Real-life effectiveness of inhaler device switch from dry powder inhalers to pressurized metred-dose inhalers in patients with asthma treated with ICS/LABA.

BACKGROUND AND OBJECTIVE: Mixed inhaler device use for asthma is associated with worse inhaler technique and outcomes. Given that relievers are commonly prescribed as pressurized metred-dose inhalers (pMDI), changing preventers from dry powder inhalers (DPI) to pMDI may improve asthma outcomes. This study aimed to assess the persistence and effectiveness of switching from DPI to pMDI for inhaled corticosteroid and long-acting ß2 -agonist combination therapy (ICS/LABA). METHODS: This was a historical cohort study using Ajou University Hospital (Korea) patient records. Persistence of switch was defined as receiving ≥1 pMDI and no DPI after the switch. Effectiveness of switch was assessed as the proportion without severe asthma exacerbation and the proportion achieving risk domain asthma control (RDAC; no asthma-related hospitalization, antibiotics without upper respiratory diagnosis or acute course of oral corticosteroids) and overall asthma control (OAC; RDAC and ≤ 200 µg salbutamol/≤500 µg terbutaline average daily dose) comparing 1 year after and before the switch. RESULTS: Within 85 patients who switched from DPI to pMDI and persisted for a year, higher proportion were free from asthma exacerbation after the switch (mean difference in proportion = 0.129, 95% CI: 0.038-0.220). Switching to pMDI was also associated with better RDAC (75.3% vs 57.7%, P = 0.001) and OAC (57.7% vs 45.9%, P = 0.021). From the entire 117 patients who switched to fixed-dose combination (FDC)/ICS LABA pMDI, 76.1% (95% CI: 69.0-100.0%) patients persisted in the following 6 months. CONCLUSION: Switching to and persisting with pMDI was associated with decreased asthma exacerbations and improved asthma control. The majority of patients persisted with the switch to pMDI for ICS/LABA treatment.

Rhinitis in the first 18 months of life: exploring the role of respiratory viruses.

BACKGROUND: Rhinitis is common in early childhood, but allergic rhinitis is considered a later manifestation of the atopic march. This study aimed to evaluate rhinitis (allergic and non-allergic) in the first 18 months of life, its link with other atopic manifestations and the role of respiratory viruses. METHODS: Subjects (n = 1237) of the Singapore GUSTO birth cohort were followed up quarterly until 18 months of age with questionnaires to screen for rhinitis symptoms lasting at least 2 wk and with monthly calls to positive subjects to detect prolonged/recurrent rhinitis symptoms (total duration ≥ 4 wk). Anterior nasal swabbing for molecular-based virus detection was conducted during these visits and near (within a month) rhinitis episodes. Skin prick testing to common environmental and food allergens was conducted at the 18 month visit. RESULTS: Prolonged/recurrent rhinitis was significantly associated with history of parental atopy (mother: aOR = 2.17; father: aOR = 1.82) and atopic comorbidities of eczema (aOR = 2.53) and wheeze (aOR = 4.63) (p < 0.05), though not with allergen sensitization. Although the frequency of nasal respiratory virus detection during scheduled quarterly visits did not differ between prolonged/recurrent rhinitis and matched controls (p > 0.05), virus detection was higher in swabs obtained within a month following rhinitis episodes in prolonged/recurrent rhinitis subjects compared with scheduled visits (adjusted p = 0.04). CONCLUSIONS: Based on the duration of rhinitis symptoms, this study defined a subset of early childhood rhinitis which was associated with atopic predisposition and comorbidities. Persistent respiratory viral shedding may contribute to the symptomatology. Whether this entity is a precursor of subsequent childhood allergic rhinitis will require longer follow-up.

Maternal PUFA status and offspring allergic diseases up to the age of 18 months.

Studies have suggested that maternal PUFA status during pregnancy may influence early childhood allergic diseases, although findings are inconsistent. We examined the relationship between maternal PUFA status and risk of allergic diseases in early childhood in an Asian cohort. Maternal plasma samples from the Growing Up in Singapore Towards Healthy Outcomes mother-offspring cohort were assayed at 26-28 weeks of gestation for relative abundance of PUFA. Offspring (n 960) were followed up from 3 weeks to 18 months of age, and clinical outcomes of potential allergic diseases (rhinitis, eczema and wheezing) were assessed by repeated questionnaires. Skin prick testing (SPT) was also performed at the age of 18 months. Any allergic disease with positive SPT was defined as having any one of the clinical outcomes plus a positive SPT. The prevalence of a positive SPT, rhinitis, eczema, wheezing and any allergic disease with positive SPT was 14·1 % (103/728), 26·5 % (214/808), 17·6 % (147/833), 10·9 % (94/859) and 9·4 % (62/657), respectively. After adjustment for confounders, maternal total n-3, n-6 PUFA status and the n-6:n-3 PUFA ratio were not significantly associated with offspring rhinitis, eczema, wheezing, a positive SPT and having any allergic disease with positive SPT in the offspring (P>0·01 for all). A weak trend of higher maternal n-3 PUFA being associated with higher risk of allergic diseases with positive SPT in offspring was observed. These findings do not support the hypothesis that the risk of early childhood allergic diseases is modified by variation in maternal n-3 and n-6 PUFA status during pregnancy in an Asian population.

Discovery and characterization of novel cyclotides originated from chimeric precursors consisting of albumin-1 chain a and cyclotide domains in the Fabaceae family.

The tropical plant Clitoria ternatea is a member of the Fabaceae family well known for its medicinal values. Heat extraction of C. ternatea revealed that the bioactive fractions contained heat-stable cysteine-rich peptides (CRPs). The CRP family of A1b (Albumin-1 chain b/leginsulins), which is a linear cystine knot CRP, has been shown to present abundantly in the Fabaceae. In contrast, the cyclotide family, which also belongs to the cystine knot CRPs but with a cyclic structure, is commonly found in the Rubiaceae, Violaceae, and Cucurbitaceae families. In this study, we report the discovery of a panel of 15 heat-stable CRPs, of which 12 sequences (cliotide T1-T12) are novel. We show unambiguously that the cliotides are cyclotides and not A1bs, as determined by their sequence homology, disulfide connectivity, and membrane active properties indicated by their antimicrobial activities against Escherichia coli and cytotoxicities to HeLa cells. We also show that cliotides are prevalent in C. ternatea and are found in every plant tissue examined, including flowers, seeds, and nodules. In addition, we demonstrate that their precursors are chimeras, half from cyclotide and the other half from Albumin-1, with the cyclotide domain displacing the A1b domain in the precursor. Their chimeric structures likely originate from either horizontal gene transfer or convergent evolution in plant nuclear genomes, which are exceedingly rare events. Such atypical genetic arrangement also implies a different mechanism of biosynthetic processing of cyclotides in the Fabaceae and provides new understanding of their evolution in plants.

Characteristics of patients in platform C19, a COVID-19 research database combining primary care electronic health record and patient reported information.

BACKGROUND: Data to better understand and manage the COVID-19 pandemic is urgently needed. However, there are gaps in information stored within even the best routinely-collected electronic health records (EHR) including test results, remote consultations for suspected COVID-19, shielding, physical activity, mental health, and undiagnosed or untested COVID-19 patients. Observational and Pragmatic Research Institute (OPRI) Singapore and Optimum Patient Care (OPC) UK established Platform C19, a research database combining EHR data and bespoke patient questionnaire. We describe the demographics, clinical characteristics, patient behavior, and impact of the COVID-19 pandemic using data within Platform C19. METHODS: EHR data from Platform C19 were extracted from 14 practices across UK participating in the OPC COVID-19 Quality Improvement program on a continuous, monthly basis. Starting 7th August 2020, consenting patients aged 18-85 years were invited in waves to fill an online questionnaire. Descriptive statistics were summarized using all data available up to 22nd January 2021. FINDINGS: From 129,978 invitees, 31,033 responded. Respondents were predominantly female (59.6%), white (93.5%), and current or ex-smokers (52.6%). Testing for COVID-19 was received by 23.8% of respondents, of which 7.9% received positive results. COVID-19 symptoms lasted ≥4 weeks in 19.5% of COVID-19 positive respondents. Up to 39% respondents reported a negative impact on questions regarding their mental health. Most (67%-76%) respondents with asthma, Chronic Obstructive Pulmonary Disease (COPD), diabetes, heart, or kidney disease reported no change in the condition of their diseases. INTERPRETATION: Platform C19 will enable research on key questions relating to COVID-19 pandemic not possible using EHR data alone.

Risk Predictors and Symptom Features of Long COVID Within a Broad Primary Care Patient Population Including Both Tested and Untested Patients.

INTRODUCTION: Symptoms may persist after the initial phases of COVID-19 infection, a phenomenon termed long COVID. Current knowledge on long COVID has been mostly derived from test-confirmed and hospitalized COVID-19 patients. Data are required on the burden and predictors of long COVID in a broader patient group, which includes both tested and untested COVID-19 patients in primary care. METHODS: This is an observational study using data from Platform C19, a quality improvement program-derived research database linking primary care electronic health record data (EHR) with patient-reported questionnaire information. Participating general practices invited consenting patients aged 18-85 to complete an online questionnaire since 7th August 2020. COVID-19 self-diagnosis, clinician-diagnosis, testing, and the presence and duration of symptoms were assessed via the questionnaire. Patients were considered present with long COVID if they reported symptoms lasting ≥4 weeks. EHR and questionnaire data up till 22nd January 2021 were extracted for analysis. Multivariable regression analyses were conducted comparing demographics, clinical characteristics, and presence of symptoms between patients with long COVID and patients with shorter symptom duration. RESULTS: Long COVID was present in 310/3151 (9.8%) patients with self-diagnosed, clinician-diagnosed, or test-confirmed COVID-19. Only 106/310 (34.2%) long COVID patients had test-confirmed COVID-19. Risk predictors of long COVID were age ≥40 years (adjusted Odds Ratio [AdjOR]=1.49 [1.05-2.17]), female sex (adjOR=1.37 [1.02-1.85]), frailty (adjOR=2.39 [1.29-4.27]), visit to A&E (adjOR=4.28 [2.31-7.78]), and hospital admission for COVID-19 symptoms (adjOR=3.22 [1.77-5.79]). Aches and pain (adjOR=1.70 [1.21-2.39]), appetite loss (adjOR=3.15 [1.78-5.92]), confusion and disorientation (adjOR=2.17 [1.57-2.99]), diarrhea (adjOR=1.4 [1.03-1.89]), and persistent dry cough (adjOR=2.77 [1.94-3.98]) were symptom features statistically more common in long COVID. CONCLUSION: This study reports the factors and symptom features predicting long COVID in a broad primary care population, including both test-confirmed and the previously missed group of COVID-19 patients.

Historical database cohort study addressing the clinical patterns prior to idiopathic pulmonary fibrosis (IPF) diagnosis in UK primary care.

OBJECTIVE: To explore the clinical pathways, including signs and symptoms, and symptom progression patterns preceding idiopathic pulmonary fibrosis (IPF) diagnosis. DESIGN AND SETTING: A historical cohort study was conducted using primary care patient records from the Optimum Patient Care Research Database. PARTICIPANTS: Patients included were at least 30 years, had IPF diagnosis, identified via clinical-coding and free-text records and had a consultation with a chest specialist prior to IPF diagnosis. OUTCOME MEASURES: The signs and symptoms in the year prior to IPF diagnosis from clinical codes and free-text in primary care electronic records included: cough, dyspnoea, dry cough, weight loss, fatigue/malaise, loss of appetite, crackles and clubbed fingers. The time course of presentations of clinical features and investigations in the years prior to IPF diagnosis were mapped. RESULTS: Within 462 patients identified, the majority (77.9%) had a respiratory consultation within 365 days prior to the chest specialist visit preceding the IPF diagnosis recorded in their primary care records. The most common symptoms recorded in the 1 year prior to IPF diagnosis were dyspnoea (48.7%) and cough (40.9%); other signs and symptoms were rarely recorded (<5%). The majority of patients with cough (58.0%) and dyspnoea (55.0%) in the 1 year before IPF diagnosis had multiple recordings of the respective symptoms. Both cough and dyspnoea were recorded in 23.4% of patients in the year prior to diagnosis. Consultation rates for cough, dyspnoea and both, but not other signs or symptoms, began to increase 4 to 5 years prior diagnosis, with the sharpest increase in the last year. Cough and dyspnoea were often preceded by a reduction in measured weight over 5 years leading to IPF diagnosis. CONCLUSION: Prolonged cough and/or progressive dyspnoea, especially if accompanied with weight loss, should signal for a referral to specialist assessment at the earliest opportunity.

A Comparison of the Real-Life Clinical Effectiveness of the Leading Licensed ICS/LABA Combination Inhalers in the Treatment for COPD.

Introduction: The Fostair® 100/6 (BDP/FF) pressurized metered-dose inhaler, delivering an extrafine formulation, is licensed for asthma and COPD in the UK. However, its real-life effectiveness for COPD has not been evaluated. This study compared the clinical effectiveness of BDP/FF against other licensed ICS/LABA combination inhalers: the Seretide® Accuhaler® (FP/SAL) and the Symbicort® Turbohaler® (BUD/FF). Methods: A matched historical cohort study was conducted using records of patients with diagnostic codes for COPD from the Optimum Patient Care Research Database (OPCRD). Patients who had received BDP/FF as their first ICS/LABA were matched 1:1 with patients who had received FP/SAL or BUD/FF, resulting in two matched comparisons. Additional analysis was conducted on patients who had never had diagnostic codes for asthma. Noninferiority in terms of the proportion of patients with moderate/severe COPD exacerbations on the different inhalers in the following year was assessed. Noninferiority was achieved if the upper CI limit were ≤1.2. Results: This study included 537 and 540 patient pairs in the BDP/FF vs FP/SAL cohort and the BDP/FF vs BUD/FF cohort, respectively. The proportion of patients with COPD exacerbations in the BDP/FF group was not significantly different from either the FP/SAL (68.7% vs 70.2%, AOR 0.89, 95% CI 0.67-1.19) or BUD/FF group (68.5% vs 69.4%, AOR 0.79, 95% CI 0.58-1.08). Noninferiority of BDP/FF in preventing COPD exacerbations was fulfilled in both comparisons. In patients without asthma, BDP/FF was also noninferior to BUD/FF (proportion with COPD exacerbations, 67.8% vs 64.7%, AOR 0.79, 95% CI 0.51-1.1997). Additionally, a significantly lower proportion of patients prescribed BDP/FF had COPD exacerbations than FP/SAL (64.8% vs 73.7%, AOR 0.64 95% CI 0.43-0.96). Conclusion: Initiating ICS/LABA treatment of COPD with extrafine-formulation BDP/FF was noninferior in preventing moderate/severe exacerbations compared to FP/SAL and BUD/FF.

Asthma Across Age: Insights From Primary Care.

Asthma is a heterogeneous disease comprising of multiple phenotypes and affects patients from childhood up to old age. In this review, we summarize the current knowledge on the similarities and differences in asthma across different age-groups, with emphasis on the perspective from primary care. Despite the similar disease presentation, phenotyping studies showed that there are differences in the distribution of phenotypes of asthma presenting in childhood compared to that in adulthood. Whereas, asthma with early age of onset tends to be of the atopic phenotype, the disease shifts toward the non-atopic phenotypes at later ages. Studies within primary care patients aiming to elucidate risk factors for future asthma exacerbation have shown pediatric and elderly patients to be at higher risk for future asthma attacks compared to other adult patients. Regardless, both pediatric and adult studies demonstrated previous asthma episodes and severity, along with high blood eosinophil to predict subsequent asthma attacks. Differences in childhood and adult asthma are not limited to the underlying phenotypes but also extends to the challenges in the diagnosis, treatment, and management of the disease. Diagnosis of asthma is complicated by age-specific differential diagnoses such as infectious wheezing and nasal obstruction in children, and aging-related problems such as heart disease and obesity in the elderly. There are also age-related issues leading to decreased disease control such as non-adherence, tobacco use, difficulty in using inhalers and corticosteroid-related side effects which hinder asthma control at different patient age-groups. Several clinical guidelines are available to guide the diagnosis and drug prescription of asthma in pediatric patients. However, there are conflicting recommendations for the diagnostic tools and treatment for pediatric patients, posing additional challenges for primary care physicians in working with multiple guidelines. While tools such as spirometry and peak flow variability are often available in primary care, their usage in preschool patients is not consistently recommended. FeNO measurement may be a valuable non-invasive tool which can be adopted by primary physicians to assist asthma diagnosis in preschool-age patients.

Physiological predictors Of peak inspiRatory flow using Observed lung function resultS (POROS): evaluation at discharge among patients hospitalized for a COPD exacerbation.

BACKGROUND: Peak inspiratory flow (PIF) as generated through the resistance of a dry powder inhaler (DPI) device is a critical patient-dependent maneuver impacting the success of DPI medication delivery. Despite its importance, it is not routinely measured in clinical practice. Little is currently known about the relationship, if any, between PIF through DPI devices, routine spirometry and disease outcomes. AIM: The aim of this study was to identify potential predictors of PIF for different DPIs from spirometric parameters and patient characteristics and explore the association between PIF and follow-up events. PATIENTS AND METHODS: A retrospective observational study at discharge among patients hospitalized for a COPD exacerbation at Attikon hospital, Athens, Greece. Spirometry was performed using an Easy on-PC™ spirometer. PIF was measured through four DPI resistances using the In-Check™ DIAL. Regression analyses were used to investigate the association between PIF through resistances and spirometric parameters obtained at discharge, comorbidities and demographic parameters. RESULTS: Forty-seven COPD patients (mean [±SD], age 71 [±9] years, 72% males, 51% current smokers) were included in this study. Overall, 85% and 15% were classified as GOLD (2017) groups D and C, respectively. Most prevalent comorbidities were hypertension (70%) and cardiovascular disease (53%). In the final regression model, higher PIF was significantly associated with the following: higher FEV1 and % predicted peak expiratory flow (PEF) for Turbohaler® (R-squared value 0.374); higher FEV1 and diagnosis of gastroesophageal reflux disease (GERD) for Aerolizer® (R-squared value 0.209) and higher FEV1, younger age and diagnosis of ischemic heart disease (IHD) for Diskus® (R-squared value 0.350). However, R-squared values for all three devices were weak (<0.4). CONCLUSION: The study did not provide evidence to support the use of surrogate measurements for PIF through device resistance, which could assist in determining the appropriateness of inhaler device type. Although PIF measurement is feasible in patients at discharge and could be a valuable addition to the standard of care in COPD management, it needs to be measured directly.

Validation of a Natural Language Processing Algorithm for Detecting Infectious Disease Symptoms in Primary Care Electronic Medical Records in Singapore.

BACKGROUND: Free-text clinical records provide a source of information that complements traditional disease surveillance. To electronically harness these records, they need to be transformed into codified fields by natural language processing algorithms. OBJECTIVE: The aim of this study was to develop, train, and validate Clinical History Extractor for Syndromic Surveillance (CHESS), an natural language processing algorithm to extract clinical information from free-text primary care records. METHODS: CHESS is a keyword-based natural language processing algorithm to extract 48 signs and symptoms suggesting respiratory infections, gastrointestinal infections, constitutional, as well as other signs and symptoms potentially associated with infectious diseases. The algorithm also captured the assertion status (affirmed, negated, or suspected) and symptom duration. Electronic medical records from the National Healthcare Group Polyclinics, a major public sector primary care provider in Singapore, were randomly extracted and manually reviewed by 2 human reviewers, with a third reviewer as the adjudicator. The algorithm was evaluated based on 1680 notes against the human-coded result as the reference standard, with half of the data used for training and the other half for validation. RESULTS: The symptoms most commonly present within the 1680 clinical records at the episode level were those typically present in respiratory infections such as cough (744/7703, 9.66%), sore throat (591/7703, 7.67%), rhinorrhea (552/7703, 7.17%), and fever (928/7703, 12.04%). At the episode level, CHESS had an overall performance of 96.7% precision and 97.6% recall on the training dataset and 96.0% precision and 93.1% recall on the validation dataset. Symptoms suggesting respiratory and gastrointestinal infections were all detected with more than 90% precision and recall. CHESS correctly assigned the assertion status in 97.3%, 97.9%, and 89.8% of affirmed, negated, and suspected signs and symptoms, respectively (97.6% overall accuracy). Symptom episode duration was correctly identified in 81.2% of records with known duration status. CONCLUSIONS: We have developed an natural language processing algorithm dubbed CHESS that achieves good performance in extracting signs and symptoms from primary care free-text clinical records. In addition to the presence of symptoms, our algorithm can also accurately distinguish affirmed, negated, and suspected assertion statuses and extract symptom durations.

Rhinitis in children less than 6 years of age: current knowledge and challenges.

Rhinitis is a disease of the upper airway characterized by runny and/or blocked nose and/or sneezing. Though not viewed as a life threatening condition, it is also recognized to impose significant burden to the quality of life of sufferers and their caretakers and imposes an economic cost to society. Through a PubMed online search of the literature from 2006 to September 2011, this paper aims to review the published literature on rhinitis in young children below the age of 6 years. It is apparent from epidemiology studies that rhinitis in this age group is a relatively common problem. The condition has a heterogenous etiology with classification into allergic and non-allergic rhinitis. Respiratory viral infections may play a role in the pathogenesis of long standing rhinitis, but definitive studies are still lacking. Treatment guidelines for management are lacking for this age group, and is a significant unmet need. Although the consensus is that co-morbidities including otitis media with effusion, adenoidal hypertrophy and asthma, are important considerations of management of these children. Pharmacotherapy is limited for young children especially for those below the age of 2 years. This review underscores the lack of understanding of rhinitis in early childhood and therefore the need for further research in this area.