Efficacy and immunologic effects of extracorporeal photopheresis plus interleukin-2 in chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) affects >50% of hematopoietic stem cell transplant patients. Extracorporeal photopheresis (ECP), an immunomodulatory therapy, provides clinical benefit in steroid-refractory (SR) cGVHD, possibly via regulatory T (Treg) and natural killer (NK) cell expansion. We demonstrated that low-dose interleukin-2 (IL2) led to clinical improvement in SR-cGVHD and stimulated preferential Treg and NK-cell expansion with minimal effect on conventional T (Tcon) cells. We evaluated the effect of ECP (weeks 1-16) plus IL2 (1 × 106 IU/m2, weeks 9-16) in 25 adult patients with SR-cGVHD in a prospective phase 2 trial. Objective responses occurred in 29% and 62% of evaluable patients at weeks 8 (ECP alone) and 16 (ECP plus IL2), respectively. Eight weeks of ECP alone was associated with a marked decline in CD4+ Tcon (P = .03) and CD8+ T cells (P = .0002), with minimal change in Treg cells, Treg:Tcon cell ratio, or NK cells. Adding IL2 induced an increase in Treg cells (P < .05 at weeks 9-16 vs week 8), Treg:Tcon cell ratio (P < .0001 at weeks 9-16 vs week 8), and NK cells (P < .05 at weeks 9-16 vs week 8). Patients responding to ECP alone had significantly fewer CD4+ Tcon and CD8+ T cells at baseline compared with patients who responded after IL2 addition and patients who did not respond; neither Treg nor NK cells were associated with response to ECP alone. Altogether, ECP plus IL2 is safe and effective in patients with SR-cGVHD. ECP and IL2 have distinct immunologic effects, suggesting different therapeutic mechanisms of action. This trial was registered at www.clinicaltrials.gov as #NCT02340676.

Safety of acoustic separation in plastic devices for extracorporeal blood processing.

BACKGROUND: Acoustic cell separation uses ultrasound waves to separate cells from plasma to perform plasmapheresis. Although the fundamental process has been studied for decades, no acoustic cell separation has been studied in a disposable plastic format suitable for clinical applications. STUDY DESIGN AND METHODS: We developed a disposable, rectangular, polystyrene microchannel acoustic cell-separation system and applied acoustic energy relevant for plasmapheresis. Fresh blood from healthy volunteers was exposed in vitro to acoustic energy in an open microfluidic circuit with and without ultrasound applied. Blood was tested for perturbations in red blood cells, platelets, and coagulation using clinical assays. RESULTS: Red blood cell and platelet size parameters as well as coagulation activation all were within 3% of baseline values. P-selectin expression on platelets increased by an average of 10.9% relative to baseline. Hemolysis increased with flow through the microfluidic channel, but percentage hemolysis remained below 0.3%. CONCLUSION: Blood parameters in a single-pass, microfluidic acoustic cell-separation apparatus remained within normal limits. In vivo animal studies that model continuous separation in a physiologic environment are warranted.

Post-Babesiosis Warm Autoimmune Hemolytic Anemia.

Background Babesiosis, a tickborne zoonotic disease caused by intraerythrocytic protozoa of the genus babesia, is characterized by nonimmune hemolytic anemia that resolves with antimicrobial treatment and clearance of parasitemia. The development of warm-antibody autoimmune hemolytic anemia (also known as warm autoimmune hemolytic anemia [WAHA]) in patients with babesiosis has not previously been well described. Methods After the observation of sporadic cases of WAHA that occurred after treatment of patients for babesiosis, we conducted a retrospective cohort study of all the patients with babesiosis who were cared for at our center from January 2009 through June 2016. Data on covariates of interest were extracted from the medical records, including any hematologic complications that occurred within 3 months after the diagnosis and treatment of babesiosis. Results A total of 86 patients received a diagnosis of babesiosis during the 7.5-year study period; 18 of these patients were asplenic. WAHA developed in 6 patients 2 to 4 weeks after the diagnosis of babesiosis, by which time all the patients had had clinical and laboratory responses to antimicrobial treatment of babesiosis, including clearance of Babesia microti parasitemia. All 6 patients were asplenic (P<0.001) and had positive direct antiglobulin tests for IgG and complement component 3; warm autoantibodies were identified in all these patients. No alternative explanation for clinical hemolysis was found. WAHA required immunosuppressive treatment in 4 of the 6 patients. Conclusions We documented post-babesiosis WAHA in patients who did not have a history of autoimmunity; asplenic patients appeared to be particularly at risk.

Transfusion Reactions.

Transfusion reactions are common occurrences, and clinicians who order or transfuse blood components need to be able to recognize adverse sequelae of transfusion. The differential diagnosis of any untoward clinical event should always consider adverse sequelae of transfusion, even when transfusion occurred weeks earlier. There is no pathognomonic sign or symptom that differentiates a transfusion reaction from other potential medical problems, so vigilance is required during and after transfusion when a patient presents with a change in clinical status. This review covers the presentation, mechanisms, and management of transfusion reactions that are commonly encountered, and those that can be life-threatening.

Hemolysis from ABO Incompatibility.

ABO incompatibility of red blood cells leads to brisk complement-mediated lysis, particularly in the setting of red cell transfusion. The ABO blood group is the most clinically significant blood group because of preformed immunoglobulin M (IgM) and IgG antibodies to ABO blood group antigens (isohemagglutinins) in everyone except group AB individuals. In addition to transfusion, ABO incompatibility can cause hemolysis in hematopoietic and solid organ transplantation, hemolytic disease of the newborn, and intravenous immunoglobulin infusion. It is important to prevent ABO incompatibility when possible and to anticipate complications when ABO incompatibility is unavoidable.

Transfusion and component characteristics are not associated with allergic transfusion reactions to apheresis platelets.

BACKGROUND: Transfusion-related characteristics have been hypothesized to cause allergic transfusion reactions (ATRs) but they have not been thoroughly studied. The primary objective of this study is to evaluate the associations of infusion rate, infusion volume, ABO mismatching, component age, and pretransfusion medication with the incidence and severity of ATRs. A secondary objective is to compare the risk of these attributes relative to the previously reported risk factor for aeroallergen sensitization in transfusion recipients, as measured by an aeroallergen-specific immunoglobulin (Ig)E antibody screen. STUDY DESIGN AND METHODS: Clinical and transfusion-related data were collected on subjects with reported ATRs and uneventful (control) apheresis platelet (PLT) transfusions over a combined 21-month period at two academic medical centers. Control transfusions were selected as the next uneventful transfusion after an ATR was reported. Logistic regression, Mann-Whitney, and t tests were used to assess associations with ATRs. Previously reported aeroallergen-specific IgE screening data were incorporated into a multivariable logistic regression. RESULTS: A total of 143 ATRs and 61 control transfusions were evaluated among 168 subjects, ages 2 to 86 years. Infusion rate, infusion volume, ABO mismatching, component age, and pretransfusion medication showed no significant association with ATRs (p > 0.05). Neither infusion rate nor infusion volume increased the risk of anaphylaxis versus mucocutaneous-only ATRs. Aeroallergen sensitization has previously been associated with ATRs. After transfusion-related covariates were controlled for, aeroallergen sensitization remained significantly associated with ATRs (odds ratio, 2.68; 95% confidence interval, 1.26-5.69). CONCLUSIONS: Transfusion- and component-specific attributes are not associated with ATRs. An allergic predisposition in transfusion recipients is associated most strongly with ATR risk.

Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members.

IMPORTANCE: Sickle cell disease (SCD) is a life-threatening genetic disorder affecting nearly 100,000 individuals in the United States and is associated with many acute and chronic complications requiring immediate medical attention. Two disease-modifying therapies, hydroxyurea and long-term blood transfusions, are available but underused. OBJECTIVE: To support and expand the number of health professionals able and willing to provide care for persons with SCD. EVIDENCE REVIEW: Databases of MEDLINE (including in-process and other nonindexed citations), EMBASE, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, CINAHL, TOXLINE, and Scopus were searched using prespecified search terms and keywords to identify randomized clinical trials, nonrandomized intervention studies, and observational studies. Literature searches of English-language publications from 1980 with updates through April 1, 2014, addressed key questions developed by the expert panel members and methodologists. FINDINGS: Strong recommendations for preventive services include daily oral prophylactic penicillin up to the age of 5 years, annual transcranial Doppler examinations from the ages of 2 to 16 years in those with sickle cell anemia, and long-term transfusion therapy to prevent stroke in those children with abnormal transcranial Doppler velocity (≥200 cm/s). Strong recommendations addressing acute complications include rapid initiation of opioids for treatment of severe pain associated with a vasoocclusive crisis, and use of incentive spirometry in patients hospitalized for a vasoocclusive crisis. Strong recommendations for chronic complications include use of analgesics and physical therapy for treatment of avascular necrosis, and use of angiotensin-converting enzyme inhibitor therapy for microalbuminuria in adults with SCD. Strong recommendations for children and adults with proliferative sickle cell retinopathy include referral to expert specialists for consideration of laser photocoagulation and for echocardiography to evaluate signs of pulmonary hypertension. Hydroxyurea therapy is strongly recommended for adults with 3 or more severe vasoocclusive crises during any 12-month period, with SCD pain or chronic anemia interfering with daily activities, or with severe or recurrent episodes of acute chest syndrome. A recommendation of moderate strength suggests offering treatment with hydroxyurea without regard to the presence of symptoms for infants, children, and adolescents. In persons with sickle cell anemia, preoperative transfusion therapy to increase hemoglobin levels to 10 g/dL is strongly recommended with a moderate strength recommendation to maintain sickle hemoglobin levels of less than 30% prior to the next transfusion during long-term transfusion therapy. A strong recommendation to assess iron overload is accompanied by a moderate strength recommendation to begin iron chelation therapy when indicated. CONCLUSIONS AND RELEVANCE: Hydroxyurea and transfusion therapy are strongly recommended for many individuals with SCD. Many other recommendations are based on quality of evidence that is less than high due to the paucity of clinical trials regarding screening, management, and monitoring for individuals with SCD.

Length of red cell unit storage and risk for delirium after cardiac surgery.

BACKGROUND: The time that red cell units are stored before transfusion may be associated with postoperative complications, although the evidence is conflicting. However, the association between the length of red cell unit storage and postoperative delirium has not been explored. We hypothesized that the length of storage of transfused red cell units would be associated with delirium after cardiac surgery. METHODS: We conducted a case-control study in which patients undergoing coronary artery bypass, valve, or ascending aorta surgery with cardiopulmonary bypass at Johns Hopkins from 2005 to 2011 were eligible for inclusion. Patients were excluded if they did not receive red cell units, received >4 red cell units during hospitalization, received any transfusion after the first postoperative day, or received red cell units that were not exclusively stored for ≤14 days or >14 days. Eighty-seven patients met transfusion-related inclusion criteria and developed postoperative delirium. Controls who did not develop delirium were selected from the same source population of eligible patients and were matched 1:1 based on age (± 5 years), 2- to 2.5-year band of date of surgery, and surgical procedure. For each patient, we calculated the average storage duration of all transfused red cell units. The primary outcome was odds of delirium in patients who were transfused red cell units with exclusive storage duration >14 days compared with that of ≤14 days. Secondary outcomes were odds of delirium with each increasing day of average red cell unit storage duration. We used conditional multivariable regression to test our hypotheses. RESULTS: In conditional multivariable analysis of 87 case-control pairs, there was no difference in the odds of patients developing delirium if they were transfused red cell units with an exclusive storage age >14 days compared with that ≤14 days (odds ratio [OR] 1.83; 95% confidence interval, 0.73-4.58, P = 0.20). Each additional day of average red cell unit storage beyond 14 days was associated with a 1.01- to 1.13-fold increase in the odds of postoperative delirium (OR, 1.07; P = 0.03). Each additional day of average storage beyond 21 days was associated with a 1.02- to 1.23-fold increase in the odds of postoperative delirium (OR, 1.12; P = 0.02). CONCLUSIONS: Transfusion of red cell units that have been stored for >14 days is not associated with increased odds of delirium. However, each additional day of storage >14 or 21 days may be associated with increased odds of postoperative delirium in patients undergoing cardiac surgery. More research is needed to further characterize the association between delirium and storage duration of transfused red cell units.

Economic evaluation of a hypothetical screening assay for alloimmunization risk among transfused patients with sickle cell disease.

BACKGROUND: Prophylactic antigen-matching can reduce alloimmunization rates among chronically transfused patients with sickle cell disease (SCD), but this matching increases costs and may only benefit 30% of patients. We assessed the clinical and financial value of a potential assay for alloimmunization risk that would allow for targeted antigen-matching. STUDY DESIGN AND METHODS: A Markov-based model evaluated direct medical costs and alloimmunization events over 10 to 20 years among transfused (simple or exchange) patients with SCD. Four matching strategies were evaluated: prospective matching (for all patients), history-based matching (only for patients with prior alloimmunization), perfectly informed matching (assay with 100% sensitivity, 100% specificity), and imperfectly informed matching (reduced accuracy). Under all matching protocols, matching included C, E, K, and any additional alloantibodies present. A hospital perspective was adopted, with costs (2012US$) and events discounted (3%). RESULTS: Perfectly informed antigen-matching using a $1000 assay is expected to save $82,334 per patient over 10 years, compared to prospective matching. Perfectly informed antigen-matching is more costly than history-based matching, but reduces alloimmunization events by 45.6% over 10 years. Averting each alloimmunization event using this strategy would cost an additional $10,934 per patient. Imperfectly informed antigen-matching using an assay with 75% specificity and 75% sensitivity is less costly than prospective matching, but increases alloimmunization events. Compared to history-based matching, imperfectly informed matching would decrease alloimmunization events by 32.61%, at an additional cost of $147,915 per patient over 10 years. Cost-effectiveness of informed antigen-matching is largely driven by assay specificity. CONCLUSIONS: A sufficiently specific assay to inform antigen-matching may be cost-effective in reducing alloimmunization among transfused patients with SCD.

Odds of transfusion for older adults compared to younger adults undergoing surgery.

BACKGROUND: Recent randomized controlled trials have shown no benefit for transfusion to a hemoglobin >10 g/dL compared with lower hemoglobin thresholds in the perioperative period, even among older adults. Nevertheless, physicians may choose to transfuse older adults more liberally than younger adults. It is unclear whether older patients have higher odds than younger patients of being transfused in the perioperative period. Our objective in this study was to determine whether the odds of transfusion are higher in older patients than in younger patients in the perioperative period. METHODS: We conducted this retrospective observational cohort study at a tertiary care academic medical center. We included adults who had undergone a surgical procedure as an inpatient at our institution from January 2010 to February 2012. The primary analysis compared the odds of transfusion for patients >65 years old with the odds of transfusion in younger patients based on multilevel multivariable logistic regression analyses including adjustment for comorbidities, surgical service, lowest in-hospital hemoglobin value, gender, and estimated surgical blood loss and accounted for clustering by the surgeon and procedure. RESULTS: We included 20,930 patients in this analysis. In multilevel models adjusted for comorbidities, surgical service, estimated surgical blood loss, and lowest in-hospital hemoglobin value, with surgeon and procedure as random effects, patients > 65 years old had 62% greater odds (odds ratio, 1.62; 95% confidence interval, 1.40-1.88; P < 0.0001) of being transfused than did younger patients. When patients were stratified by lowest in-hospital hemoglobin (7.00-7.99, 8.00-8.99, 9.00-9.99, and ≥10.00 g/dL), the odds of transfusion generally increased with each additional decade of age in every stratum, except for that containing patients in whom the lowest in-hospital hemoglobin did not decrease below 10 g/dL. When the odds of transfusion were compared between younger and older patients, significant differences were observed among surgical services (P = 0.02) but not among anesthesia specialty divisions (P = 0.9). CONCLUSIONS: Older adults have greater odds of receiving red blood cell transfusion in the perioperative period than do younger patients, despite the lack of evidence supporting higher hemoglobin triggers in elderly patients. Further research is needed to determine whether transfusion practice in the elderly is an opportunity for education to improve blood management.

Cost-effectiveness of prospective red blood cell antigen matching to prevent alloimmunization among sickle cell patients.

BACKGROUND: Sickle cell disease is associated with extensive health care utilization; estimated lifetime costs exceed $460,000 per patient. Approximately 30% of chronically transfused sickle cell patients become alloimmunized to red blood cell antigens, but these patients cannot be identified a priori. Prospective antigen matching can prevent alloimmunization, but is costly and may not benefit most patients. STUDY DESIGN AND METHODS: A Markov-based model was constructed to compare the health and financial implications of four alternative antigen-matching strategies for chronically transfused sickle cell patients. The strategies varied by the group of patients receiving matched blood (all patients prophylactically or only patients with a history of alloimmunization [history-based]), and by the extent of antigen matching (limited to C, E, and K, or extended to 11 antigens). Direct medical costs and alloimmunization events were assessed over 10- and 20-year periods, for a hypothetical cohort of initially transfusion-naive patients and for a dynamic population. RESULTS: Within a hypothetical cohort of initially transfusion-naive patients, implementing prophylactic limited matching for all chronically transfused patients instead of history-based limited matching is expected to cost an additional $765.56 million over 10 years, but result in 2072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482 to $769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358.34 million more than history-based limited matching. CONCLUSIONS: While prospective matching for all transfused patients would reduce alloimmunization, this strategy requires considerable expenditure.

Partial manual exchange reduces iron accumulation during chronic red cell transfusions for sickle cell disease.

Iron overload is an inevitable consequence of chronic red cell transfusions without erythrocytapheresis or chelation therapy. The effectiveness of partial manual exchange, a technique used to slow iron loading, has not been evaluated. We evaluated all children with sickle cell disease (SCD) receiving chronic transfusion to identify chelation-naive subjects who had quantitative liver iron concentration (LIC) studies. Seventeen chelation-naive children with SCD received a median of 29 transfusions before first LIC determination. Serum ferritin concentrations were assessed before each transfusion. The mean volume of blood phlebotomized before each transfusion was 5.1±1.8 mL/kg, which cumulatively resulted in a calculated median of 35.0 mg/kg iron removal. Using linear regression, pretransfusion phlebotomy resulted in a statistically significant reduction in ferritin (-8.8 ng/mL of ferritin for each mg/kg of iron phlebotomized, P=0.02). A reduction in LIC from pretransfusion phlebotomy could not be established (P=0.4). Partial manual exchanges appear to be an effective strategy for slowing the pace of iron loading in the setting of chronic transfusion for SCD.

The cost-effectiveness of platelet additive solution to prevent allergic transfusion reactions.

BACKGROUND: Allergic transfusion reactions (ATRs) are among the most common complications of transfusion. Storage in platelet additive solution (PAS) has been shown to reduce ATRs from apheresis platelets (APs). This study evaluated the cost-effectiveness of using PAS storage as an alternative method to reduce ATRs. STUDY DESIGN AND METHODS: A Markov-based decision tree was constructed to compare ATR rates and associated costs expected from current practice and from alternative strategies of using APs stored in PAS. The potential use of pretransfusion medication was also incorporated. Using a hospital perspective and including direct medical expenses only (US$2012), Monte Carlo microsimulations were run to evaluate outcomes under a base-case analysis. One-way and probabilistic sensitivity analyses were used to assess outcome uncertainty. RESULTS: Under base-case variables, using APs stored in PAS for all patients as an initial transfusion protocol is expected to avert ATRs and associated costs, compared to current practice. Using PAS for all patients along with pretransfusion medication would be cost-saving only when the additional cost of PAS is below $9.14. If PAS storage could eliminate pretransfusion medication use, it is expected to result in cost savings when the additional unit cost of PAS is under $11.90. At a PAS cost of $15, averting one ATR would cost $701.95. Using PAS storage only in response to recurring mild ATRs is associated with cost savings under all costs of PAS evaluated. CONCLUSIONS: Using PAS storage for all AP transfusions to prevent ATRs may be financially and clinically beneficial, compared to current practice.