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Patients with cirrhosis have coagulopathy often necessitating correction with blood products, such as plasma products (fresh frozen plasma and plasma frozen within 24 h) prior to certain invasive procedures. However, plasma administration has the potential for substantial negative adverse effects such as volume overload, transfusion-related lung injury and allergic/anaphylactic reactions. In addition, its effectiveness in preventing bleeding is similarly unclear. The purpose of this study was to determine the safety and efficacy of plasma administration in cirrhotic patients undergoing minimally invasive procedures, specifically vascular access placement, transjugular liver biopsies, renal biopsies and thoracenteses. In this retrospective cohort study, we identified patients receiving plasma products in preparation for an invasive procedure, with the primary outcomes of volume overload and bleeding. Of the 145 transfusion events that met the criteria from 2015 to 2018, the median INR decreased from 2.7 to 2.2 pre and post plasma administration and 13.8% of recipients had complications of volume overload. The cost of acquisition of plasma administered below clinically impactful doses accumulates to an estimated 19 000 dollars over this time period, not including nursing preparation or production costs. Plasma products minimally, if at all, improved laboratory values of coagulation and in some patients led to adverse effects.

Objective Insulin antibody (IA)-mediated insulin resistance (IR) is a rare condition for which immunosuppressive regimens have been described. However, these raise the risk of infection, and the drugs may not be effectively metabolized in patients with liver disease. A 61-year old male with type 2 diabetes mellitus and antibody-mediated IR who required >800 units of daily insulin presented with acute decompensation of his preexisting cirrhosis from recurrent diabetic ketoacidosis. Laboratory tests confirmed an IA level of >625 μU/mL (reference: Methods Centrifugal plasmapheresis and mycophenolate mofetil (MMF) were used to treat the patient to achieve glycemic control. Continuous glucose monitoring was implemented to monitor glycemic control pre- and posttherapy. Laboratory evaluation included levels of IA, C-peptide, insulin-like growth factor-1, growth hormone, salivary cortisol, zinc transporter 8, glutamic acid decarboxylase 65-kilodalton isoform antibody, and islet-cell antibodies. Results We initiated MMF followed by 5 sessions of plasmapheresis, leading to an overall 77.3% reduction from pretherapy insulin requirements after 6 months without further episodes of diabetic ketoacidosis or infection. The cirrhosis stabilized, and there was an improvement in HbA1C from 8.7% (72 mmol/mol) to 6.6% (49 mmol/mol) and time in euglycemic range from 30% to 61%. Conclusion This is the first report of MMF and centrifugal plasmapheresis use to mitigate the effects of IA-mediated IR in a patient with cirrhosis. We recommend further studies to determine the utility of this treatment to improve care for patients at high risk for IA-mediated IR.

Summary: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The proportion of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can be detected up to 3 months after symptom resolution. We investigated both seroconversion and PCR positivity in a large cohort of convalescent serum donors in the New York City (NY, USA) region. Methods: In this observational study, we ran an outreach programme in the New York City area. We recruited participants via the REDCap (Vanderbilt University, Nashville, TN, USA) online survey response. Individuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via ELISA for presence of anti-SARS-CoV-2 spike antibodies. One-way ANOVA and Fisher's exact test were used to measure the association of age, gender, symptom duration, and days from symptom onset and resolution with positive antibody results. Findings: Between March 26 and April 10, 2020, we measured SARS-CoV-2 antibody titres in 1343 people. Of the 624 participants with confirmed SARS-CoV-2 infection who had serologies done after 4 weeks, all but three seroconverted to the SARS-CoV-2 spike protein, whereas 269 (37%) of 719 participants with suspected SARS-CoV-2 infection seroconverted. PCR positivity was detected up to 28 days from symptom resolution. Interpretation: Most patients with confirmed COVID-19 seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks after symptom resolution, but it is unclear whether this signal represents infectious virus. Analysis of our large cohort suggests that most patients with mild COVID-19 seroconvert 4 weeks after illness, and raises questions about the use of PCR to clear positive individuals. Funding: None.

BackgroundSaliva is an optimal specimen for detection of viruses that cause upper respiratory infections including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to its cost-effectiveness and non-invasive collection. However, together with intrinsic enzymes and oral microbiota, children’s unique dietary habits may introduce substances that interfere with diagnostic testing.MethodsTo determine whether children’s dietary choices impact SARS-CoV-2 detection in saliva, we performed a diagnostic study that simulates testing of real-life specimens provided from healthy children (n=5) who self-collected saliva at home before and at 0, 20, and 60 minutes after eating from 20 foods they selected. Each of seventy-two specimens was split into two volumes and spiked with SARS-CoV-2-negative or -positive standards prior to side-by-side testing by reverse-transcription polymerase chain reaction matrix-assisted laser desorption ionization time-of-flight (RT-PCR/MALDI-TOF) assay.ResultsDetection of internal extraction control and SARS-CoV-2 nucleic acids was reduced in replicates of saliva collected at 0 minutes after eating 11 of 20 foods. Interference resolved at 20 and 60 minutes after eating all foods except hot dog in one participant. This represented a significant improvement in detection of nucleic acids compared to saliva collected at 0 minutes after eating (P=0.0005).ConclusionsWe demonstrate successful detection of viral nucleic acids in saliva self-collected by children before and after eating a variety of foods. Fasting is not required before saliva collection for SARS-CoV-2 testing by RT-PCR/MALDI-TOF, but waiting 20 minutes after eating is sufficient for accurate testing. These findings should be considered for SARS-CoV-2 testing and broader viral diagnostics in saliva specimens.

Background Daratumumab (DARA) is a monoclonal antibody for treatment of plasma cell myeloma targeting CD38, a surface molecule expressed on plasma cells and red blood cells (RBCs). This complicates blood bank testing, requiring dithiothreitol (DTT) to remove DARA interference. A simple in-house method of removing DARA interference without use of DTT, a potentially hazardous chemical, is desirable. We demonstrate a trypsin-based method to remove interference in antibody testing at a medical center (MC), with parallel testing at an immunohematology reference laboratory (IRL). Study design and methods Pre-DARA type and screen (T&S) samples were obtained from 61 patients for antibody testing and RBC phenotyping using untreated reagent RBCs. Subsequent post-DARA T&S testing was performed with untreated reagent RBCs to demonstrate interference and repeated after trypsin treatment. Positive trypsin-treated antibody screens were reflexed to antibody identification using trypsin-treated panel cells. Parallel testing was performed on the same post-DARA samples at IRL. Results DARA interference was detected in 61/61 (100%) samples by MC and IRL. After trypsin treatment, DARA interference was eliminated in 60/61 (98.4%) antibody screens by both institutions with an overall percent agreement of 96.7% (95% confidence interval [CI] 88.7%-99.6%). Identification of known alloantibodies was confirmed in 3/3 patients with 100% concordant results between MC and IRL. There were no false-negative results demonstrated by IRL's functionally CD38-negative controls. Conclusion Our in-house trypsin-based method enables pretransfusion testing of patients receiving DARA in an accurate and cost-effective manner without missing clinically significant alloantibodies. This presents an additional testing option where DTT use is undesirable.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people globally. Virus infection requires the receptor-binding domain (RBD) of the spike protein. Although studies have demonstrated anti-spike and -RBD antibodies to be protective in animal models, and convalescent plasma as a promising therapeutic option, little is known about immunoglobulin isotypes capable of blocking infection. Methods We studied spike- and RBD-specific immunoglobulin isotypes in convalescent and acute plasma/serum samples using a multiplex bead assay. We also determined virus neutralization activities in plasma and serum samples, and purified immunoglobulin fractions using a vesicular stomatitis pseudovirus assay. Results Spike- and RBD-specific immunoglobulin (Ig) M, IgG1, and IgA1 were produced by all or nearly all subjects at variable levels and detected early after infection. All samples displayed neutralizing activity. Regression analyses revealed that IgM and IgG1 contributed most to neutralization, consistent with IgM and IgG fractions’ neutralization potency. IgA also exhibited neutralizing activity, but with lower potency. Conclusion IgG, IgM, and IgA are critical components of convalescent plasma used for treatment of coronavirus disease 2019 (COVID-19).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected millions of people globally. Virus infection requires the receptor-binding domain (RBD) of the spike protein. Although studies have demonstrated anti-spike and -RBD antibodies to be protective in animal models, and convalescent plasma as a promising therapeutic option, little is known about immunoglobulin isotypes capable of blocking infection.We studied spike- and RBD-specific immunoglobulin isotypes in convalescent and acute plasma/serum samples using a multiplex bead assay. We also determined virus neutralization activities in plasma and serum samples, and purified immunoglobulin fractions using a vesicular stomatitis pseudovirus assay.Spike- and RBD-specific immunoglobulin (Ig) M, IgG1, and IgA1 were produced by all or nearly all subjects at variable levels and detected early after infection. All samples displayed neutralizing activity. Regression analyses revealed that IgM and IgG1 contributed most to neutralization, consistent with IgM and IgG fractions' neutralization potency. IgA also exhibited neutralizing activity, but with lower potency.IgG, IgM, and IgA are critical components of convalescent plasma used for treatment of coronavirus disease 2019 (COVID-19).

More than 24 million infections with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were confirmed globally by September 2020. While polymerase chain reaction–based assays are used for diagnosis, there is a need for high-throughput, rapid serologic methods. A Luminex binding assay was developed and used to assess simultaneously the presence of coronavirus disease 2019 (COVID-19)–specific antibodies in human serum and plasma. Clear differentiation was achieved between specimens from infected and uninfected subjects, and a wide range of serum/plasma antibody levels was delineated in infected subjects. All 25 specimens from 18 patients with COVID-19 were positive in the assays with both the trimeric spike and the receptor-binding domain proteins. None of the 13 specimens from uninfected subjects displayed antibodies to either antigen. There was a highly statistically significant difference between the antibody levels of COVID-19–infected and –uninfected specimens (P

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The percentage of infected individuals who seroconvert is still an open question. In addition, it has been shown in some individuals that viral genome can still be detected at considerable time post symptom resolution. Here we investigated both seroconversion and PCR-positivity in a large cohort of convalescent serum donors in New York City.MethodsIndividuals with confirmed or suspected SARS-CoV-2 infection were screened via PCR for presence of viral genome and via enzyme-linked immunosorbent assay for presence of anti SARS-CoV-2 spike antibodies.ResultsAll but three confirmed SARS-CoV-2 patients seroconverted to the SARS-CoV-2 spike while only 37.4% of suspected SARS-CoV-2 patients seroconverted. PCR-positivity was detected up to 28 days from symptom resolution.ConclusionsHere we show that the vast majority of confirmed COVID19 patients seroconvert, potentially providing immunity to reinfection. We also report that in a large proportion of individuals, viral genome can be detected via PCR in the upper respiratory tract for weeks post symptom resolution, but it is unclear if this signal represents infectious virus.

Introduction Daratumumab, a human CD38 monoclonal antibody approved for multiple myeloma (MM) treatment, binds red blood cells (RBCs), resulting in panagglutination in compatibility tests. Published mitigation methods avoid additional testing, ensuring timely release of blood products. Blood transfusion management and transfusion-related outcomes of daratumumab-treated patients in the SIRIUS study are reported, with emphasis on 2 clinical sites. Patients and Methods Patients had MM treated with ≥ 3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or were refractory to a proteasome inhibitor and an immunomodulatory drug. RBC typing and alloantibody screening were performed in gel cards. Antibody identification using RBC panels was performed on patients with positive antibody screens. Hematology panels and serum chemistry were analyzed ≤ 2 days before each daratumumab infusion and the first daratumumab dose within each treatment cycle, respectively. Pre- and posttransfusion hemoglobin values were analyzed retrospectively. Results At clinical cutoff, patients received 236 transfusions; 47 (37.9%) of 124 patients received 147 packed RBC transfusions, and 17 (13.7%) received 89 platelet transfusions. No hemolysis was reported, and 1 platelet transfusion reaction was observed. At Mount Sinai, no transfusion adverse events were observed, no new unexpected RBC alloantibodies were identified, and transfusions increased hemoglobin values (median, 1.2 g/dL). At Levine Cancer Institute, 6 of 7 patients responded to transfusions, with a median hemoglobin change of 1.7 g/dL. Conclusion In SIRIUS, no RBC transfusion reactions, including hemolysis, were observed. Observations from Mount Sinai and Levine Cancer Institute confirm that transfusions may be administered safely to daratumumab-treated patients.

The goal of blood component therapy is to achieve the desired effect without adverse outcomes. The desired effect may be to increase oxygen carrying capacity, correct coagulation factor deficiencies, or provide cellular components. However, adverse outcomes due to errors, accidents, or transfusion reactions cannot be completely avoided. Despite risk mitigation, the rate of transfusion reactions is 2.4 reactions per 1000 units transfused. Transfusion reactions can be just an annoyance (e.g., urticarial), but more severe reactions can be life threatening (e.g., anaphylaxis). The Transfusion Medicine specialist must be able to recognize, treat, and prevent future reactions by providing a comprehensive consultation for all reported reactions. The blood banking community has been very successful at reducing the risk of transfusion transmitted infections and is continually improving transfusion safety and risk mitigation. The purpose of this chapter on noninfectious risks of transfusion is to enhance the ability of the user to recognize, treat, and prevent these transfusion reactions.

Hereditary hemochromatosis (HH) is a genetic disorder of iron metabolism that may lead to iron overload. Clinical penetrance is low, however those afflicted may develop cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy. Treatment of HH involves regular phlebotomy to reduce the systemic iron burden. In many countries-including the United States-numerous blood centers do not accept donated blood obtained from HH patients during therapeutic phlebotomy and there are inconsistent positions regarding this globally. This refusal of blood is borne out of a few concerns. First, there is a theoretical increase in the infectious risk of these blood products, particularly by siderophilic organisms such as Yersinia enterocolitica. Second, given the increased incidence of hepatitis C infection from nonvoluntary donors in the 1970s, there is a concern that blood units from HH donors may harbor additional risk given the nonvoluntary nature of their presentation. In this review, we examine the existing biological and clinical data concerning infectious risk and summarize clinical experience from centers allowing HH donors, and demonstrate that blood from HH patients is safe and should be allowed into the donor pool. We conclude that there is no convincing evidence to exclude this population from serving as blood donors. (Hepatology 2018;67:1150-1157).

Background Daratumumab (DARA) is a human IgG1 kappa monoclonal antibody that targets cells expressing CD38, which is highly expressed in multiple myeloma (MM) cells. In the phase 2 MMY2002 (Sirius) trial, treatment with single agent DARA resulted in a 29% overall response rate, with a median PFS of 3.7 months in heavily pretreated MM patients (Lonial S. J Clin Oncol. 2015; 33(suppl): abstrLBA8512). However, CD38 is also expressed on red blood cells (RBCs) and DARA binding to RBCs results in pan-reactivity on RBC panel testing using an indirect antiglobulin test (IAT). Recently, it was reported that treating RBCs with dithiothreitol (DTT) removes DARA to allow for accurate antibody testing (Chapuy CI, et al. Transfusion. 2015;55(6pt2):1545-1554) but also denatures Kell antigen in the process. To date, little is known about the impact of DARA interference with IAT on the outcomes of patients requiring packed RBC (PRBC) transfusions. Methods The frequencies of PRBC transfusions and any transfusion-related adverse events from all 124 patients treated on the Sirius study were obtained from the clinical database as of the data cut off of January 9th, 2015. Although details of transfusions were not prospectively collected, surrogate outcomes of transfusion reactions within 4 weeks of the transfusion were analyzed including change in hemoglobin (Hb), elevated bilirubin, fever, and hypotension. In addition, we evaluated IAT results and transfusion outcomes of the 8 patients treated at our institution. Results During the study, 47 patients received 147 transfusions with a total of 235 units of PRBCs. To date, no transfusion-related reactions were noted. Of the 47 patients, 8 patients were treated at our institution. One patient showed multiple alloantibodies (anti-E, -K, -Jkb, -Fya, -Fy3, -S, Knops) on IAT prior to DARA. This individual and 6 others agglutinated all RBCs on panel testing with weak reactivity at the antihuman globulin phase of testing. Reactivity was enhanced by gel testing compared to reactivity in low ionic strength saline and was unaffected by enzymatic treatment with ficin. Six out of 7 patients had a negative autocontrol. The one patient with a positive autocontrol had a weakly positive direct antiglobulin test with IgG. Six out of these 7 patients with panagglutinin had a positive result on the first IAT after initiation of DARA, ranging from 7 to 175 days (median 49). One patient did not have an IAT after initiation of DARA. A total of 9 leuko-reduced, irradiated, phenotypically matched RBCs were given to 3 patients during DARA treatment, and additional 9 units were given to 3 patients after DARA completion while their IATs remained positive. All transfusions resulted in an appropriate rise in Hb (median 1.0 g/dL, range 0.5-2.7) without any associated transfusion reactions. None of the patients made new unexpected RBC alloantibodies while receiving phenotypically matched RBCs. Conclusion For the 7 patients at our site with IAT testing after DARA treatment, all demonstrated pan-reactivity on RBC panel testing. Treatment with DTT removes this interference but also denatures Kell antigen in the process. Most hospitals do not use DTT as part of routine immunohematology workups; therefore, we recommend obtaining a red cell phenotype prior to initiating DARA treatment and providing phenotypically matched blood thereafter to avoid resultant difficulties in new alloantibody identification and delays in providing compatible PRBCs. Based on a database query of all 124 patients as well as all patients at our site, PRBC transfusions did not appear to be associated with complications. In a MM patient population that will frequently require PRBC transfusion, blood bank and hematologist/oncologist awareness of these findings is important to minimize errors or delays in providing compatible PRBCs. Disclosures Chari: Novartis: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Research Funding; Biotest: Other: Institutional Research Funding; Array Biopharma: Consultancy, Other: Institutional Research Funding, Research Funding. Jagannath:Celgene: Honoraria; BMS: Honoraria; MERCK: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Janssen: Honoraria. Catamero:Celgene: Honoraria, Other: Lecturer; Onyx: Other: Lecturer; Millennium/Takeda: Other: Lecturer. Verina:Celgene: Other: Lecturer. Doshi:Janssen: Employment. Feng:Janssen: Employment. Uhlar:Janssen: Employment. Khan:Janssen: Employment. Ahmadi:Janssen: Employment. Voorhees:Millennium/Takeda and Novartis: Honoraria; Array Biopharma, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Celgene, GlxoSmithKline, and Oncopeptides: Research Funding.