Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic, Omalizumab, in Severe Asthma in Adults: Results of the SoMOSA Study.

BACKGROUND: The anti-IgE monoclonal, omalizumab, is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during one year of omalizumab treatment. METHODS: 1-year, open-label, Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 severe (GINA step 4/5) uncontrolled atopic asthmatics (≥2 severe exacerbations in previous year) on high-dose inhaled corticosteroids, long-acting ß-agonists, ± mOCS. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE), and 16-52 weeks, to assess late responses by ≥50% reduction in exacerbations or dose of maintenance oral corticosteroids (mOCS). All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. RESULTS: 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ≥50%, while 57% (37/65) on mOCS reduced their dose by ≥50%. The primary outcome 2, 3-dinor-11-ß-PGF2α, GETE and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five breathomics (GC-MS) and 5 plasma lipid biomarkers strongly predicted the ≥50% reduction in exacerbations (receiver operating characteristic area under the curve (AUC): 0.780 and 0.922, respectively) and early responses (AUC:0.835 and 0.949, respectively). In independent cohorts, the GC-MS biomarkers differentiated between severe and mild asthma. Conclusions This is the first discovery of omics biomarkers that predict improvement to a biologic for asthma. Their prospective validation and development for clinical use is justified. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Use of CompEx in eosinophilic patients with severe, uncontrolled asthma on benralizumab.

Background: CompEx Asthma, a composite end-point for asthma exacerbations, captures clinically relevant, diary-based acute worsening events (AWEs) (defined as deterioration in daily peak expiratory flow concurrent with deterioration in asthma symptoms and/or rescue therapy use) and severe exacerbations (SevEx) (defined by American Thoracic Society/European Respiratory Society guidelines). We hypothesised that CompEx and SevEx would show similar benralizumab treatment effects and correlations to blood eosinophil counts in patients with severe asthma. Methods: This post hoc analysis of pooled 12-month data from two phase 3 studies included patients aged ≥16 years with severe, uncontrolled asthma who were randomised to benralizumab 30 mg or placebo. Annualised event rates were analysed using a negative binomial model. The impact of blood eosinophil count on treatment effect was assessed. Results: Among patients with a blood eosinophil count ≥300 cells·µL-1 (n=913), benralizumab reduced the annualised event rate versus placebo for CompEx (1.57 versus 2.57; risk ratio 0.61, 95% CI 0.53-0.70, p<0.001), SevEx (0.94 versus 1.55; risk ratio 0.60, 95% CI 0.52-0.70, p<0.001) and AWE (0.92 versus 1.57; risk ratio 0.59, 95% CI 0.48-0.72, p<0.001), with greater treatment effects observed for higher blood eosinophil counts. In patients with blood eosinophil count ≥300 cells·µL-1, benralizumab was associated with shorter median event duration (CompEx: 10.5 days versus 17.0 days; SevEx: 10.0 days versus 15.0 days; AWE: 5.0 days versus 6.0 days). Conclusions: Benralizumab reduced the risk of CompEx events with treatment effects similar to those for SevEx and AWEs across a range of blood eosinophil counts. Use of CompEx supports the evaluation of benralizumab and other novel drugs in clinical studies.

The Anti-Inflammatory Reliever (AIR) Algorithm Study: a protocol for a single-group study of an AIR stepwise approach to the treatment of adult asthma.

Background: The stepwise approach to long-term asthma management, which traditionally incorporates short-acting ß2-agonist reliever therapy, has been a core feature of asthma guidelines for over 30 years. There have been no studies, however, directly investigating the use of an entire guideline-recommended track. Recently, inhaled corticosteroid-formoterol has been recommended as the preferred reliever therapy in adult asthma, in accordance with a stepwise "Anti-Inflammatory Reliever" (AIR) treatment track. Objective: The aim of this study was to evaluate the AIR stepwise approach recommended by the New Zealand adolescent and adult asthma guidelines, in combination with a novel algorithm for transitioning between treatment steps. Methods: This 52-week, open-label, single-group study will recruit 100 adults aged 18 to 75 years with mild, moderate and moderate-severe asthma (ACTRN12620001010987). Participants will be allocated to budesonide-formoterol 200/6 µg, one actuation as needed (Step 1), one actuation twice daily and as needed (Step 2), or two actuations twice daily and one as needed (Step 3). Treatment steps will be adjusted throughout the study, in response to reliever use and asthma attacks, according to a stepwise AIR algorithm. Following a 26-week period of investigator-led transitions, participants will adjust their own treatment step. The primary outcome is participant satisfaction as measured by the Global Satisfaction score of the Treatment Satisfaction Questionnaire for Medication. Secondary outcomes will assess efficacy and safety, and describe patterns of medication use and participant flow through the treatment steps. Conclusion: This is the first trial to assess the AIR treatment track and algorithm. The results will provide knowledge to guide the clinical use of this approach.

Low host immune pressure may be associated with the development of hepatocellular carcinoma: a longitudinal analysis of complete genomes of the HBV 1762T, 1764A mutant.

Background: It has been reported that hepatitis B virus (HBV) double mutations (A1762T, G1764A) are an aetiological factor of hepatocellular carcinoma (HCC). However, it is unclear who is prone to develop HCC, among those infected with the mutant. Exploring HBV quasispecies, which are strongly influenced by host immune pressure, may provide more information about the association of viral factors and HCC. Materials and methods: Nine HCC cases and 10 controls were selected from the Long An cohort. Serum samples were collected in 2004 and 2019 from subjects with HBV double mutations and the complete genome of HBV was amplified and sequenced using next-generation sequencing (NGS). Results: The Shannon entropy values increased from 2004 to 2019 in most cases and controls. There was no significant difference in mean intrahost quasispecies genetic distances between cases and controls. The change in the values of mean intrahost quasispecies genetic distances of the controls between 2004 and 2019 was significantly higher than that of the cases (P<0.05). The viral loads did not differ significantly between cases and controls in 2004(p=0.086) but differed at diagnosed in 2019 (p=0.009). Three mutations occurring with increasing frequency from 2004 to 2019 were identified in the HCC cases, including nt446 C→G, nt514 A→C and nt2857T→C. Their frequency differed significantly between the cases and controls (P<0.05). Conclusions: The change in the values of mean intrahost quasispecies genetic distances in HCC was smaller, suggesting that HBV in HCC cases may be subject to low host immune pressure. Increasing viral loads during long-term infection are associated with the development of HCC. The novel mutations may increase the risk for HCC.

Financial analysis of revision hip surgery at a tertiary referral centre as classified using the British Hip Society Revision Hip Complexity Classification.

Aims: The burden of revision total hip arthroplasty (rTHA) continues to grow. The surgery is complex and associated with significant costs. Regional rTHA networks have been proposed to improve outcomes and to reduce re-revisions, and therefore costs. The aim of this study was to accurately quantify the cost and reimbursement for a rTHA service, and to assess the financial impact of case complexity at a tertiary referral centre within the NHS. Methods: A retrospective analysis of all revision hip procedures was performed at this centre over two consecutive financial years (2018 to 2020). Cases were classified according to the Revision Hip Complexity Classification (RHCC) and whether they were infected or non-infected. Patients with an American Society of Anesthesiologists (ASA) grade ≥ III or BMI ≥ 40 kg/m2 are considered "high risk" by the RHCC. Costs were calculated using the Patient Level Information and Costing System (PLICS), and remuneration based on Healthcare Resource Groups (HRG) data. The primary outcome was the financial difference between tariff and cost per patient episode. Results: In all, 199 revision episodes were identified in 168 patients: 25 (13%) least complex revisions (H1); 110 (55%) complex revisions (H2); and 64 (32%) most complex revisions (H3). Of the 199, 76 cases (38%) were due to infection, and 78 patients (39%) were "high risk". Median length of stay increased significantly with case complexity from four days to six to eight days (p = 0.006) and for revisions performed for infection (9 days vs 5 days; p < 0.001). Cost per episode increased significantly between complexity groups (p < 0.001) and for infected revisions (p < 0.001). All groups demonstrated a mean deficit but this significantly increased with revision complexity (£97, £1,050, and £2,887 per case; p = 0.006) and for infected failure (£2,629 vs £635; p = 0.032). The total deficit to the NHS Trust over two years was £512,202. Conclusion: Current NHS reimbursement for rTHA is inadequate and should be more closely aligned to complexity. An increase in the most complex rTHAs at major revision centres will likely place a greater financial burden on these units.

Total femoral arthroplasty for non-oncological indications.

Aims: Total femoral arthroplasty (TFA) is a rare procedure used in cases of significant femoral bone loss, commonly from cancer, infection, and trauma. Low patient numbers have resulted in limited published work on long-term outcomes, and even less regarding TFA undertaken for non-oncological indications. The aim of this study was to evaluate the long-term clinical outcomes of all TFAs in our unit. Methods: Data were collected retrospectively from a large tertiary referral revision arthroplasty unit's database. Inclusion criteria included all patients who underwent TFA in our unit. Preoperative demographics, operative factors, and short- and long-term outcomes were collected for analysis. Outcome was defined using the Musculoskeletal Infection Society (MSIS) outcome reporting tool. Results: Overall, 38 TFAs were identified. The mean age was 73 years (42 to 80). All patients underwent TFA for non-oncological indications, most commonly as a consequence of infection (53%) and periprosthetic fracture (26%). The mean follow-up time was ten years (0 to 26); 63% of TFAs were considered a success based upon the MSIS outcome reporting tool. The mean time between TFA and death was 8.5 years (0.2 to 19.2), with two patients dying within one year of surgery. Within the cohort, 66% suffered at least one complication, dislocation being most common (37%); 55% of the total cohort required at least one subsequent operation. In total, 70% of TFAs undertaken for infection were considered infection-free at time of final follow-up. The percentage of mobile patients improved from 52% to 65% between pre- and postoperation, with all patients being able to at least transfer from bed to chair at time of final review. Conclusion: This study is the largest in the UK assessing the use of TFA in patients with bone loss secondary to non-oncological conditions. It demonstrates that TFA has a significant complication profile, however it is favourable in terms of mortality and rehabilitation when compared to amputation and disarticulation.

Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control.

BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.

Systemic antibiotics are not required for successful two-stage revision hip arthroplasty.

The duration of systemic antibiotic treatment following first-stage revision surgery for periprosthetic joint infection (PJI) after total hip arthroplasty (THA) is contentious. Our philosophy is to perform an aggressive debridement, and to use a high local concentration of targeted antibiotics in cement beads and systemic prophylactic antibiotics alone. The aim of this study was to assess the success of this philosophy in the management of PJI of the hip using our two-stage protocol. The study involved a retrospective review of our prospectively collected database from which we identified all patients who underwent an intended two-stage revision for PJI of the hip. All patients had a diagnosis of PJI according to the major criteria of the Musculoskeletal Infection Society (MSIS) 2013, a minimum five-year follow-up, and were assessed using the MSIS working group outcome-reporting tool. The outcomes were grouped into 'successful' or 'unsuccessful'. A total of 299 two-stage revision THAs in 289 patients met the inclusion criteria, of whom 258 (86%) proceeded to second-stage surgery. Their mean age was 68.1 years (28 to 92). The median follow-up was 10.7 years (interquartile range (IQR) 6.3 to 15.0). A 91% success rate was seen in those patients who underwent reimplantation, decreasing to 86% when including those who did not proceed to reimplantation. The median duration of postoperative systemic antibiotics following the first stage was five days (IQR 5 to 9). There was no significant difference in outcome between those patients who were treated with antibiotics for ≤ 48 hours (p = 0.961) or ≤ five days (p = 0.376) compared with those who were treated with longer courses. Greater success rates were seen for Gram-positive PJIs (87%) than for Gram-negative (84%) and mixed-Gram PJIs (72%; p = 0.098). Aggressive surgical debridement with a high local concentration of targeted antibiotics at the time of first-stage revision surgery for PJI of the hip, without prolonged systemic antibiotics, provides a high rate of success, responsible antibiotic stewardship, and reduced hospital costs.

Severe Asthma Standard-of-Care Background Medication Reduction With Benralizumab: ANDHI in Practice Substudy.

BACKGROUND: The phase IIIb, randomized, parallel-group, placebo-controlled ANDHI double-blind (DB) study extended understanding of the efficacy of benralizumab for patients with severe eosinophilic asthma. Patients from ANDHI DB could join the 56-week ANDHI in Practice (IP) single-arm, open-label extension substudy. OBJECTIVE: Assess potential for standard-of-care background medication reductions while maintaining asthma control with benralizumab. METHODS: Following ANDHI DB completion, eligible adults were enrolled in ANDHI IP. After an 8-week run-in with benralizumab, there were 5 visits to potentially reduce background asthma medications for patients achieving and maintaining protocol-defined asthma control with benralizumab. Main outcome measures for non-oral corticosteroid (OCS)-dependent patients were the proportions with at least 1 background medication reduction (ie, lower inhaled corticosteroid dose, background medication discontinuation) and the number of adapted Global Initiative for Asthma (GINA) step reductions at end of treatment (EOT). Main outcomes for OCS-dependent patients were reductions in daily OCS dosage and proportion achieving OCS dosage of 5 mg or lower at EOT. RESULTS: For non-OCS-dependent patients, 53.3% (n = 208 of 390) achieved at least 1 background medication reduction, increasing to 72.6% (n = 130 of 179) for patients who maintained protocol-defined asthma control at EOT. A total of 41.9% (n = 163 of 389) achieved at least 1 adapted GINA step reduction, increasing to 61.8% (n = 110 of 178) for patients with protocol-defined EOT asthma control. At ANDHI IP baseline, OCS dosages were 5 mg or lower for 40.4% (n = 40 of 99) of OCS-dependent patients. Of OCS-dependent patients, 50.5% (n = 50 of 99) eliminated OCS and 74.7% (n = 74 of 99) achieved dosages of 5 mg or lower at EOT. CONCLUSIONS: These findings demonstrate benralizumab's ability to improve asthma control, thereby allowing background medication reduction.

A novel subgenotype I3 of hepatitis B virus in Guangxi, China: a 15-year follow-up study.

Genotype I of hepatitis B virus (HBV) was proposed recently following sequencing of complete HBV genomes from Vietnam and Laos. However, its long-term molecular evolution is unknown. The objectives of this study were to study the molecular evolution of this genotype from an asymptomatic HBsAg carrier from the Long An cohort over a 15-year period was studied using both NGS and clone-based sequencing. The number of complete genome sequences obtained in 2004, 2007, 2013, and 2019 are 17, 20, 19, and 10, respectively. All strains belong to subgenotype I1, except for six (five from 2007 and one from 2019) and 8 further strains from 2007 which form a cluster branching out from other subgenotype I sequences, supported by a 100% bootstrap value. Based on complete genome sequences, all of the estimated intragroup nucleotide divergence values between these strains and HBV subgenotypes I1-I2 exceed 4%. These strains are recombinants between genotype I1 and subgenotype C but the breakpoints vary. The median intrahost viral evolutionary rate in this carrier was 3.88E-4 substitutions per site per year. The Shannon entropy (Sn) ranged from 0.55 to 0.88 and the genetic diversity, D, ranged from 0.0022 to 0.0041. In conclusion, our data provide evidence of novel subgenotypes. Considering that the 8 strains disappeared after 2007, while one of the 6 strains appears again in 2019, we propose these 6 strains as a new subgenotype, provisionally designated HBV subgenotype I3 and the 8 strains as aberrant genotype.

The burden of mild asthma: Clinical burden and healthcare resource utilisation in the NOVELTY study.

BACKGROUND: Patients with mild asthma represent a substantial proportion of the population with asthma, yet there are limited data on their true burden of disease. We aimed to describe the clinical and healthcare resource utilisation (HCRU) burden of physician-assessed mild asthma. METHODS: Patients with mild asthma were included from the NOVEL observational longiTudinal studY (NOVELTY; NCT02760329), a global, 3-year, real-world prospective study of patients with asthma and/or chronic obstructive pulmonary disease from community practice (specialised and primary care). Diagnosis and severity were based on physician discretion. Clinical burden included physician-reported exacerbations and patient-reported measures. HCRU included inpatient and outpatient visits. RESULTS: Overall, 2004 patients with mild asthma were included; 22.8% experienced ≥1 exacerbation in the previous 12 months, of whom 72.3% experienced ≥1 severe exacerbation. Of 625 exacerbations reported, 48.0% lasted >1 week, 27.7% were preceded by symptomatic worsening lasting >3 days, and 50.1% required oral corticosteroid treatment. Health status was moderately impacted (St George's Respiratory Questionnaire score: 23.5 [standard deviation ± 17.9]). At baseline, 29.7% of patients had asthma symptoms that were not well controlled or very poorly controlled (Asthma Control Test score <20), increasing to 55.6% for those with ≥2 exacerbations in the previous year. In terms of HCRU, at least one unscheduled ambulatory visit for exacerbations was required by 9.5% of patients, including 9.2% requiring ≥1 emergency department visit and 1.1% requiring ≥1 hospital admission. CONCLUSIONS: In this global sample representing community practice, a significant proportion of patients with physician-assessed mild asthma had considerable clinical burden and HCRU.

Evaluation of Budesonide-Formoterol for Maintenance and Reliever Therapy Among Patients With Poorly Controlled Asthma: A Systematic Review and Meta-analysis.

IMPORTANCE: The Global Initiative for Asthma (GINA) recommends 2 alternative treatments for patients receiving treatment at steps 3 to 5: single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) or inhaled corticosteroid-long-acting ß2-agonist as maintenance plus short-acting ß2-agonist as reliever. OBJECTIVE: To assess whether switching to SMART is associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA treatment step with maintenance inhaled corticosteroid-long-acting ß2-agonist plus short-acting ß2-agonist reliever among patients with poorly controlled asthma. DATA SOURCES: For this systematic review and meta-analysis, the literature, internal study databases at AstraZeneca and the Medical Research Institute of New Zealand, and references from a previous systematic review and meta-analysis on SMART were searched to identify randomized clinical trials published from January 1990 to February 2018, that compared budesonide-formoterol by SMART with maintenance inhaled corticosteroid-long-acting ß2-agonist plus short-acting ß2-agonist reliever. STUDY SELECTION: Trials of at least 24 weeks' duration were included if they reported baseline data on GINA treatment step, asthma control status, and efficacy measures of severe exacerbations. Included patients were adults and adolescents with asthma and baseline Asthma Control Questionnaire 5-item version scores of 1.5 or higher. DATA EXTRACTION AND SYNTHESIS: Patient-level data were identified by independent extraction, and analyses were performed using a fixed-effect model. Data analysis was performed from August 2018 to November 2021. MAIN OUTCOMES AND MEASURES: The primary outcome was time to first severe asthma exacerbation associated with each treatment, analyzed by Cox proportional hazards regression. RESULTS: Overall, 4863 patients were included (3034 [62.4%] female; mean [SD] age, 39.8 [16.3] years). Switching patients with uncontrolled asthma at GINA step 3 (n = 1950) to SMART at either step 3 or 4 was associated with a prolonged time to first severe asthma exacerbation, with a 29% reduced risk compared with stepping up to step 4 inhaled corticosteroid-long-acting ß2-agonist maintenance plus short-acting ß2-agonist reliever (hazard ratio, 0.71; 95% CI, 0.52-0.97). For patients with uncontrolled asthma at step 3 and step 4 (n = 2913), switching to SMART was associated with a prolonged time to first severe asthma exacerbation and a 30% reduced risk compared with remaining at the same treatment step (hazard ratio, 0.70; 95% CI, 0.58-0.85). CONCLUSIONS AND RELEVANCE: In this systematic review and meta-analysis, for patients with poorly controlled asthma, SMART was associated with longer time to first severe asthma exacerbation compared with a step up or continuation of GINA step with maintenance inhaled corticosteroid-long-acting ß2-agonist plus short-acting ß2-agonist reliever. These findings suggest that if an adult or adolescent receiving treatment at GINA step 3 or 4 has poorly controlled asthma, it is preferable to switch to the SMART regimen rather than to step up or continue the GINA treatment step with maintenance inhaled corticosteroid-long-acting ß2-agonist plus short-acting ß2-agonist reliever therapy.

Perspectives of mild asthma patients on maintenance versus as-needed preventer treatment regimens: a qualitative study.

OBJECTIVES: As-needed low-dose combination budesonide-formoterol is recommended by asthma guidelines in many countries as an alternative to maintenance inhaled corticosteroids (ICS) for treatment of mild asthma, but there are few data on patient attitudes toward these regimens. This study explored the comparative implementation experiences and future treatment preferences of mild asthma patients who had experienced these two treatment regimens. SETTING: A subgroup of adults randomised to maintenance ICS or as-needed ICS-formoterol in a multinational, 52-week open-label randomised controlled trial (NovelSTART) in mild asthma patients were interviewed to explore their motivations for treatment use during the study and their preferences for future treatment. PARTICIPANTS: Semistructured interviews were conducted with 74 participants (Maintenance group: n=39, As-needed group n=35, mean age 38 (range 19-69)) and thematically analysed from transcribed audiorecordings. RESULTS: Emergent themes from analysis comprised: 'How much my asthma affects me' (how their asthma's impact affected their self-management motivation); 'What I know about asthma' (limited knowledge impeded appropriate self-management decision making); 'How much effort this treatment regimen involves for me' (treatment complexity and/or difficulty establishing a medication routine impeded implementation, particularly in the Maintenance group); and 'My beliefs about the benefits and risks of this treatment' (patients who considered their treatment as ineffective, eg, limited difference in symptoms relative to salbutamol (both groups) or slower onset of relief (As-needed group) had poor motivation to use the treatment). Due to the simplicity of the as-needed combination strategy, this was the preferred future regimen, even by patients who had not yet tried it. CONCLUSIONS: Key patient perspectives on the implementation of preventer treatments for mild asthma included factors relating to perceived asthma burden, disease knowledge, treatment complexity and treatment usefulness or safety. The as-needed budesonide-formoterol regimen was preferred to maintenance ICS treatment in mild asthma though patient education is urgently needed to address implementation motivation. TRIAL REGISTRATION NUMBER: ACTRN12615000999538.

Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.

BACKGROUND: Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. METHODS: We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. RESULTS: Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. CONCLUSIONS: Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.

Benralizumab improves symptoms of patients with severe, eosinophilic asthma with a diagnosis of nasal polyposis.

BACKGROUND: Clinically meaningful improvement in the Sino-Nasal Outcome Test-22 (SNOT-22) was observed in patients with severe, eosinophilic asthma, and nasal polyposis (NP) treated with benralizumab in the ANDHI trial. A post hoc assessment of the effects of benralizumab on SNOT-22 response and asthma efficacy measures in these patients was conducted for further characterization of the efficacy and safety of benralizumab for patients with severe asthma and NP. METHODS: Adults with severe, eosinophilic asthma who had experienced ≥2 prior-year exacerbations despite high-dosage inhaled corticosteroid plus additional controller[s] were randomized to 24 weeks of benralizumab or placebo. Patients with physician-diagnosed chronic rhinosinusitis with NP of any severity ongoing at baseline who consented to participate were included in the current ANDHI NP substudy population. Effect on NP symptoms was assessed by the SNOT-22, with an improvement of at least 8.9 defined as clinically significant (responder). Effects on chronic asthma outcomes were assessed by means of annualized asthma exacerbation rate (AER), St. George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in one second (FEV1 ), and Asthma Control Questionnaire-6 (ACQ-6). All p-values were nominal. RESULTS: Of the ANDHI population (n = 656), 23% (n = 153) participated in the NP substudy (n = 96 benralizumab; n = 57 placebo). Patients were 50% female, with mean age of 53 years, had prior-year AER = 3.3; mean pre-bronchodilator FEV1  = 55% predicted; and median blood eosinophil count â€‹= 510 cells/µl. For patients with high baseline SNOT-22 scores (>30), benralizumab treatment improved symptoms of NP as measured by SNOT-22 from baseline to Week 24 compared with placebo (Week 24: -10.44 [p = .0176]). Percentage of responders to SNOT-22 was greater for benralizumab vs. placebo (71.3% vs. 45.5%; p = .0036), and effect was enhanced for patients with high baseline SNOT-22 scores (>30). A 69% reduction vs. placebo in annualized AER (0.77 vs. 2.47; p < .0001) and greater clinically meaningful improvements from baseline in SGRQ total score (-16.7), FEV1 (+0.32 L), and ACQ-6 (-0.88) were observed (p < .0001). Benralizumab was well-tolerated. Frequency of adverse events (AEs) was similar for benralizumab (76.0%) and placebo (73.7%) groups. Most common AEs (frequency ≥5%) reported at a greater frequency in benralizumab vs. placebo included headache, sinusitis, pyrexia, and influenza. CONCLUSIONS: These substudy data from ANDHI demonstrated the efficacy profile of benralizumab for patients with severe, eosinophilic asthma and NP, with improvement in SNOT-22 and asthma outcomes.

Analysis of entire hepatitis B virus genomes reveals reversion of mutations to wild type in natural infection, a 15 year follow-up study.

It has been reported that some mutations in the genome of hepatitis B virus (HBV) may predict the outcome of the virus infection. However, evolutionary data derived from long-term longitudinal analysis of entire HBV genomes using next generation sequencing (NGS) remain rare. In this study, serum samples were collected from asymptomatic hepatitis B surface antigen (HBsAg) carriers from a long-term prospective cohort. The entire HBV genome was amplified by polymerase chain reaction (PCR) and sequenced using NGS. Twenty-eight time series serum samples from nine subjects were successfully analysed. The Shannon entropy (Sn) ranged from 0 to 0.89, with a median value of 0.76, and the genetic diversity (D) ranged from 0 to 0.013, with a median value of 0.004. Intrahost HBV viral evolutionary rates ranged from 2.39E-04 to 3.11E-03. Double mutations at nt1762(A â†’ T) and 1764(G â†’ A) and a stop mutation at nt1896(G â†’ A) were seen in all sequences from subject BO129 in 2007. However, in 2019, most sequences were wild type at these positions. Deletions between nt 2920-3040 were seen in all sequences from subject TS115 in 2007 and 2013 but these were not present in 2004 or 2019. Some sequences from subject CC246 had predicted escape substitutions (T123N, G145R) in the surface protein in 2004, 2013 and 2019 but none of the sequences from 2007 had these changes. In conclusion, HBV mutations may revert to wild type in natural infection. Clinicians should be wary of predicting long-term prognoses on the basis of the presence of mutations.

A low exhaled nitric oxide level excludes a short-term benefit from inhaled corticosteroids in suspected asthma: A randomized placebo-controlled trial.

BACKGROUND AND OBJECTIVE: Fractional exhaled nitric oxide (FeNO) is a non-invasive biomarker that reflects IL-4/IL-13 production and therefore represents T2 allergic inflammation. FeNO has previously been used to guide inhaled corticosteroid (ICS) treatment in asthma. The purpose of this study was to determine if a low FeNO (≤27 ppb) could be used to reliably identify patients with symptoms suggestive of asthma who would not benefit from initiating treatment with an ICS. METHODS: A total of 180 steroid-naïve adults with healthcare professional suspected asthma and an FeNO of ≤27 ppb were randomized to receive either 400 mcg of budesonide or placebo daily for 3 months. The primary outcome was the difference in the Asthma Control Questionnaire 7 (ACQ7) between treatment groups and the study was powered to determine equivalence. Secondary outcomes were the difference in FEV1 , Medical Research Council and Leicester Cough Questionnaire scores. RESULTS: One hundred and thirty-four patients (68 budesonide and 66 placebo) completed the study and were included in the analysis. The between-group mean difference in ACQ7 from baseline to the end of the study was -0.25 and the 95% CI around this difference was -0.004 to 0.495 confirming equivalence (p < 0.05). Differences in forced expiratory volume over 1 s and other secondary outcomes were also small and clinically unimportant. CONCLUSION: The results of this study suggest that steroid-naïve patients with symptoms suggestive of asthma and an FeNO ≤ 27 ppb are unlikely to benefit from initiating treatment with an ICS over 3 months. However, further research is recommended to confirm these findings before withholding ICS treatment.

Infection with Hepatitis B Virus May Increase the Serum Concentrations of Osteopontin.

BACKGROUND: Serum osteopontin (OPN) concentrations were found to be significantly increased in patients infected with hepatitis B virus (HBV) and patients with hepatocellular carcinoma (HCC). OBJECTIVE: The aim of this study was to determine the association among HCC, OPN, and HBV. METHODS: Two hundred and forty-one subjects were recruited and divided into 6 groups: healthy controls, asymptomatic HBsAg carriers, HBsAg (-) patients with other tumors, HBsAg (+) chronic liver disease patients, HBsAg (+) patients with HCC, and HBsAg (-) patients with HCC or liver cirrhosis (LC). Serum concentrations of OPN and HBsAg were measured and analyzed. RESULTS: OPN concentrations in the HBsAg (+) HCC group were significantly higher than the healthy control group and the HBsAg (-) patients with other cancers (both p = 0.0001). The OPN concentrations of the HBsAg (-) patients with HCC or LC also did not differ significantly from those of the healthy control group (p = 0.075). There is a correlation between the titer of HBsAg and concentrations of OPN in all 3 HBsAg (+) groups (all p values <0.05). CONCLUSIONS: Infection with HBV may increase the serum concentrations of OPN. The association of OPN and HCC may be not attributable to tumor development per se but, rather, to HBV infection.

Array-based measurements of aero-allergen-specific IgE correlate with skin-prick test reactivity in asthma regardless of specific IgG4 or total IgE measurements.

Skin prick testing (SPT) and measurement of serum allergen-specific IgE (sIgE) are used to investigate asthma and other allergic conditions. Measurement of serum total IgE (tIgE) and allergen-specific IgG4 (sIgG4) may also be useful. The aim was to ascertain the correlation between these serological parameters and SPT. Sera from 60 suspected asthmatic patients and 18 healthy controls were assayed for sIgE and sIgG4 reactivity against a panel of 70 SPT allergen preparations, and for tIgE. The patients were also assessed by skin prick tests for reactivity to cat, dog, house dust mite and grass allergens. Over 50% of the patients had tIgE levels above the 75th percentile of the controls. 58% of patients and 39% of controls showed sIgE reactivity to ≥1 allergen. The mean number of allergens detected by sIgE was 3.1 in suspected asthma patients and 0.9 in controls. 58% of patients and 50% of controls showed sIgG4 reactivity to ≥1 allergen. The mean number of allergens detected by sIgG4 was 2.5 in patients and 1.7 in controls. For the patients, a strong correlation was observed between clinical SPT reactivity and serum sIgE levels to cat, dog, house dust mite (HDM) and grass allergens. SPT correlations using sIgE/sIgG4 or sIgE/tIgE ratios were not markedly higher. The measurement of serum sIgE by microarray using SPT allergen preparations showed good correlation with clinical SPT reactivity to cat, dog, HDM and grass allergens. This concordance was not improved by measuring tIgE or sIgG4.