 ml/m²) were included and divided according to the etiology of the small LA (determined or indeterminate) and investigated according to the specific etiology.

Results: The cohort consisted of 288 patients with a mean age of 56 ± 18 years. An etiology for small LA was determined in 84% (n=242). The 1-year mortality rate of the entire cohort was 20.5%. Patients with indeterminate etiology (n=46) demonstrated a lower mortality rate compared with determined etiologies (8.7% vs. 22.7%, P = 0.031). However, following propensity score adjustments for baseline characteristics, there was no significant difference between the groups (P = 0.149). The only specific etiology independently associated with 1-year mortality was the presence of space occupying lesions (odds ratio 3.26, 95% confidence interval 1.02–10.39, P = 0.045).

Conclusions: Small LA serve as a marker for negative outcomes, and even in cases of undetected etiology, the prognosis remains poor. The presence of small LA should alert the physician to a high risk of mortality, regardless of the underlying disease.

Background: Perivascular cuffing as the sole imaging manifestation of pancreatic ductal adenocarcinoma (PDAC) is an under-recognized entity.

Objectives: To present this rare finding and differentiate it from retroperitoneal fibrosis and vasculitis.

Methods: Patients with abdominal vasculature cuffing were retrospectively collected (January 2011 to September 2017). We evaluated vessels involved, wall thickness, length of involvement and extra-vascular manifestations.

Results: Fourteen patients with perivascular cuffing were retrieved: three with celiac and superior mesenteric artery (SMA) perivascular cuffing as the only manifestation of surgically proven PDAC, seven with abdominal vasculitis, and four with retroperitoneal fibrosis. PDAC patients exhibited perivascular cuffing of either or both celiac and SMA (3/3). Vasculitis patients showed aortitis with or without iliac or SMA cuffing (3/7) or cuffing of either or both celiac and SMA (4/7). Retroperitoneal fibrosis involved the aorta (4/4), common iliac (4/4), and renal arteries (2/4). Hydronephrosis was present in 3/4 of retroperitoneal fibrosis patients. PDAC and vasculitis demonstrated reduced wall thickness in comparison to retroperitoneal fibrosis (PDAC: 1.0 ± 0.2 cm, vasculitis: 1.2 ± 0.5 cm, retroperitoneal fibrosis: 2.4 ± 0.4 cm; P = 0.002). There was no significant difference in length of vascular involvement (PDAC: 6.3 ± 2.1 cm, vasculitis: 7.1 ± 2.6 cm, retroperitoneal fibrosis: 8.7 ± 0.5 cm).

Conclusions: Celiac and SMA perivascular cuffing can be the sole finding in PDAC and may be indistinguishable from vasculitis. This entity may differ from retroperitoneal fibrosis as it spares the aorta, iliac, and renal arteries and demonstrates thinner walls and no hydronephrosis.

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.

Background: Group A Streptococcus (GAS), the predominant bacterial pathogen of pharyngitis, is sometimes difficult to distinguish clinically from viral pharyngitis. Despite the high prevalence of viral pharyngitis in children, antibiotic treatment is common.

Objective: To investigate the effectiveness of an antibiotic stewardship program (ASP) on antibiotic prescription in children with GAS pharyngitis (GAS-P) at a large pediatric community clinic.

Methods: Antibiotic prescription data were collected from October 2016 to March 2017 (pre-intervention period) and from October 2017 to March 2018 (post-intervention period). The intervention was a one-day seminar for primary care pediatricians on the diagnosis and treatment of GAS-P in children according to national guidelines.

Results: The overall prevalence of testing differed between the two time periods. There was a decrease in children who did not undergo any testing (from 68% to 63%), an increase in streptococcal rapid antigen detection testing (28% to 32%), and a slight increase in throat cultures (3% to 4%) (p = 0.02). There was no change in the types of antibiotics prescribed before and after the intervention (p = 0.152).

Conclusions: The ASP resulted in a slight reduction in the percentage of children who did not undergo laboratory testing for GAS-P and a slight reduction in the percentage of children who received antibiotic treatment. The ASP did not reduce the use of broad-spectrum antibiotics and macrolides.

The prevalence of choroidal nevi associated with choroidal neovascular membrane (CNV) is estimated to range between 0.58% and 8.6% [1]. The pathogenesis of CNV is not completely understood. Researchers have suggested that damage caused to the choroid capillaries above the nevi affects the overlying retinal pigment epithelium and triggers production of angiogenic factors that, in turn, cause the development of CNV [2,3]. Hypoxia and inflammation may be involved in the process. Data have been inconsistent with both theories [4].

Background: Cancellation of transesophageal echocardiography (TEE) tests leads to inefficient use of echocardiography laboratory (echo lab) time and wastes resources.

Objectives: To identify the causes of same-day TEE cancellations in hospitalized patients, to formulate a TEE order screening protocol, and to evaluate its efficacy at implementation.

Methods: We performed a prospective analysis of inpatients referred to a single tertiary hospital echo lab for TEE study by inpatient wards. A comprehensive screening protocol emphasizing active participation of all links directly involved in the chain of inpatient TEE referral was developed and implemented. Comparison of pre- and post-implementation of the new screening protocol on two consecutive periods of 6 months on TEE cancellation rates out of total ordered TEEs stratified by cause categories was performed.

Results: In total, 304 inpatient TEE procedures were ordered during the initial observation period; 54(17.8%) were canceled on the same day. The most common cancellation reasons were equally respiratory distress and patient not in fasted state (20.4% of total cancellations and 3.6% of all scheduled TEEs for each cause). Following implementation of the new screening process, total TEEs ordered (192) and cancelled (16) dropped significantly. A decrease in the rate of each cancellation category was observed, with statistical significance achieved for the overall cancellation rate (8.3% vs. 17.8%, P = 0.003), but not for the individual cancellation categories in split analysis.

Conclusions: A concerted effort to implement a comprehensive screening questionnaire significantly reduced same-day cancellations of scheduled TEEs.

Pancreaticopleural fistula (PPF) is a rare complication of pancreatitis and usually constitutes a diagnostic challenge. There are many causes for recurrent and chronic pancreatitis, with the main etiology being alcohol and choledocholithiasis [1]. However, the association between pancreatic divisum (PD), a common congenital anomaly of the pancreas that is rarely symptomatic, and complications of pancreatitis is still not firmly established [2]. Furthermore, the optimal management of PPF is still uncertain due to its rarity [3]. We describe a rare case of a 45-year-old woman with recurrent pancreatitis that presented with a PPF on the background of PD, successfully managed with conservative treatment. The purpose of this report is to highlight the rare association between PPF and PD together with the excellent response to conservative therapy.

Fetal hydrops is a life-threatening condition defined as abnormal accumulation of fluid in two or more fetal compartments: ascites, pleural effusion, pericardial effusion, or generalized skin edema [1]. Fetal hydrops may also be associated with polyhydramnios and placental edema [2].

Based on pathophysiology results, fetal hydrops is classified as either immune or non-immune. The frequency of immune fetal hydrops has decreased dramatically since the development of Rh (D) immunization given to mothers at risk. Nonimmune hydrops fetalis (NIHF) accounts for almost 90% of cases [1]. The etiology of NIHF is further classified as cardiovascular (17–35%), chromosomal (7–16%), hematologic (4–12%), infectious (5–7%), and unknown (15–25%). Inborn errors of metabolism account for only 1–2% of NIHF cases [1]. NIHF is commonly progressive. Complete resolution of NIHF before birth is rare.

The health of survivors of the Shoah has been investigated, both at early and late stages in their lives. There have been findings of multiple morbidities, but survivors have enjoyed slightly prolonged longevity when compared to the general population [1]. Less attention has been granted to investigations and descriptions of illnesses that presented inside the ghettos and the Nazi camps. Some of the surviving records from those sites have yet to be interpreted. Documented diagnoses of both insulin dependent and mature onset diabetes mellitus and of malignancy has been conspicuously absent. We present our meta-analysis and interpretations of surviving medical documents covering a large population of prisoners from a range of ghettos and concentration camps and specifically note the absence of recorded incidence of malignancy and a relatively low incidence of diabetes mellitus.

Background: Acute kidney injury (AKI) is a risk factor for morbidity and mortality during critical illness especially in very old patients admitted to intensive care units.

Objectives: To identify prognostic markers for AKI patients.

Methods: This single-center retrospective study was based on a patient registry of a medical intensive care unit. Hospital records of patients aged 80 years or older admitted between 2005 and 2015 were examined. Patients who developed AKI according to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines within 4 days of admission were included in this study.

Results: The study comprised 96 patients with AKI and 81 age- and sex-matched controls without AKI. Mean acute physiology and chronic health evaluation (APACHE) II score was 30 with an ICU mortality of 27% in very old patients with AKI. The odds ratio of hospital mortality for these patients was 5.02 compared to controls (49% vs. 16%). APACHE II score and fluid balance in the first 2 days of ICU admission were the strongest predictors of ICU mortality with an area under the receiver operating characteristic of 0.76. Of the 47 patients with AKI who survived hospital admission, 30 were discharged home.

Conclusions: Mortality was increased in very old ICU patients with AKI. Among survivors, two-thirds returned home.

Background: The two cerebral hemispheres influence the immune response differently. While the left hemisphere enhances cellular immunity, the right hemisphere inhibits it.

Objectives: To determine whether immune and inflammatory markers correlated with stroke severity and hospitalization duration as a function of stroke side.

Methods: The study included 137 patients with unilateral ischemic stroke. The medical records were reviewed for demographic and clinical laboratory data, including C-reactive protein (CRP), white blood cell (WBC) count, its differential stroke side and stroke severity according to the National Institute of Health Stroke Scale (NIHSS), and length of hospital stay (LOS). We examined differences between right side (RS) and left side (LS) stroke on immune and inflammatory markers and compared correlations between these markers and NIHSS and LOS as a function of stroke side.

Results: RS stroke patients had higher CRP and monocytes than LS stroke patients. In RS stroke patients, CRP, total WBC, and lymphocyte levels positively correlated with both NIHSS and LOS, whereas levels of neutrophils were positively correlated with NIHSS alone. No correlations were found for LS stroke patients.

Conclusions: Immune-inflammatory markers correlated with stroke severity and LOS only in patients with RS stroke. Neuroimmunological processes influence short-term clinical outcomes after stroke, especially considering the differential effects of the hemispheres on immunity. Prospective studies that evaluate long-term clinical outcomes are needed. Testing the effects of anti-inflammatory treatments on prognosis of RS stroke patients should be considered.

Background: Intrathoracic cancer can cause hyponatremia, but it is uncertain whether mild hyponatremia in the outpatient setting should be regarded as an early sign of intrathoracic cancer.

Objectives: To evaluate the risk of undiagnosed intrathoracic cancer in patients with new persistent mild hyponatremia.

Methods: We conducted a retrospective cohort study using the electronic health record database of a large healthcare organization. The hyponatremia group included patients with sodium concentration of 130–134 mmol/L twice, after a previous normal value and without previous history of cancer or diseases related to hyponatremia. A control group with normal sodium concentration was matched by sex, age, and year of testing. We measured specific intrathoracic cancer incidence during 3 years of follow-up after sodium concentration test date. A logistic regression was used to adjust for further clinical information including smoking history, symptoms, and medications.

Results: The study comprised 1539 participants with mild hyponatremia and 7624 matched controls. New intrathoracic cancer diagnosis was more common in the hyponatremia group during a 3-year follow-up; 1.49% in the hyponatremia group and 0.39% in the control group, crude odds ratio (OR) 3.84, 95% confidence interval (95%CI) 2.22–6.63. After adjustment, hyponatremia remained a significant risk factor for the diagnosis of intrathoracic cancer; adjusted OR 3.61, 95%CI 2.08–6.28.

Conclusions: New mild persistent hyponatremia might be a significant predictive marker to a yet undiagnosed intrathoracic cancer.