The efficacy of convalescent plasma for coronavirus disease 2019 (COVID-19) is unclear. Although most randomized controlled trials have shown negative results, uncontrolled studies have suggested that the antibody content could influence patient outcomes. We conducted an open-label, randomized controlled trial of convalescent plasma for adults with COVID-19 receiving oxygen within 12 d of respiratory symptom onset (NCT04348656). Patients were allocated 2:1 to 500 ml of convalescent plasma or standard of care. The composite primary outcome was intubation or death by 30 d. Exploratory analyses of the effect of convalescent plasma antibodies on the primary outcome was assessed by logistic regression. The trial was terminated at 78% of planned enrollment after meeting stopping criteria for futility. In total, 940 patients were randomized, and 921 patients were included in the intention-to-treat analysis. Intubation or death occurred in 199/614 (32.4%) patients in the convalescent plasma arm and 86/307 (28.0%) patients in the standard of care arm—relative risk (RR) = 1.16 (95% confidence interval (CI) 0.94–1.43, P = 0.18). Patients in the convalescent plasma arm had more serious adverse events (33.4% versus 26.4%; RR = 1.27, 95% CI 1.02–1.57, P = 0.034). The antibody content significantly modulated the therapeutic effect of convalescent plasma. In multivariate analysis, each standardized log increase in neutralization or antibody-dependent cellular cytotoxicity independently reduced the potential harmful effect of plasma (odds ratio (OR) = 0.74, 95% CI 0.57–0.95 and OR = 0.66, 95% CI 0.50–0.87, respectively), whereas IgG against the full transmembrane spike protein increased it (OR = 1.53, 95% CI 1.14–2.05). Convalescent plasma did not reduce the risk of intubation or death at 30 d in hospitalized patients with COVID-19. Transfusion of convalescent plasma with unfavorable antibody profiles could be associated with worse clinical outcomes compared to standard care.
Background Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life‐threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. Methods We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. Results During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty‐four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine‐based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. Conclusion Upfront genotyping before fluoropyrimidine‐based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. Implications for Practice Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life‐threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine‐based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.
BACKGROUND Alloantibodies to the low‐frequency antigen Scianna‐2 (Sc2) have been implicated in cases of hemolytic disease of the fetus and newborn but never in hemolytic transfusion reactions (HTRs); thus, the clinical significance of anti‐Sc2 has yet to be fully addressed. STUDY DESIGN AND METHODS A 26‐year‐old woman with thalassemia presented rigors, fever, nausea, abdominal pain, and hemolytic biochemistry after exposure to 75 mL of plasma‐reduced red blood cells (RBCs). The RBC unit was issued by electronic crossmatch but was 3+ incompatible on recrossmatch by gel indirect antiglobulin test (IAT). The patient had anti‐Sc2 previously identified, but considered to be clinically insignificant. The transfusion history was reviewed and a monocyte monolayer assay (MMA) was performed. RESULTS The patient was investigated for a RBC reaction 9 years prior, when she developed symptoms of HTR. The RBC unit was crossmatched by immediate spin due to consistent screen negativity. Full crossmatch found the RBC 1+ incompatible by gel IAT with both pre/post samples, while direct antiglobulin test was negative (pre) and 1+ immunoglobulin G positive (post). The antibody remained unidentified and she was committed to gel IAT crossmatch. Two‐years later, the specificity to Sc2 was deduced when one RBC unit was found 3+ incompatible. Finally, the transfusion reaction reported herein occurred when she received by happenstance RBCs from the same donor who was associated with the remote reaction 9 years earlier. MMA yielded highly positive phagocytic indices only for Sc2+ RBCs, including the donor's RBCs that triggered the severe HTR. CONCLUSION This is the first case of HTR caused by anti‐Sc2 confirmed by clinical findings and MMA.
650 Background: Fluoropyrimidines (FU) are part of chemotherapy combinations for multiple gastrointestinal cancers. Deficient dihydropyrimidine deshydrogenase (DPD) activity can lead to severe life-threatening toxicities in 3-5% of populations tested. The DPYD*2A polymorphism leading to deficient DPD activity is one of the most studied variants. Methods: We retrospectively performed chart reviews of all patients that tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec (Canada). The study objective was to document the impact of implementing this test in routine clinical practice, including the effects on treatment types, delays and toxicities. Results: 2,617 patients were tested by PCR for the presence of DPYD*2A in a period of 17 months: 25 patients tested positive. All were Caucasian. 24 of the 25 patients were heterozygous (0.92%) and one was homozygous (0.038%). A chart review was available for 20 patients: 15 were tested upfront while five were performed following severe toxicities on the first cycle of FU-based chemotherapy. Of the five patients identified following toxicities, all had grade 4 cytopenias, 80% grade ≥ 3 mucositis, 20% grade 3 rash and 20% grade 3 diarrhea, with an average of 15 days of hospitalisations due to febrile neutropenia. Seven of the 13 patients identified upfront received FU-based chemotherapy at reduced initial doses ranging from 25 to 50%. The average dose during the course of chemotherapy was 50% and two patients reached 100% dosage. No grade ≥ 3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation according to 99% of queried physicians. Conclusions: Upfront genotyping before FU-based treatment is feasible in clinical practice. It may prevent severe toxicities and hospitalisations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A.
Introduction Thrombotic thrombocytopenic purpura (TTP) is a prothrombotic disorder characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. It has been associated with a deficiency or dysfunction of ADAMTS13, an enzyme responsible for cleaving ultra-large von Willebrand factor multimers, thus preventing spontaneous platelet adhesion and aggregation. In its absence, platelet aggregates accumulate in the microvasculature causing neurological symptoms, cardiac ischemia and renal dysfunction. Most cases in adults are idiopathic, and associated with severe ADAMTS13 deficiency (<10%) and anti-ADAMTS13 antibodies. Acquired TTP due to various conditions, such as HIV, drugs, malignancy, collagen disease, bone marrow transplant and acute pancreatitis (AP), have also been described. Some cases of these secondary TTP may be associated with no to moderate ADAMTS13 deficiency and are referred to as thrombotic microangiopathies (TMAs). If plasma exchange (PLEX) has been the treatment of choice for acquired TTP, it has not been shown to be very effective for TMAs. AP-associated MAHA and thrombocytopenia (MAHA-T) might be one exception. Methods To better understand the relationship between AP and MAHA-T and to evaluate its response to PLEX, we retrospectively reviewed all cases of suspected TTP/ MAHA-T treated by PLEX in the context of AP in our institution from 2005 to 2015. For the purpose of this report, we preferred to use the term MAHA-T to describe this phenomenon since TMA usually refers to a pathologic diagnosis. Finally, a literature review of published cases was also performed. Results Five patients were treated with PLEX for suspicion of TTP in the context of AP between January 1st, 2005 and December 31st, 2015 at our centre. Median age was 36 (31-60). Etiologies for pancreatitis were alcohol (3/5) or idiopathic (2/5). Peak lipase level ranged between 426 and 5853 U/L. One patient had 3 episodes of MAHA-T following AP, always in the context of alcohol abuse. Two patients had evidence of MAHA-T on admission, while the remaining 3 patients had an unremarkable CBC at presentation followed by an abrupt drop in platelet count (nadir, 9-23 x 109/L). All patients showed simultaneously signs of MAHA (Hb nadir between 47 and 93 g/L) with fragmentation on the blood smear and abnormal hemolytic parameters: LD level 1104-8097 U/L, bilirubin 36-176 umol/L, reticulocyte count 130-541 x109/L and undetectable haptoglobin. The median time from AP presentation to the development of laboratory or clinical features of MAHA-T in these cases was 2 days (1-3). Acute kidney injury was present in all cases with creatinine levels ranging between 118-906 umol/L. One patient required hemodialysis. Other observed end organ damage included neurologic symptoms (3/5 patients), elevated troponin (5/5 patients) and transaminitis (4/5). One patient experienced a cardiac arrest. All patients had ADAMTS13 activity measured. One patient had severe deficiency on two separate episodes (ADAMTS13 was <1% and 6% respectively). Three other patients had normal ADAMTS13 activity (average 69%) and one had a moderate deficiency by a qualitative assay. In 4 patients, where tests were performed, there was significant heterogeneity in complement protein and function studies between patients ranging from normal to depressed C3 and C4 and normal to elevated CH50. Complement genetics screen was performed in 3 cases and was normal in all 3 cases. PLEX was initiated in all patients and remission (platelet count over 150 x 109/L) was seen for all after a median of 10 daily treatments (2-12). High dose steroids were used in 4 patients. All patients survived to discharge and completely recovered their kidney function. Conclusion TTP/MAHA-T precipitated by AP is increasingly recognized and more than 40 cases have been described in the literature. Similar to our findings, time to MAHA-T occurrence is generally reported within the first 4 days after admission for AP, often when markers for pancreatitis are improving, and most patients do not have severe ADAMTS13 deficiency. While many have looked at ADAMTS13 level, to our knowledge, none have yet reported thorough complement studies and genetics. The 3 cases described herein are then the first cases suggesting this is not a complement mediated disorder. Finally, our review and cases confirm that PLEX is effective and prognosis is good in almost all cases. Disclosures Pavenski: Alexion Pharmaceuticals Inc.: Honoraria, Other: attended an entity's advisory boards.
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