Transfusion of ever-pregnant donor red blood cells and mortality of male patients.

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from ever-pregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR]=0.91, 95% confidence interval [CI]: 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR=1.81, 95% CI: 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Donor pregnancies and transfusion recipient mortality: A role for red blood cell storage?

BACKGROUND AND OBJECTIVES: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients. MATERIALS AND METHODS: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model. RESULTS: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding. CONCLUSION: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage.

Personalized Medicine in Epidemics.

Before you lies the Special Issue "Personalized Medicine in Epidemics" [...].

Association between cardiovascular risk factors and intracranial hemorrhage in patients with acute leukemia.

BACKGROUND: Intracranial hemorrhage is seen more frequently in acute leukemia patients compared to the general population. Besides leukemia-related risk factors, also risk factors that are present in the general population might contribute to hemorrhagic complications in leukemia patients. Of those, cardiovascular risk factors leading to chronic vascular damage could modulate the occurrence of intracranial hemorrhage in these patients, as during their disease and treatment acute endothelial damage occurs due to factors like thrombocytopenia and inflammation. OBJECTIVES: Our aim was to explore if cardiovascular risk factors can predict intracranial hemorrhage in acute leukemia patients. METHODS: In a case-control study nested in a cohort of acute leukemia patients, including 17 cases with intracranial hemorrhage and 55 matched control patients without intracranial hemorrhage, data on cardiovascular risk factors were collected for all patients. Analyses were performed via conditional logistic regression. RESULTS: Pre-existing hypertension and ischemic heart disease in the medical history were associated with intracranial hemorrhage, with an incidence rate ratio of 12.9 (95% confidence interval [CI] 1.5 to 109.2) and 12.1 (95% CI 1.3 to110.7), respectively. CONCLUSION: Both pre-existing hypertension and ischemic heart disease seem to be strong predictors of an increased risk for intracranial hemorrhage in leukemia patients.

Association of Ethnicity With Multisystem Inflammatory Syndrome in Children Related to SARS-CoV-2 Infection: An International Case-Referent Study.

Background: It has been suggested that children and infants can develop multisystem inflammatory syndrome in children (MIS-C) in response to a SARS-CoV-2 infection and that Black children are overrepresented among cases. The aim of the current study was to quantify the association between Black, Asian, or other non-White genetic background and COVID-19-related MIS-C in children and infants. Methods: Eight different research groups contributed cases of MIS-C, potentially related to SARS-CoV-2 infection. Several sensitivity analyses were performed, including additional data available from the literature. Analyses were stratified by geographical region. Results: Seventy-three cases from nine distinct geographical regions were included in the primary analyses. In comparison to White children, the relative risk for developing MIS-C after SARS-CoV-2 infection was 15 [95% confidence interval (CI): 7.1 to 32] for Black children, 11 (CI: 2.2 to 57) for Asian, and 1.6 (CI: 0.58 to 4.2) for other ethnic background. Conclusion: Pediatricians should be aware of the fact that the risk of COVID-19-related MIS-C is severely increased in Black children.

COVID RADAR app: Description and validation of population surveillance of symptoms and behavior in relation to COVID-19.

BACKGROUND: Monitoring of symptoms and behavior may enable prediction of emerging COVID-19 hotspots. The COVID Radar smartphone app, active in the Netherlands, allows users to self-report symptoms, social distancing behaviors, and COVID-19 status daily. The objective of this study is to describe the validation of the COVID Radar. METHODS: COVID Radar users are asked to complete a daily questionnaire consisting of 20 questions assessing their symptoms, social distancing behavior, and COVID-19 status. We describe the internal and external validation of symptoms, behavior, and both user-reported COVID-19 status and state-reported COVID-19 case numbers. RESULTS: Since April 2nd, 2020, over 6 million observations from over 250,000 users have been collected using the COVID Radar app. Almost 2,000 users reported having tested positive for SARS-CoV-2. Amongst users testing positive for SARS-CoV-2, the proportion of observations reporting symptoms was higher than that of the cohort as a whole in the week prior to a positive SARS-CoV-2 test. Likewise, users who tested positive for SARS-CoV-2 showed above average risk social-distancing behavior. Per-capita user-reported SARS-CoV-2 positive tests closely matched government-reported per-capita case counts in provinces with high user engagement. DISCUSSION: The COVID Radar app allows voluntarily self-reporting of COVID-19 related symptoms and social distancing behaviors. Symptoms and risk behavior increase prior to a positive SARS-CoV-2 test, and user-reported case counts match closely with nationally-reported case counts in regions with high user engagement. These results suggest the COVID Radar may be a valid instrument for future surveillance and potential predictive analytics to identify emerging hotspots.

Thrombocytopenia and the effect of platelet transfusions on the occurrence of intracranial hemorrhage in patients with acute leukemia - a nested case-control study.

We designed a study to describe the incidence of intracranial hemorrhage according to severity and duration of thrombocytopenia and to quantify the associations of platelet transfusions with intracranial hemorrhage in patients with acute leukemia. In this case-control study nested in a cohort of 859 leukemia patients, cases (n = 17) were patients diagnosed with intracranial hemorrhage who were matched with control patients (n = 55). We documented platelet counts and transfusions for seven days before the intracranial hemorrhage in cases and in a "matched" week for control patients. Three measures of platelet count exposure were assessed in four potentially important time periods before hemorrhage. Among these leukemia patients, we observed the cumulative incidence of intracranial hemorrhage of 3.5%. Low platelet counts were, especially in the three to seven days preceding intracranial hemorrhage, associated with the incidence of intracranial hemorrhage, although with wide confidence intervals. Platelet transfusions during the week preceding the hemorrhage were associated with higher incidences of intracranial hemorrhage; rate ratios (95% confidence interval) for one or two platelet transfusions and for more than two transfusions compared with none were 4.04 (0.73 to 22.27) and 8.91 (1.53 to 51.73) respectively. Thus, among acute leukemia patients, the risk of intracranial hemorrhage was higher among patients with low platelet counts and after receiving more platelet transfusions. Especially, the latter is likely due to clinical factors leading to increased transfusion needs.

Association between renal failure and red blood cell alloimmunization among newly transfused patients.

BACKGROUND: Renal failure and renal replacement therapy (RRT) affect the immune system and could therefore modulate red blood cell (RBC) alloimmunization after transfusion. STUDY DESIGN AND METHODS: We performed a nationwide multicenter case-control study within a source population of newly transfused patients between 2005 and 2015. Using conditional multivariate logistic regression, we compared first-time transfusion-induced RBC alloantibody formers (N = 505) with two nonalloimmunized recipients with similar transfusion burden (N = 1010). RESULTS: Renal failure was observed in 17% of the control and 13% of the case patients. A total of 41% of the control patients and 34% of case patients underwent acute RRT. Renal failure without RRT was associated with lower alloimmunization risks after blood transfusion (moderate renal failure: adjusted relative rate [RR], 0.82 [95% confidence interval (CI), 0.67-1.01]); severe renal failure, adjusted RR, 0.76 [95% CI, 0.55-1.05]). With severe renal failure patients mainly receiving RRT, the lowest alloimmunization risk was found in particularly these patients [adjusted RR 0.48 (95% CI 0.39-0.58)]. This was similar for patients receiving RRT for acute or chronic renal failure (adjusted RR, 0.59 [95% CI, 0.46-0.75]); and adjusted RR, 0.62 [95% CI 0.45-0.88], respectively). CONCLUSION: These findings are indicative of a weakened humoral response in acute as well as chronic renal failure, which appeared to be most pronounced when treated with RRT. Future research should focus on how renal failure and RRT mechanistically modulate RBC alloimmunization.

Risk factors for bleeding in haemato-oncology patients-a nested case-control study: The BITE study protocol (Bleeding In Thrombocytopenia Explained).

INTRODUCTION: Haemato-oncological patients often receive platelet count driven prophylactic platelet transfusions to prevent bleeding. However, many prophylactically transfused patients still bleed. More knowledge on risk factors for bleeding is therefore needed. This will enable identification of bleeding risk profiles on which future transfusion policy can be optimised. The present BITE study (Bleeding In Thrombocytopenia Explained) aims to identify clinical conditions and biomarkers that are associated with clinically relevant bleeding events. METHODS AND ANALYSIS: A matched case-control study nested in a cohort of haemato-oncological patients in the Netherlands. We collect a limited number of variables from all eligible patients, who together form the source population. These patients are followed for the occurrence of clinically relevant bleeding. Consenting patients of the source population form the cohort. Cases from the cohort are frequency matched to selected control patients for the nested case-control study. Of both case and control patients more detailed clinical data is collected. STUDY POPULATION: Adult haemato-oncological patients, who are admitted for intensive chemotherapeutic treatment or stem cell transplantation, or who received such treatments in the past and are readmitted for disease or treatment-related adverse events. STATISTICAL ANALYSIS: Bleeding incidences will be calculated for the total source population, as well as for different subgroups. The association between potential risk factors and the occurrence of bleeding will be analysed using conditional logistic regression, to account for matching of case and control patients. ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee Leiden Den Haag and Delft, and the Radboudumc Committee on Research Involving Human Subjects. Approval in seven other centres is foreseen. Patients will be asked for written informed consent and data is coded before analyses, according to Dutch privacy law. Results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL62499.058.17. NCT03505086; Pre-results.

COVID-19: How to make between-country comparisons.

BACKGROUND: Different countries have adopted different containment and testing strategies for SARS-CoV-2. The difference in testing makes it difficult to compare the effect of different containment strategies. This study proposes methods to allow a direct comparison and presents the results. DESIGN: Publicly available data on the numbers of reported COVID-19-related deaths between 01 January and 17 April 2020 were compared between countries. RESULTS: The numbers of cases or deaths per 100,000 inhabitants gave severely biased comparisons between countries. Only the number of deaths expressed as a percentage of the number of deaths on day 25 after the first reported COVID-19-related death allowed a direct comparison between countries. From this comparison clear differences were observed between countries, associated with the timing of the implementation of containment measures. CONCLUSIONS: Comparisons between countries are only possible when simultaneously taking into account that the virus does not arrive in all countries simultaneously, absolute numbers are incomparable due to different population sizes, rates per 100,000 of the population are incomparable because not all countries are affected homogeneously, susceptibility to death by COVID-19 can differ between populations, and a death is only reported as a COVID-19-related death if the patient was diagnosed with SARS-CoV-2 infection. With the current methods, all these factors were accounted for and an unbiased direct comparison between countries was established. This comparison confirmed that early adoption of containment strategies is key in flattening the curve of the epidemic.

Effect of storage of platelet concentrates in PAS-B, PAS-C, or plasma on transfusion reactions.

BACKGROUND: Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are associated with a higher risk of transfusion reactions. STUDY DESIGN AND METHODS: We gathered storage times of pooled platelet concentrates related to transfusion reactions reported to the national hemovigilance office from 2004 to 2015. These were combined with storage times of platelet concentrates in the reference population to compare incidences of transfusion-associated circulatory overload, transfusion-related acute lung injury, allergic reactions, febrile nonhemolytic reactions, and "other" reactions between storage time categories. RESULTS: A total of 567,053 platelet concentrates and 1870 transfusion reactions were analyzed. Among platelet additive solution (PAS)-B platelet recipients, the odds ratio of a storage time of 4 to 5 days compared to 1 to 3 days was 1.60 (95% confidence interval [CI], 1.17-2.18) for allergic, and 1.47 (1.09-1.98) for febrile reactions. For PAS-C platelet recipients, the odds ratio for allergic reactions was 3.78 (95% CI, 1.31-10.9) for 4 to 5 days, and 4.57 (95% CI, 1.57-13.4) for 6- to 7-day-old platelets when compared to 1- to 3-day-old units. In all other studied reaction types, no statistically significant association was observed in platelets in plasma, PAS-B, and PAS-C. CONCLUSIONS: In plasma platelets, longer storage time was not associated with a higher incidence of transfusion reactions. In PAS platelets, longer storage time was associated with higher transfusion reaction incidences, in particular for allergic reactions with both PAS fluids and febrile reactions with PAS-B. This indicates that the effect of storage time is different for different reaction types and depends on the storage fluid.

Fresh frozen plasma and platelet concentrate storage duration not associated with in hospital mortality risk.

BACKGROUND AND OBJECTIVES: To date, the effects of FFP and PC storage duration on mortality have only been studied in a few studies in limited patient subpopulations. The aim of the current study was to determine whether FFP and PC storage duration is associated with increased in hospital mortality risk across cardiac surgery, acute medicine, ICU and orthopaedic surgery patients. MATERIALS AND METHODS: Two-stage individual patient data meta-analyses were performed to determine the effects of FFP and PC storage duration on in hospital mortality. Preset random effects models were used to determine pooled unadjusted and adjusted (adjusted for age, gender and units of product transfused) effect estimates. RESULTS: The FFP storage duration analysis included 3625 patients across four studies. No significant association was observed between duration of storage and in hospital mortality in unadjusted analysis, but after adjusting for patient age, gender and units of product a small increased risk of in hospital mortality was observed for each additional month of storage (OR: 1·05, 95% CI: 1·01-1·08). This effect was no longer statistically significant when donor ABO blood group was incorporated into the random effects model on post hoc analyses. A total of 547 patients across five studies were incorporated in the PC storage duration analysis. No association was observed between PC storage duration and odds of in hospital morality (adjusted OR: 0·94, 95% CI: 0·79-1·11). CONCLUSIONS: There is insufficient evidence to support shortening FFP or PC shelf life based on in hospital mortality.

Predicting anaemia and transfusion dependency in severe alloimmune haemolytic disease of the fetus and newborn in the first 3 months after birth.

Infants with haemolytic disease of the fetus and newborn (HDFN) often require erythrocyte transfusions in the first 3 months of life. We aimed to evaluate the incidence, timing and potential predictors of transfusion-dependent anaemia. An observational cohort of 298 term and near-term infants with severe HDFN treated with or without intrauterine transfusion (IUT) was evaluated. Transfusions were administered to 88% (169/193) of infants with IUT and 60% (63/105) without IUT. The following potential predictors were associated with less anaemia: K compared to D immunisation [odds ratio (OR) 0·13, 95% confidence interval (CI): 0·03-0·55], higher reticulocyte count at birth [per 10 parts per thousand (‰) higher, OR 0·99, CI: 0·97-1·00] and exchange transfusion (OR 0·11, 95% CI: 0·03-0·50). Without IUT, these variables were: lower reticulocyte count at birth (per 10‰ lower, OR 1·02, 95% CI: 1·00-1·03), lower maximum bilirubin after birth (per 10 µmol/l lower, OR 1·01, 95% CI: 1·01-1·02) and exchange transfusion (OR 0·07, 95% CI: 0·01-0·20). In conclusion, potential predictors for anaemia in infants with severe HDFN varied between infants treated with and without IUT and are useful for selecting subgroups of infants at increased risk of anaemia.

The quality of platelet concentrates related to corrected count increment: linking in vitro to in vivo.

BACKGROUND: Storage of platelet concentrates (PCs) results in reduced recovery and survival of transfused platelets (PLTs). Upon storage PLTs develop storage lesion that can be monitored by several laboratory tests. However, correlation of these descriptive tests with corrected count increments (CCIs), a marker frequently used to establish the effectiveness of PLT transfusions, is limited or unknown. This study investigated to what extent a functional test or a combined in vitro rating score improves the correlation of laboratory tests with 1-hour CCI. STUDY DESIGN AND METHODS: PCs were analyzed using six different laboratory tests (n = 123) before transfusion in a prophylactic setting to 74 hematooncologic patients. Linear regression and Spearman correlation were used to determine associations between descriptive (either separately or combined in an in vitro rating score) or functional test results and 1-hour CCIs obtained after transfusion. RESULTS: CD62P expression (r = -0.45), annexin V binding (r = -0.36), the updated in vitro rating score (r = 0.50), and PLT responsiveness after thrombin receptor activator for peptide-6 (TRAP) (r = 0.43-0.57) or adenosine diphosphate stimulation (r = 0.11-0.51) significantly correlated to 1-hour CCIs obtained after transfusion, whereas lactate concentration, ThromboLUX score, and thromboelastography measurements did not. The strongest correlations were observed for in vitro rating score and PLT responsiveness after TRAP stimulation and these tests could explain 24 and 33% of the observed variation in 1-hour CCI, respectively. CONCLUSION: Combining descriptive markers in one in vitro rating score improved correlation to 1-hour CCI compared to the tests separately. Of all tests investigated, mean PLT responsiveness after TRAP stimulation showed the strongest clinical correlation and was best able to predict the 1-hour CCI.

Personalization of medicine requires better observational evidence.

Evidence-based medicine has become associated with a preference for randomized trials. Randomization is a powerful tool against both known and unknown confounding. However, due to cost-induced constraints in size, randomized trials are seldom able to provide the subgroup analyses needed to gain much insight into effect modification. To apply results to an individual patient, effect modification needs to be considered. Results from randomized trials are therefore often difficult to apply in daily clinical practice. Confounding by indication, which randomization aims to prevent, is caused by more severely ill patients being less or more likely to be treated. Therefore, the prognostic indicators that physicians use to make treatment decisions become confounders. However, these same prognostic indicators are also effect modifiers. This is in fact exactly why they are relevant to decision-making. We use simple, fictive numerical examples to illustrate these concepts. Then we argue that if we would record all relevant variables, it would simultaneously solve the problem of confounding by indication and allow quantification of effect modification. It has previously been argued that it is practically more feasible to "simply" randomize treatment allocation, than to adequately correct for confounding by indication. We will argue that, in the current age of evidence-based medicine and highly regulated randomized trials, this balance has shifted. We therefore call for better observational clinical research. However, careless acceptance of results from poorly performed observational research can lead clinicians seriously astray. Therefore, a more interactive approach toward the medical literature might be needed, where more room is made for scientific discussion and interpretation of results, instead of one-way reporting.

The identification of cases of major hemorrhage during hospitalization in patients with acute leukemia using routinely recorded healthcare data.

INTRODUCTION: Electronic health care data offers the opportunity to study rare events, although detecting these events in large datasets remains difficult. We aimed to develop a model to identify leukemia patients with major hemorrhages within routinely recorded health records. METHODS: The model was developed using routinely recorded health records of a cohort of leukemia patients admitted to an academic hospital in the Netherlands between June 2011 and December 2015. Major hemorrhage was assessed by chart review. The model comprised CT-brain, hemoglobin drop, and transfusion need within 24 hours for which the best discriminating cut off values were taken. External validation was performed within a cohort of two other academic hospitals. RESULTS: The derivation cohort consisted of 255 patients, 10,638 hospitalization days, of which chart review was performed for 353 days. The incidence of major hemorrhage was 0.22 per 100 days in hospital. The model consisted of CT-brain (yes/no), hemoglobin drop of ≥0.8 g/dl and transfusion of ≥6 units. The C-statistic was 0.988 (CI 0.981-0.995). In the external validation cohort of 436 patients (19,188 days), the incidence of major hemorrhage was 0.46 per 100 hospitalization days and the C-statistic was 0.975 (CI 0.970-0.980). Presence of at least one indicator had a sensitivity of 100% (CI 95.8-100) and a specificity of 90.7% (CI 90.2-91.1). The number of days to screen to find one case decreased from 217.4 to 23.6. INTERPRETATION: A model based on information on CT-brain, hemoglobin drop and need of transfusions can accurately identify cases of major hemorrhage within routinely recorded health records.

Transfusion of packed red blood cells at the end of shelf life is associated with increased risk of mortality - a pooled patient data analysis of 16 observational trials.

Observational studies address packed red blood cell effects at the end of shelf life and have larger sample sizes compared to randomized control trials. Meta-analyses combining data from observational studies have been complicated by differences in aggregate transfused packed red blood cell age and outcome reporting. This study abrogated these issues by taking a pooled patient data approach. Observational studies reporting packed red blood cell age and clinical outcomes were identified and patient-level data sets were sought from investigators. Odds ratios and 95% confidence intervals for binary outcomes were calculated for each study, with mean packed red blood cell age or maximum packed red blood cell age acting as independent variables. The relationship between mean packed red blood cell age and hospital length of stay for each paper was analyzed using zero-inflated Poisson regression. Random effects models combined paper-level effect estimates. Extremes analyses were completed by comparing patients transfused with mean packed red blood cell aged less than ten days to those transfused with mean packed red blood cell aged at least 30 days. sixteen datasets were available for pooled patient data analysis. Mean packed red blood cell age of at least 30 days was associated with an increased risk of in-hospital mortality compared to mean packed red blood cell of less than ten days (odds ratio: 3.25, 95% confidence interval: 1.27-8.29). Packed red blood cell age was not correlated to increased risks of nosocomial infection or prolonged length of hospital stay.

Thrombocytopenia and bleeding in myelosuppressed transfusion-dependent patients: a simulation study exploring underlying mechanisms.

BACKGROUND: Hematology-oncology patients often become severely thrombocytopenic and receive prophylactic platelet transfusions when their platelet count drops below 10×109 platelets/L. This so-called "platelet count trigger" of 10×109 platelets/L is recommended because currently available evidence suggests this is the critical concentration at which bleeding risk starts to increase. Yet, exposure time and lag time may have biased the results of studies on the association between platelet counts and bleeding risks. METHODS: We performed simulation studies to examine possible effects of exposure time and lag time on the findings of both randomized trials and observational data. RESULTS: Exposure time and lag time reduced or even reversed the association between the risk of clinically relevant bleeding and platelet counts. The frequency of platelet count measurements influenced the observed bleeding risk at a given platelet count trigger. A transfusion trigger of 10×109 platelets/L resulted in a severely distorted association, which closely resembled the association reported in the literature. At triggers of 0, 5, 10, and 20×109 platelets/L the observed percentages of patients experiencing bleeding were 18, 19, 19, and 18%. A trigger of 30×109 platelets/L showed an observed bleeding risk of 16% and triggers of 40 and 50×109 platelets/L both resulted in observed bleeding risks of 13%. CONCLUSION: The results from our simulation study show how minimal exposure times and lag times may have influenced the results from previous studies on platelet counts, transfusion strategies, and bleeding risk and caution against the generally recommended universal trigger of 10×109 platelets/L.