Benralizumab in severe eosinophilic asthma by previous biologic use and key clinical subgroups: real-world XALOC-1 programme.

BACKGROUND: Pivotal Phase 3 trials and real-world studies have demonstrated benralizumab's overall efficacy and safety in severe eosinophilic asthma (SEA). Additional large-cohort data are needed to confirm its real-world effectiveness in SEA according to previous biologic use and key baseline characteristics important for treatment selection. METHODS: XALOC-1 is a large, multinational, retrospective, observational, real-world study programme of benralizumab in adults with SEA. This 48-week integrated analysis assessed annualised exacerbation rate (AER), maintenance oral corticosteroid (mOCS) use, asthma symptom control and lung function during a 12-month baseline period and up to 48 weeks after benralizumab initiation. Subgroup analyses were based on previous biologic use and key baseline clinical characteristics (mOCS use, blood eosinophil count, exacerbation history, age at asthma diagnosis, fractional exhaled nitric oxide level and presence of atopy and chronic rhinosinusitis with nasal polyps). RESULTS: Of 1002 patients analysed, 380 were biologic-experienced. At Week 48, 71.3% were exacerbation-free (versus 17.2% at baseline); relative reduction in AER was 82.7% overall and 72.9% in biologic-experienced patients; rates were maintained across all key clinical characteristic subgroups. Of patients using mOCS at baseline (n=274), 47.4% (130/274) eliminated their use by Week 48; the mean reduction from baseline in daily dose was 51.2% and, notably, 34.9% in biologic-experienced patients (n=115). Clinically significant improvements in asthma symptom control and lung function were observed. CONCLUSION: In this large, real-world programme, SEA patients treated with benralizumab had substantial improvements in clinical outcomes irrespective of previous biologic use and key clinical characteristics important to therapeutic decision-making in clinical practice.

Asthma exacerbations are associated with a decline in lung function: a longitudinal population-based study.

RATIONALE: Progressive lung function (LF) decline in patients with asthma contributes to worse outcomes. Asthma exacerbations are thought to contribute to this decline; however, evidence is limited with mixed results. METHODS: This historical cohort study of a broad asthma patient population in the Optimum Patient Care Research Database, examined asthma patients with 3+eligible post-18th birthday peak expiratory flow rate (PEF) records (primary analysis) or records of forced expiratory flow in 1 s (FEV1) (sensitivity analysis). Adjusted linear growth models tested the association between mean annual exacerbation rate (AER) and LF trajectory. RESULTS: We studied 1 09 182 patients with follow-up ranging from 5 to 50 years, of which 75 280 had data for all variables included in the adjusted analyses. For each additional exacerbation, an estimated additional -1.34 L/min PEF per year (95% CI -1.23 to -1.50) were lost. Patients with AERs >2/year and aged 18-24 years at baseline lost an additional -5.95 L/min PEF/year (95% CI -8.63 to -3.28) compared with those with AER 0. These differences in the rate of LF decline between AER groups became progressively smaller as age at baseline increased. The results using FEV1 were consistent with the above. CONCLUSION: To our knowledge, this study is the largest nationwide cohort of its kind and demonstrates that asthma exacerbations are associated with faster LF decline. This was more prominent in younger patients but was evident in older patients when it was related to lower starting LF, suggesting a persistent deteriorating phenotype that develops in adulthood over time. Earlier intervention with appropriate management in younger patients with asthma could be of value to prevent excessive LF decline.

[Emphysema after cochlear implantation - risk factors and therapeutic options]. / Emphyseme nach Cochlea-Implantation ­ Risikofaktoren und Therapieoptionen.

OBJECTIVE: In case of cochlear implantation seroma, hematoma, local wound infections or vertigo are rare but typical complications. In contrast, emphysema is seldom reported. They can occur after cochlear implantation both in the postoperative healing phase and years later. A therapeutic algorithm does not yet exist. METHODS: We report on 3 patients with subcutaneous emphysema in the area of the receiver-stimulator. An unsystematic review of the literature of cases with emphysema after cochlear implantation highlights possible risk factors and the therapeutic options. RESULTS: The 3 cases developed subcutaneous emphysema 2-11 month after cochlear implantation due to nose blowing or CPAP therapy in obstructive sleep apnea. The current literature reports another 35 cases of emphysema after cochlear implantation. Air insufflation via the Eustachian tube is the most frequently described cause. Diseases of the nose and sinuses, tube dysfunction and obstructive sleep apnea are potential risk factors. Pressure bandage, puncture, tympanic tubes, and surgical revision are common treatments. CONCLUSIONS: Most emphysema can be controlled by conservative methods such as pressure bandaging and behavioral instruction. Punctures should be avoided due to the risk of upcoming infections. The prophylactic use of antibiotics seems dispensable. Surgical revision should be considered especially in cases of pneumocephalus with suspected leakage in the dura. The coverage of the mastoidectomy by a bony cap can be precautious and beneficial in cases with risk factors.

Clinical and economic burden of chronic rhinosinusitis with nasal polyposis: A U.S. administrative claims analysis.

Background: Limited data exist on the clinical and economic burden of chronic rhinosinusitis with nasal polyposis (CRSwNP). Objective: To describe patient characteristics, health-care resource utilization (HCRU), and health-care costs among patients with CRSwNP with and without comorbid asthma (primary analysis) and with surgical management of nasal polyps (secondary analysis). Methods: This was a retrospective study of patients diagnosed with CRSwNP conducted using administrative claims data from January 1, 2013, through March 31, 2019. Study outcomes were assessed over a 2-year follow-up. Results were stratified by baseline asthma status (primary analysis) and presented separately for patients with surgically managed CRSwNP (secondary analysis). Results: The primary analysis included 10,999 patients with CRSwNP (2649 with asthma, 8350 without asthma). Patients with versus without asthma had higher medication use, HCRU, and all-cause medical costs (mean ± standard deviation $34,667 ± $42,234 versus $27,122 ± $45,573; p < 0.001) across the full follow-up period. CRSwNP-related medical costs were significantly higher for patients with versus without asthma in year 2 of follow-up. In the surgical management analysis (n = 4943), most categories of medication use and CRSwNP-related HCRU declined from baseline levels during follow-up, and CRSwNP-related pharmacy costs in year 2 were less than half of baseline levels. Conclusion: Patients diagnosed with CRSwNP and asthma had a greater burden of illness than those without asthma. Higher CRSwNP-related medical costs in year 2 of follow-up for patients with asthma may indicate worsening symptoms over time. Among patients with surgically managed CRSwNP, HCRU and costs increased in year 1 of follow-up but decreased below baseline levels in year 2, potentially reflecting improved symptom severity.

DNA Methylation and Immune Cell Markers Demonstrate Evidence of Accelerated Aging in Patients with Chronic Hepatitis B Virus or Hepatitis C Virus, with or without Human Immunodeficienct Virus Co-infection.

BACKGROUND: Several chronic diseases accelerate biological aging. We investigated age acceleration and the association between peripheral blood DNA methylation (DNAm) and immune cell markers in patients chronically infected with the hepatitis B virus (HBV) or the hepatitis C virus (HCV) with and without human immunodeficiency virus (HIV) co-infection. METHODS: Age acceleration was measured as the difference between epigenetic age (Horvath clock) and chronological age. The immune marker model of age acceleration was developed using Elastic Net regression to select both the immune markers and their associated weights in the final linear model. RESULTS: Patients with chronic HBV (n = 51) had a significantly higher median epigenetic age compared to chronological age (age accelerated) (P < .001). In patients with chronic HCV infection (n = 63), age acceleration was associated with liver fibrosis as assessed by histology (P < .05), or presence of HIV co-infection (P < .05), but not HCV mono-infection. Age acceleration defined by immune markers was concordant with age acceleration by DNA methylation (correlation coefficient = .59 in HBV; P = .0025). One-year treatment of HBV patients with nucleoside therapy was associated with a modest reduction in age acceleration, as measured using the immune marker model (-.65 years, P = .018). CONCLUSION: Our findings suggest that patients with chronic viral hepatitis have accelerated epigenetic aging, that immune markers define biological age, and have the potential to assess the effects of therapeutic intervention on age acceleration.

Metabolic Changes in Chronic Hepatitis C Patients Who Carry IFNL4-ΔG and Achieve Sustained Virologic Response With Direct-Acting Antiviral Therapy.

BACKGROUND: Clearance of hepatitis C virus (HCV) results in rapid changes in metabolic parameters early in direct-acting antiviral (DAA) therapy. Long-term changes after sustained virologic response (SVR) remain unknown. METHODS: We investigated longitudinal changes in metabolic and inflammatory outcomes in chronic hepatitis C (CHC) patients: low-density lipoprotein (LDL), high-density lipoprotein, triglycerides, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) using a general linear model for repeated measurements at 5 clinical time points and by human immunodeficiency virus (HIV) coinfection and IFNL4 genotype. RESULTS: The mean LDL increased markedly during DAA therapy (pre-DAA, 86.6 to DAA, 107.4 mg/dL; P < .0001), but then it decreased to 97.7 mg/dL by post-SVR year 1 (P < .001 compared with DAA; P = .0013 compared with SVR). In patients who carry the IFNL4-ΔG allele, mean LDL increased during treatment, then decreased at post-SVR year 1; however, in patients with TT/TT, genotype did not change during and after DAA treatment. The mean ALT and AST normalized rapidly between pre-DAA and DAA, whereas only mean ALT continued to decrease until post-SVR. Metabolic and inflammatory outcomes were similar by HIV-coinfection status. CONCLUSIONS: Changes in LDL among CHC patients who achieved SVR differed by IFNL4 genotype, which implicates the interferon-λ4 protein in metabolic changes observed in HCV-infected patients.

A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY).

BACKGROUND & AIMS: Cure rates in response to retreatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) are high, but this regimen has not been studied in patients with a history of poor adherence or treatment interruption, nor in patients with HIV/HCV coinfection. Herein, we aimed to assess the safety and efficacy of this combination in patients with genotype 1 HCV infection who had relapsed following combination direct-acting antiviral (DAA) therapy, regardless of HIV infection or previous treatment course. METHODS: The RESOLVE study was a multicenter, open-label, phase IIb study investigating the safety, tolerability and efficacy of SOF/VEL/VOX in 77 patients with virologic rebound following combination DAA therapy. Efficacy was defined as HCV RNA below the lower limit of detection 12 weeks after the end of treatment (SVR12), while safety endpoints included the incidence of grade 3 and 4 adverse events (AEs) following treatment, and the proportion of patients who stopped treatment prematurely due to AEs. RESULTS: In an intent-to-treat analysis, 70/77 (90.9%, 95% CI 82.1-95.8%) patients achieved SVR12, including 14/17 (82.4%) HIV coinfected participants and 18/22 (81.8%) of those with previous non-completion of DAA therapy. In an analysis of all patients who completed 12 weeks of study medication, 70/71 patients (99%) achieved SVR12. One patient experienced a grade 3 AE, and 4 experienced a grade 4 AE, all unrelated to study participation. Reported AEs were similar in HIV-coinfected patients, and patients receiving dolutegravir-based antiretroviral treatment experienced no clinically significant increases in aminotransferases. CONCLUSION: Retreatment with 12 weeks of SOF/VEL/VOX was safe and effective in patients with relapsed HCV following initial combination DAA-based treatment. Treatment response was not affected by HIV coinfection or previous treatment course. LAY SUMMARY: Twelve weeks of the combination of direct-acting antivirals (SOF/VEL/VOX) was safe and effective in patients with relapsed hepatitis C virus infection who had previously received combination therapy with direct-acting antivirals. Treatment response was not diminished by HIV coinfection, or non-completion of previous direct-acting antiviral-based therapy.

Implementation of a unique hepatitis C care continuum model in Rwanda.

BACKGROUND: There has been an evolution in the treatment of chronic hepatitis C (HCV) due to highly effective direct-acting antivirals, however, restriction of treatment to medical specialists hinders escalation of HCV treatment. This is particularly true in resource-limited settings (RLS), which disproportionately represent the burden of HCV worldwide. The ASCEND study in Washington, DC, demonstrated that complete task-shifting can safely and effectively overcome a low provider-to-patient ratio and expand HCV treatment. However, this model has not been applied internationally to RLS. METHOD: The validated ASCEND model was translated to an international clinical program in Kigali, Rwanda, aimed at training general medicine providers on HCV management and obtaining HCV prevalence data. RESULTS: The didactic training program administered to 11 new HCV providers in Rwanda increased provider's knowledge about HCV management. Through the training program, 26% of patients seen during the follow-up period were screened for HCV and a prevalence estimate of 2% was ascertained. Of these patients, 30% were co-infected with hepatitis B. CONCLUSION: The ASCEND paradigm can be successfully implemented in RLS to escalate HCV care, in a self-sustaining fashion that educates more providers about HCV management, while increasing the public's awareness of HCV and access to treatment.

Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis.

Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV-specific T cell phenotype and function. Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375 mg/m2 ) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme-Linked Immunospot assay, the number of activated and tissue-like B cells and number of T cells expressing Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and multiple cytokines were measured before and after rituximab therapy. B cell depletion therapy is associated with a significant (P < 0.0001) decline in peripheral T cells with exhaustive phenotype, from pre-therapy to post-therapy-of rituximab (mean ± standard error): CD4+ (16.9 ± 0.9% to 8.9 ± 1.0%) and CD8+ (6.8 ± 0.6% to 3.0 ± 0.5%) T cells expressing PD-1 and CD4+ (11.0 ± 1.0% to 6.1 ± 0.8%) and CD8+ (12.7 ± 0.7% to 6.4 ± 0.4%) T cells expressing TIM-3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN-γ (4.55 ± 0.3 to 9.6 ± 1.0 IFN-γ/106 PBMCs, P < 0.0001), and more than one cytokine (1.3 ± 0.1% to 3.8 ± 0.2%, P < 0.0001) after therapy compared to pre-therapy. B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis.

Expansion of Treatment for Hepatitis C Virus Infection by Task Shifting to Community-Based Nonspecialist Providers: A Nonrandomized Clinical Trial.

Background: Direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection has resulted in high rates of disease cure; however, not enough specialists currently are available to provide care. Objective: To determine the efficacy of HCV treatment independently provided by nurse practitioners (NPs), primary care physicians (PCPs), or specialist physicians using DAA therapy. Design: Nonrandomized, open-label clinical trial initiated in 2015. (ClinicalTrials.gov: NCT02339038). Setting: 13 urban, federally qualified health centers (FQHCs) in the District of Columbia. Patients: A referred sample of 600 patients, of whom 96% were black, 69% were male, 82% were treatment naive, and 20% had cirrhosis. Seventy-two percent of the patients had HCV genotype 1a infection. The baseline characteristics of patients seen by each provider type were similar. Intervention: Patients were assigned in a nonrandomized but specified manner to receive treatment from 1 of 5 NPs, 5 PCPs, or 6 specialists. All providers underwent an identical 3-hour training session based on guidelines. Patients received treatment with ledipasvir-sofosbuvir, which was provided on site, according to U.S. Food and Drug Administration labeling requirements. Measurements: Sustained virologic response (SVR). Results: 516 patients achieved SVR, a response rate of 86% (95% CI, 83.0% to 88.7%), with no major safety signals. Response rates were consistent across the 3 provider types: NPs, 89.3% (CI, 83.3% to 93.8%); PCPs, 86.9% (CI, 80.6% to 91.7%); and specialists, 83.8% (CI, 79.0% to 87.8%). Patient loss to follow-up was the major cause of non-SVR. Limitation: Nonrandomized patient distribution; possible referral bias. Conclusion: In a real-world cohort of patients at urban FQHCs, HCV treatment administered by nonspecialist providers was as safe and effective as that provided by specialists. Nurse practitioners and PCPs with compact didactic training could substantially expand the availability of community-based providers to escalate HCV therapy, bridging existing gaps in the continuum of care for patients with HCV infection. Primary Funding Source: National Institutes of Health and Gilead Sciences.

Age and geographic patterns of Plasmodium falciparum malaria infection in a representative sample of children living in Burkitt lymphoma-endemic areas of northern Uganda.

BACKGROUND: Falciparum malaria is an important risk factor for African Burkitt lymphoma (BL), but few studies have evaluated malaria patterns in healthy BL-age children in populations where both diseases are endemic. To obtain accurate current data, patterns of asymptomatic malaria were investigated in northern Uganda, where BL is endemic. METHODS: Between 2011 and 2015, 1150 apparently healthy children under 15 years old were sampled from 100 villages in northern Uganda using a stratified, multi-stage, cluster survey design. Falciparum malaria prevalence (pfPR) was assessed by questionnaire, rapid diagnostic test (RDT) and thick film microscopy (TFM). Weighted pfPR and unadjusted and adjusted associations of prevalence with covariates were calculated using logistic models and survey methods. RESULTS: Based on 1143 children successfully tested, weighted pfPR was 54.8% by RDT and 43.4% by TFM. RDT sensitivity and specificity were 97.5 and 77.8%, respectively, as compared to TFM, because RDT detect malaria antigens, which persist in peripheral blood after clinical malaria, thus results based on RDT are reported. Weighted pfPR increased from 40% in children aged under 2 years to 61.8% in children aged 6-8 years (odds ratio 2.42, 95% confidence interval (CI) 1.26-4.65), then fell slightly to 49% in those aged 12-15 years. Geometric mean parasite density was 1805.5 parasites/µL (95% CI 1344.6-2424.3) among TFM-positive participants, and it was higher in children aged <5 years at 5092.9/µL (95% CI 2892.7-8966.8) and lower in those aged ≥10 years at 983.8/µL (95% CI 472.7-2047.4; P = 0.001). Weighted pfPR was lower in children residing in sub-regions employing indoor residual spraying (IRS) than in those residing in non-IRS sub-regions (32.8 versus 65.7%; OR 0.26, 95% CI 0.14, 0.46). However, pfPR varied both within IRS (3.2-55.3%) and non-IRS sub-regions (29.8-75.8%; Pheterogeneity <0.001). pfPR was inversely correlated with a child's mother's income (P = 0.011) and positively correlated with being enrolled in the wet season (P = 0.076), but sex was irrelevant. CONCLUSIONS: The study observed high but geographically and demographically heterogenous patterns of asymptomatic malaria prevalence among children living in northern Uganda. These results provide important baseline data that will enable precise evaluation of associations between malaria and BL.

Moderate Sustained Virologic Response Rates With 6-Week Combination Directly Acting Anti-Hepatitis C Virus Therapy in Patients With Advanced Liver Disease.

BACKGROUND: Treatment of genotype 1 hepatitis C virus (HCV) infection with combination directly acting antivirals (DAA) for 8-24 weeks is associated with high rates of sustained virologic response (SVR). We previously demonstrated that adding a third DAA to ledipasvir and sofosbuvir (LDV/SOF) can result in high SVR rates in patients without cirrhosis. In this study, we investigated whether a similar regimen would yield equivalent rates of cure in patients with advanced liver fibrosis. METHODS: Fifty patients were enrolled at the Clinical Research Center of the National Institutes of Health and associated healthcare centers. Enrollment and follow-up data from April 2014 to June 2015 are reported here. Eligible participants were aged ≥18 years, had chronic HCV genotype 1 infection (serum HCV RNA ≥2000 IU/mL), and stage 3-4 liver fibrosis. HCV RNA was measured using a reverse-transcription polymerase chain reaction assay. RESULTS: Of patients treated with LDV, SOF, and the NS3/4A protease inhibitor GS-9451 for 6 weeks, 76% (38 of 50; 95% confidence interval, 60%-85%) had SVR achieved 12 weeks after the end of treatment. There was no statistically significant difference in treatment efficacy between treatment-naive patients (72%, 18 of 25) and those with treatment experience (80%; 20 of 25) (P = .51). Overall, 11 patients (22%) experienced virologic relapse, and 1 (2%) was lost to follow-up at 4 weeks after treatment. No serious adverse events, discontinuations, or deaths were associated with this regimen. CONCLUSIONS: Adding a third DAA to LDV/SOF may result in a moderate SVR rate, lower than that observed in patients without cirrhosis. Significant liver fibrosis remains an impediment to achieving SVR with short-duration DAA therapy. CHINESE CLINICAL TRIALS REGISTRATION: CT01805882.

Four-Week Direct-Acting Antiviral Regimens in Noncirrhotic Patients With Hepatitis C Virus Genotype 1 Infection: An Open-Label, Nonrandomized Trial.

BACKGROUND: Treatment of chronic hepatitis C virus (HCV) infection with direct-acting antivirals (DAAs) for 6 weeks achieves sustained virologic response (SVR) rates of 95% in some patients. If effective, shorter therapeutic courses could improve adherence and treatment costs. OBJECTIVE: To determine factors predictive of SVR to 4 weeks of DAA treatment in patients with stage F0 to F2 liver fibrosis. DESIGN: Open-label, nonrandomized, phase 2a trial. (Clinical Trials.gov: NCT01805882). SETTING: Single-center. PATIENTS: 50 treatment-naive and predominantly African American patients with HCV genotype 1 infection and early-stage liver fibrosis were sequentially enrolled into 2 treatment groups. INTERVENTION: 25 participants received a 3-drug regimen consisting of ledipasvir and sofosbuvir plus GS-9451 for 4 weeks, and 25 received a 4-drug regimen consisting of ledipasvir, sofosbuvir, GS-9451, and GS-9669 for 4 weeks. MEASUREMENTS: The primary efficacy end point was SVR12 (HCV RNA level below the lower limit of quantification at posttreatment week 12). RESULTS: Forty percent (10 of 25) (95% CI, 21% to 61%) of patients in the 3-drug group and 20% (5 of 25) (CI, 7% to 41%) of those in the 4-drug group achieved SVR12. Exploratory analysis suggested that lower baseline HCV viral load, younger age, and HCV genotype 1b were associated with SVR12. Ten patients had baseline HCV variants conferring greater than 20-fold resistance in vitro to at least 1 study DAA; all had viral relapse. Forty-eight percent (12 of 25) of patients receiving the 3-drug regimen and 72% (18 of 25) of those receiving the 4-drug regimen had adverse events, most of which were mild. One participant was lost to follow-up. LIMITATION: Nonrandomized study design and small sample of patients with early-stage fibrosis. CONCLUSION: Combination DAA therapy with 3 or 4 drugs for 4 weeks was well-tolerated but resulted in limited cure rates. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases, National Cancer Institute, and Clinical Center Intramural Program; supported in part by a cooperative research and development agreement between the National Institutes of Health and Gilead Sciences.

Endemic Burkitt lymphoma is associated with strength and diversity of Plasmodium falciparum malaria stage-specific antigen antibody response.

Endemic Burkitt lymphoma (eBL) is linked to Plasmodium falciparum (Pf) infection geographically, but evidence from individual-level studies is limited. We investigated this issue among 354 childhood eBL cases and 384 age-, sex-, and location-matched controls enrolled in Ghana from 1965 to 1994. Immunoglobulin G1 (IgG1) and immunoglobulin G3 (IgG3) antibodies to antigens diagnostic of recent infection Pf histidine-rich protein-II (HRP-II) and 6NANP, Pf-vaccine candidates SE36 and 42-kDa region of the 3D7 Pf merozoite surface protein-1 (MSP-1), and tetanus toxoid were measured by indirect enzyme-linked immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) for association with eBL were estimated using unconditional logistic regression. After adjustments, eBL was positively associated with HRP-IIIgG3 seropositivity (adjusted OR: 1.60; 95% CI 1.08-2.36) and inversely associated with SE36IgG1 seropositivity (adjusted OR: 0.37; 95% CI 0.21-0.64) and with tetanus toxoidIgG3 levels equal or higher than the mean (adjusted OR: 0.46; 95% CI 0.32-0.66). Anti-MSP-1IgG3 and anti-6NANPIgG3 were indeterminate. eBL risk was potentially 21 times higher (95% CI 5.8-74) in HRP-IIIgG3-seropositive and SE36IgG1-seronegative responders compared with HRP-IIIgG3-seronegative and SE36IgG1-seropositive responders. Our results suggest that recent malaria may be associated with risk of eBL but long-term infection may be protective.

Benralizumab in Severe Eosinophilic Asthma and Chronic Rhinosinusitis with Nasal Polyps: The Real-World, Multi-Country RANS Observational Study.

Purpose: Real-world evidence of benralizumab effectiveness on nasal polyps (NP) and asthma outcomes in patients with severe eosinophilic asthma (SEA) and comorbid chronic rhinosinusitis with NP are limited. The objective of this study was to assess NP and asthma outcomes in benralizumab-treated patients with SEA and comorbid NP in a real-world setting. Patients and Methods: RANS was a retrospective, multi-country observational study (ClinicalTrials.gov: NCT05180357) using medical chart reviews of adults with SEA and comorbid NP. Total NP Score (NPS), SinoNasal Outcome Test-22 (SNOT-22) total score, annualized exacerbation rate (AER), and 6-item Asthma Control Questionnaire (ACQ-6) and Asthma Control Test (ACT) scores during the 12 months pre-index (baseline) and post-index (follow-up) were measured. Clinically meaningful improvement from baseline following treatment, in terms of total NPS (≥1-point reduction), SNOT-22 total (≥8.9-point reduction), ACQ-6 (≥0.5-point reduction) or ACT (≥3-point increase) scores, were reported. Results: A total of 233 patients were included. Baseline mean (standard deviation [SD]) NPS and SNOT-22 total scores were 3.8 (2.4) and 47.5 (22.6), respectively. The mean change (95% confidence interval [CI]) from baseline was -1.2 (-1.7, -0.6) for NPS, and -19.8 (-23.6, -15.9) for SNOT-22. The AER (95% CI) was 1.2 (0.96, 1.41) at baseline and 0.2 (0.13, 0.28) at follow-up. Mean (SD) ACQ-6 and ACT scores were 1.6 (1.3) and 15.0 (5.2) at baseline and 0.8 (1.0) and 22.0 (3.9) at follow-up, respectively. The proportion of patients who achieved clinically meaningful improvements in NPS, SNOT-22 total, ACQ-6, and ACT scores was 49.1%, 67.6%, 56.6%, and 81.1%, respectively. Conclusion: In this real-world study, improvements in NP and asthma outcomes in patients with SEA and comorbid NP were observed during the 12 months following benralizumab initiation.

Longitudinal patterns of intermittent oral corticosteroid therapy for asthma in the United Kingdom.

Background: Increasing frequency of intermittent oral corticosteroid (OCS) prescription and cumulative OCS exposure increase the risk of OCS-related adverse outcomes. Objective: We sought to describe the evolution and trajectory of intermittent OCS prescription patterns in patients with asthma and investigate risk factors independently associated with transitioning to a frequent prescription pattern. Methods: This historical cohort study included patients with active asthma managed in UK primary care and included in the Optimum Patient Care Research Database (OPCRD; opcrd.co.uk). Intermittent OCS prescription patterns were categorized as sporadic, infrequent, moderately frequent, or frequent. Prescription pattern sequences were described for those who had a frequent sequence in their final year of prescribing. We examined associations between OCS prescription pattern and the hazard of transitioning into a frequent intermittent OCS prescription pattern using multivariable Cox regression with a 10-year look-back period. Results: Of 105,229 patients with intermittent OCS prescriptions, 57.1% (n = 60,083) had a frequent OCS prescription pattern at some point. Irrespective of baseline pattern, most patients transitioned to frequent prescription during the look back. The strongest risk factors were a more frequent prescription pattern at the start of look-back period, a lower percentage peak expiratory flow rate, and higher Global Initiative for Asthma treatment step. Older age, female sex, obesity, and active smoking were also associated with a higher risk of transitioning. Conclusion: Our findings help identify those most at risk of transitioning to frequent intermittent OCS receipt and encourage earlier intervention with OCS-sparing treatments.

Trends in Systemic Glucocorticoid Utilization in the United Kingdom from 1990 to 2019: A Population-Based, Serial Cross-Sectional Analysis.

Purpose: Associations between systemic glucocorticoid (SGC) exposure and risk for adverse outcomes have spurred a move toward steroid-sparing treatment strategies. Real-world changes in SGC exposure over time, after the introduction of steroid-sparing treatment strategies, reveal areas of successful risk mitigation as well as unmet needs. Patients and Methods: A population-based ecological study was performed from the Optimum Patient Care Research Database to describe SGC prescribing trends of steroid-sparing treatment strategies in primary care practices before and after licensure of biologics in the United Kingdom from 1990 to 2019. Each analysis year included patients aged ≥5 years who were registered for ≥1 year with a participating primary care practice. The primary analysis was SGC exposure, defined as total cumulative SGC dose per patient per year, for asthma, severe asthma, chronic obstructive pulmonary disease (COPD), nasal polyps, Crohn's disease, rheumatoid arthritis, ulcerative colitis, and systemic lupus erythematosus. Secondary outcomes were percentages of patients prescribed SGCs and number of SGC prescriptions per patient per year. Results: The number of patients who met study inclusion criteria ranged from 219,862 (1990) to 1,261,550 (2019). At the population level, patients with asthma or COPD accounted for 67.7% to 73.2% of patients per year with an SGC prescription. Over three decades, decreases in SGC total yearly dose ≥1000 mg have been achieved in multiple conditions. Patients with COPD prescribed SGCs increased from 5.8% (1990) to 34.8% (2017). SGC prescribing trends for severe asthma, Crohn's disease, and ulcerative colitis show decreased prescribing trends after the introduction of biologics. Conclusion: Decreases in total yearly SGC doses have been shown in multiple conditions; however, for conditions such as severe asthma and COPD, an unmet need remains for increased awareness of SGC burden and the adoption or development of SGC-sparing alternatives to reduce overuse.

Population-based assessment of kaposi sarcoma-associated herpesvirus DNA in plasma among Ugandans.

Risk of Kaposi sarcoma (KS) is linked to detection of Kaposi sarcoma-associated herpesvirus (KSHV) DNA in plasma, but little is known about the prevalence and risk factors for plasma KSHV DNA detection among the general population where KS is endemic. Correlates of KSHV plasma detection were investigated in a population-based sample of adult Ugandans (15-59 years) who participated in an HIV/AIDS serobehavioral survey in 2004/2005. KSHV DNA was measured in plasma of 1,080 KSHV seropositive and 356 KSHV seronegative persons using polymerase chain reaction (PCR). KSHV DNA in plasma was detected in 157 (8.7%) persons; of these 149 (95%) were KSHV seropositive and 8 (5%) were seronegative. Detection of KSHV DNA in plasma was significantly associated with male sex (P < 0.001), older age (P = 0.003), residence in a rural versus urban area (P = 0.002), geographic region (P = 0.02), and being KSHV seropositive (13.8% seropositive vs. 2.3% seronegative, P < 0.001). In a multivariable model, KSHV DNA plasma quantity was significantly higher in men (P = 0.002), inversely associated with age (P = 0.05), and residing in an urban area (P = 0.01). In Uganda, KSHV is detected more frequently in the plasma of adult males and residents of rural regions, potentially explaining the increased risk of KS in these subsets of the Ugandan population.

A Long-Term Study of Adverse Outcomes Associated With Oral Corticosteroid Use in COPD.

Background: Oral corticosteroids (OCS) are often prescribed for chronic obstructive pulmonary disease (COPD) exacerbations. Methods: This observational, individually matched historical cohort study used electronic medical records (1987-2019) from the UK Clinical Practice Research Datalink linked to English Hospital Episode Statistics (HES) to evaluate adverse outcomes in patients with COPD who used OCS (OCS cohort) and those not exposed to OCS (non-OCS cohort). Risk of 17 adverse outcomes was estimated using proportional hazard regression. Results: Of 323,722 patients, 106,775 (33.0%) had COPD-related OCS prescriptions. Of the 106,775 patients in the overall cohort, 58,955 had HES linkage and were eligible for inclusion in the OCS cohort. The individual matching process identified 53,299 pairs of patients to form the OCS and non-OCS cohorts. Median follow-up post-index was 6.9 years (OCS cohort) and 5.4 years (non-OCS cohort). Adjusted risk of multiple adverse outcomes was higher for the OCS cohort versus the non-OCS cohort, including osteoporosis with/without fractures (adjusted hazard ratio [aHR] 1.80; 95% confidence interval [CI] 1.70-1.92), type 2 diabetes mellitus (aHR 1.44; 95% CI 1.37-1.51), cardiovascular/cerebrovascular disease (aHR 1.26; 95% CI 1.21-1.30), and all-cause mortality (aHR 1.04; 95% CI 1.02-1.07). In the OCS cohort, risk of most adverse outcomes increased with increasing categorized cumulative OCS dose. For example, risk of cardiovascular/cerebrovascular disease was 34% higher in the 1.0-<2.5 g group versus the <0.5 g group (HR 1.34; 95% CI 1.26-1.42). Conclusion: Any OCS use was associated with higher risk of adverse outcomes in patients with COPD, with risk generally increasing with greater cumulative OCS dose.