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The New England Journal of Medicine Jun 2024Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal...
BACKGROUND
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells.
METHODS
We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×10 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored.
RESULTS
Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×10 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×10 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56CD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased.
CONCLUSIONS
In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).
Topics: Adult; Aged; Animals; Female; Humans; Male; Mice; Middle Aged; Antibodies, Monoclonal; Platelet Count; Purpura, Thrombocytopenic, Idiopathic
PubMed: 38899695
DOI: 10.1056/NEJMoa2400409 -
Journal of Controlled Release :... Jun 2024We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of...
PURPOSE
We report our experience disrupting the blood-brain barrier (BBB) to improve drug delivery in glioblastoma patients receiving temozolomide chemotherapy. The goals of this retrospective analysis were to compare MRI-based measures of BBB disruption and vascular damage to the exposure levels, acoustic emissions data, and acoustic simulations. We also simulated the cavitation detectors.
METHODS
Monthly BBB disruption (BBBD) was performed using a 220 kHz hemispherical phased array focused ultrasound system (Exablate Neuro, InSightec) and Definity microbubbles (Lantheus) over 38 sessions in nine patients. Exposure levels were actively controlled via the cavitation dose obtained by monitoring subharmonic acoustic emissions. The acoustic field and sensitivity profile of the cavitation detection system were simulated. Exposure levels and cavitation metrics were compared to the level of BBBD evident in contrast-enhanced MRI and to hypointense regions in T2*-weighted MRI.
RESULTS
Our treatment strategy evolved from using a relatively high cavitation dose goal to a lower goal and longer sonication duration and ultimately resulted in BBBD across the treatment volume with minimal petechiae. Subsonication-level feedback control of the exposure using acoustic emissions also improved consistency. Simulations of the acoustic field suggest that reflections and standing waves appear when the focus is placed near the skull, but their effects can be mitigated with aberration correction. Simulating the cavitation detectors suggest variations in the sensitivity profile across the treatment volume and between patients. A correlation was observed with the cavitation dose, BBBD and petechial hemorrhage in 8/9 patients, but substantial variability was evident. Analysis of the cavitation spectra found that most bursts did not contain wideband emissions, a signature of inertial cavitation, but biggest contribution to the cavitation dose - the metric used to control the procedure - came from bursts with wideband emissions.
CONCLUSION
Using a low subharmonic cavitation dose with a longer duration resulted in BBBD with minimal petechiae. The correlation between cavitation dose and outcomes demonstrates the benefits of feedback control based on acoustic emissions, although more work is needed to reduce variability. Acoustic simulations could improve focusing near the skull and inform our analysis of acoustic emissions. Monitoring additional frequency bands and improving the sensitivity of the cavitation detection could provide signatures of microbubble activity associated with BBB disruption that were undetected here and could improve our ability to achieve BBB disruption without vascular damage.
PubMed: 38897294
DOI: 10.1016/j.jconrel.2024.06.036 -
EJHaem Jun 2024Bleeding and thrombosis are common complications during immune thrombocytopenic purpura (ITP) treatment. There is a strong need to predict bleeding and thrombosis risks...
Bleeding and thrombosis are common complications during immune thrombocytopenic purpura (ITP) treatment. There is a strong need to predict bleeding and thrombosis risks before ITP treatment to optimize therapy and appropriately manage these complications. We performed a retrospective cohort study of 120 patients with primary ITP to identify a biomarker to predict bleeding and thrombosis. We compared blood test results at diagnosis between patients with and without bleeding or thrombosis episodes. The standard deviation of red blood cell distribution width (RDW-SD) differed significantly between those with and without bleeding and between those with and without thrombosis, leading us to identify it as a variable representative of risk. RDW-SD was significantly associated with patient age and with histories of several vascular diseases. Multivariate regression analyses showed that RDW integrated several variables associated with vascular risks. RDW-SD was significantly associated with difficulty with corticosteroid discontinuation (hazard ratio [HR], 2.22, = 0.01), incidence of bleeding (HR, 2.75, < 0.01), incidence of thrombosis (HR, 2.67, < 0.01) and incidence of infection (HR, 1.78, = 0.04). The RDW-SD value at the time of ITP diagnosis is a useful biomarker to predict the risks of bleeding, thrombosis, and other complications.
PubMed: 38895062
DOI: 10.1002/jha2.897 -
The Neurohospitalist Jul 2024Acute focal neurological deficits demand immediate evaluation. In this report, we present the case of a woman 20-some years of age with a history of hemolytic anemia and...
Acute focal neurological deficits demand immediate evaluation. In this report, we present the case of a woman 20-some years of age with a history of hemolytic anemia and thrombocytopenia who presented with altered mental status and focal neurological deficits including aphasia, acute left gaze preference, right homonymous hemianopsia, right lower facial weakness, and right arm and leg weakness. Extensive neurological and hematological workup revealed that the patient suffered from focal status epilepticus associated with an extreme delta brush patten on electroencephalogram, likely secondary to thrombotic thrombocytopenic purpura. This case underscores the connection between hematological disorders and the neurological axis, emphasizing the critical role of integrating the neurological examination and neuroimaging findings to formulate an effective management plan.
PubMed: 38894999
DOI: 10.1177/19418744241245454 -
Healthcare (Basel, Switzerland) May 2024During the COVID-19 pandemic, there have been multiple reports about an unforeseen surge in adolescents and young adults exhibiting sudden onset functional tic-like... (Review)
Review
During the COVID-19 pandemic, there have been multiple reports about an unforeseen surge in adolescents and young adults exhibiting sudden onset functional tic-like behaviors. This phenomenon has been mainly associated with the female gender and occasionally after exposure to social media content featuring similar patterns of functional tic-like behaviors. A significant portion of these individuals have been directed to specialist clinics for movement disorders with initial misdiagnoses of late-onset refractory Tourette syndrome. Distinguishing between rapid onset functional tic-like behaviors and neurodevelopmental tics as part of Tourette syndrome can be challenging; however, the differential diagnosis is facilitated by focusing on specific clinical and demographic factors, which we have explored in a systematic literature review. Compared to neurodevelopmental tics, functional tic-like behaviors typically present with a more abrupt and intense manifestation of symptoms, onset at a later age, higher prevalence among females, inability to suppress tics, coexisting anxiety and depression, and sometimes a history of exposure to social media content portraying tic-like behaviors of a similar nature. This novel manifestation of a functional neurological disorder may thus be viewed as an emerging neuropsychiatric condition potentially triggered/exacerbated by the psychosocial repercussions of the COVID-19 crisis.
PubMed: 38891181
DOI: 10.3390/healthcare12111106 -
Advances in Skin & Wound Care Jun 2024To synthesize the literature on skin failure and pressure injuries among hospitalized patients with COVID-19.
OBJECTIVE
To synthesize the literature on skin failure and pressure injuries among hospitalized patients with COVID-19.
DATA SOURCES
An electronic literature search using relevant keywords and controlled vocabulary was conducted in March 2023 on MEDLINE/PubMed, Embase, and CINAHL. Manual citation searches of included articles and grey literature, including the Wound, Ostomy, and Continence Nurses Society website were performed. Articles published in English between 2020 and April 2023 were considered.
STUDY SELECTION
Articles were included if they reported on COVID-19 positive hospitalized adults with wounds that were not present upon admission. A total of 31 articles met these criteria.
DATA EXTRACTION
Covidence was used to extract the data and was reviewed by multiple team members.
DATA SYNTHESIS
Of the 31 studies, 27 reported new onset skin lesions during hospitalization. Wounds were classified as pressure injuries, skin failure, livedo racemosea and/or, retiform purpura, and associated with microvascular thrombosisthrombotic vasculopathy. Most pressure injuries were associated with prone position and affected patients often had multiple comorbidities including hypertension, diabetes mellitus, end-stage renal disease, heart disease, and COPD. Four articles highlighted an increased risk of new onset wounds, and three emphasized the importance of distinguishing deep tissue pressure injuries from ischemic-related lesions in patients with COVID-19.
CONCLUSIONS
The evidence suggests an increased risk of ischemic lesions and pressure injuries (PI) in patients with COVID-19 infection. This phenomenon may have inflated the numbers of PI during the pandemic and adversely affected nursing quality measures in acute care environments.
PubMed: 38884316
DOI: 10.1097/ASW.0000000000000188 -
Clinical Case Reports Jun 2024Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research...
KEY CLINICAL MESSAGE
Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research to establish standard management guidelines for COVID-19-vaccine-associated ITP.
ABSTRACT
Adult immune thrombocytopenia (ITP) can occur as a rare complication following several viral infections or a rare adverse event or complication of vaccination. In this paper, we report a case of a 39-year-old male patient with severe refractory ITP that began 4-weeks after receiving his third (booster) dose of the COVID-19 vaccine (BNT162b2, Pfizer-BioNTech). He was given oral dexamethasone 40 mg daily for 4 days followed by prednisone at 1 mg/kg (85 mg daily) for 10 days. In the following weeks, we attempted several other lines of therapy to treat his ITP, including anti-RhD immunoglobulin, which, unfortunately, caused moderate hemolysis requiring packed red blood cell transfusion, intravenous immunoglobulin (given at a subtherapeutic dose of 0.4 g/kg for only 1 day since it was not available), rituximab, and eltrombopag. The patient, unfortunately, showed no response to any of these treatments. This was an indicator to initiate salvage therapy with vincristine 2 mg weekly for 3 weeks. The patient's platelet count started to increase remarkably during the third week of vincristine and normalized after 4 weeks. We review the findings, clinical characteristics, and management approaches that were reported in the literature regarding COVID-19-vaccine-induced ITP. More in-depth research is needed to delineate standard guidelines for the management of such cases. This report underscores the importance of resorting to vincristine and eltrombopag as great options for severe and refractory ITP related to the COVID-19 vaccine.
PubMed: 38883219
DOI: 10.1002/ccr3.9070 -
European Journal of Internal Medicine Jun 2024Eosinophilic granulomatosis with polyangiitis (EGPA), is a rare ANCA-associated systemic vasculitis. Its overlapping features with other vasculitic or eosinophilic...
BACKGROUND
Eosinophilic granulomatosis with polyangiitis (EGPA), is a rare ANCA-associated systemic vasculitis. Its overlapping features with other vasculitic or eosinophilic diseases, and the wide and heterogeneous range of clinical manifestations, often result in a delay to diagnosis.
OBJECTIVE
To identify red flags that raise a suspicion of EGPA to prompt diagnostic testing and to present an evidence-based clinical checklist tool for use in routine clinical practice.
METHODS
Systematic literature review and expert consensus to identify a list of red flags based on clinical judgement. GRADE applied to generate a strength of recommendation for each red flag and to develop a checklist tool.
RESULTS
86 studies were included. 40 red flags were identified as relevant to raise a suspicion of EGPA and assessed by the experts as being clinically significant. Experts agreed that a diagnosis of EGPA should be considered in a patient aged ≥6 years with a blood eosinophil level >1000 cells/µL if untreated and >500 cells/µL if previously treated with any medication likely to have altered the blood eosinophil count. The presence of asthma and/or nasal polyposis should reinforce a suspicion of EGPA. Red flags of asthma, lung infiltrates, pericarditis, cardiomyopathy, polyneuropathy, biopsy with inflammatory eosinophilic infiltrates, palpable purpura, digital ischaemia and ANCA positivity, usually anti-myeloperoxidase, among others, were identified.
CONCLUSION
The identification of a comprehensive set of red flags could be used to raise a suspicion of EGPA in patients with eosinophilia, providing clinicians with an evidence-based checklist tool that can be integrated into their practice.
PubMed: 38880725
DOI: 10.1016/j.ejim.2024.06.008 -
Indian Journal of Gastroenterology :... Jun 2024
PubMed: 38878255
DOI: 10.1007/s12664-024-01627-w