Infections In Sickle Cell Disease Research Articles

Guarding Health: A Comprehensive Review of Nosocomial Infections in Sickle Cell Anemia, a Multifaceted Approach to Prevention.

This comprehensive review explores the complex dynamics of nosocomial infections in individuals with sickle cell anemia (SCA) and advocates for a collaborative strategy to enhance prevention. SCA patients, marked by compromised immunity and susceptibility to infections, face unique challenges that necessitate tailored preventive measures. The review underscores the importance of vaccination, antibiotic prophylaxis, education, and environmental hygiene in mitigating the risk of nosocomial infections. Addressing socioeconomic factors, healthcare system limitations, patient-related issues, and cultural considerations is imperative for effective prevention. The call to action emphasizes the pivotal roles of healthcare professionals, policymakers, researchers, and community engagement in implementing targeted interventions. By fostering a collective effort, this review envisions an improved landscape for infection prevention in SCA patients, enhancing their overall health outcomes and quality of life.

Relationship between Glutathione S Transferase P1 and Toll like Receptor 2 Polymorphisms and Infections in Sickle Cell Anemia

Relationship between Glutathione S Transferase P1 and Toll like Receptor 2 Polymorphisms and Infections in Sickle Cell Anemia

Analyzing Treatment Patterns and Clinical Outcomes within the First 24 Hours of Hospitalization in Patients with Sickle Cell Disease and Infection: Evidence from a Retrospective Cohort Study

Introduction: Sickle Cell Disease (SCD) is a deadly, painful set of genetic abnormalities primarily affecting patients of African and Mediterranean descent. Although the hallmark symptom of SCD is pain, it is a multi-system disease that results in an amalgam of severe and life-threatening health consequences including increased susceptibility to bacterial, viral, and fungal infections. Infection remains the leading cause of morbidity and mortality in individuals diagnosed with SCD. We identified no research focused on the treatment patterns of antibiotic utilization in adults with SCD. This dearth of literature specific to SCD is surprising since the first 24 hours of antibiotic treatment in patients with SCD, especially those at risk for recurrent infection could reduce life threatening complications, length of hospital stay, and overall healthcare expenditures. A standardized protocol for treatment of infections in SCD does not exist and the first 24 hours of treatment varies among physicians and institutions. Treatment plans are determined by consensus guidelines, clinical experience and modifying treatment practices that have have shown promise in other diseases. The purpose of this study is to analyze treatment patterns within the first 24 hours of hospitalization in patients with SCD and infection to identify major factors influencing outcomes and clinical management. Methods: We conducted a retrospective cohort study using electronic health records from hospitalizations with a documented infection in North-Central Florida. Encounters from patients with sickle cell disease (SCD) were identified using ICD codes (ICD-9 codes: 282.41, 282.42, 282.61, 282.62, 282.63, 282.64, 282.68, 282.69). Demographics, comorbid conditions, empiric antibiotic use, causative infectious organism, and the presenting infectious syndrome were extracted from EHR for each hospitalization. Outcomes of interest were length of hospitalization and 90-day all-cause mortality. Patients with no listed comorbid conditions at the time of hospital admission were excluded. Patient characteristics and clinical factors between groups were summarized descriptively and compared between SCD encounters. Results: Among approximately 140,000 eligible encounters, 988 (0.71%) encounters were from those with SCD and of those 837 were included in the analysis: Median Age: 47 y/o Sex: Female 583 (69.7%) Male: 254 (30.3%) 209 (0.25%) had an infection fromE. coli and (12.4%) had an infection from staphylococcus aureus. 332 (39.7%) of hospital admissions were secondary to genitourinary infections Vancomycin (28.7) was the most frequently used antibiotic within the first 24 hours of admission More than half (67.4%) of patients had chronic pulmonary disease The median length of stay during our study period was 7 days 12.1% of encounters required intensive care unit hospitalization 90 Day All-Cause Mortality was 5.5% Results: We examined the key comorbid conditions and factors that influence the hospitalization and their outcomes in SCD Future studies are needed to examine the key factors resulting in an increased risk of infection among SCD genotypes and the treatment patterns within the first 24 hours of treatment in patients with SCD and non-SCD to identify major factors influencing differences in outcomes and clinical management. . Machine learning approaches could aid in stratifying patients to direct more intensive interventions towards high-risk groups to improve the health outcomes of patients with SCD

Evaluation of two red cell inclusion staining methods for assessing spleen function among sickle cell disease patients in North-East Nigeria.

The loss of splenic function is associated with an increased risk of infection in sickle cell disease (SCD); however, spleen function is rarely documented among SCD patients in Africa, due partly to the non-availability of sophisticated techniques such as scintigraphy. Methods of assessing splenic function which may be achievable in resource-poor settings include counting red blood cells (RBC) containing Howell Jolly Bodies (HJB) and RBC containing silver-staining (argyrophilic) inclusions (AI) using a light microscope. We evaluated the presence of HJB-and AI-containing RBC as markers of splenic dysfunction among SCD patients in Nigeria. We prospectively enrolled children and adults with SCD in steady state attending outpatient clinics at a tertiary hospital in North-East Nigeria. The percentages of HJB-and AI-containing red cells were estimated from peripheral blood smears and compared to normal controls. There were 182 SCD patients and 102 healthy controls. Both AI- and HJB-containing red cells could be easily identified in the participants blood smears. SCD patients had a significantly higher proportion of red cells containing HJB (1.5%; IQR 0.7%-3.1%) compared to controls (0.3%; IQR 0.1%-0.5%) (P <0.0001). The AI red cell counts were also higher among the SCD patients (47.4%; IQR 34.5%-66.0%) than the control group (7.1%; IQR 5.1%-8.7%) (P < 0.0001). The intra-observer reliability for assessment of HJB- (r = 0.92; r2 = 0.86) and AI- containing red cells (r = 0.90; r2 = 0.82) was high. The estimated intra-observer agreement was better with the HJB count method (95% limits of agreement, -4.5% to 4.3%; P = 0.579).We have demonstrated the utility of light microscopy in the assessment of red cells containing-HJB and AI inclusions as indices of splenic dysfunction in Nigerian SCD patients. These methods can be easily applied in the routine evaluation and care of patients with SCD to identify those at high risk of infection and initiate appropriate preventive measures.

Acute kidney injury in Jamaicans with sickle cell disease hospitalized with COVID-19 infection.

Despite a high occurrence of acute kidney injury (AKI) with COVID-19 infection, there are no data on its incidence in sickle cell disease (SCD). We performed a single-center retrospective chart review of persons aged >1 year with SCD, COVID-19 infection and no prior dialysis requirement hospitalized from June 1, 2020 to May 31, 2022. Demographics, clinical, laboratory characteristics and outcomes were abstracted. AKI was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria. Of 38 patients meeting study criteria (60.6% female, mean age ± SD 38.6 ± 15.9 years), 3 (7.9%) were COVID vaccinated. Fifty-five percent (55%) developed AKI with 7.9% (n= 3) requiring dialysis. Participants with AKI were older (44.9 versus 30.8 years, p= 0.005), with a higher proportion having baseline chronic kidney disease (52% versus 0%, p = 0.001). Severe COVID infection [age-adjusted odds ratio (aOR): 8.93, 95%CI: 1.73-45.99, p = 0.033], red cell transfusion (aOR 7.92, 1.47-42.69) and decrease in hemoglobin per unit from baseline (aOR 2.85, 1.24-2.28) were associated with AKI. Five persons died in hospital, with AKI resulting in higher median length of stay (12 versus 5 days, p = 0.007). Targeted COVID-19 preventative measures and multinational longitudinal studies to ascertain the impact of AKI and COVID-19 infection in SCD are needed.

COVID-19 Vaccination Status and Disease Burden in Patients with Sickle Cell Disease

Background: Patients with sickle cell disease (SCD) are immunocompromised due to impaired splenic function, dysfunctional antibody production and opsonization, and defects in complement activation leading to increased susceptibility to infections (PMID: 19497774). Therefore, severe acute respiratory syndrome coronavirus 2, also known as COVID-19, may potentially cause severe complications in patients with SCD. The clinical course of COVID-19 infection in SCD has been described in larger cohorts with disease severity varying widely among patients (PMID: 34882837, 33570644). The COVID-19 vaccines have been used since becoming available in late 2020 but data regarding COVID-19 vaccination status, efficacy, and safety in patients with SCD is lacking. The purpose of this study is to investigate COVID-19 vaccination acceptance rates and its efficacy and safety in SCD. Methods: A total of 535 adults (age ≥ 18 years old) with the diagnosis of SCD who had encounters at the University of Illinois Hospital and Health Sciences System (UIHealth) between January 1st, 2021 and December 31st, 2021 were included in this retrospective study. Demographic information, COVID-19 vaccination status, COVID-19 infection and other relevant clinical information were collected. The COVID-19 vaccination status for residents in Chicago was collected from the official website of the city of Chicago. Univariate analyses of patient characteristics were conducted using the Kruskal-Wallis test for continuous variables and the Chi-square test for categorical variables. Stepwise logistic regression analysis was used to identify clinical correlates of COVID-19 vaccination status and infection. Results: In this retrospective cohort, 52.3% received at least one dose and 48.6% completed the primary series of COVID-19 vaccination by December 31, 2021 (Figure 1). This vaccination rate is lower than that of the general African American population (64.7% and 59.1%, respectively). Older age, being employed or a student, and previous influenza immunization history were significant predictors of COVID-19 vaccination completion (Table 1). Approximately 23% of the patients contracted COVID-19 infection with the highest incidence in patients with a higher number of acute healthcare encounters. COVID-19 vaccination decreased the infection risk by 70% (OR 0.311, 95%CI: 0.127-0.766, p = 0.01), but no significant difference in COVID-19 infection severity was found in patients with versus without COVID-19 vaccination. The incidence of side effects associated with COVID-19 vaccination was evaluated by comparing the number of ACC/ED/hospitalization after receiving the vaccine to the same time period in the previous year. No significant difference was found for each dose received (for the 1st door dose: p = 0.105; for the 2nd dose: p = 0.143; and for the 3rd dose: p = 0.397). Summary: We conclude that COVID-19 vaccination did not cause significant side effects and was effective in patients with SCD, but the completion rate is not ideal considering the greater need for vaccination in this patient population. Our findings further emphasize the importance of developing strategies to address vaccination hesitance in patients with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

National Burden of Encapsulated Bacterial Infections in Sickle Cell Disease

Introduction: Patients with sickle cell disease (SCD) are at much higher risk for infections from encapsulated organisms, particularly Streptococcus pneumoniae (pneumococcus), Neisseria meningitidis (meningococcus), and Hemophilus influenzae. Vaccinations and prophylactic penicillin (for pneumococcus) have declined but not eliminated their incidence. We aim to study the SCD admissions with infections from above mentioned encapsulated organisms. Methods: We performed a retrospective analysis using the National Inpatient Sample (NIS) database from 2016 to 2019 to identify SCD hospitalizations with either S. pneumoniae, N. meningitidis, or H. influenzae infections using appropriate International Classification of Diseases, Tenth Revision, Clinical Modification (ICD 10-CM) codes. SCD included HbSS (D57.0x), HbSC (D57.2x) and others (D57.1, D57.4x and D57.8x). Infections from S. pneumoniae and H. influenzae included sepsis (A40.3, A41.3), pneumonia (J13, J14), meningitis (G00.1, G00.0), and others (M00.1x, B95.3, A49.2, B96.3, and J20.1). N. meningitidis infections were identified by ICD-10-CM code A39.x. Admissions were divided into pediatric (<18 years) and adult (≥18 years) age groups and descriptive analysis was performed to compare demographics, hospital characteristics, and comorbid conditions/complications. We also calculated the annual hospitalization rate for encapsulated organisms per 10,000 SCD admissions. The methodology provided by the HCUP (Healthcare Cost and Utilization Project) was utilized, and weights were applied to produce national estimates. Results: Out of 533,175 SCD admissions from 2016-2019, 830 (0.16%) had an infection from S. pneumoniae or H. influenzae. There were no admissions with N. meningitidis during our study period. The annual hospitalization rate for encapsulated bacterial infection per 10,000 SCD admissions ranged from 15.6/year to 40.6/year for the pediatric population and 11/year to 15.2/year among adults (Figure 1). Overall rate was 30 per 10,000 SCD admissions in pediatric population and 12 per 10,000 in adults (p <0.001). Among S. pneumoniae infections, hospitalizations were highest for children ≤5 years at 64 per 10,000 SCD admissions, followed by 14 per 10,000 in children aged >5 & <18 years and lowest in adults (≥18 years) at 12 per 10,000 (p <0.001). Among 695 SCD admissions with S. pneumoniae, 325 (46.8%) were HbSS, and 65 (9.4%) had HbSC disease. Furthermore, 260 (37.4%) were <18 years and 435 (62.6%) were ≥18 years. The median age for children was 5 (2-10) years and 34 (27-47) for adults (p <0.001). Most admissions were males (56.1%), without significant comorbidities (Charlson comorbidity index 0 in 59.7%) and belonged to lowest income communities (47.8%). More than a quarter of adults (26.4%) had tobacco use disorder, and 8.1% had HIV/AIDS. Incidence of acute respiratory failure and acute kidney failure was higher in adults than in children (25.3% vs. 1.9%; p <0.001 and 29.9% vs. 3.9%; p <0.001 respectively). The median length of stay was 6 (4-11) days for adults and 4 (3-7) days for <18-year-olds (p <0.001). There were 26.4% adults compared to 9.6% children with a length of stay >10 days (p 0.02). Median hospital charges and costs were also higher for adults compared to children. Whereas there were no pediatric discharges requiring home health care, 17.4% of adults had home health care arranged (p 0.01). All-cause-in-hospital mortality was 1.4%. Out of 145 H. influenzae admissions, 40 (27.6%) were <18 years, and 105 (72.4%) were ≥18 years. Like S. pneumoniae, the majority of SCD admissions with H. influenzae admissions were males (65.5%), belonged to the lowest income communities (51.7%), admitted to large (48.3%), teaching hospitals (89.7%), and had no significant comorbidities (Charlson comorbidity index 0 in 55.2%). Around 24.1% stayed in the hospital for >10 days, and 20.7% required invasive mechanical ventilation. The median length of stay was 7 (5-10) days, and all-cause-in-hospital mortality was 3.5% (Table 1). Conclusion: Despite vaccinations and prophylactic penicillin, the burden of encapsulated bacterial infections in pediatric SCD hospitalizations remains disproportionately higher than in adults. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Procalcitonin as a diagnostic marker for infection in sickle cell disease

ABSTRACT Background Patients with sickle cell disease (SCD) are at increased risks of infection. Fever often occurs with vaso-occlusive crisis (VOC), posing a diagnostic challenge in SCD. Procalcitonin (PCT) is an infectious biomarker validated in the general population but with limited data on use in SCD. Methods We performed a retrospective single-center study (n = 145) with primary objective of assessing ability of PCT to differentiate infection from VOC in SCD presenting with fever. Subgroups included confirmed bacterial infection (CBI), suspected bacterial infection, viral infection, and VOC. A secondary objective examined the association of PCT with acute chest syndrome. Clinical characteristics and data were collected and analyzed to assess the diagnostic performance of PCT and associated variables. Results Of the cohort, 16% had CBI and 8% had viral infection. PCT was able to discriminate CBI from viral infection [AUC = 0.89 (95%CI, 0.78–0.99)] and VOC [AUC = 0.87 (95%CI, 0.78–0.97)]. PCT had an association with ACS but poor diagnostic performance [AUC = 0.69 (95% CI, 0.54–0.84)]. Conclusion PCT has utility in distinguishing confirmed bacterial infection from VOC or viral infection and is a promising biomarker when investigating fever in SCD.

Hepatitis C virus (HCV) infection among patients with sickle cell disease at the Korle-Bu teaching hospital

BackgroundHepatitis C virus (HCV) infection is a blood borne infection that remains potentially transmissible through blood transfusions. Sickle cell disease (SCD) is a common inheritable haemoglobinopathy in Ghana that requires multiple blood transfusions as part of its management. The SCD patient is therefore at a high risk of HCV infection; however, data on the occurrence of HCV in SCD patients has not been documented in Ghana. This study sought to determine the prevalence and genotypes of HCV infection in SCD patients.Materials and methodsThis was a cross-sectional study which enrolled 141 sickle-cell disease patients from the Ghana Institute for Clinical Genetics, Korle-Bu Teaching Hospital (KBTH). Patient information was obtained through a structured questionnaire. Aliquots of the plasma obtained was used for both serology with Advanced Quality Rapid Anti-HCV Test Strip and molecular testing by RT-PCR with primers targeting the HCV core gene. The amplified DNA were purified and subjected to phylogenetic analysis to characterize HCV genotypes.ResultsTwelve (9%) out of the 141 patients were sero-positive for HCV total antibodies. HCV RNA was amplified from 8 (6%) out of the total number of patients’ samples. One of the 12 sero-positives was HCV RNA positive. Five (63%) out of the 8 HCV RNA positive samples were successfully sequenced. The phylogenetic tree constructed with the study and GenBank reference sequences, clustered all five study sequences into HCV genotype 1.ConclusionThe HCV seroprevalence of 9% among sickle cell disease patients is higher than reported for the general Ghanaian population which is 3%. Genotype 1 is the common HCV genotype infecting SCD patients. Sickle cell disease is likely to be a high-risk group for HCV inapparent infections in Ghana as seroprevalence does not correlate with viremia. However, even with higher seroprevalence, the group must be given priority in resource allocation for preventive, diagnostic and therapeutic strategies.

Bloodstream Infections in Children With Sickle Cell Disease: 2010-2019.

Children with sickle cell disease (SCD) are at increased risk for bloodstream infections (BSIs), mainly because of functional asplenia. Immunizations and antibiotic prophylaxis have reduced the prevalence of invasive bacterial infections, but contemporary analysis of BSI in children with SCD is limited. We conducted a retrospective cohort study of children aged <18 years with SCD who had blood cultures collected at our institution from 2010 to 2019 to identify BSI. Probable contaminant organisms were identified and not included as BSI. We calculated the annual incidence of BSI at our institution with 95% confidence intervals (CIs) and used multivariate logistic regression to evaluate associations. There were 2694 eligible patients with 19 902 blood cultures. Excluding repeated cultures and contaminant cultures, there were 156 BSI episodes in 144 patients. The median age at BSI was 7.5 years. The average incidence rate of BSI was 0.89 per 100 person-years (95% CI 0.45-1.32). The most common pathogens were Streptococcus pneumoniae (16.0%), Streptococcus viridans group (9.0%), Escherichia coli (9.0%), Staphylococcus aureus (7.7%), Bordetella holmesii (7.7%), Haemophilus influenzae (7.1%), and Salmonella species (6.4%). Odds of BSI were higher with sickle cell anemia genotypes (odds ratio [OR] 1.88; 95% CI 1.20-2.94) and chronic transfusions (OR 2.66; 95% CI 1.51-4.69) and lower with hydroxyurea (OR 0.57; 95% CI 0.39-0.84). BSI remains a risk for children with SCD. Overall incidence, risk factors, and spectrum of pathogens are important considerations to guide prevention and empirical treatment of suspected infection in SCD.

Mortality of covid19 in sickle cell disease systematic review

The covid19 infection is pandemic disease are more commonly in chronic diseases. As covid19 case pulmonary infection, the current study focuses on sickle cell disease patients are suitable to acute chest syndrome. It will clarify the risk factors for covid19 infection and its clinical features in sickle cell disease. It also reviews the radiological findings to gain more data on this pandemic disease. The current study includes 44 cases of sickle cell disease having covid19 infection. The entire cases include sickle cell disease only in 89% whereas the other sickle cell disease cases are coexisted with beta- thalassemia in 9.1%. The fourth decade is the highest peak incidence. There are several complications found to be in sickle cell disease are acute chest syndrome, chronic leg ulcer, renal failure exceeding 10%. The bronchial asthma found to be in 6.9% and avascular necrosis found to be 11.4% whereas the cerebrovascular accident found to be in 13.8%. The radiological changes include lung tissues, alveoli, pleural cavities and pulmonary arteries in different rate. The incidence of recovery found to be in 93% whereas the death found to be in 7%. It found to be involving in respiratory and gastrointestinal systems result in different clinical features in different rate. This study compares the clinical features, findings investigation and complications between sex and decades. Further, this study clarifies recovery and mortality rate between sex and decades. Knowing and understanding covid19 infection in sickle cell disease, physicians will be able to provide high quality of medical services.

Prognostic factors associated with COVID-19 related severity in sickle cell disease

BackgroundEquipoise exists regarding sickle cell disease (SCD) as a risk factor for COVID-19 disease severity and variables that increase risk of COVID-19 severity in SCD. Given our health system's large SCD patient catchment, we analyzed our own experience in this regard. Study methodsRetrospective analysis of the clinical course and factors associated with need for hospitalization and ICU admission of SCD patients diagnosed with COVID-19 through the Northwell Health system from March 1 to Dec 31, 2020. ResultsOf 1098 patients with SCD, 3.3% were diagnosed with COVID-19. Overall rates of hospitalization, ICU admission, cohort mortality, and in-hospital mortality were 80%, 19%, 2.5%,and 3.1%, respectively. By multivariable analysis, hospitalization risk was decreased by 60% for every 1 g/dL increase in admission Hb. ICU admission risk was increased by 84% as a health care worker; increased by 45% for every 1000/uL increase in admission immature granulocyte count; and decreased by 17% with hydroxyurea use. DiscussionHigh hospitalization rates are compatible with worsened severity upon COVID-19 infection in SCD compared to the general population. Patients should be placed on hydroxyurea to increase their Hb and perhaps lower their neutrophil counts. Health care workers with SCD may warrant special safety precautions.

Upregulation of Antiviral Factors That Inhibit HIV-1 Infection in Sickle Cell Disease

IntroductionPatients with Sickle cell disease (SCD) have lower risk for HIV-1 infection. We showed that ex vivo HIV-1 replication is blocked in SCD PBMCs in part because of the increased expression of ferroportin (FPN) and activation of SAMHD1, a host antiviral restriction factor. We hypothesized that rupture of sickling red blood cells releases sickle cell hemoglobin (HbS) that is phagocyted by macrophages leading to upregulation of innate antiviral response and inhibition of HIV-1 replication. We accessed changes in antiviral gene expression in PBMCs obtained from SCD patients compared to healthy controls. We also analyzed antiviral gene expression in macrophages treated with HbS compared to the HbA treatment.MethodsThe study was approved by Howard University review board (IRB) and all subjects consented to sample collection. Whole blood was collected from 9 SCA patients and 9 age and gender- matched healthy controls. PBMCs were activated with PHA (0.5 μg/ml) for 24-48 hrs followed by IL-2 (10 U/ml) for 24 hrs. Human THP-1 cells were differentiated into macrophages with PMA (25nM) for 72 hrs and treated with purified HbS or HbA (5µM). RNA strand-specific libraries were constructed using TruSeq Stranded Total RNA Gold kit (Illumina) and sequenced on an Illumina NextSeq 500 using 75 bp paired-end sequencing on two v2.5 150 cycle High-Output kits, generating 40-50 million paired-end reads per sample. The sequencing data were mapped using Dragen RNA and compared using Dragen differential expression software (Illumina). Ingenuity Pathway analysis (IPA, Qiagen) was used for pathway analysis.ResultsIn activated SCD PBMCs compared to control PBMCs, 40432 genes were detected including 2230 differentially expressed genes (5.5%, 1.5-fold difference, 287 down and 1943 up) at 5% false discovery rate. In non-activated SCD PBMCs compared to control PBMCs, 33119 genes were detected including 5299 differentially expressed genes (16%, 923 down and 4376 up). In THP-1-differentiated macrophages treated with HbS versus HbA, 28362 genes were detected including 322 differentially expressed genes (1.1%, 187 down and 135 up).We focused our analysis on 61 genes including viral restriction factors and iron regulatory genes. In activated SCD PBMCs, four genes had highest upregulation: APOBEC3A (23-fold, p=2 x 10 -5), CH25H (11-fold, p=4 x 10 -5), heme oxygenase-1 (HMOX1, 13-fold, p=1.5 x 10 -12) and FPN (SLC40A1, 5-fold, p = 9 x 10 -8) (Fig.1). Several additional genes were upregulated with 1.5-3-fold increase and high significance including APOBEC3B, BRD4, CD40, CDKN1A (p21), GDR1, IFIT3, IFITM3 and SAMHD1. In non-activated SCD PBMCs, the most upregulated gene was PKR (EIF2AK2, 15-fold, p=1 x 10 -11) and genes with 1.5-3 fold upregulation included APOBEC3B, BST2, CPSF6, IFI16, IFITM3, ISG15, LGALS3BP, PML and RTF1 (Fig.1). Of these genes, only IFITM3 overlapped between activated and non-activated PBMCs.To test whether circulating HbS leads to the upregulation of antiviral response, we analyzed HbS-treated macrophages and found upregulation of several antiviral restriction factors (1.5-2.3 fold): IFIT3, LGALS3BP, MX2 and RTF1 (Fig.1). Unsupervised IPA showed upregulation of IRF-7 signaling pathway and down regulation of viral infection and replication (Fig.2). We validated the CH25 and HO-1 antiviral role in activated SCD PBMCs using small molecule inhibitors. We also confirmed overexpression of CH25H and HO-1 by western blot and ELISA. We observed higher levels of IRF7 in the activated SCD PBMCs confirming that it may play a role in the induction of antiviral response.ConclusionWe propose that HbS released by hemolysis and uptaken by macrophages leads to the IRF-7-triggered induction of antiviral state in macrophages that will induced antiviral state in non-activated circulating PBMCs likely though the cytokines and interferons secretion known to be elevated in SCD patients. Upregulation of PKR (EIFAK2) levels in non-activated PBMCs strongly argue toward this possibility. Upon activation of PBMCs, additional factors are expressed including CH25H, HO-1, APOBEC3A and FPN that facilitated stronger and more robust anti-HIV-1 effect and block viral replication. Taken together, our study point to novel mechanism of upregulation of antiviral factors mediated by sickle cell hemoglobin that included induction of antiviral, heme- and iron- regulatory pathways. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ERN-EuroBloodNet European Registry of Patients Affected by Red Blood Cell Disorders and COVID-19

ERN-EuroBloodNet European Registry of Patients Affected by Red Blood Cell Disorders and COVID-19

Frequency of bacteremia in patients with sickle cell disease: a longitudinal study.

Bacterial infections in sickle cell disease (SCD) are associated with major risks of morbidity and mortality. Here, we describe the occurrence of bacteremia in SCD patients from 2000 to 2017. This is an observational study which included children and adults with SCD and fever and had confirmed positive blood cultures. During the study period, there were 1095 SCD patients with 17,053 blood cultures. Of all the patients, 699 (63.8%) were children and 396 (36.2%) adults with 576 (52.6%) males and 519 (47.4%) females. The mean age ± SD was 17.8 (± 14.7), and a median age (IQR) of 13.6 (6.8-23.5) years. The mean (SD) follow up was 7.4 (5.4) years and the total number of patient-years was 8069.1 years. Out of the 1095 patients, 91 (8.3%) had bacteremia with 35 (38.5%) children and 65 (61.5%) adults (p = .079). The rate of bacteremia in all patients, children, and adults were 1.5 (95% CI: 1.3-1.8), 0.6 (95% CI: 0.4-0.8), and 2.4 (95% CI: 1.8-3.1) per 100 patient-years, respectively. The risk of Gram-positive bacteremia was 0.5 (96% CI: 0.36-0.69) in all patients, 0.1 (95% CI: 0.06-0.20) in children, and 1.4 (95% CI: 1.0-2.0) in adults per 100 patient-years. The risk of Gram-negative bacteremia was 1.0 (95% CI: 0.81-1.3) in all patients, 0.6 (95% CI: 0.4-0.8) in children, and 2 (95% CI: 1.5-2.7) in adults per 100 patient-years. The risk of Gram-negative bacteremia was higher than Gram-positive bacteremia in children (p < .001) but not in adults (p = .113) and adults had higher risk in general than children. In this study of SCD cohort, 8.3% had bacteremia with predominant Gram-negative infections. Bacteremia was more frequently encountered in the adult age group. Further studies are needed to verify the findings and explore possible reasons predisposing SCD patients to bacteremia.

Respiratory Viral Infections in Sickle Cell Anemia: Special Emphasis on H1N1 Co-infection.

ObjectivesPatients with sickle cell anemia (SCA) are immunocompromised and at an increased risk of developing infections. Our aim was to establish the clinical, laboratory, and radiological manifestations of respiratory viral infections in SCA at Sultan Qaboos University Hospital (SQUH), Oman and assess its impact on disease morbidity and mortality, with special emphasis on H1N1.MethodsWe undertook a retrospective study in SCA patients with respiratory viral infections following up at the hematology department at SQUH. We collected demographic data and clinical, radiological, and laboratory parameters.ResultsIn 84 SCA patients with 109 admission episodes for vaso-occlusive crisis (VOC), molecular diagnostic techniques confirmed 125 respiratory viral infections. Rhinovirus was the most prevalent infection (35.8%), whereas H1N1 virus infection was seen only in 10.1%. Laboratory investigations revealed a significant fall in mean hemoglobin levels, mean white blood cell, and platelet counts from baseline, whereas there was a significant rise in the mean lymphocyte and retic count, serum lactate dehydrogenase, and C-reactive protein levels during infective episodes (p < 0.050, Wilcoxon signed rank test). One-third (32.1%) of the VOC episodes progressed to acute chest syndrome (ACS), but in the H1N1 cohort, only two episodes of ACS was seen (18.2%).ConclusionsRhinovirus was the commonest respiratory virus infections in SCA patients, whereas parainfluenza 3 was associated with a significant adverse outcome. H1N1 was associated with a mild course. ACS was seen in approximately one-third of this group of patients.

Parvovirus B19 infection in sickle cell disease: An analysis from the Centers for Disease Control haemoglobinopathy blood surveillance project.

In the multicentre Haemoglobinopathy Blood Surveillance Project, to evaluate the seroprevalence of parvovirus B19 and DNA viral load in sickle cell disease (SCD). Although the epidemiology of parvovirus B19 seropositivity in SCD has been well documented, there are few studies that have assessed possible persistent parvovirus DNAemia and associated risk factors including blood transfusion. A qualitative analysis of parvovirus B19 serology using ELISA and quantitative parvovirus B19 DNA by RT-PCR was performed in patients with SCD. Of 322 patients, 113 (35%) were parvovirus IgG positive and 119 (37%) were IgM positive at enrolment. The prevalence of IgG positivity increased with age. 71/322 (22%) were parvovirus DNA positive at enrolment with a mean viral load of 15 227 ± 55 227 SD. (range 72-329 238 IU/mL). Patients who were positive for parvovirus B19 DNA received a significantly higher red blood cell transfusion volume in the prior year compared to patients who were negative (mean RBC volume = 8310 mL vs 5435 mL, respectively; P = .0073). Seventy-seven patients had follow-up testing approximately 1 year after enrolment and 11/28 (39%) patients had persistently positive IgM. Further studies are needed to better understand the natural history of parvovirus B19 infection in SCD especially in relation to RBC transfusion as a risk factor, as well as disease outcome and severity.

Implications of COVID-19 infections in sickle cell disease.

Sickle cell disease is a major concern of public health significance in Africa. Nearly 2/3rd of the global burden of sickle cell disease (SCD) is found to be in sub-Saharan Africa. There is increased mortality risk in sickle cell disease patients in Africa due to associated complications such as acute chest syndrome, asthma, pulmonary emboli and sepsis. Sickle cell disease management is the major contributor of financial burden on the government. Moreover, there is a shortage of medical specialists in Africa. COVID-19 pandemic has further led to devastating impact on economy and health globally. The chances of SCD patient contracting COVID-19 infections are higher as these patients are immunocompromised and may be at a higher risk of mortality. Practicing preventive measures including isolation and social distancing by these patients will prevent mortality rates as well as economic burden on government in the present unprecedented COVID-19 pandemic.

Polymorphisms in Inflammatory Genes Modulate the Occurrence of Clinical Complications in Patients with Sickle Cell Disease

Background: Patients (pts) with sickle cell disease (SCD) show a high phenotype variability that is not fully understood. Because inflammation plays a major role in SCD pathophysiology, we hypothesized that single nucleotide polymorphisms (SNPs) in genes of innate and adaptative inflammatory response modulate the occurrence of SCD complications. Objective: to establish associations between SNPs and clinical complications in pts with SCD. Methods: Case-control retrospective study; 500 pts were included, followed at Senegal (n=56), Brazil (n=230) and France (n=214). We analyzed the effect of 20 SNPs in 6 clinical complications: acute chest syndrome (ACS), stroke, leg ulcers, cholelithiasis, osteonecrosis and retinopathy. Using TaqMan 5'-nuclease assay, we genotyped SNPs in genes encoding Toll-like receptor (TLR) 1 (rs4833095), 2 (rs4308099, rs4308100, rs4696480), 6 (rs5743810), 10 (rs11466653, rs11096957), natural killer (NK) group 2 member D (NKG2D) receptor (rs1982536, rs2617160, rs2617169, rs2617170, rs2617171, rs1049174, rs2246809, rs2255336), human leukocyte antigen (HLA)-G (rs9380142), HLA-E (rs2517523), major histocompatibility complex class I polypeptide-related sequence A (MICA, rs1051792) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) (rs5742909, rs231775). All SNPs had a call rate &gt;90% and minimum allele frequency &gt;1%. We performed analyses of correspondence for indicating associations between SNPs and number of clinical complications. Logistic regressions were used to identify associations between SNPs and each complication, using geographical origin, SCD genotype, rate of transfusions and gender for modeling adjustment; the significance was adjusted for multiple testing using false discovery rate. Comparisons of genotype frequencies with the population of African descent from 1000 genomes database were done by chi-square. Results: Pts were originally from Brazil (n=228), Sub-Saharan Africa (n=200), French West Indies (n=53), North Africa (n=7) and 12 unknown. SCD genotype (available n=498) was SS (n=402), SC (n=46), SB (n=42), SD or SE (n=4). 280 pts were female; median age was 32 years (range 0-69); 184 pts received at least 20 transfusions. 71 pts presented stroke, 200 had at least 1 episode of ACS, 69 had leg ulcers, 271 had cholelithiasis, 150 had retinopathy and 90 osteonecrosis. 97 pts did not present complications, 135 had 1 type of clinical complication, 134 had 2, 94 had 3, 34 had 4 and 6 had 5. 21 pts underwent hematopoietic stem cell transplantation. 11 pts died during follow-up, mostly from ACS and hemorrhagic stroke. Indication of association with number of complications: TLR2 rs4696480 TA, TLR2rs3804099 CC and HLA-Grs9380142 AA were associated with occurrence of 0-1 clinical complications, MICA rs1051792 AA/AG with up to 2 complications and NKG2D rs2617169 AA with 5 complications. Association between genotypes/haplotypes and each complication: no association was found between SNPs and stroke, ACS, leg ulcers and osteonecrosis. Rs9380142 was the only SNP significantly associated with cholelithiasis in the logistic regression additive model. The G allele increased the risk of cholelithiasis (AG x AA, OR 1.57, 95%CI 1.16-2.15; GGxAA, OR 2.47, 95%CI 1.34-4.64; P=0.02). For retinopathy, in the logistic regression additive model, the presence of the A allele decreased the risk of retinopathy for rs2246809 in pts of same origin (AAxGG: OR 0.22, 95%CI 0.09-0.50; AGxGG: OR 0.47, 95%CI 0.31-0.71; P=0.004), rs2617160 (ATxTT: OR 0.67, 95%CI 0.48-0.92; AAxTT: OR 0.45, 95%CI 0.23-0.84; P=0.04) and rs2617169 in pts of same SCD genotype (AAxTT: OR 0.33,95%CI 0.13-0.82; ATxTT: OR 0.58, 95%CI 0.36-0.91, P=0.049). No haplotype was associated with complications. The genotype distribution of SNPs rs4696480, rs3804099, rs1051792 and rs2617169 differed significantly from the population of African descent from the 1000 genomes database. Discussion: We have previously shown that TLR2 rs4696480 TA decreases occurrence of bacterial infections in SCD; in this study, TA is also associated with less complications. Also, HLA-G rs9380142 AA had less complications and cholelithiasis, and 3 SNPs in NKG2D modulated occurrence of retinopathy. TLR and NKG2D may be activated by heat shock proteins, released in ischemia-reperfusion injury that occurs in SCD. Our findings help to better understand the role of inflammation in phenotype heterogeneity in SCD. Disclosures No relevant conflicts of interest to declare.

Control of HIV-1 Infection By Ferroportin Q248H Mutation

BACKGROUND: We recently showed that patients with Sickle Cell Disease (SCD), a hereditary hemolytic disorder, have low incidence of HIV-1 infection [1] and reduced ex vivo HIV-1 infection [2]. PBMC from SCD patients exhibited increased expression of iron export protein, ferroportin and reduced cellular iron levels leading to CDK2 inhibition, reduced SAMHD1 phosphorylation and increased expression of IkBα. Ferroportin expression is regulated by liver-produced hepcidin that facilitates ferroportin internalization and degradation. Ferroportin Q248H mutation has an allele frequency of 2.2-13.4% in African populations. We previously reported reduced sensitivity of ferroportin Q248H mutant to physiologic hepcidin concentrations in patients with sickle cell disease [3]. OBJECTIVES: To analyze the effect of ferroportin Q248H mutation on HIV-1 infection in vitro and in disease progression among a cohort of HIV-1 infected African-American women. METHODS: HEK293 cells were used to express ferroportin Q248H mutant and test cellular ferritin and intracellular labile iron using calcein-AM. Confocal microscopy was used to visualize ferroportin expression. HIV-1 transcription was measured in 293T cells transfected with HIV-1 LTR-Luciferase vector and Tat expressing vector. Ex vivo infection was analyzed in monocyte-derived macrophages infected with VSVg-pseudotyped HIV-1 virus. Ferroportin Q248H mutation was genotyped using Thermo Fisher probe (C_25753769_10) and genotyping services at University of Utah. RESULTS: We observed reduced intracellular iron in ferroportin Q248H expressing cells compared to WT ferroportin even when the cells were treated with hepcidin. In the absence of hepcidin, both WT ferroportin and Q248H ferroportin efficiently inhibited HIV-1 transcription and replication. Hepcidin induced HIV-1 transcription and replication in the cells with WT ferroportin but not Q248H mutant ferroportin. HIV-1 replication was reduced in primary macrophages obtained from patients with ferroportin Q248H mutation. To test whether expression of ferroportin Q248H offered protection from HIV-1 infection, we analyzed a cohort of HIV-1 infected women (WIHS). We genotyped 970 African-American subjects of whom 628 were HIV-1 infected and 342 were non-infected. The prevalence of Q248H hetero or homozygote mutations was 7.0% in non-infected and 11.8% among HIV-1 infected individuals (Odds Ratio=1.77, p=0.02). Analysis of HIV viral load showed significant lower viral load in the subjects with ferroportin Q248H mutation compared to WT. CONCLUSIONS: Our findings point to the contribution of iron metabolism in HIV-1 restriction and the potential role of the ferroportin Q248H mutation in the regulation of HIV-1 infection in vivo. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 5G12MD007597 and P30AI087714). We thank Women's Interagency HIV-1 study (WIHS) for sharing DNA samples and providing access to the clinical data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. REFERENCES: Nouraie M, Nekhai S, Gordeuk VR. Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect. 2012;88(7):528-533. Kumari N, Ammosova T, Diaz S, et al. Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease. Blood Adv. 2016;1(3):170-183. Nekhai S, Xu M, Foster A, et al. Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin. Haematologica. 2013;98(3):455-463. Disclosures Anastos: NINR: Research Funding; NHGRI: Research Funding; NICHD: Research Funding; NIMH: Research Funding; NHLBI: Research Funding; NCI: Research Funding; NIAID: Research Funding; NINDS: Research Funding; NIDCR: Research Funding; NIMHD: Research Funding; NLM: Research Funding; Fogarty: Research Funding; NIDDK: Research Funding; NIA: Research Funding; NIAAA: Research Funding; NIDA: Research Funding.