The burden of hospital-acquired infections (HAI) in sub-Saharan Africa: a systematic review and meta-analysis.

Background: Hospital-acquired infections (HAI) are a leading cause of morbidity and mortality globally. These infections are diverse, but the majority are lower respiratory tract infection (LRTI), surgical site infection (SSI), bloodstream infection (BSI), and urinary tract infection (UTI). For most sub-Saharan African countries, studies revealing the burden and impact of HAI are scarce, and few systematic reviews and meta-analysis have been attempted. We sought to fill this gap by reporting recent trends in HAI in sub-Saharan Africa (SSA) with attention to key patient populations, geographic variation, and associated mortality. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a literature search of six electronic databases (Web of Science, Pubmed, APA PsycInfo, CINAHL, Embase, and the Cochrane Library) to identify studies assessing the prevalence of HAI in SSA countries. Studies published between 01 January 2014 and 31 December 2023 were included. We applied no language or publication restrictions. Record screening and data extractions were independently conducted by teams of two or more reviewers. Using the R software (version 4.3.1) meta and metafor packages, we calculated the pooled prevalence estimates from random-effect meta-analysis, and further explored sources of heterogeneity through subgroup analyses and meta-regression. This study is registered with PROSPERO, CRD42023433271. Findings: Forty-one relevant studies were identified for analysis, consisting of 15 from West Africa (n = 2107), 12 from Southern Africa (n = 2963), 11 from East Africa (n = 2142), and 3 from Central Africa (n = 124). A total of 59.4% of the patient population were associated with paediatric admissions. The pooled prevalence of HAI was estimated at 12.9% (95% CI: 8.9-17.4; n = 7336; number of included estimates [k] = 41, p < 0.001). By subregions, the pooled current prevalence of HAI in the West Africa, Southern Africa, East Africa and Central Africa were estimated at 15.5% (95% CI: 8.3-24.4; n = 2107; k = 15), 6.5% (95% CI: 3.3-10.7; n = 2963; k = 12), 19.7% (95% CI: 10.8-30.5; n = 2142; k = 11) and 10.3% (95% CI: 1.1-27.0; n = 124; k = 3) of the patient populations respectively. We estimated mortality resulting from HAI in SSA at 22.2% (95% CI: 14.2-31.4; n = 1118; k = 9). Interpretation: Our estimates reveal a high burden of HAI in SSA with significant heterogeneity between regions. Variations in HAI distribution highlight the need for infection prevention and surveillance strategies specifically tailored to enhance prevention and management with special focus on West and East Africa, as part of the broader global control effort. Funding: No funding was received for this study.

Development of a Hematology-General Medicine Hybrid Team to Improve Care of Patients With Sickle Cell Disease.

PROBLEM: Approximately 100,000 individuals in the United States have sickle cell disease (SCD). These individuals face multiple barriers to equitable care. At Brigham and Women's Hospital, existing health inequities for these patients were compounded by admitting, rounding, and team structures that assigned patients with SCD to multiple medicine teams with a hematologist attending, leading to delays in patient care and gaps in residents' hematology knowledge. APPROACH: A hematology-general medicine hybrid team was created in September 2021 to enhance trainee knowledge, skill, and confidence in managing hematology conditions and improve the quality of care delivered to individuals with SCD. This allowed for regionalization of patients with classical hematology conditions to specific hospital floors under the care of one team with a hematologist as the attending of record. OUTCOMES: From October 1, 2021, to January 11, 2022, the majority (745/824, 90%) of in-hospital days for patients with a primary hematology diagnosis were under the care of the hematology-general medicine hybrid team. Regionalization to the home floor of the hybrid team was achieved on 331 (40%) of these 824 hospital days, consistent with regionalization rates for other teams. From October 1, 2021, to September 30, 2022, there were 128 unique patients with SCD admitted over 511 encounters and cared for by approximately 78 residents and 12 medical students. Feedback from residents reported improved knowledge in the management of hematology conditions, especially SCD. NEXT STEPS: The authors are working on a comprehensive analysis of the hybrid team's impact on trainee skill and confidence in managing SCD. The authors believe that this model can be replicated at other institutions to optimize trainee education, consolidate care, and address implicit bias against patients with SCD, even with the hematology attending as a consultant instead of as the attending of record.

Development of Duffy Null-Specific Absolute Neutrophil Count Reference Ranges.

This study establishes a Duffy null phenotype­specific absolute neutrophil count reference range to optimize care and improve health equity.

A systematic literature review and meta-analysis of the incidence of serious or severe hypersensitivity reactions after administration of ferric derisomaltose or ferric carboxymaltose.

BACKGROUND: Intravenous iron is the preferred treatment for patients with iron deficiency anemia in a variety of clinical situations. Although uncommon, administration of modern IV iron formulations can result in hypersensitivity reactions (HSRs) and, rarely, anaphylactic or anaphylactoid reactions. AIM: The objective of the present study was to systematically review the literature to identify and analyze data on the incidence of HSRs after administration of ferric derisomaltose (FDI) or ferric carboxymaltose (FCM). METHOD: A prospectively-registered systematic literature review was conducted to identify prospective randomized controlled trials comparing FDI and FCM with other intravenous iron formulations or oral iron. Searches were conducted in PubMed (including MEDLINE), EMBASE, and the Cochrane Library in November 2020. The relative incidence of serious or severe HSRs occurring on the day or day after dosing of intravenous iron, recorded under the standardized Medical Dictionary for Regulatory Activities query for anaphylactic reaction. RESULTS: Data were obtained from seven randomized controlled trials of FCM (N = 2683) and ten of FDI (N = 3474) enrolling 10,467 patients in total. The number of patients experiencing any serious or severe HSR event was 29/2683 (1.08%) with FCM versus 5/3474 with FDI (0.14%). Bayesian inference of proportions showed the event rates to be significantly lower with FDI relative to FCM. CONCLUSION: HSR events were uncommon with both intravenous iron formulations; however, the present study showed a significantly lower incidence of HSRs with FDI relative to FCM. Further large-scale, head-to-head trials of the iron formulations would be required to confirm this finding.

Persistence of Unequal Access to Classical Hematology Telemedicine Visits by Race and Other Demographics During the COVID-19 Pandemic.

Background: Unequal access to telemedicine services exacerbates health inequities and was evident at the start of the COVID-19 pandemic. We sought to explore whether unequal access persisted within a classical hematology division beyond the peak of COVID-19. Methods: Patient demographics by virtual visit type (telephone only [TO] or video only [VO]) between March 2020 and December 2021 were analyzed using adjusted odds ratio (aOR). Results: Of 8,207 patients, 18.4% had TO and 28.4% had VO visits. Fewer Black (21.8%; aOR 0.5 [0.4-0.62]), Hispanic or Latino (18.8%; 0.45 [0.34-0.59]), Spanish-speaking (7.6%; 0.32 [0.19-0.54]), high school (21.2%; 0.64 [0.52-0.78]), and older (24.2%) patients used VO compared with White (30.6%), English-speaking (29.5%), college (31%), postgraduate (34.9%), and younger (35.4%) patients. Conclusions: Groups that historically experience health inequities had fewer VO visits during and beyond the pandemic peak. Thus, there is a need to continue digital inclusion efforts to promote video access equity.

Absolute neutrophil count by Duffy status among healthy Black and African American adults.

Many people of African ancestry have lower absolute neutrophil counts (ANCs) without increased risk for infection. This is associated with the Duffy-null phenotype (nonexpression of the Duffy antigen on red blood cells), which is commonly found in those of African descent. Currently, there are no studies that compare the ANC of individuals with Duffy-null phenotype to those with Duffy non-null phenotypes within a self-identified Black population. The aim of this study was to assess the impact of Duffy status on ANCs based on complete blood counts with differential and Duffy testing in a healthy population of self-identified Black individuals at a single primary care center. This study found that 66.7% (80 of 120) of Black individuals have the Duffy-null phenotype and that there is a significant difference in ANCs between Duffy-null and Duffy non-null individuals (median, 2820 cells per µL vs 5005 cells per µL; P < .001). Additionally, 19 of 80 (23.8%) Duffy-null individuals had an ANC of <2000 cells per µL compared with no (0) Duffy non-null individuals. The Duffy-null phenotype is clinically insignificant; however, inappropriate reference ranges can propagate systemic racism. Therefore, we advocate for the development of Duffy-null-specific ANC reference ranges as well as replacing the term benign ethnic neutropenia with Duffy-nullassociated neutrophil count.

How Would You Treat This Patient With Acute and Chronic Pain From Sickle Cell Disease? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Sickle cell disease is prevalent in large numbers of patients in the United States and has a significant global impact. Its complications span numerous organs and lead to reduced life expectancy. Acute and chronic sickle cell pain is a common cause of patient suffering. The American Society of Hematology published updated guidelines on management of acute and chronic pain from sickle cell disease in 2019. Several of the recommendations are conditional and leave specific decisions to the treating physician. These include conditional recommendations about the use of ketamine for acute pain and the initiation and discontinuation of long-term opioid therapy for chronic pain. Here, 2 hematologists discuss these guidelines and make contrasting recommendations for the management of acute and chronic pain for a patient with sickle cell disease.

Efficacy and safety of ferric derisomaltose (FDI) compared with iron sucrose (IS) in patients with iron deficiency anemia after bariatric surgery.

PURPOSE: Iron deficiency is common following bariatric surgery, and treatment with intravenous iron is often required. This post hoc analysis of data from two randomized, open-label, multicenter trials evaluated the efficacy and safety of ferric derisomaltose (FDI; formerly iron isomaltoside 1000) versus iron sucrose (IS) over 4 weeks in adults with iron deficiency anemia (IDA) resulting from prior bariatric surgery. MATERIALS AND METHODS: Data were pooled for participants who received FDI or IS in the PROVIDE or FERWON-IDA trials for the treatment of IDA post bariatric surgery. Efficacy outcomes included changes in hemoglobin (Hb) and iron parameters; safety outcomes included the incidence of adverse drug reactions (ADRs), serious or severe hypersensitivity reactions (HSRs), and hypophosphatemia. RESULTS: The analysis included 159 patients. Mean (standard deviation) cumulative iron doses were 1199 (± 347) mg for FDI and 937 (± 209) mg for IS. Compared with IS, FDI resulted in a faster and more pronounced Hb response, and a higher proportion of responders (Hb level increase ≥ 2 g/dL from baseline) at all time points. The incidence of ADRs was similar with FDI and IS (15.1% and 18.2%, respectively), with no serious ADRs or serious or severe HSRs reported. The incidence of hypophosphatemia was low and similar in both treatment groups, with no cases of severe hypophosphatemia observed. CONCLUSIONS: In patients with IDA resulting from bariatric surgery, FDI produced a faster and more pronounced Hb response than IS. Both FDI and IS were well tolerated.

Impact of sickle cell trait on morbidity and mortality from SARS-CoV-2 infection.

The COVID-19 pandemic has highlighted racial health disparities within the United States. Although social determinants of health are the most likely drivers of this disparity, it is possible that genetic traits enriched in the black population like sickle cell trait (SCT) could worsen the morbidity and mortality of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients admitted for SARS-CoV-2 infection who identified as black or African American were included in the study (n = 166). Blood remnants were tested for SCT, and clinical data were abstracted from the chart. There was no difference in mortality between those with SCT and those without. There was no difference in respiratory complications between groups, but those without SCT had a much higher burden of chronic lung disease (P = .004). Those with SCT had higher creatinine on admission (P = .004), but no difference in in-hospital renal complications (P = .532). Notably, 12% of the cohort had SCT, which is higher than the expected 7.31% (P = .025). Our study did not show any evidence of increased end organ damage, morbidity, or mortality from SARS-CoV-2 infection among patients with SCT but did show differences in admission creatinine and preexisting lung disease.

Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: For decades, patients with sickle cell disease have had only a limited number of therapies available. In 2019, voxelotor (1500 mg), an oral once-daily sickle haemoglobin polymerisation inhibitor, was approved in the USA for the treatment of sickle cell disease in patients aged 12 years and older on the basis of HOPE trial data. To further describe the applicability of voxelotor as a treatment for this chronic illness, we report the long-term efficacy and safety of this drug at 72 weeks of treatment; the conclusion of the placebo-controlled HOPE trial. METHODS: HOPE is an international, randomised, double-blind, placebo-controlled, phase 3 trial done at 60 clinical sites in Canada, Egypt, France, Italy, Jamaica, Kenya, Lebanon, Netherlands, Oman, Turkey, the USA, and the UK. Patients (aged 12-65 years) with confirmed sickle cell disease, a haemoglobin concentration of 5·5-10·5 g/dL at enrolment, and who had between one and ten vaso-occlusive crisis events in the previous 12 months were enrolled. Patients receiving regularly scheduled transfusion therapy, who had received a transfusion in the previous 60 days, or who had been admitted to hospital for a vaso-occlusive crisis in the previous 14 days were excluded. Patients were randomly assigned (1:1:1) to receive either once-daily oral voxelotor 1500 mg, voxelotor 900 mg, or placebo for 72 weeks. Randomisation was done centrally by use of an interactive web response system, stratified by baseline hydroxyurea use (yes vs no), age group (adolescents [12 to <18 years] vs adults [18 to 65 years]), and geographic region (North America vs Europe vs other). The primary endpoint (already reported) was the proportion of patients who achieved a haemoglobin response at week 24. In this final analysis, we report prespecified long-term efficacy assessments by intention to treat, including changes in haemoglobin concentrations from baseline to week 72, changes in the concentration of haemolysis markers (absolute and percentage reticulocytes, indirect bilirubin concentrations, and lactate dehydrogenase concentrations) from baseline to week 72, the annualised incidence of vaso-occlusive crises, and patient functioning, as assessed with the Clinical Global Impression of Change (CGI-C) scale. Safety was assessed in patients who received at least one dose of treatment (modified intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT03036813. FINDINGS: Between Dec 5, 2016, and May 3, 2018, 449 patients were screened, of whom 274 were randomly assigned to the voxelotor 1500 mg group (n=90), the voxelotor 900 mg group (n=92), or the placebo group (n=92). At week 72, the adjusted mean change in haemoglobin concentration from baseline was 1·0 g/dL (95% CI 0·7 to -1·3) in the voxelotor 1500 mg group, 0·5 g/dL (0·3 to -0·8) in the voxelotor 900 mg group, and 0·0 g/dL (-0·3 to 0·3) in the placebo group, with a significant difference observed between the voxelotor 1500 mg group and the placebo group (p<0·0001), and between the voxelotor 900 mg group and the placebo group (p=0·014). Significant improvements in markers of haemolysis, as assessed by the difference in adjusted mean percentage change from baseline at week 72 versus placebo, were observed in the voxelotor 1500 mg group in indirect bilirubin concentrations (-26·6% [95% CI -40·2 to -12·9]) and percentage of reticulocytes (-18·6% [-33·9 to -3·3]). The proportion of patients in the voxelotor 1500 mg group who were rated as "moderately improved" or "very much improved" at week 72 with the CGI-C was significantly greater than in the placebo group (39 [74%] of 53 vs 24 [47%] of 51; p=0·0057). Serious adverse events unrelated to sickle cell disease were reported in 25 (28%) of 88 patients in the voxelotor 1500 mg group, 20 (22%) of 92 patients in the voxelotor 900 mg group, and 23 (25%) of 91 patients in the placebo group. Grade 3 or 4 adverse events were infrequent (ie, occurred in <10% of patients); anaemia occurred in five or more patients (two [2%] patients in the voxelotor 1500 mg group, seven [8%] patients in the voxelotor 900 mg group, and three [3%] patients in the placebo group). Of all 274 patients, six (2%) deaths occurred during the study (two deaths in each treatment group), all of which were judged as unrelated to treatment. INTERPRETATION: Voxelotor 1500 mg resulted in rapid and durable improvements in haemoglobin concentrations maintained over 72 weeks and has potential to address the substantial morbidity associated with haemolytic anaemia in sickle cell disease. FUNDING: Global Blood Therapeutics.

Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease.

BACKGROUND: Sickle cell disease is characterized by hemolytic anemia, pain, and progressive organ damage. A high level of erythrocyte fetal hemoglobin (HbF) comprising α- and γ-globins may ameliorate these manifestations by mitigating sickle hemoglobin polymerization and erythrocyte sickling. BCL11A is a repressor of γ-globin expression and HbF production in adult erythrocytes. Its down-regulation is a promising therapeutic strategy for induction of HbF. METHODS: We enrolled patients with sickle cell disease in a single-center, open-label pilot study. The investigational therapy involved infusion of autologous CD34+ cells transduced with the BCH-BB694 lentiviral vector, which encodes a short hairpin RNA (shRNA) targeting BCL11A mRNA embedded in a microRNA (shmiR), allowing erythroid lineage-specific knockdown. Patients were assessed for primary end points of engraftment and safety and for hematologic and clinical responses to treatment. RESULTS: As of October 2020, six patients had been followed for at least 6 months after receiving BCH-BB694 gene therapy; median follow-up was 18 months (range, 7 to 29). All patients had engraftment, and adverse events were consistent with effects of the preparative chemotherapy. All the patients who could be fully evaluated achieved robust and stable HbF induction (percentage HbF/(F+S) at most recent follow-up, 20.4 to 41.3%), with HbF broadly distributed in red cells (F-cells 58.9 to 93.6% of untransfused red cells) and HbF per F-cell of 9.0 to 18.6 pg per cell. Clinical manifestations of sickle cell disease were reduced or absent during the follow-up period. CONCLUSIONS: This study validates BCL11A inhibition as an effective target for HbF induction and provides preliminary evidence that shmiR-based gene knockdown offers a favorable risk-benefit profile in sickle cell disease. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT03282656).

Clinical outcomes following bone marrow transplantation in patients with sickle cell disease: A cohort study of US Medicaid enrollees.

OBJECTIVES: Bone marrow transplantation (BMT) is currently the only curative therapy available for patients with sickle cell disease (SCD), but clinical outcomes in routine care are not well understood. We describe the rates of vaso-occlusive crises (VOCs), transplant complications, and mortality in SCD patients after BMT. METHODS: A cohort study of SCD patients who underwent BMT was designed using US Medicaid claims data (2000-2013). RESULTS: A total of 204 SCD patients undergoing BMT were identified with a mean (SD) age of 10.6 (7.3) years, with 52.9% male and 67.6% African American. The overall VOC rate was 0.99 per person-year (95% CI: 0.91-1.07) over a median follow-up time of 2.1 years (IQR: 0.8-4.3 years). A total of 138 (67.6%) remained free of VOCs. The mortality rate was 1.7 (95% CI: 0.9-3.1) per 100 person-years, transplant-related complications occurred among 113 (55.4%) patients with an incidence rate of 38.2 (95% CI: 31.7-45.9) per 100 person-years, while 47 (23%) patients had GvHD with an incidence rate of 8.0 (95% CI: 6.0-10.7) per 100 person-years. CONCLUSION: Two thirds of the BMT recipients remained VOC-free over 2 years of follow-up, but transplant-related complications, including GvHD occurred with high frequency. This highlights a continuing unmet need for alternative curative interventions in SCD.

When non-Whiteness becomes a condition.

The term "benign ethnic neutropenia" describes the phenotype of having an absolute neutrophil count (ANC) <1500 cells/µL with no increased risk of infection. It is most commonly seen in those of African ancestry. In addition, ANC reference ranges from countries in Africa emphasize that ANC levels <1500 cells/µL are common and harmless. The lower ANC levels are driven by the Duffy null [Fy(a-b-)] phenotype, which is protective against malaria and seen in 80% to 100% of those of sub-Saharan African ancestry and <1% of those of European descent. Benign ethnic neutropenia is clinically insignificant, but the average ANC values differ from what are typically seen in those of European descent. Thus, the predominantly White American medical system has described this as a condition. This labeling implicitly indicates that common phenotypes in non-White populations are abnormal or wrong. We believe that it is important to examine and rectify practices in hematology that contribute to systemic racism.

Clinical outcomes and healthcare utilization in patients with sickle cell disease: a nationwide cohort study of Medicaid beneficiaries.

To add to the limited existing evidence on clinical outcomes and healthcare use in sickle cell disease (SCD) among beneficiaries of the US Medicaid program, we conducted a cohort study using nationwide Medicaid claims data (2000-2013). Patients were included based on HbSS SCD diagnosis and followed until Medicaid disenrollment, death, bone marrow transplant, or end of data availability to assess vasoocclusive crises (VOC), emergency room (ER) visits, hospitalizations, outpatient visits, and blood transfusions. Annualized event rates (with 95% confidence intervals [CI]) were reported. The impact of VOCs on the risk of mortality was analyzed using a multivariable Cox model with VOC modeled as time-varying and updated annually. In a total of 44,033 SCD patients included with a mean (SD) age of 15.7 (13.6) years, the VOC rate (95% CI) was 3.71 (3.70-3.72) per person-year, with highest rate among patients 19-35 years who had ≥ 5 VOCs at baseline (13.20 [13.15-13.26]). Event rates (95% CI) per person per year for other outcomes were 2.97 (2.97-2.98) ER visits, 2.39 (2.38-2.40) hospitalizations, 5.80 (5.79-5.81) outpatient visits, and 0.91 (0.90-0.91) blood transfusions. A higher VOC burden in the preceding year was associated with an increased risk of mortality, with a hazard ratio (95% CI) of 1.26 (1.14-1.40) for 2-4 VOC vs. < 2 and 1.57 (1.41-1.74) for ≥ 5 VOC vs < 2. In conclusion, we documented a substantial burden of SCD in US Medicaid enrollees, especially during early adulthood and noted that ongoing burden of VOC is associated with mortality in these patients.

Clinical data for intravenous iron - debunking the hype around hypersensitivity.

BACKGROUND: Reluctance to use intravenous (IV) iron for the treatment of iron deficiency continues due to a perceived high risk of severe hypersensitivity reactions (HSRs). Additionally, it has been hypothesized that 'dextran-derived' IV iron products (e.g., ferumoxytol [FER] and ferric derisomaltose/iron isomaltoside 1000 [FDI]) have a higher risk of severe HSRs than 'non-dextran-derived' products (e.g., ferric carboxymaltose [FCM] and iron sucrose [IS]). In the present analysis, HSR data from head-to-head randomized controlled trials (RCTs) with IV iron products were evaluated to determine if differences in safety signals are present among these IV iron formulations. STUDY DESIGN AND METHODS: Reported serious or moderate-to-severe HSR incidence data from five RCTs (FIRM; FERWON-NEPHRO/-IDA; PHOSPHARE-IDA04/-IDA05) were used to calculate risk differences with 95% confidence intervals (CIs) for FER, FCM, FDI, and IS. The rates and risk differences for these HSRs were compared. RESULTS: The analysis included data for 5247 patients: FER (n = 997), FCM (n = 1117), FDI (n = 2133) and IS (n = 1000). Overall rates of serious or moderate to severe HSRs were low (0.2%-1.7%). The risk differences (95% CIs) showed small differences between the IV iron formulations: FER versus FCM, -0.1 (-0.8 to 0.6); FDI versus IS, 0.1 (-0.3 to 0.5); FDI versus FCM, -0.9 (-3.7 to 1.9). CONCLUSION: RCT evidence confirms a low risk of serious or moderate to severe HSRs with newer IV iron formulations and no significant differences among existing commercially available products. Thus, RCT data show that the supposed classification of dextran-derived versus non-dextran-derived IV iron products has no clinical relevance.