Simultaneous Multifocal Intracranial Haemorrhages Associated with Staphylococcus Aureus Endocarditis: A Plausible Role for Diclofenac Administration.

Introduction: Intracranial haemorrhage may complicate infective endocarditis, caused by ruptured mycotic aneurysms or haemorrhagic transformation of brain septic emboli. The risk of intracranial bleeding may increase with the use of non-steroidal anti-inflammatory agent (NSAIDs). Case description: We report on a 53-year-old male patient with a past history of intravenous drug abuse, who was treated with diclofenac (75 mg IM) for a few hours of preceding fever and arthralgia. Seven hours later he was hospitalised with impaired consciousness and hemiparesis. Evaluation revealed multiple intracranial haemorrhages, at least one originating from a mycotic aneurysm. Repeated blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA), and echocardiography revealed a vegetation on the mitral valve, establishing the diagnosis of bacterial endocarditis. Conclusion: The abrupt simultaneous multifocal intracranial bleeds shortly following the administration of NSAIDs for a few hours of febrile disease, one clearly originating from a mycotic aneurism, are exceptional. This raises a possibility of a role for diclofenac the intracranial bleeding diathesis in this unique clinical presentation. Intracranial haemorrhage in the set-up of undiagnosed infective endocarditis (IE) might be added to the long list of potential adverse outcomes of NSAID administration, and the possibility of IE should be considered before their administration for febrile disease of undetermined cause. LEARNING POINTS: Intracranial haemorrhage in the set-up of undiagnosed infective endocarditis might be added to the long list of potential adverse outcomes of NSAID administration.The possibility of infective endocarditis should be considered before the administration of NSAIDs for febrile disease of an undetermined cause.

SARS-CoV-2 spike antibody concentration in gamma globulin products from high-prevalence COVID-19 countries are transmitted to X-linked agammaglobulinemia patients.

Purpose: Patients with X-linked agammaglobulinemia (XLA) are characterized by humoral impairment and are routinely treated with intravenous immunoglobulin (IVIG). In this study, we aimed to investigate the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in IVIG preparations harvested globally and evaluate the transfer of SARS-CoV-2 antibodies to the XLA patient. Methods: A single-center, prospective cohort study was conducted in the period of November 2020 to November 2022. Clinical and laboratory data, specifically, SARS-CoV-2 spike IgG levels from the serum of 115 IVIG preparations given to 5 XLA patient were collected. Concurrently, SARS-CoV-2 spike IgG levels from the serum of the 5 XLA was collected monthly. Results: Five XLA patients were evaluated within the study period. All were treated monthly with commercial IVIG preparations. A total of 115 IVIG treatments were given over the study period. The origin country and the date of IVIG harvesting was obtained for 111 (96%) of the treatments. Fifty-four IVIG preparations (49%) were harvested during the COVID-19 pandemic of which 76% were positive (>50AU/mL) for SARS-CoV-2 spike antibodies which were subsequently transmitted to the XLA patients in an approximate 10-fold reduction. SARS-CoV2 spike IgG was first detected in IVIG batches that completed their harvest date by September 2021. Positive products were harvested from origin countries with a documented prevalence over 2,000 per 100,000 population. Conclusion: As the prevalence of COVID-19 infections rises, detection of SARS-CoV-2 spike IgG in commercial IVIG products increases and is then transmitted to the patient. Future studies are needed to investigate the neutralizing capabilities of SARS-CoV-2 IgG and whether titer levels in IVIG remain consistent as the incidence of infection and vaccination rates in the population changes.

D-Dimer as a Prognostic Factor in a Tertiary Center Intensive Coronary Care Unit.

INTRODUCTION: D-dimer is a small protein fragment produced during fibrinolysis. High D-dimer levels were shown to have prognostic impact in critically ill patients. Nevertheless, data regarding D-dimer's prognostic impact among tertiary care intensive coronary care unit (ICCU) patients is scarce. MATERIAL AND METHOD: All patients admitted to the ICCU between 1-12/2020 were prospectively included. Based on admission D-dimer level, patients were categorized into low and high D-dimer groups (< 500 ng/ml and ≥ 500 ng/ml) and also to age-adjusted D-dimer cutoff (500 ng/ml for ages ≤ 50 years old and age*10 for ages>50 years old). RESULTS AND DISCUSSION: A total of 959 consecutive patients were included, including 296 (27.4%) and 663 (61.3%) patients with low and high D-Dimer levels, respectively. Patients with high D-dimer level were older compared with patients with low D-dimer level (age 70.4 ± 15 and 59 ± 13 years, p = 0.004) and had more comorbidities. The most common primary diagnosis on admission among the low D-dimer group was acute coronary syndrome (ACS) (74.3%), while in the high D-dimer group it was a combination of ACS (33.6%), cardiac structural interventions (26.7%) and various arrhythmias (21.1%). High D-dimer levels were associated with increased mortality rate, even after adjustment for age, gender, comorbidities and left ventricular ejection fraction (LVEF). High D-dimer levels were independently associated with increased overall 1-year mortality rate (HR = 5.8; 95% CI; 1.7-19.1; p = 0.004). CONCLUSION: Elevated D-dimer levels on admission in ICCU patients is an independently poor prognostic factor for in-hospital morbidity and 1-year overall mortality rate following hospitalization.

Anti-CD20 monoclonal antibodies inhibit seropositive response to Covid-19 vaccination in non-Hodgkin lymphoma patients within 6 months after treatment.

The Covid-19 pandemic has caused millions of deaths worldwide. Although vaccines have been developed, patients on immunosuppressive therapy are less likely to respond. This study was aimed at investigating the efficacy of a Covid-19 vaccine (Pfizer-BioNTech) in patients with non-Hodgkin lymphoma treated with anti-CD20 monoclonal antibodies. Only 1 of 28 lymphoma patients (3.6%) developed a seropositive response, compared with 100% (28/28) of the healthy volunteers. The low levels of CD19+ lymphocytes among the lymphoma patients suggest that anti-CD20 treatment prevents the seropositive response to the vaccine. An additional vaccination might be indicated in these patients once B cells are repopulated.

Emerging Monoclonal Antibody Therapy for the Treatment of Acute Lymphoblastic Leukemia.

The treatment of adults with ALL has undergone tremendous progress over the past 15 years. The advances have been particularly marked with B-lineage ALL. The development of bispecific antibodies directed against CD19 ushered in a new era in overcoming persistent minimal disease in newly diagnosed ALL patients as well as successfully treating those with relapsed disease. The immune-conjugates targeting CD22 have also had a similarly impressive role in improving the outcome in such patients. These advances are now being extended to frontline regimens for B-lineage ALL, including the Philadelphia-chromosome-positive subtype. Over the past decade, the development of chimeric antigen receptor T-cell therapy (CAR-T) has ushered in a new era, opening up hope when none was available for patients with particularly advanced disease. Such advances come at a considerable price for toxicity, which, however, are lessening with experience and the development of new agents to ameliorate some of the toxicities. Unfortunately, the progress for T-cell in ALL has lagged behind that of B-lineage ALL. Of late, however, there are preliminary results of potentially exciting data using monoclonal antibodies against CD38, in the form of daratumumab, and it is hoped that these will lead to an equally successful advance in the treatment of T-ALL. Despite all these advances, ALL in adults remains a formidable disease. While ongoing progress is being made, also in the therapy of older patients, we are still lagging behind the almost totally curative potential of current therapy for childhood ALL.

Predictors of Hypoxemia and Related Adverse Outcomes in Patients Hospitalized with COVID-19: A Double-Center Retrospective Study.

Hypoxemia is a hallmark of coronavirus disease 2019 (COVID-19) severity. We sought to determine predictors of hypoxemia and related adverse outcomes among patients hospitalized with COVID-19 in the two largest hospitals in Jerusalem, Israel, from 9 March through 16 July 2020. Patients were categorized as those who developed reduced (<94%) vs. preserved (≥94%) arterial oxygen saturation (SpO2) within the first 48 h after arrival to the emergency department. Overall, 492 hospitalized patients with COVID-19 were retrospectively analyzed. Patients with reduced SpO2 were significantly older, had more comorbidities, higher body surface area (BSA) and body mass index (BMI), lower lymphocyte counts, impaired renal function, and elevated liver enzymes, c-reactive protein (CRP), and D-dimer levels as compared to those with preserved SpO2. In the multivariable regression analysis, older age (odds ratio (OR) 1.02 per year, p < 0.001), higher BSA (OR 1.16 per 0.10 m2, p = 0.003) or BMI (OR 1.05 per 1 kg/m2, p = 0.011), lower lymphocyte counts (OR 1.72 per 1 × 103/µL decrease, p = 0.002), and elevated CRP (1.11 per 1 mg/dL increase, p < 0.001) were found to be independent predictors of low SpO2. Severe hypoxemia requiring ventilatory support, older age, and pre-existing comorbidities, including underlying renal dysfunction and heart failure, were found to be significantly associated with in-hospital mortality. These findings suggest that assessment of predictors of hypoxemia early at the time of hospitalization with COVID-19 may be helpful in risk stratification and management.

Bone loss and hematological malignancies in adults: a pilot study.

PURPOSE: Bone loss-osteopenia and osteoporosis-is a recognized consequence of solid tumors in adults, of pediatric hematological malignancies, and of the treatment for these diseases, but little research has been published on the adverse effects of hematological malignancies on the bone in adults. The aim of this study is to identify hematological diseases that are associated with the highest prevalence and severity of osteoporosis. METHODS: We evaluated DXA (dual-energy X-ray absorptiometry) in a cross-section of 181 adult patients with hematological neoplasms, excluding multiple myeloma. All patients were over 18 years of age, signed a local institutional review board (IRB)-approved consent form, and had completed a questionnaire regarding predisposing factors to osteoporosis. This data was supplemented by hospital charts. RESULTS: Bone loss as measured by DXA T scores was found in 65% of patients, of whom 38% had osteopenia and 27% osteoporosis. DXA Z scores under - 2.0 were found in 11.4% of patients, compared to the expected 2.5% of the normal population. The DXA Z scores varied by diagnosis, showing bone loss in 49% of chronic lymphocytic leukemia/small lymphocytic lymphoma, compared to 67% of non-Hodgkin lymphoma and 88% of Hodgkin disease; the scores were not affected by the duration of time from diagnosis to DXA (3.6, 2.0, and 1.6 years, respectively). CONCLUSION: Adult patients with hematological malignancies have significant bone loss compared to a normal age-matched population. The type of diagnosis is more important than the time from diagnosis in predicting risk for bone loss. Recognition of bone loss in these patients may warrant prophylactic measures and lifestyle changes before, during, and after therapy.

Inotuzumab ozogamicin for the treatment of acute lymphoblastic leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is an uncommon disorder that affects about 20% of adults with acute leukemia. Historically, those who relapse from this condition have a dismal prognosis. Recent developments in immunoconjugate usage has changed the landscape of lymphoid B-cell malignancy therapy. One recent development is the FDA approved therapy inotuzumab ozogamicin which has the potential to reduce the overall toxicity of intensive regimens for ALL, as well as to possibly increase the number of patients who may achieve a state of minimal residual disease. Areas covered: In this review, the pre-clinical and clinical experiences with inotuzumab ozogamicin in lymphoma and ALL are reviewed. The article further includes the published phase I, II and III studies in ALL and considers the safety and efficacy of this treatment. Expert opinion: Inotuzumab ozogamicin is likely to be used, primarily, as a potent agent for relapsed ALL, either as the first choice or for those who fail treatment with blinatumumab. Its potential in newly diagnosed patients is currently unknown, such that the overall impact is likely to be important, but limited.

Treatment of Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia.

Opinion statementOver the past 15 years, the landscape of Ph+ ALL has changed dramatically. No longer the most dreaded form of acute leukemia, the advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era, as TKIs have become the backbone of any treatment regimen for Ph+ ALL. A greater number achieve a complete remission allowing for more patients to get the transplant, although probably less patients need a transplant. For the first time in decades, there is hope for older patients with Ph+ ALL. Defining residual disease at an increasingly lower level of disease burdens termed minimal residual disease (MRD) has allowed treatment algorithms to be designed based on deep molecular responses. The aggregate of recent data suggest that this is the most important endpoint to predict for long-term outcome and to decide on the optimal post-remission approach, including transplant. Novel agents, such as blinatumumab, are likely to be incorporated into therapy for relapse and as initial therapy in an attempt to increase the number of patients who may have deep molecular responses. Many more patients with Ph+ ALL are long-term survivors, and the future is looking brighter for this group of patients.

Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia in Adults.

Patients with relapsed and refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis with less than 10 % of patients surviving 5 years. Most such patients cannot be rescued with currently available therapies, whatever the initial treatment they receive. Therefore, there is an urgent need for novel treatment options. Fortunately, over the past several years, an improved understanding of the biology of the disease has allowed the identification of rational molecular targets for therapeutic endeavors and the emergence of novel therapies has sparked great interest. This review will discuss the current treatment landscape for adult patients with relapsed and/or refractory ALL.

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity.

BACKGROUND: Factor XIII (FXIII), a plasma pro-transglutaminase, consists of two A subunits and two B subunits (FXIIIA2B2). Following activation by thrombin, it cross-links fibrin chains at the final step of coagulation. We previously reported that FXIII subunit A (FXIIIA) serves as a protein disulfide isomerase (PDI), and that PDI promotes platelet adhesion and aggregation. OBJECTIVE: This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. METHODS: Ex vivo experiments: Blood platelets derived from five patients with hereditary FXIIIA deficiency before and after treatment with Fibrogammin-P (FXIIIA2B2 concentrate) were washed and incubated on immobilized fibrinogen. Bound platelets were stained and counted by microscopy. In vitro experiments: Platelets derived from patients before treatment and five healthy controls were washed and analyzed for adhesion in the presence or absence of Fibrogammin-P or recombinant FXIII (FXIIIA2 concentrate). RESULTS: In ex vivo experiments, one hour after Fibrogammin-P treatment, mean (±SEM) platelet adhesion to fibrinogen increased by 27±2.32% (p<0.001). In in vitro experiments, treatment with Fibrogammin-P or recombinant FXIII (10IU/mL each) enhanced platelet adhesion to fibrinogen (in patients, by 29.95±6.7% and 29.05±5.3%, respectively; in controls, by 26.06±3.24% and 26.91±4.72, respectively; p<0.04 for all). Iodoacetamide-treated FXIII (I-FXIII), where transglutaminase activity is blocked, showed similar enhanced adhesion as untreated FXIII. By contrast, addition of an antibody that specifically blocks FXIIIA-PDI activity inhibited FXIII-mediated platelet adhesion to fibrinogen by 65%. CONCLUSION: These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.