Lessons learned from the use of COVID-19 convalescent plasma at Kaiser Permanente.

Background: In April 2020, the Mayo Clinic helped establish the US Food and Drug Administration Expanded Access Protocol for COVID-19 (coronavirus disease 2019) convalescent plasma (CCP). The effectiveness of CCP in the published literature is contradictory because some retrospective studies showed benefit in reducing mortality and severe illness, whereas prospective randomized controlled trials demonstrated no benefit of CCP. Objectives: To discuss (1) the implementation of CCP across Kaiser Permanente Southern California between April 2020 and April 2021, (2) retrospective multivariable analysis of 2,831 patients with COVID-19 who were transfused with CCP compared with 18,475 patients with COVID-19 who did not receive CCP, (3) how to reconcile contradictory published data regarding the efficacy of CCP, and (4) guidance regarding the future use of convalescent plasma in a large community hospital setting. Methods: Multivariable analysis was controlled for demographic characteristics, level of oxygen delivery, intensive care unit stay, selected laboratory findings, and other concurrent treatment-related variables. Tubing segments from 151 CCP units transfused between October 2020 and April 2021 were retrospectively tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) anti-spike protein receptor-binding domain IgG. Multivariable analysis showed that CCP transfusion did not affect mortality rates at 30 days and 5 months (odds ratio, 1.04, 95% CI, 0.87-1.25, and hazard ratio, 1.05, 95% CI, 0.93-1.19). Conclusions: If convalescent plasma is offered as a therapeutic in a future viral pandemic, we recommend (1) transfusing only those patients who are negative for neutralizing antibodies, (2) transfusing very early during the disease course, (3) only using convalescent plasma with known levels of neutralizing antibodies, or (4) alternatively providing fractionated hyperimmune globulin.

Elevated von Willebrand Factor Antigen Is an Early Predictor of Mortality and Prolonged Length of Stay for Coronavirus Disease 2019 (COVID-19) Inpatients.

CONTEXT.­: Coagulation factor and endothelial injury marker, von Willebrand factor antigen (vWF:Ag), is elevated in coronavirus disease 2019 (COVID-19). OBJECTIVE.­: To assess the prognostic value of vWF:Ag for COVID-19 inpatients. DESIGN.­: Citrated plasma samples collected from COVID-19 inpatients for D-dimer measurement were tested for vWF:Ag. Measurements of vWF:Ag and common acute-phase reactants were correlated with clinical outcomes and length of stay (LOS). RESULTS.­: We included 333 samples from a diverse group of 120 COVID-19 inpatients. There was a clear association of higher peak measurements of vWF:Ag and other acute-phase reactants with adverse clinical outcomes. Peak vWF:Ag >300% was associated with a 5-fold increased risk of death (odds ratio [OR], 5.08; P < .001) and a 30-fold increased risk of prolonged (>4 days) LOS (OR, 29.65; P = .001). Peak D-dimer >3.8 fibrinogen equivalent units (FEUs) mg/L was associated with a 15-fold increase in risk of death (OR, 14.73; P < .001) and a 5-fold increased risk of prolonged LOS (OR, 4.55; P = .02). Using the earliest paired measurements of vWF:Ag and D-dimer from each patient and the same cutoffs, vWF:Ag was associated with a 3.5-fold increase in risk of death (OR, 3.54; P = .004) and a 20-fold risk of prolonged LOS (OR, 20.19; P = .004). Yet D-dimer was not significantly associated with either death (OR, 1.9; P = .29) or prolonged LOS (OR, 1.02; P = .98). CONCLUSIONS.­: Both peak and early postadmission vWF:Ag >300% were highly predictive of death and prolonged LOS among COVID-19 inpatients. Measurement of vWF:Ag may prove a valuable tool to guide escalation of COVID-19 treatment, particularly anticoagulation.

A probable case of West Nile virus transfusion transmission.

BACKGROUND: Transfusion-transmitted West Nile virus (WNV) infection is infrequent as a result of minipool (MP) and individual-donation (ID) nucleic acid testing (NAT) of blood donations. ID-NAT is triggered on the basis of local WNV activity identified by MP-NAT. STUDY DESIGN AND METHODS: A 78-year-old male patient who was treated for cardiac disease received 14 blood components from 30 donors in August 2016. He was discharged 7 days after aortic valve replacement and coronary bypass surgery, but was re-admitted on Day 12 with symptoms of viral infection, and eventually was diagnosed with aseptic meningitis. The patent died on Day 51. RESULTS: The patient was positive for WNV-immunoglobulin M (IgM) antibodies in his cerebrospinal fluid on Day 14 and was positive for WNV-IgM (on Days 14 and 16) and WNV-IgG antibodies (on Day 16) in his serum. All associated donations were nonreactive by MP-NAT or ID-NAT. However, one MP-NAT was noted to have an elevated (but negative) signal-to-cutoff ratio, and one donor from that MP was subsequently found positive for WNV-IgM and IgG antibodies; the donor was diagnosed with a WNV-like viral syndrome that had an onset 3 to 5 days postdonation. The donor's plasma was transfused 12 days before the patient's onset of WNV-meningoencephalitis. Conversion to ID-NAT was triggered for the region 7 days after the implicated donation, which was associated with the region's first human WNV case. CONCLUSION: Despite the possibility of mosquito-borne transmission, this was considered to be a case of transfusion-transmitted WNV infection from an MP-NAT-nonreactive donation collected just before triggering conversion to ID-NAT; a rare event recognized once in 84 million donations.

Successful reduction of plasma free-hemoglobin using therapeutic plasma exchange: A case report.

Massive intravascular hemolysis may overwhelm hemoglobin (Hgb) clearance mechanisms leading to accumulation of excess plasma free-Hgb and subsequent acute kidney injury. We present the case of a 44-year-old male with cardiac failure necessitating placement of a subcutaneous left ventricular assist device. Following insertion, the patient developed mechanical hemolysis and an acute decline in renal function. Three therapeutic plasma exchange procedures were performed resulting in a dramatic decrease in plasma free-Hgb levels and stabilization of renal function. This demonstrates that therapeutic plasma exchange can be used to decrease plasma free-Hgb in cases of intravascular hemolysis, possibly protecting the patient from hemoglobinuric acute kidney injury.

Extracorporeal photopheresis in heart transplant rejection.

Up to 25% of heart transplant recipients develop rejection requiring intervention. While the majority respond to augmentation of immunomodulatory drug therapy, a subset of patients will remain refractory. Extracorporeal photopheresis (ECP) appears particularly useful in the management of select heart transplant recipients at risk of rejection, with recurrent rejection, or rejection associated with hemodynamic compromise. This chapter summarizes the current clinical experience of ECP in heart transplantation. ECP appears to favorably affect both the cellular and humoral arms of the immune response to the allograft and promote a tolerogenic profile. These immunomodulatory effects also appear to decrease development of cardiac allograft vasculopathy. ECP is generally well tolerated with few adverse effects and low infection risk.

Defining early trauma-induced coagulopathy using thromboelastography.

Early trauma-induced coagulopathy (ETIC) is abnormal coagulation detected on presentation, but a clear description is lacking. We used thromboelastography (TEG) to characterize ETIC. Data were prospectively collected on high-acuity trauma activations at an urban Level I trauma center between July 2012 and May 2013. Patients with admission TEG before any blood transfusion were stratified by Injury Severity Score (ISS): mild (less than 16), moderate (16 to 24), severe (25 or greater). TEG parameters were compared between groups. ETIC was defined as any abnormality detected on TEG. Fifty-two patients were included; mean age was 49 years and mean time to the emergency department was 26 minutes. Mean ISS for the cohort was 17 with 28 patients in mild, eight in moderate, and 16 in severe. Glasgow Coma Score was lower and head Abbreviated Injury Scale was higher in severe (P < 0.001). Forty-three (83%) patients had an abnormal TEG. Shortened reaction (R) time was noted in 42 patients. There were no differences in any TEG parameters between the injury severity groups. Hyperfibrinolysis was detected in four (8%) patients. ETIC was present in over 80 per cent of high-acuity trauma activations irrespective of injury severity and characterized primarily by shortened R time, indicating ETIC is initially described by a hypercoagulable state as a result of thrombin generation.

Clinicopathological significance of HER2/neu genetic heterogeneity in HER2/neu non-amplified invasive breast carcinomas and its concurrent axillary metastasis.

BACKGROUND: HER2/neu (HER2) is a significant prognostic marker for breast carcinomas. Recently, new guidelines defining HER2 genetic heterogeneity (GH) were published by the College of American Pathologists. AIMS: To determine the prevalence of HER2 GH as defined in primary invasive breast carcinoma, to determine its relationship with prognostic variables and to investigate its impact on concurrent axillary metastasis. METHODS: 235 consecutive infiltrating breast carcinomas were evaluated for GH (defined as presence of 5-50% of neoplastic cells with HER2/CEP17 ratio >2.2) using fluorescence in situ hybridisation. Pathological features of carcinomas with GH were compared with those lacking GH. GH was also evaluated in a subset of 37 paired primary carcinomas and its concurrent axillary nodal metastases using dual in situ hybridisation. RESULTS: HER2 GH was noted in 27% of HER2 negative breast carcinomas. These carcinomas demonstrated aggressive characteristics (larger size, higher grade and greater incidence of lymph node metastasis) in comparison with HER2 negative cases without GH. Higher levels of GH were associated with the equivocal HER2 status. GH was maintained in the concurrent lymph node metastases with some variations; however, two cases with clusters of HER2 amplified cells in the primary carcinoma showed HER2 amplification in the nodal metastasis. CONCLUSIONS: HER2 GH is present in 27% of breast carcinomas, portends an aggressive phenotype and contributes to the equivocal HER2 status. Evaluation of the HER2 status in nodal metastasis of select primary carcinomas with GH may be beneficial before treatment selection.

The effect of recentrifugation of serum separator tubes on concentration of serum analytes.

In clinical laboratories, sometimes there is a need to recentrifuge the original tubes ("clot" tubes) in order to better clarify and clean the serum or plasma for further analysis. Also, the original tubes are recentrifuged to ensure there is an adequate volume of serum or plasma for multiple repeating or different tests, and/or to run additional tests that are ordered hours after the original analysis was completed. In our practice, we have encountered that recentrifugation of original tubes, including those with gel separators, does slightly change the concentration of analytes. Although there are two reports on the effect of recentrifugation on serum potassium concentration [1, 2], to the best of our knowledge there are no other studies to show the impact of re-centrifugation on the concentrations of multiple analytes that are routinely measured as part of "metabolic panel". This study investigated the effect of recentrifugation on the concentrations of glucose, sodium, potassium, chloride, BUN, creatinine, bicarbonate, calcium, phosphorus, and magnesium.

Use of IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies with atypical histology or suspicious for malignancy.

Histologic evaluation of an endoscopic bile duct biopsy for malignancy is a known challenge. Our prior study has shown that the insulin-like growth factor-II mRNA binding protein-3 (IMP3), S100P, and the von Hippel-Lindau gene product (pVHL) are a useful immunopanel for the distinction between adenocarcinoma and benign biliary epithelium. To further evaluate the usefulness of the IMP3, S100P, and pVHL immunopanel to aid in the interpretation of bile duct biopsies, 16 histologically challenging bile duct biopsies that exhibited atypical histology or features suspicious for malignancy were immunohistochemically stained for IMP3, S100P, and pVHL. Clinical follow-up data were obtained for each case. The results showed that in the 11 cases that showed adenocarcinoma during follow-up, the following staining patterns in atypical/suspicious cells in the initial biopsies were observed: IMP3-positive/S100P-positive/pVHL-negative or reduced (n=6), IMP3-negative/S100P-positive/pVHL-negative or reduced (n=4), and IMP3-positive/S100P-negative/pVHL-negative (n=1). In the 5 follow-up-proven benign cases, 2 biopsies showed an IMP3-negative/S100P-positive/pVHL-positive pattern in atypical cells and 1 was negative for all 3 proteins. The remaining 2 biopsies exhibited an IMP3-positive/S100P-positive/pVHL-negative or reduced pattern in atypical cells that were histologically considered dysplastic on retrospective review. These observations reaffirm that bile duct adenocarcinoma frequently shows positive IMP3 and/or S100P staining with reciprocal negative or reduced pVHL expression. This staining pattern can also be seen in dysplastic epithelium in the absence of invasive carcinoma. On the contrary, benign biliary epithelium typically lacks IMP3 immunoreactivity and may retain normal pVHL expression. However, caution should be exercised when using this immunopanel in the interpretation of challenging bile duct biopsies, because S100P and pVHL stains may give rise to variable patterns that can be difficult to interpret.