How do I: Evaluate the safety and legitimacy of unproven cellular therapies?

BACKGROUND: Unproven cellular therapies are being offered to patients for a variety of conditions and diseases for which other treatments have failed. The use of untested cellular therapies is a worldwide problem. Practitioners (e.g., physicians, scientists, QA/QI facility managers, and policy advocates) are perhaps unaware of the risks involved with such therapies. Therefore, a critical need exists to bring attention to the potential limitations and adverse effects of these therapies to inform and limit misinformation. STUDY DESIGN AND METHODS: We describe the extent of the unproven cellular therapy problem through a search of scientific literature and social media coverage. We also describe the regulatory framework that can be used by the practitioner to review and evaluate both proven and unproven cellular therapies. RESULTS: We report on the current state of unproven cellular therapies across the globe. A workflow to facilitate an understanding of the regulatory processes involved in the approval of cellular therapies is provided as well as a list of warnings required by regulatory agencies on various products. It is hoped that this article will serve as a tool kit to educate the practitioner on navigating the field of unproven cellular therapy products. DISCUSSION: Increasing awareness of the issues associated with unproven therapies through education is important to help in reducing misinformation and risks to patients.

How do I Incorporate a two-sample blood type verification in a pediatric hospital?

BACKGROUND: The AABB (American Association of Blood Banks) and the College of American Pathologists (CAP) regulations call on blood banks to address the risk of misidentification of a patient's blood type, which can result in transfusion of a mismatched product. Transfusion of mismatched blood product is potentially fatal due to acute hemolytic transfusion reaction and is considered a preventable event. CAP regulations outline options to reduce risk of mistransfusion by either documenting the ABO group of the intended recipient on a second sample collected at a separate phlebotomy, or utilizing a mechanical barrier system or electronic identification verification system that ensures the patient from whom the pretransfusion specimen was collected is the same patient who is about to be transfused. STUDY DESIGN AND METHODS: An electronic or barrier system was not available for implementation at our institution, therefore we developed a protocol for a two-sample verification system. The first determination is performed on a current sample and the second by one of the following methods: (a) comparison with previous laboratory records, (b) testing a second sample collected at a time different from the first sample (i.e., laboratory specimen available with a different timestamp, or a new blood sample). RESULTS: We improved our transfusion process and implemented a policy to require a second sample to confirm a patient's blood type. We also implemented workflows to obtain blood type confirmation from history of a second blood type result from previous laboratory records, including a policy to accept previous blood type records from an outside laboratory. CONCLUSIONS: We describe a practice change for two-sample verification for type and screen in a large-scale pediatric hospital. We outline specific workflows for pre-operative and emergency transfusion scenarios, and pediatric-specific challenges.

Convalescent plasma for pediatric patients with SARS-CoV-2-associated acute respiratory distress syndrome.

There are no proven safe and effective therapies for children who develop life-threatening complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma (CP) has demonstrated potential benefit in adults with SARS-CoV-2, but has theoretical risks.We present the first report of CP in children with life-threatening coronavirus disease 2019 (COVID-19), providing data on four pediatric patients with acute respiratory distress syndrome. We measured donor antibody levels and recipient antibody response prior to and following CP infusion. Infusion of CP was not associated with antibody-dependent enhancement (ADE) and did not suppress endogenous antibody response. We found CP was safe and possibly efficacious. Randomized pediatric trials are needed.

Whole Blood in Pediatric Craniofacial Reconstruction Surgery.

BACKGROUND: Pediatric complex cranial vault reconstruction (CCVR) surgery is often associated with significant blood loss and transfusion. The authors recently changed our transfusion practice during CCVR to using whole blood (WB) instead of reconstituted blood (RB). The aim of this study was to assess the impact of this practice change. Our hypothesis was that replacement with WB would be as effective as RB for the outcomes of total perioperative blood donor exposures (BDEs) and the incidence of laboratory evidence of postoperative coagulopathy. METHODS: The authors queried the Pediatric Craniofacial Surgery Perioperative Registry for children ages ≤48 months from our institution who underwent CCVR and received either RB or WB. The primary outcomes of total perioperative BDEs and the incidence of laboratory evidence of postoperative coagulopathy were compared between the 2 cohorts. RESULTS: The query returned 59 subjects in the RB cohort and 52 subjects in the WB cohort. There were no significant differences in demographic variables between the 2 groups. Patients in the WB cohort were more likely to have ≤1 BDEs when compared to the RB cohort (62% versus 39%, respectively, P = 0.02). There was no significant difference in the incidence of postoperative coagulation laboratory test abnormalities between the WB and RB cohorts (0% versus 3.4%, respectively, P = 0.50). CONCLUSION: There was no postoperative coagulopathy in the WB cohort. Whole blood was also associated with significantly fewer perioperative BDEs. Whole blood appears to be as effective as RB for replacement of blood loss in craniofacial surgery.

Platelet transfusion: a clinical practice guideline from the AABB.

BACKGROUND: The AABB (formerly, the American Association of Blood Banks) developed this guideline on appropriate use of platelet transfusion in adult patients. METHODS: These guidelines are based on a systematic review of randomized, clinical trials and observational studies (1900 to September 2014) that reported clinical outcomes on patients receiving prophylactic or therapeutic platelet transfusions. An expert panel reviewed the data and developed recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RECOMMENDATION 1: The AABB recommends that platelets should be transfused prophylactically to reduce the risk for spontaneous bleeding in hospitalized adult patients with therapy-induced hypoproliferative thrombocytopenia. The AABB recommends transfusing hospitalized adult patients with a platelet count of 10 × 109 cells/L or less to reduce the risk for spontaneous bleeding. The AABB recommends transfusing up to a single apheresis unit or equivalent. Greater doses are not more effective, and lower doses equal to one half of a standard apheresis unit are equally effective. (Grade: strong recommendation; moderate-quality evidence). RECOMMENDATION 2: The AABB suggests prophylactic platelet transfusion for patients having elective central venous catheter placement with a platelet count less than 20 × 109 cells/L. (Grade: weak recommendation; low-quality evidence). RECOMMENDATION 3: The AABB suggests prophylactic platelet transfusion for patients having elective diagnostic lumbar puncture with a platelet count less than 50 × 109 cells/L. (Grade: weak recommendation; very-low-quality evidence). RECOMMENDATION 4: The AABB suggests prophylactic platelet transfusion for patients having major elective nonneuraxial surgery with a platelet count less than 50 × 109 cells/L. (Grade: weak recommendation; very-low-quality evidence). RECOMMENDATION 5: The AABB recommends against routine prophylactic platelet transfusion for patients who are nonthrombocytopenic and have cardiac surgery with cardiopulmonary bypass. The AABB suggests platelet transfusion for patients having bypass who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction. (Grade: weak recommendation; very-low-quality evidence). RECOMMENDATION 6: The AABB cannot recommend for or against platelet transfusion for patients receiving antiplatelet therapy who have intracranial hemorrhage (traumatic or spontaneous). (Grade: uncertain recommendation; very-low-quality evidence).

Immune hemolytic anemia with drug-induced antibodies to carboplatin and vincristine in a pediatric patient with an optic pathway glioma.

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is a rare, but important condition requiring specialized laboratory testing for diagnosis. We report a case of DIIHA with antibodies against carboplatin and vincristine (VCR) in a child with an optic pathway glioma. Platinum-based drugs are established to cause DIIHA; to our knowledge, this is the first report implicating VCR. STUDY DESIGN AND METHODS: A 35-month-old girl with an optic pathway glioma developed hemolytic anemia while receiving carboplatin and VCR. Specialized blood bank testing was performed to determine the presence of drug-dependent antibodies and thus DIIHA. RESULTS: Initial direct antiglobulin test (DAT) was negative. A repeat DAT 3 days later was positive, 3+ with polyspecific-antiglobulin sera, weak+ with anti-immunoglobulin (Ig)G, and 2+ with anti-C3d. An eluate from the DAT-positive red blood cells (RBCs) was nonreactive. The patient's serum reacted without specificity to all RBC tested using papain-IgG-antiglobulin test (AGT) and polyethylene glycol-IgG-AGT. No alloantibodies to common RBC antigens were detected. When the serum was evaluated for the presence of drug-specific antibody, reactivity was shown with VCR and carboplatin using the drug addition solution method, but only with carboplatin using the drug-coating method. CONCLUSION: The patient developed hemolytic anemia during chemotherapy. Initial detection of a panagglutinin suggested a warm-type autoimmune process. However, since DIIHA could not be excluded, chemotherapy was discontinued and further work-up was initiated. The findings confirmed the presence of antibodies to carboplatin and VCR. This case highlights the importance for clinicians to maintain a high index of suspicion for DIIHA in patients with unexplained hemolysis and the importance of specialized serologic testing.

SARS-CoV-2 Convalescent Sera Binding and Neutralizing Antibody Concentrations Compared with COVID-19 Vaccine Efficacy Estimates against Symptomatic Infection.

Previous COVID-19 vaccine efficacy (VE) studies have estimated neutralizing and binding antibody concentrations that correlate with protection from symptomatic infection; how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. Here, we assessed quantitative neutralizing and binding antibody concentrations using standardized SARS-CoV-2 assays on 3,067 serum specimens collected during 27 July 2020 to 27 August 2020 from COVID-19-unvaccinated persons with detectable anti-SARS-CoV-2 antibodies. Neutralizing and binding antibody concentrations were severalfold lower in the unvaccinated study population compared to published concentrations at 28 days postvaccination. In this convenience sample, ~88% of neutralizing and ~63 to 86% of binding antibody concentrations met or exceeded concentrations associated with 70% COVID-19 VE against symptomatic infection; ~30% of neutralizing and 1 to 14% of binding antibody concentrations met or exceeded concentrations associated with 90% COVID-19 VE. Our study not only supports observations of infection-induced immunity and current recommendations for vaccination postinfection to maximize protection against COVID-19, but also provides a large data set of pre-COVID-19 vaccination anti-SARS-CoV-2 antibody concentrations that will serve as an important comparator in the current setting of vaccine-induced and hybrid immunity. As new SARS-CoV-2 variants emerge and displace circulating virus strains, we recommend that standardized binding antibody assays that include spike protein-based antigens be utilized to estimate antibody concentrations correlated with protection from COVID-19. These estimates will be helpful in informing public health guidance, such as the need for additional COVID-19 vaccine booster doses to prevent symptomatic infection. IMPORTANCE Although COVID-19 vaccine efficacy (VE) studies have estimated antibody concentrations that correlate with protection from COVID-19, how these estimates compare to those generated in response to SARS-CoV-2 infection is unclear. We assessed quantitative neutralizing and binding antibody concentrations using standardized assays on serum specimens collected from COVID-19-unvaccinated persons with detectable antibodies. We found that most unvaccinated persons with qualitative antibody evidence of prior infection had quantitative antibody concentrations that met or exceeded concentrations associated with 70% VE against COVID-19. However, only a small proportion had antibody concentrations that met or exceeded concentrations associated with 90% VE, suggesting that persons with prior COVID-19 would benefit from vaccination to maximize protective antibody concentrations against COVID-19.

Toward a definition of "fresh" whole blood: an in vitro characterization of coagulation properties in refrigerated whole blood for transfusion.

BACKGROUND: The hemostatic property of "fresh" whole blood (WB) has been observed in military application and cardiac surgery and is associated with reduced blood loss, transfusion requirements, and donor exposures. The time from donation to transfusion defining "fresh" has not been systematically studied. We undertook an in vitro study of coagulation properties of refrigerated WB stored for 31 days. STUDY DESIGN AND METHODS: Twenty-one WB units were obtained from healthy volunteer donors and stored under standard AABB refrigerated conditions. Samples were obtained on the day after donation and again on Days 2, 4, 7, 11, 14, 17, 21, 24, and 31. Tests included complete blood count, pH, pO2, pCO2, glucose, lactate, thromboelastography (TEG), and platelet function by light transmission aggregometry (LTA). RESULTS: There was progressive decline in pH, pO2, glucose, and sodium, but progressive increase in potassium, pCO2, and lactate. TEG variables in all units were normal through Day 11; abnormal values in some variables in some units began on Day 14. Final aggregation levels exhibited no change from Day 1 to Day 21 with adenosine diphosphate and epinephrine, but a decline with collagen (Day 7) and ristocetin (Day 17). CONCLUSION: This in vitro study of coagulation properties demonstrates preservation of normal integrated coagulation function to a minimum of 11 days under standard conditions of refrigerated storage of WB for transfusion. These observations strongly suggest that the hemostatic quality of WB may extend beyond current transfusion practices. If confirmed clinically, this would increase availability and extend benefits of reduced donor exposure and transfusion requirements.

Reconstituted blood reduces blood donor exposures in children undergoing craniofacial reconstruction surgery.

OBJECTIVE/AIMS: To assess the effect of prophylactic administration of fresh-frozen plasma (FFP) in the form of reconstituted blood in children undergoing craniofacial reconstruction. The outcomes of interest included immediate postoperative coagulation laboratory test results, postoperative surgical drain output, and the number of unique blood donor exposures incurred. BACKGROUND: We recently changed our intraoperative transfusion strategy in children undergoing craniofacial reconstruction surgery to one in which blood loss is replaced with donor-matched reconstituted blood rather than traditional blood component therapy. METHODS: We performed a query of our prospective craniofacial surgery perioperative registry for children who underwent fronto-orbital advancement or posterior cranial vault reconstruction. Registry data from this query were compared to data from a historical cohort. RESULTS: Data for 46 registry cases were compared to 150 historical cohort cases. The median number of unique donor exposures for the reconstituted blood group was 2 vs 3 in the historical cohort (P=0.004). The reconstituted blood group had a decreased incidence of postoperative derangements in soluble clotting factor tests (fibrinogen, PT, or aPTT; 2% vs 24%, P=0.001), while there was no evidence for a difference in the incidence of thrombocytopenia. There was no evidence for differences in postoperative surgical drain output in the reconstituted blood group and historical cohort over the first 12, 24, and 48 h. CONCLUSIONS: Prophylactic administration of FFP in the form of donor-matched reconstituted blood in children undergoing craniofacial reconstruction was associated with improved postoperative coagulation parameters, reduced blood donor exposures, and unchanged postoperative surgical drain output.

Inventory Management and Product Selection in Pediatric Blood Banking.

Blood banks need to understand patterns of use and ordering practices to provide the blood donor centers with the best information with which to develop daily scheduled deliveries of blood products. Blood use is a large component of this process through maximizing physician education about appropriate ordering practices and use of appropriate tools. Simple measures can help provide guidance on the number of available components and the need to order more from the blood donor center. Special product requests in pediatrics, such as fresh blood, leukoreduction, irradiation, and antigen-negative units can also drive inventory practices and use patterns.

Measures to reduce red cell use in patients with sickle cell disease requiring red cell exchange during a blood shortage.

The COVID-19 pandemic has created major disruptions in health care delivery, including a severe blood shortage. The inventory of Rh and K antigen-negative red cell units recommended for patients with hemoglobinopathies became alarmingly low and continues to be strained. Because patients with sickle cell disease requiring chronic red cell exchange (RCE) incur a large demand for red cell units, we hypothesized that implementation of 2 measures could reduce blood use. First, obtaining the pretransfusion hemoglobin S (HbS) results by procedure start time would facilitate calculation of exact red cell volume needed to achieve the desired post-RCE HbS. Second, as a short-term conservation method, we identified patients for whom increasing the targeted end procedure hematocrit up to 5 percentage points higher than the pretransfusion level (no higher than 36%) was not medically contraindicated. The goal was to enhance suppression of endogenous erythropoiesis and thereby reduce the red cell unit number needed to maintain the same target HbS%. These 2 measures resulted in an 18% reduction of red cell units transfused to 50 patients undergoing chronic RCE during the first 6 months of the COVID-19 pandemic. Despite reduction of blood use, pretransfusion HbS% target goals were maintained and net iron accumulation was low. Both strategies can help alleviate a shortage of Rh and K antigen-negative red cells, and, more generally, transfusing red cell units based on precise red cell volume required can optimize patient care and judicious use of blood resources.

Blood loss, replacement, and associated morbidity in infants and children undergoing craniofacial surgery.

BACKGROUND: Pediatric craniofacial reconstruction (CFR) procedures involve wide scalp dissections with multiple osteotomies and have been associated with significant morbidity. The aim of this study was to document the incidence of clinically important problems, particularly related to blood loss, and perform a risk factor analysis. METHODS: Records of all patients who underwent craniofacial surgery at the Children's Hospital of Philadelphia between December 1, 2001 and January 1, 2006 were reviewed. Data were collected from the electronic anesthesia record, intensive care unit (ICU) progress notes, and discharge summary. All intraoperative laboratory values and all laboratory values obtained upon arrival in the ICU were recorded. A multivariable analysis was performed to evaluate associations between elements of intraoperative management and the following clinical outcomes: intraoperative hypotension, intraoperative metabolic acidosis, presence of a postoperative coagulation test abnormality, and postoperative administration of hemostatic blood products. RESULTS: Data for 159 patients were reviewed. The mean volume of packed red blood cells transfused intraoperatively was 51 ml x kg(-1). Multivariable analysis revealed that intraoperative administration of albumin was strongly correlated with both an increased incidence of postoperative coagulation derangements and postoperative administration of hemostatic blood products (Odds Ratio 5.9, 2.8, respectively), while intraoperative fresh frozen plasma (FFP) administration was associated with an opposite effect (Odds Ratio 0.94, 0.97, respectively). CONCLUSIONS: In pediatric CFR procedures where the volume of blood loss routinely exceeds one blood volume, intraoperative administration of FFP favorably impacted postoperative laboratory coagulation parameters.

Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

Impact and predictors of positive response to desensitization in pediatric heart transplant candidates.

BACKGROUND: Desensitization, the process of reducing anti-human leukocyte antigen (HLA) antibodies in sensitized patients awaiting heart transplantation (HT), has unclear efficacy in pediatric HT candidates. METHODS: Pediatric HT candidates listed at our institution between January 1, 2013 and June 30, 2018 were retrospectively evaluated. Sensitization was defined as the calculated panel reactive antibody (cPRA) ≥ 10% with ≥ 1 a strong positive antibody. The desensitization response was defined as a ≥ 25% reduction in the mean fluorescence intensity (MFI) for ≥ 90% of the strong positive antibodies on follow-up panel reactive antibody (PRA) testing before waitlist removal, HT, or death (data available for 13 patients). RESULTS: The HT candidates were categorized as sensitized receiving desensitization therapy (ST, n = 14), sensitized not receiving therapy (SNT, n = 18), or non-sensitized (n = 55). A desensitization response was observed in 8 (62%) of the ST upon repeat PRA testing, with the ST responders receiving more doses of intravenous immunoglobulin (IVIG) (8 vs 2, p < 0.05). The anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10-4). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10-4). However, these sensitization risk factors did not impact the desensitization response. The ST was associated with a higher likelihood of remaining listed and a longer waitlist time without substantially impacting the HT rate, waitlist mortality, or early post-HT outcomes. CONCLUSIONS: Most ST patients had a favorable response to desensitization, with a dose-dependent response observed for IVIG. The anti-HLA class likely impacts the ST response, whereas traditional sensitization risk factors had no impact on the response.

Care Standardization Reduces Blood Donor Exposures and Transfusion in Complex Cranial Vault Reconstruction.

BACKGROUND: Complex cranial vault reconstruction (CCVR) often requires a large-volume transfusion of blood products. We implemented a series of improvement interventions to reduce blood donor exposures (BDE) and transfusion requirements in CCVR. METHODS: We implemented interventions over 4 epochs: (E1) reconstituted blood (1:1 ratio of donor-matched red blood cells and fresh-frozen plasma) for intraoperative transfusions, (E2) reconstituted blood plus postoperative transfusion guidelines, (E3) reconstituted blood plus intraoperative antifibrinolytics and postoperative guidelines, and (E4) fresh whole blood for intraoperative transfusion, antifibrinolytics, and postoperative guidelines. Primary outcomes, BDE, and total volume of blood products transfused are presented by using statistical process control charts, with statistical comparisons between each epoch and baseline data. RESULTS: We included 347 patients <72 months old who underwent CCVR between 2008 and 2016 (E1: n = 50; E2: n = 41; E3: n = 87; and E4: n = 169). They were compared with a baseline sample group of 138 patients who were managed between 2001 and 2006. Compared with our baseline group, patients in each epoch had a significant reduction in BDE (P = .02-<.0001). Conversely, compared with the baseline group, we observed an increase the volume of blood products transfused in E1 (P = .004), no difference in E2 (P = .6) or E3 (P = .46), and a reduction in the volume of blood products transfused in E4 (P < .0001). CONCLUSIONS: The implementation of sequential clinical improvement strategies resulted in a sustained reduction in BDE whereas only the use of whole blood resulted in a significant reduction in the total volume of blood products transfused in children undergoing CCVR.

Reduced transfusion requirement with use of fresh whole blood in pediatric cardiac surgical procedures.

BACKGROUND: Pediatric patients undergoing cardiac operations are at high risk for blood loss and transfusion. A practice intended to reduce transfusion using a standard order of 2 units fresh whole blood (< 48 hours from donation) for elective cardiac operations in patients younger than 2 years of age was in place from 1995 to 2010. The objective of this study was to describe blood use in this population and to compare the results with those in published reports describing the use of blood components exclusively for transfusion. METHODS: Retrospective data from a surgical registry and blood bank records for 15 consecutive years were analyzed. Transfusion requirements were identified as donor exposures for the day of operation and the next postoperative day. Transfusions were fresh whole blood, packed red blood cells, platelets, and cryoprecipitate. Donor exposures for subgroups according to procedure and age were compared with those in published reports. RESULTS: The cohort consisted of 4,111 patients with a median age of 94 days and a median weight of 4.4 kg. The median donor exposure was 2 (range, 0 to 28). Younger patients having complex procedures had the most donor exposures. Fewer donor exposures were incurred in all subgroups compared with reports of component use in the literature. CONCLUSIONS: The use of fresh whole blood for cardiac operations in children younger than 2 years old reduces donor exposures compared with published reports of component use.