Dual anti-viral treatment for persistent COVID-19 in immunocompromised hemato-oncological patients is associated with a favorable prognosis and minor side effects.

In hemato-oncological patients, COVID-19 can present as a persistent infection with ongoing symptoms and viral replication over a prolonged period of time. Data are scarce on the preferred treatment options for these patients. We describe our experience with a five-day course of dual anti-viral treatment with remdesivir and nirmatrelvir/ritonavir for hemato-oncological immunocompromised patients with persistent COVID-19. Fifteen patients with a history of lymphoma, CLL, and MM were included. Eight were male, median age was 74. All patients had an immediate clinical and virological response. In 73 % of patients, PCR for SARS-CoV-2 became negative at the end of treatment and the rest had an increase in PCR cycle threshold (CT) values, with a median increase of 6 cycles. After a follow-up of three months, 60 % of patients remained in full clinical and virological remission. None required invasive mechanical ventilation or died. The side effects we observed, neutropenia, lactatemia and elevated transaminases, were mild and almost all transient in nature. We conclude that dual anti-viral treatment appears to be a valid treatment option for persistent COVID-19.

New Insights on DR and DQ Human Leukocyte Antigens in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: To explore the clinical characteristics and HLA associations of patients with anti-leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients. METHODS: Seventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples. RESULTS: Our cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9 p < 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1 p < 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2 p < 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9 p < 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles. DISCUSSION: Our cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

Bilateral hearing loss preceding rhomboencephalitis - a hint for Kelch-like 11 syndrome.

BACKGROUND: Paraneoplastic neurological syndromes have diverse clinical presentations and offer an opportunity for early diagnosis of malignancy and treatment. Recently, a new paraneoplastic syndrome associated with seminoma was described, consisting of rhombencephalitis with antibodies targeting the Kelch-like protein 11 (KLHL11). Questions were raised as to the spectrum of clinical symptoms and strength of association to seminoma. METHODS: We present a 45-year-old man with bilateral sensorineural hearing loss, vertigo, and progressive ataxia. An extensive diagnostic workup led to the diagnosis of anti-KLHL11 paraneoplastic syndrome based on an immunofluorescence assay showing a typical pattern and a confirmatory serological assay. As a result, the patient underwent a meticulous search for an underlying seminoma. RESULTS: Although initially, all images were interpreted as negative, a revision of the positron emission tomography-CT (PET-CT) examination identified a small mediastinal suspicious mass. The mass was resected, and pathological examination confirmed it to be an extra-testicular seminoma. CONCLUSIONS: Patients presenting with progressive sensorineural hearing loss, vertigo, and ataxia should be evaluated for KLHL11 paraneoplastic syndrome. Furthermore, we support a strong association between anti-KLH11 rhombencephalitis and an underlying seminoma and recommend a thorough search for an undiagnosed germ cell tumor in these patients.

The importance of tissue-based assay in the diagnosis of autoimmune encephalitis.

BACKGROUND: The evaluation of autoimmune encephalitis (AIE) usually includes antibody testing with commercial kits capable of detecting only preselected antibodies. A non-antigen-specific assay may help detect other antibodies. In this study, we evaluate the utility and clinical relevance of an immunofluorescence assay (IFA) in the evaluation of AIE. METHODS: Immunofluorescence assay was performed on 1949 patients' serum/CSF between 2017 and 2020 and clinical relevance was designated to each case based on clinical course, suggested criteria and ancillary testing. RESULTS: Sixty-one patients (3.1%) had positive serum IFA, positive CSF, or both. Twenty-eight out of 42 patients who were positive only on IFA were designated as clinically relevant (67%), 8 inconclusive (19%), and 6 non-relevant (14%). Pleocytosis was significantly higher in the clinically relevant cases (74% vs. 20% for non-clinically relevant cases). Encephalopathy was the most common presentation (36%), followed by cerebellar syndrome (32%) and seizures (25%). The initial diagnosis changed due to IFA results in 13/28 (46%) cases and IFA result led to the initiation or modification of treatment in all cases (68% and 43%, respectively). Twenty-five patients were treated with 1st line immunotherapy and 12 with 2nd line immunotherapy, with 92% responding to treatment. Twenty-six clinically relevant patients underwent cancer workup: seven (25%) had confirmed malignancy and three had high suspicion of malignancy (total of 37%). CONCLUSION: Non-antigen-specific assays, such as IFA, can identify antibodies not detected in commercially available kits and therefore are recommended in the evaluation of autoimmune encephalitis.

An uncommon presentation of paraneoplastic limbic encephalitis.

Paraneoplastic limbic encephalitis (PLE) is a rare disease with established diagnostic criteria. We describe a case of an uncommon presentation of PLE in a female who presented with a one- year duration of short-term memory loss and mild behavioral changes who was eventually diagnosed with PLE associated with breast cancer. Our case demonstrates atypical presentation of PLE, with chronic presentation and an uncharacteristic mild neurological symptoms. This case aims to highlight the importance of a diagnostic work up of autoimmune encephalitis in selected cases that does not present with common diagnostic criteria.

Chronic schistosomiasis in African immigrants in Israel: Lessons for the non-endemic setting.

To study the clinical presentation of Chronic Schistosomiasis (CS) in immigrants from East Africa to Israel and the tests that were useful in confirming the diagnosis.A retrospective study of all medical notes pertaining to hospitalized patients who were immigrants from East Africa with a pathological or microscopic confirmation of CS. Literature review was also conducted focusing on diagnosis of schistosomiasis among immigrants from endemic countries.We identified 32 suspected and 11 confirmed cases of CS. Most of the patients (82%) presented with gastrointestinal symptoms. Sensitivity of stool smear, serology and tissue diagnosis (by histopathology or microscopy) were 14%, 100%, 89%, respectively. Patients have undergone extensive diagnostic evaluation with long hospitalization stays (median 10 days, range 4 to 33 days).CS has multiple presentations and is seen in Israel among refugees from Eritrea and Sudan. Most of the manifestations are gastrointestinal, suggestive of infection with Schistosoma mansoni (S. mansoni). Standard diagnostic techniques used in endemic countries, such as microscopy for ova and parasites were unhelpful, necessitating more advanced procedures like colonoscopic or liver biopsy. We propose a diagnostic algorithm for CS in this patient population in order to make an accurate diagnosis and avoid unnecessary invasive procedures.

Semaphorin-3A inhibits multiple myeloma progression in a mouse model.

Previous studies revealed that progression of multiple myeloma (MM) is associated with downregulation of semaphorin-3A (sema3A) expression in bone marrow endothelial cells. We therefore determined if serum sema3A concentrations are correlated with MM progression and if sema3A can affect MM progression. We find that the concentration of sema3A in sera of MM patients is strongly reduced and that the decrease is correlated with disease progression. A similar depletion is found in patients having acute myeloid leukemia and acute lymphoblastic leukemia but not in cancer forms that do not involve the bone marrow such as in colon cancer. Expression of a modified sema3A [furin-resistant sema3A (FR-sema3A)] stabilized against cleavage by furin-like proprotein convertases in CAG MM cells did not affect their behavior in-vitro. CAG cells injected into the tail vein of severe combined immunodeficient (SCID) mice home to the bone marrow and proliferate, mimicking MM disease progression. Disease progression in mice injected with CAG cells expressing FR-sema3A was inhibited, resulting in prolonged survival and a lower incidence of bone lesions. Histological examination and fluorescence-activated cell sorting analysis revealed that FR-sema3A expression reduced the infiltration of the CAG cells into the bone marrow, reduced bone marrow necrosis and reduced angiogenesis induced by the MM cells in the bone marrow. Our results suggest that measurement of sema3A serum concentrations may be of use for the diagnosis and for the monitoring of malignancies of the bone marrow such as MM. Furthermore, our results suggest that FR-sema3A may perhaps find use as an inhibitor of MM disease progression.

Extended vs Bolus Infusion of Broad-Spectrum ß-Lactams for Febrile Neutropenia: An Unblinded, Randomized Trial.

Background: Febrile neutropenia may be a sign of severe infection and is associated with significant morbidity and mortality in high-risk patients with hematologic malignancies. Extended infusion of ß-lactam antibiotics is associated with greater clinical response than is bolus infusion in nonneutropenic critically ill patients, but data are lacking for febrile neutropenic patients. Methods: We designed a single-center, nonblinded, randomized trial to compare extended infusion (4 hours) and bolus infusion (30 minutes) of piperacillin-tazobactam or ceftazidime in high-risk patients with febrile neutropenia. The primary endpoint was overall response on day 4, defined as the combination of resolution of fever, sterile blood cultures, resolution of clinical signs and symptoms, and no need for a change in the antibiotic regimen. Outcome was adjudicated by investigators blinded to treatment allocation. Results: Of 123 enrolled patients, 105 had febrile neutropenia and were included in the intention-to-treat analysis: 47 in the extended infusion arm and 58 in the bolus infusion arm. Overall response occurred in 35 (74.4%) patients treated with extended infusion and 32 (55.1%) patients treated with bolus infusion (P = .044). The superiority of extended infusion was greatest for patients with clinically documented infections (overall response, 68.4% [13/19] vs 35.7% [10/28]; P = .039) and specifically for those with pneumonia (80% [4/5] vs 0% [0/8]; P = .007). Conclusions: Extended infusion of ß-lactams is associated with superior treatment outcomes compared with bolus infusion for high-risk patients with febrile neutropenia. The benefit of extended ß-lactam infusion may be greatest for patients with pulmonary infections. Clinical Trials Registration: NCT02463747.

Mycetoma of the Foot Caused by Madurella Mycetomatis in Immigrants from Sudan.

BACKGROUND: Mycetoma is a chronic and destructive infection caused by either fungus or bacteria. Mycetoma has a characteristic clinical presentation of a triad of tumor-like swelling, draining sinuses, and macroscopic grains. Mycetoma infection is extremely rare in Israel; however, in view of the recent immigration from mycetoma-hyperendemic regions of Africa to Israel, physicians in Israel may encounter this infection. OBJECTIVES: To present two cases of mycetoma caused by Madurella mycatomatis in immigrants from endemic regions in Sudan treated at our hospital, and review the current literature. CONCLUSIONS: Health care professionals in Israel should suspect mycetoma in patients from endemic countries who present with tumor-like swelling especially in the lower extremity. Health care workers should be able to recognize mycetoma and provide the optimal treatment before the lesion progresses to an advanced and disabling disease.

Thrombosis following acute cytomegalovirus infection: a community prospective study.

Infection might be associated with increased risk of venous thromboembolism (VTE) and arterial thrombosis. Specific hypotheses have been raised regarding the procoagulant response induced by acute cytomegalovirus (CMV) infection. Accordingly, we investigated the 6-month incidence of VTE and/or arterial thrombosis in patients that had been tested positive for CMV-IgM antibodies in a large health maintenance organization. Logistic regression analysis was used to identify independent risk factors for VTE and arterial thrombosis. Among 90,515 patients eligible for the VTE analysis and 90,805 patients eligible for the arterial thrombosis analysis, 6,205 (6.9%) and 6,222 (6.9%) patients were tested positive for CMV-IgM antibodies, respectively. During 6 months of follow-up from index date, the incidence rates per 1,000 capita of VTE among CMV-IgM seropositive and CMV-IgM seronegative patients were 3.06 (19 patients) and 1.36 (115 patients), respectively (odds ratio (OR) 2.25; 95% confidence intervals (95% CI) 1.38-3.66; p = 0.003). CMV-IgM seropositivity was independently associated with VTE appearance (OR 2.49; 95% CI 1.53-4.06; p < 0.0001) following adjustment for age, sex, and other confounders. The incidence rates per 1,000 capita of arterial thrombosis among CMV-IgM seropositive and CMV-IgM seronegative patients were 1.12 (7 patients) and 1.06 (90 patients), respectively (OR 1.06; 95% CI 0.49-2.28; p = 0.840). CMV-IgM seropositivity was not associated with arterial thrombosis. We conclude that acute CMV infection might be associated with an increased short-term VTE risk. To the best of our knowledge, this is the largest study ever to confirm this association.

Significantly elevated C-reactive protein serum levels are associated with very high 30-day mortality rates in hospitalized medical patients.

BACKGROUND: There is insufficient data regarding the differential diagnosis and the prognostic value of significantly elevated serum levels of C-reactive protein (CRP) in hospitalized medical patients. DESIGN AND METHODS: A retrospective review of medical charts of patients admitted to a tertiary hospital's Internal Medicine ward during a period of 1 year who had at least one CRP serum level measurement of 200mg/L or more. RESULTS: Overall, 341 patients with a mean age of 69.8+/-1.0 years were included in the study. Acute infection was the most prevalent diagnosis (n=293; 85.9%) with community-acquired pneumonia being the most common acute infection (n=115; 33.7%). Non-infectious conditions accounted for 9.1% (n=31) of the diagnoses and included mainly malignant metastatic diseases (n=19; 5.6%). Overall, 70 (20.5%) patients died within 30 days of admission. Age and active malignancy, with metastasis or without metastasis, were independently associated with 30-day mortality. CONCLUSION: Significantly elevated CRP serum levels are associated with bacterial infections, malignant diseases, and very high rates of 30-day mortality in hospitalized medical patients.

Range and determinants of white blood cell count in a large survey of Israelis without inflammation.

BACKGROUND: The white blood cell count and its differential are established inflammation-sensitive biomarkers with a proven prognostic value in the field of atherothrombosis. However, the WBCC count range and determinants havenot been explored in the absence of a significant inflammatory response. OBJECTIVE: To analyze the WBCC range and determinants in a large Israeli sample of individuals, excluding patients with a significant inflammatory response. METHODS: WBCC and differential count reference ranges were determined in a large sample of apparently heal participants with high sensitivity C-reactive protein concentrations below 10 mg/L. Linear regression models were used to identify the determinants of the WBCC. The central 95% areas under the distribution curves were established for each gender. RESULTS: The study population comprised 8247 individuals (5391 males and 2856 females). The main laboratory and clinical variables found to affect the WBCC were gender, hemoglobin level, smoking status, triglycerides, and body mass index (all P < 0.001). Similar results were obtained for the differential count. The reference ranges for men and women were 3.6-9.9 and 3.4-10.0 x10(3) microl, respectively.The reference ranges for currently smoking men and women were 3.6-11.5 and 3.6-11.2 x10(3) microl, respectively, and were significantly higher compared with those of the never smokers and past smokers. CONCLUSIONS: We have demonstrated new limits of normal values for the WBCC in apparently healthy individuals who lack a significant "background" acute-phase response in a large Israeli sample. Our data might be useful for the risk stratification of apparently healthy individuals in the field of atherothrombosis.

C-reactive protein velocity to distinguish febrile bacterial infections from non-bacterial febrile illnesses in the emergency department.

INTRODUCTION: C-reactive protein (CRP) is a real-time and low-cost biomarker to distinguish febrile bacterial infections from non-bacterial febrile illnesses. We hypothesised that measuring the velocity of the biomarker instead of its absolute serum concentration could enhance its ability to differentiate between these two conditions. METHODS: We prospectively recruited adult patients (age >or= 18 years) who presented to the emergency department with fever. We recorded their data regarding the onset of fever and accompanying symptoms. CRP measurements were obtained upon admission. CRP velocity (CRPv) was defined as the ratio between CRP on admission and the number of hours since the onset of fever. Patients were diagnosed by clinical symptoms, blood cultures and imaging studies, and the diagnoses were confirmed by an infectious disease specialist. The efficacy of CRPv as a diagnostic marker was evaluated by using receiver operator curves (ROC). Excluded were patients who did not know the time fever started with certainty, patients with malignancy, patients with HIV infection and patients who had been using antibiotics upon presentation. RESULTS: Of 178 eligible patients, 108 (60.7%) had febrile bacterial infections (mean CRP: 63.77 mg/L, mean CRPv: 3.61 mg/L/hour) and 70 (39.3%) had non-bacterial febrile illnesses (mean CRP: 23.2 mg/L, mean CRPv: 0.41 mg/L/hour). The area under the curve for CRP and CRPv were 0.783 (95% confidence interval (CI) = 0.717 to 0.850) and 0.871 (95% CI = 0.817 to 0.924), respectively. In a 122-patient subgroup with a CRP level of less than 100 mg/L, the area under the curve increased from 0.689 (95% CI = 0.0595 to 0.782) to 0.842 (95% CI = 0.77 to 0.914) by using the CRPv measurements. CONCLUSIONS: CRPv improved differentiation between febrile bacterial infections and non-bacterial febrile illnesses compared with CRP alone, and could identify individuals who need prompt therapeutic intervention.

Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients.

AIMS: We reviewed all the publications concerning methadone-associated Torsades de Pointes (TdP) (polymorphic ventricular tachycardia) in opioid-dependent patients in order to characterize the clinical circumstances leading to this serious complication. METHODS: Our literature search yielded 14 reports on 40 patients with methadone-associated TdP. We gathered and recorded the risk factors for TdP mentioned in those reports, among other clinical aspects. RESULTS: The most prevalent risk factors for TdP were high-dose methadone (n = 39, 97.5%) and concomitant use of agents that increase serum methadone levels or trigger TdP (n = 22, 55%). HIV infection (n = 16), hypokalaemia (n = 14), female sex (n = 13), liver cirrhosis or renal failure (n = 11) and heart disease (n = 9) were also described. All the patients had at least one and 34 (85%) had two or more risk factors for TdP during methadone treatment. CONCLUSIONS: We wish to raise the level of awareness of risk factors for TdP among physicians in heroin-treatment clinics who frequently prescribe methadone.

Water diffusion in the different microenvironments of breast cancer.

The parameters that characterize the intricate water diffusion in tumors may serve to reveal their distinct pathology. Specifically, the application of diffusion magnetic resonance imaging (MRI) can aid in characterizing breast cancer, as well as monitoring response to therapy. We present here a non-invasive, quantitative MRI investigation, at high spatial resolution, of water diffusion in hormonal dependent MCF7 breast tumors implanted orthotopically in immunodeficient mice. Distinctive MRI protocols were designed in this study, utilizing a broad range of diffusion times and diffusion gradient strengths. Application of these protocols allowed water diffusion in the tissue extracellular and intracellular compartments to be distinguished, and the effect of restricted diffusion and water exchange on the water diffusion in these compartments to be evaluated. Pixel-by-pixel analysis yielded parametric maps of the estimated volume fraction and apparent diffusion coefficient of each compartment. The diffusion of the water in the extracellular microenvironment was approximately two fold slower than that of free water, and in the intracellular compartment was about one order of magnitude slower than that of free water and demonstrated restriction of water diffusion at long diffusion times. Mapping of the water fraction in each compartment was further employed to monitor changes during tumor progression and to assess tumor response to hormonal manipulation with a new antiestrogenic drug, tamoxifen methiodide (TMI). It was found that, in parallel to the growth arrest by this drug, the volume fraction of the slowly diffusing water increased, suggesting a TMI-induced cell swelling. This study can serve as a basis for extending diffusion breast MRI in the clinical setting.