Excess deaths among adults with sickle cell disease in 2020 compared to prior years.

In 2020, there was a 20% increase in excess deaths in the USA due to COVID infections but also to changes in the healthcare system due to the pandemic. We hypothesized that people living with sickle cell disease (SCD) may be vulnerable to these changes as SCD can lead to rapid decompensation. We examined all deaths of people with SCD at our center in 2020. Cause of death was determined, clinical variables, and healthcare utilization, and the presence of COVID infection, sepsis, and acute organ failure during the death event was obtained from the electronic medical record. Deaths in 2020 were compared to deaths in 2017-2019. In 2020, deaths increase 244% (22 vs 9), but acute or previous COVID infections were identified in only 36% of 2020 deaths. People who died in 2020 were more likely to have developed acute organ failure during the death event (70.6% vs 21.1%, p = 0.003) compared to prior years. They were also more likely to have a history of stroke and more frequent hematology clinic visits. Deaths in 2020 doubled compared to prior years and COVID infection could not account for all of this excess mortality. People who died in 2020 may have had more severe disease as suggested by having more clinic visits and higher rates of stroke and were more likely to develop organ failure during the death event. This demonstrates that people with SCD may be especially vulnerable to delays in care. Larger multicenter studies should be conducted to examine this further.

Non-crisis related pain occurs in adult patients with sickle cell disease despite chronic red blood cell exchange transfusion therapy.

BACKGROUND: Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics. STUDY METHOD AND DESIGN: Eleven participants receiving chronic exchange transfusion (CET) for at least one year were compared to 33 participants not receiving CET. Participants completed validated patient-reported outcomes regarding pain impact and quality of life at regularly scheduled visits or before CET. One year of health care utilization and opioid prescriptions were examined. RESULTS: After 1:1 propensity matching was performed for age, genotype, WBC and neutrophil counts, patients on CET had lower Pain Impact scores (-5.1, p = 0.03) and higher Neuropathic (7.4, p < 0.001) and Nociceptive Pain Quality (3.7, p < 0.001) scores, all indicating worse pain. However, CET was associated with a reduction in annual all cause admissions (-3.1, p < 0.001), length of stay (-2.1 days, p < 0.001) and ED visits (-2.7, p < 0.001). CET was not associated with differences in opioids dispensed. CONCLUSIONS: After adjusting for disease characteristics, CET was associated with worse pain impact and neuropathic and nociceptive pain quality, lower health care utilization and with similar levels of opioids dispensed. This data suggest that CET may reduce hospitalizations for acute pain but may not adequately treat nociceptive or neuropathic pain in SCD.

Characterization of circulating and cultured Tfh-like cells in sickle cell disease in relation to red blood cell alloimmunization status.

BACKGROUND: People living with sickle cell disease (SCD) are prone to red blood cell (RBC) alloimmunization. We hypothesized that subjects with alloantibodies (responders) would have differences in circulating T-follicular helper (Tfh)-like cells compared to subjects without alloantibodies (non-responders). MATERIALS AND METHODS: Peripheral blood mononuclear cells were collected from 28 subjects, including those with SCD and controls. Circulating CD4 T-cell subsets were first evaluated at baseline. CD4 T-cell subsets were also evaluated after naïve CD4 T-cells were differentiated into Tfh-like cells following in vitro culture with CD3/CD28 beads, IL-7, IL-12, and Activin A. Transfusion and alloantibody histories were extracted from the electronic medical record. RESULTS: Non-responders had a lower percentage of CD45RA negative Tmemory cells than responders or controls (p<0.05). Notably, there were no differences in circulating Tfh-like cells between any group. However, naïve CD4 T-cells from subjects with SCD were more likely to express CXCR5 after in vitro culture than cells from controls. After culture, CXCR5 expressing cells from responders were more likely to express PD1 and ICOS (16.43 %, sd. 20.23) compared to non-responders (3.69 %, s.d. 3.09) or controls (2.78 %, s.d. 2.04). DISCUSSION: The tendency for naïve CD4 T-cells from responders to differentiate into Tfh-like cells after in vitro culture may suggest these cells are prepared to assist B-cells with antibody production regardless of antigen specificity. Further studies are needed, but it is possible that these results may explain why some responders form RBC alloantibodies with multiple specificities, in addition to RBC autoantibodies and HLA alloantibodies.

Red blood cell alloimmunization is associated with lower expression of FcγR1 on monocyte subsets in patients with sickle cell disease.

BACKGROUND: Despite the clinical significance of red blood cell (RBC) alloantibodies, there are currently no laboratory tests available to predict which patients may be at risk of antibody formation after transfusion exposure. Given their phagocytic and inflammatory functions, we hypothesized that differences in circulating monocytes may play a role in alloimmunization. STUDY DESIGN AND METHODS: Forty-two adults with sickle cell disease (SCD) were recruited, with data extracted from the electronic medical record and peripheral blood analyzed by flow cytometry for total monocytes, monocyte subsets (CD14 high/CD16 low+ classical monocytes, CD14 high/CD16 high+ intermediate monocytes, and CD14 intermediate/CD16 high+ non-classical/inflammatory monocytes), and FcγR1 (CD64) expression. Thirteen "non-responder" patients (non-alloimmunized patients with documented RBC transfusion at the study institution) were compared to 20 alloimmunized "responder" patients, who had a total of 44 RBC alloantibodies identified. RESULTS: There were no significant differences in the percentages of total monocytes, monocyte subsets, or measured cytokines between non-responders and responders. However, non-responders had higher CD64 expression on classical monocytes (MFI mean 3424 ± standard deviation 1141) compared to responders (MFI mean 2285 ± 1501), p = 0.029, and on intermediate monocytes (MFI mean 3720 ± 1191) compared to responders (MFI mean 2497 ± 1640), p = 0.033. CONCLUSIONS: Monocytes and the inflammatory milieu increasingly are being appreciated to play a role in some complications of SCD. The differences in FcγR1 expression on monocyte subsets noted between responders and non-responders, which cannot be directly explained by the serum cytokines evaluated, warrant further investigation.

Be careful of the masquerades: differentiating secondary myelodysplasia from myelodysplastic syndromes in clinical practice.

In patients suspected to have myelodysplastic syndrome (MDS), especially in those patients without cytogenetic abnormalities or blast excess, accurate morphologic review by an expert hematopathologist and meticulous exclusion of other secondary causes of myelodysplasia are vital to establish the diagnosis. Errors in diagnosis can lead to dangerous consequences such as the administration of hypomethylating agents, lenalidomide, or even the use of intensive chemotherapy or allogeneic hematopoietic cell transplantation in patients who do not have an underlying MDS or even a malignant hematopoietic process. Additionally, beyond the possible harm and lack of efficacy of such therapies if the diagnosis of MDS is erroneous, the secondary myelodysplasia and resultant cytopenias are not likely to resolve unless the underlying etiology is identified and addressed. Discriminating a malignant process such as MDS from non-malignant secondary myelodysplasia can be quite challenging, and community hematologists/oncologists should consider referral to specialized physicians (both clinical experts and experienced hematopathologists) if there is any doubt regarding the diagnosis. In this article, we present a representative case series of patients from our own practice who posed diagnostic dilemmas and propose a systematic approach for assessment for secondary causes of myelodysplasia.

Gemcitabine-Induced Pseudocellulitis in a Patient With Recurrent Lymphedema: A Case Report and Review of the Current Literature.

Gemcitabine is a chemotherapeutic agent used for treatment of a variety of malignancies. It has been associated with multiple cutaneous reactions including rash, alopecia, and pruritus. Less commonly, gemcitabine has been associated with "pseudocellulitis," a noninfectious skin inflammatory reaction, which resembles cellulitis. The majority of cases reported in the literature are radiation recall reactions in which inflammation occurs in areas of previous radiation post drug treatment; however, there are also reports of pseudocellulitis occurring in areas of preexisting lymphedema. The pathophysiology of both of these reactions are still unknown, though it is theorized that areas of lymphedema may both increase concentration of gemcitabine and reduce its rate of metabolism leading to increased drug exposure time. In this study, we report a case of pseudocellulitis in a patient with chronic lower extremity lymphedema and a review of the current literature. By recognizing this side effect of gemcitabine, one can avoid unnecessary hospitalization and exposure to antibiotics.

Evolving Immunotherapy Approaches for Renal Cell Carcinoma.

Metastatic renal cell carcinoma (mRCC) continues to be associated with high rates of morbidity and mortality. Renal cell carcinoma (RCC) is typically resistant to cytotoxic chemotherapy, and while targeted therapies have activity and prolong progression-free and overall survival, responses are usually not durable. Modulating the immune system with cytokine therapy, vaccine therapy, cell therapy, and checkpoint inhibitors offers hope of prolonged survival. Standard and emerging immune therapy approaches and combinations of immune therapies and other modalities are reviewed.

Plasma free hemoglobin is associated with LDH, AST, total bilirubin, reticulocyte count, and the hemolysis score in patients with sickle cell anemia.

Plasma free hemoglobin (PFH) is a direct biomarker for hemolysis that has been associated with clinical complications such as pulmonary hypertension and death in patients with sickle cell disease (SCD). We sought to characterize the relationship between PFH and more clinically available hemolytic markers including lactate dehydrogenase (LDH), aspartate aminotransferase (AST), bilirubin, reticulocyte percentage and to derive a composite hemolysis score derived from principal component analysis (PCA) of these biomarkers. In 68 adult patients (median age 31 years old, IQR 25-39) with HbSS or HbSß0-thalassemia enrolled in the IMPROVE II study, median PFH was elevated at 21.9 mg/dL (IQR 9.9-44.9 mg/dL). Using Pearson correlation analysis, PFH had a stronger relationship to LDH (R=0.699), AST (R=0.587), and total bilirubin (R=0.475), compared to reticulocyte count (R=0.316). The hemolysis score was significantly associated with PFH (R=0.677). When compared with other laboratory measures, PFH correlated with hemoglobin (R= -0.275) and HbS (R=0.277),but did not correlate with white blood cell count (WBC) or HbF. The hemolysis score was significantly associated with WBC (R=0.307), hemoglobin (R = -0.393), HbF (R=- 0.424), and HbS (R=0.423). This study confirms that the conventional hemolytic biomarkers LDH, AST, bilirubin, and reticulocyte percentage correlate with PFH. Additionally, the hemolysis score is a valid tool to measure hemolysis and that it may be a marker of global hemolysis as opposed to PFH, which quantifies intravascular hemolysis. Further studies will be needed to elucidate the role of PFH and intravascular hemolysis in the development of clinical complications of sickle cell disease.

Concentration of voxelotor in sickle cell disease can be estimated using electrophoresis and high-performance liquid chromatography.

OBJECTIVES: Voxelotor can increase hemoglobin levels in patients living with sickle cell disease (SCD). A clinician who is monitoring voxelotor response may want to know whole-blood voxelotor concentration, but this cannot be measured in most clinical settings. However, voxelotor has been demonstrated to cause "peak splitting" in common methods of hemoglobin measurement such as capillary zone electrophoresis (CZE) and high-performance liquid chromatography (HPLC). We hypothesized that we could use the size of the peak split to estimate the whole-blood concentration. METHODS: Blood from people with SCD was dosed with known concentrations of voxelotor, and multiparameter regression was used to derive the relationship of voxelotor concentration to the degree of peak splitting observed. To validate these equations, 21 patients started on voxelotor at 1500 mg/d had blood samples drawn at days 0, 14, 30, and 60. Samples were sent out for gold standard voxelotor concentration testing. The derived equations were then used to calculate voxelotor concentration. RESULTS: Calculated concentrations correlated strongly with measured concentrations for both CZE (R2 = 0.83, P < .001) and HPLC (R2 = 0.76, P < .001). Voxelotor concentration also had a significant effect on increases in hemoglobin (R2 = 0.40, P < .001). CONCLUSIONS: Thus, peak splitting CZE and HPLC can be used to estimate voxelotor concentration.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

COVID19 vaccination in adults with sickle cell disease is not associated with increases in rates of pain crisis.

ABSTRACTPeople with sickle cell disease (SCD) are more vulnerable to hospitalization, pneumonia, and pain following COVID-19 infection. However, given the association between the inflammatory response and vaso-occlusive crises in SCD and a case report of vaso-occlusive crises following administration of the ChAdOx1 nCov-195-7/AstraZeneca vaccine, there is concern that the administration of COVID-19 vaccines in people with SCD might provoke a vaso-occlusive crisis. To address this critical gap in knowledge, we sought to examine acute care usage for vaso-occlusive crisis and frequency and severity of side effects following COVID-19 vaccination among patients at the Montefiore Sickle Cell Center for Adults. As part of regular care, patients were asked if they had received COVID-19 vaccination and any side effects were noted. Electronic medical records were reviewed for the type of vaccine, dates received, episodes of vaso-occlusive crises within seven days of a dose, and side effects noted. The risk of average hospital utilization per week in 2019 was calculated as a baseline. We found that fewer than 1 in 10 patients presented to the hospital within seven days of vaccination and that the risk of hospital utilization was similar to the average risk in a week in 2019. Of patients who reported side effects, one reported a possible case of sensorineural hearing loss otherwise no other rare side effects, including thrombosis or death, were reported.

Clinical Approaches to Cannabis: A Narrative Review.

Cannabis use in the United States is growing at an unprecedented pace. Most states in the United States have legalized medical cannabis use, and many have legalized nonmedical cannabis use. In this setting, health care professionals will increasingly see more patients who have questions about cannabis use, its utility for medical conditions, and the risks of its use. This narrative review provides an overview of the background, pharmacology, therapeutic use, and potential complications of cannabis.

Daily Cannabis Users with Sickle Cell Disease Show Fewer Admissions than Others with Similar Pain Complaints.

Introduction: Previous studies have shown that cannabis use is common in adults with sickle cell disease (SCD), and that many patients report using cannabis to treat pain. Methods: We performed a cross-sectional study of adults with SCD and compared daily users of cannabis with others using validated patient-reported measures of pain and quality of life as well as opioid and health care utilization. Results: Daily cannabis users with SCD had worse pain episode severity scores than others (56.7 vs. 48.8, p=0.02) yet had 1.8 fewer annual admissions (p=0.01) and 1.2 fewer annual emergency room (ER) visits (p=0.01), and similar amounts of opioids dispensed to others after matching for age, gender, SCD genotype, hydroxyurea use, and pain impact scores. Conclusions: We show that people with SCD with more severe pain crisis are more likely to use daily cannabis, yet have lower rates of hospital admission and ER use as compared with others with similar disease severity and pain impact. Randomized controlled trials should be performed.

Urinary cannabinoid mass spectrometry profiles differentiate dronabinol from cannabis use.

BACKGROUND: Dronabinol is used to treat a variety of conditions, including loss of appetite in people with AIDS and severe nausea and vomiting caused by cancer chemotherapy. Its therapeutic potential for pain management is now being explored in specific populations. Monitoring dronabinol compliance is challenging because its active ingredient, Δ-9-tetrahydrocannabinol (THC), is also present in cannabis. We developed a rapid LC-MS/MS assay with minimal specimen preparation to quantitate 11 cannabinoids in urine. Using this assay coupled with urine samples from normal controls, cannabis, and dronabinol users, we show the ability to differentiate cannabis from dronabinol use. METHODS: Residual clinical urine samples from 55 cannabinoid positive subjects and 31 negative controls, as well as prospective samples from 5 patients receiving dronabinol therapy were obtained for analysis. RESULTS: In the dronabinol group, only the THC metabolites 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) and 11-hydroxy-Δ-9-tetrahydrocannabinol (THC-OH) were detected. Minor cannabinoids were detected in 91% of cannabis group samples and their detection was more frequent in samples with increased THC metabolite concentrations. Of minor cannabinoids evaluated, cannabigerol (CBG) and cannabidiol (CBD) had the greatest sensitivity in detecting cannabis use. CONCLUSIONS: This method has a high sensitivity for the detection of cannabis use with implications for evaluating dronabinol compliance.