Transfusion Support in Hematopoietic Stem Cell Transplantation: A Contemporary Narrative Review.

Hematopoietic stem cell transplantation (HSCT) is a cornerstone of modern medical practice, and can only be performed safely and effectively with appropriate transfusion medicine support. Patients undergoing HSCT often develop therapy-related cytopenia, necessitating differing blood product requirements in the pre-, peri-, and post-transplant periods. Moreover, ensuring optimal management for patients alloimmunized to human leukocyte antigens (HLA) and/or red blood cell (RBC) antigens, as well as for patients receiving ABO-incompatible transplants, requires close collaboration with transfusion medicine and blood bank professionals. Finally, as updated transfusion guidelines and novel blood product modifications emerge, the options available to the transplant practitioner continue to expand. Herein, we detail contemporary blood transfusion and transfusion medicine practices for patients undergoing HSCT.

How do we ensure a safe ABO recheck process?

BACKGROUND: Collecting a patient's blood in a correctly labeled pretransfusion specimen tube is essential for accurate ABO typing and safe transfusion. Noncompliance with specimen collection procedures can lead to wrong blood in tube (WBIT) incidents with potentially fatal consequences. Recent WBIT events inspired the investigation of how various institutions currently reduce the risk of these errors and ensure accurate ABO typing of patient samples. MATERIALS AND METHODS: This article describes the techniques employed at various institutions across the United States to mitigate the risk of misidentified pretransfusion patient specimens. Details and considerations for each of these measures are provided. RESULTS: Several institutions require the order for an ABO confirmation specimen, if indicated, to be generated from the transfusion medicine (TM) laboratory. Others issue a dedicated collection tube that is available exclusively from the TM service. Many institutions employ barcoding for electronic positive patient identification. Some use a combination of these strategies, depending on the locations or service lines from which the specimens are collected. CONCLUSION: The description of various WBIT mitigation strategies will inform TM services on practices that may be effective at their respective institutions. Irrespective of the method(s) utilized, institutions should continue to monitor and mitigate specimen misidentification errors to promote sustained safe transfusion practices.

Asymptomatic immunodeficiency-associated vaccine-derived poliovirus infections in two UK children.

Increasing detections of vaccine-derived poliovirus (VDPV) globally, including in countries previously declared polio free, is a public health emergency of international concern. Individuals with primary immunodeficiency (PID) can excrete polioviruses for prolonged periods, which could act as a source of cryptic transmission of viruses with potential to cause neurological disease. Here, we report on the detection of immunodeficiency-associated VDPVs (iVDPV) from two asymptomatic male PID children in the UK in 2019. The first child cleared poliovirus with increased doses of intravenous immunoglobulin, the second child following haematopoetic stem cell transplantation. We perform genetic and phenotypic characterisation of the infecting strains, demonstrating intra-host evolution and a neurovirulent phenotype in transgenic mice. Our findings highlight a pressing need to strengthen polio surveillance. Systematic collection of stool from asymptomatic PID patients who are at high risk for poliovirus excretion could improve the ability to detect and contain iVDPVs.

Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab.

Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.

Long-Lasting Protection Induced by a Polyanhydride Nanovaccine against Respiratory Syncytial Virus in an Outbred Mouse Model.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children. In humans, natural infection with RSV affords only partial long-term protection from reinfection, and there is no licensed RSV vaccine currently available. We have developed a new vaccine candidate, termed RSVNanoVax, composed of polyanhydride nanoparticles encapsulating the RSV prefusion F protein and a CpG 1668 oligodeoxynucleotide adjuvant. We recently reported that vaccination of inbred BALB/c mice with RSVNanoVax induced both RSV-specific cellular and humoral immunity, which provided protection from viral replication and RSV-induced disease. To further assess the efficacy of RSVNanoVax, here, we utilized outbred Swiss Webster mice to examine vaccine efficacy in a more genetically diverse population. Following intranasal prime-boost vaccination with RSVNanoVax, Swiss Webster mice exhibited robust titers of systemic RSV F-directed IgG antibodies and RSV F-directed IgA within the lungs and nasal passages that were sustained out to at least 1 year post-vaccination. Serum antibodies maintained robust neutralizing activity against both RSV A and B strains. Following RSV challenge, vaccinated Swiss Webster mice exhibited rapid viral clearance from the lungs. Overall, our results indicate that RSVNanoVax represents a promising RSV vaccine candidate capable of providing long-term protection and immunity in a genetically diverse population. IMPORTANCE Respiratory syncytial virus (RSV) infection causes thousands of infections and deaths in children and elderly adults each year. Research in this field is of great importance as there remains no licensed vaccine to prevent RSV infections. We developed a novel vaccine candidate, RSVNanoVax, utilizing the RSV prefusion F protein encapsulated in polyanhydride nanoparticles. Here, we show that the intranasal delivery of RSVNanoVax protected outbred mice from viral replication within the lungs when challenged with RSV out to 1 year post-vaccination. Additionally, RSV-specific antibody responses were generated in both the serum and lung tissue and sustained long-term. These results demonstrate that our vaccine is an encouraging candidate for driving long-term protection in the lungs in a genetically diverse population.

Pharmacological ascorbate as a novel therapeutic strategy to enhance cancer immunotherapy.

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs.

Blood conservation strategies at United States hospitals during the COVID-19 pandemic: Findings from a multi-institutional analysis - International Society of Blood Transfusion survey.

BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, the transfusion medicine community has experienced unprecedented blood supply shortages since March 2020. As such, numerous changes to everyday practice have occurred with a specific emphasis on blood conservation. We sought to determine the strategies used to mitigate blood shortages and promote blood conservation during the pandemic. METHODS: An anonymous, 37-question survey was developed using Research Electronic Data Capture and distributed via e-mail to transfusion medicine specialists across the US obtained via publicly available databases. RESULTS: Amongst surveyed [41.1% response rate (51/124 institutions)], 98.0% experienced a product shortage, with the greatest number reporting red blood cell (RBC) shortages (92.0%). This led to 35.3% of institutions altering the composition and/or number of blood product suppliers, including a 100% increase in the number of institutions acquiring blood from organizations that connect hospital transfusion services with blood collection centers (e.g., Blood Buy) compared to before March 2020. Prospective triaging of blood products was the most common blood conservation strategy (68.1%), though 35.4% altered their RBC exchange or transfusion program for patients receiving chronic RBC transfusion/exchange. As a result of these changes, 78.6% of institutions reported that these changes resulted in a reduction in blood product usage, and 38.1% reported a decrease in product wastage. CONCLUSIONS: Most hospitals experienced the effects of the supply shortage, and many of them implemented blood conserving measures. Conservation strategies were associated with decreased blood utilization and waste, and future studies could evaluate whether these changes persist.

Pharmacological ascorbate improves the response to platinum-based chemotherapy in advanced stage non-small cell lung cancer.

PURPOSE: Platinum-based chemotherapy with or without immunotherapy is the mainstay of treatment for advanced stage non-small cell lung cancer (NSCLC) lacking a molecular driver alteration. Pre-clinical studies have reported that pharmacological ascorbate (P-AscH-) enhances NSCLC response to platinum-based therapy. We conducted a phase II clinical trial combining P-AscH- with carboplatin-paclitaxel chemotherapy. EXPERIMENTAL DESIGN: Chemotherapy naïve advanced stage NSCLC patients received 75 g ascorbate twice per week intravenously with carboplatin and paclitaxel every three weeks for four cycles. The primary endpoint was to improve tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 compared to the historical control of 20%. The trial was conducted as an optimal Simon's two-stage design. Blood samples were collected for exploratory analyses. RESULTS: The study enrolled 38 patients and met its primary endpoint with an objective response rate of 34.2% (p = 0.03). All were confirmed partial responses (cPR). The disease control rate was 84.2% (stable disease + cPR). Median progression-free and overall survival were 5.7 months and 12.8 months, respectively. Treatment-related adverse events (TRAE) included one grade 5 (neutropenic fever) and five grade 4 events (cytopenias). Cytokine and chemokine data suggest that the combination elicits an immune response. Immunophenotyping of peripheral blood mononuclear cells demonstrated an increase in effector CD8 T-cells in patients with a progression-free survival (PFS) ≥ 6 months. CONCLUSIONS: The addition of P-AscH- to platinum-based chemotherapy improved tumor response in advanced stage NSCLC. P-AscH- appears to alter the host immune response and needs further investigation as a potential adjuvant to immunotherapy.

Intratumoral talimogene laherparepvec injection with concurrent preoperative radiation in patients with locally advanced soft-tissue sarcoma of the trunk and extremities: phase IB/II trial.

BACKGROUND: Soft-tissue sarcomas (STS) in the extremities and trunk treated with standard-of-care preoperative external beam radiation therapy (EBRT) followed by surgical resection are associated with local and distant relapses. In preclinical studies, oncolytic virotherapy in sarcoma has demonstrated antitumor effects via direct intratumoral oncolysis and cytotoxic T-cell-mediated immune responses. Talimogene laherparepvec (TVEC) is a replication-competent, immune-enhanced, oncolytic herpes simplex virus type 1 engineered for intratumoral injection; it has been approved by the FDA for the treatment of locally advanced and metastatic melanoma. METHODS: We explored a novel combination of TVEC with standard-of-care EBRT administered preoperatively in patients with locally advanced STS of the extremities and trunk in a phase IB/II clinical trial. Thirty patients with primary STS >5 cm for which EBRT was indicated to achieve negative margins were enrolled. FDA-approved TVEC doses were used. Immune correlative studies in peripheral blood, biopsy and resected tumor tissues were performed. RESULTS: No dose-limiting toxicity was observed. Adverse events were similar to those reported in prior studies with TVEC. One patient with myxoid liposarcoma exhibited a partial response. Seven of the 29 (24%) evaluable patients achieved 95% pathological necrosis. None of the patients developed a herpes infection due to the treatment. Eight of the 29 (27%) patients developed postoperative wound complications, which is consistent with previous studies. None of the patients developed local recurrence after surgical resection of the primary sarcoma. 2-year progression-free and overall survival were 57% and 88%, respectively. Caspase-3 demonstrated increased expression of both in TVEC-treated tissue samples as compared with control samples treated with radiation alone. CONCLUSION: Preoperative intratumoral TVEC with concurrent EBRT for locally advanced STS is safe and well-tolerated. This combination treatment may enhance immune responses in some cases but did not increase the proposed rate of pathological necrosis. The Caspase-3 biomarker may be associated with a positive effect of TVEC in sarcoma tumor tissue and should be explored in future studies. TRIAL REGISTRATION NUMBER: NCT02453191.

Function and Modulation of Type I Interferons during Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory infections in infants and young children, accounting for an estimated 3 million hospitalizations annually worldwide. Despite the major health burden, there is currently no licensed RSV vaccine. RSV is recognized by a range of cellular receptors including both toll-like receptors (TLR) and retinoic acid-inducible gene-I-like receptors (RIG-I). This interaction initiates signaling through mitochondrial antiviral signaling (MAVS) and interferon regulatory factor (IRF) proteins, resulting in the induction of type I interferons (IFN). Early viral control is mediated by either IFN-α or IFN-ß signaling through the IFN receptor (IFNAR), inducing the production of antiviral interferon-stimulating genes (ISGs). Type I IFNs also initiate the early production of proinflammatory cytokines including interleukin 6 (IL-6), tumor necrosis factor (TNF), and IFN-γ. Type I IFN levels correlate with age, and inadequate production may be a critical factor in facilitating the increased RSV disease severity observed in infants. Here, we review the current literature on the function of type I IFNs in RSV pathogenesis, as well as their involvement in the differential immune responses observed in infants and adults.

Probable transfusion transmission of West Nile virus from an apheresis platelet that screened non-reactive by individual donor-nucleic acid testing.

BACKGROUND: Despite West Nile virus (WNV) blood donation screening using nucleic acid testing (NAT), donors with low viral loads not detected by mini-pool-NAT have led to transfusion transmitted (TT)-WNV infection. We describe a probable case of fatal TT-WNV infection from an individual donor (ID)-NAT non-reactive apheresis platelet donation. STUDY DESIGN AND METHODS: An apheresis platelet donation was WNV ID-NAT reactive and prior donations from the same donor were investigated. A WNV ID-NAT non-reactive apheresis platelet unit collected 26 days earlier was transfused during heart transplantation to a patient who subsequently developed WNV neuroinvasive disease and expired. The source of the recipient's WNV infection was investigated. RESULTS: Twenty-six days after collection of the suspect platelet unit, a donation from the same donor was WNV ID-NAT reactive and WNV IgM and IgG positive. In addition to the suspect platelet unit, the heart transplant recipient who developed WNV infection received 17 blood components from 24 donors. Serologic testing performed on 11 of the remaining 24 donors (46%) was WNV IgM negative. Pre-transplant recipient and heart donor samples tested WNV RNA and IgM negative. CONCLUSION: A probable case of fatal neuroinvasive TT-WNV was linked to an infectious apheresis platelet unit undetected by WNV ID-NAT. It is hypothesized that the suspect unit was collected early in the viremic period when viral RNA was below the limit-of-detection of the ID-NAT assay. Implementation of ID-NAT screening of blood donors has not entirely eliminated the risk of TT-WNV infections, which may best be addressed by pathogen inactivation technologies.

Cathepsin L-induced galectin-1 may act as a proangiogenic factor in the metastasis of high-grade serous carcinoma.

BACKGROUND: New treatment options for metastasised high-grade serous carcinoma (HGSC) are urgently needed. HGSC frequently metastasises to the omentum, inducing angiogenesis in the local omental microvasculature to facilitate tumour growth. We previously showed that HGSC-secreted cathepsin L (CathL) induces pro-angiogenic changes in disease relevant human omental microvascular endothelial cells (HOMECs), suggesting a role in tumour angiogenesis. Here we investigate whether CathL acts by inducing local production of the carbohydrate-binding protein galectin-1 (Gal1), which has been reported to be involved in tumourigenesis in other tumours. METHODS: HOMECs were used for all experiments. Gal1 mRNA and protein levels were measured by RT-PCR and ELISA respectively. Gal1-induced cell proliferation was assessed using WST-1 assay, migration using a transwell assay and in vivo Gal1 expression by immunohistochemistry. RESULTS: CathL transcriptionally regulated HOMEC production and secretion of Gal1 via activation of NFκB (significantly inhibited by sulfasalazine). Gal1 significantly enhanced HOMEC migration (p < 0.001) and proliferation (p < 0.001), suggesting an autocrine action. The latter was significantly reduced by the MEK/ERK1/2 inhibitors U0126 and PD98059 suggesting downstream activation of this pathway. Immunohistochemical analysis of omenta from HGSC patients with or without metastatic disease demonstrated a positive correlation between Gal1 expression and number of microvessels (r = 0.8702, p < 0.001), and area of vessels (r = 0.7283, p < 0.001), supporting a proangiogenic role for Gal1 in omental metastases. CONCLUSION: HOMEC Gal1 transcription and release in response to CathL secreted from metastasising HGSC acts in an autocrine manner on the local microvasculature to induce pro-angiogenic changes, highlighting a potential new therapeutic target.

Impact of Integrating Rumke Statistics to Assist with Choosing Between Automated Hematology Analyzer Differentials vs Manual Differentials.

BACKGROUND: To optimize precision of nucleated blood cell counting, the clinical laboratory scientist should post the automated differential rather than the manual differential if the former is within the 95% CI of the latter, as determined by the "Rumke statistic." The objective of this study was to determine the potential impact of real-time, computer-assisted use of Rumke statistics for more judicious use of the automated vs digitally imaged, manual differential. METHODS: Complete blood counts with automated differentials produced by a XE5000™ hematology analyzer (Sysmex) were compared with both the DM96 (CellaVision™ AB) preclassification differentials and the posted reclassified manual differentials, using the Rumke 95% CIs as calculated using the Clopper-Pearson method. RESULTS: A total of 44.7% of manual differentials had no statistical or clinical justification over the automated differential. In addition, 31.1% of manual differentials had statistical discrepancies between the instrument absolute neutrophil count (IANC) and manual absolute neutrophil count (ANC). Nineteen of these IANC/manual ANC discrepant samples had ANCs below 1500/µL, a decision level for cancer treatment. Holding the IANC when it is less than 2000/µL until after manual smear review would have prevented the posting of any IANC vs manual ANC discrepant results at the 1500/µL ANC decision threshold. CONCLUSIONS: A real-time operator alert concerning the statistical identity of imaging device differentials vs automated differentials could have reduced manual differentials by nearly 45%. Not posting unnecessary manual differentials for the cases with IANC/manual ANC discrepancies would have likely reduced clinical error/confusion.

Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior.

OBJECTIVE: This is a prospective study of the effects of maternal use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy on newborn neurobehavioral integrity, including systematic measures of behavioral state, sleep organization, motor activity, heart rate variability (HRV), tremulousness, and startles. METHODS: The sample included 17 SSRI-exposed and 17 nonexposed, full-birth-weight newborn infants who had no obvious medical problems and were matched on maternal cigarette use, social class, and maternal age. SSRI exposure was determined by medical records and maternal self-report during a standard interview. Behavioral state, startles, and tremulousness were evaluated for 1 hour between feedings. Automated recordings of motor activity and HRV were also assessed during a 15-minute subset sleep period. HRV was subjected to spectral analysis to detect rhythms in autonomic regulation. Exposed and nonexposed infant groups were compared on measures of neurobehavioral development both before and after adjustment for gestational age as a covariate. RESULTS: SSRI-exposed infants had a shorter mean gestational age; were more motorically active and tremulous; and showed fewer rhythms in HRV, fewer changes in behavioral state, fewer different behavioral states, and a lower peak behavioral state. SSRI-exposed infants also had significantly more rapid eye movement sleep, which was characterized by longer continuous bouts in that state and higher numbers of spontaneous startles or sudden arousals. After effects of gestational age were covaried, significant differences continued to be found in tremulousness and all measures of state and sleep organization, but effects on startles, motor activity, and rhythms in HRV were no longer significant. CONCLUSIONS: Results provide the first systematic evidence that women who use SSRIs during pregnancy have healthy, full-birth-weight newborn infants who show disruptions in a wide range of neurobehavioral outcomes. Effects on motor activity, startles, and HRV may be mediated through the effects of SSRI exposure on gestational age. Future research can lead to a better understanding of the effects of SSRI use during pregnancy and an improved public health outcome.