Disproportionality Analysis and Characterisation of Medication Errors in EudraVigilance: Exploring Findings on Sexes and Age Groups.

BACKGROUND: While medication errors (MEs) have been studied in the European Medicines Agency's EudraVigilance, extensive characterisation and signal detection based on sexes and age groups have not been attempted. OBJECTIVES: The aim of this study was to characterise all ME-related individual case safety reports in EudraVigilance and explore notable signals of disproportionate reporting (SDRs) among sexes and age groups for the 30 most frequently reported drugs. METHODS: Individual case safety reports were used from EudraVigilance reported between 2002 and 2021. An ME was defined as any Preferred Term from the narrow Standardised Medical Dictionary for Regulatory Activities® Query. Signals of disproportionate reporting were selected based on a lower boundary of the 95% confidence interval ≥ 1 of the reporting odds ratio, and at least 3 individual case safety reports. Analysed subgroups were female individuals, male individuals, and age groups 0-1 month, 2 months to 2 years, 3-11 years, 12-17 years, 18-64 years, 65-85 years, and >85 years. Heatmaps were utilised as a visual aid to identify striking SDRs. RESULTS: Of the 9,662,345 EudraVigilance reports, 267,262 (2.8%) contained at least one ME, with a total of 300,324 MEs, for 429,554 drugs. The most reported ME was "Inappropriate schedule of product administration" (52,646; 17.5%), followed by "Incorrect dose administered" (32,379; 10.8%) and "Wrong technique in product usage process" (26,831; 8.9%). Individual case safety reports with MEs were most frequently related to female individuals (148,009; 55.4%), most often submitted by healthcare professionals (155,711; 58.3%), originated predominantly from the USA (98,716; 36.9%), followed by France (26,678; 10.0%), and showed a median reported age of 50 years (interquartile range: 26-68). Most ME individual case safety reports (158,991; 59.5%) were associated with a serious health outcome. A total of 847 SDRs were identified, based on the entire EudraVigilance database; for subgroups, the number of SDRs ranged from 84 for the age group 0-1 month to 749 for female individuals. Signals of disproportionate reporting for female individuals and male individuals were very similar. Most MEs were reported for the vaccine against human papillomavirus (Anatomical Therapeutic Chemical [ATC]: J07BM01; 11,086 MEs, 57% being "inappropriate schedule of product administration"), with reporting odds ratios that range from 1.5 to 47.0 among age groups. The SDR for the live-attenuated vaccine against herpes zoster (ATC: J07BK02) had a reporting odds ratio that ranged from 26.6 to 78.1 among all subgroups. Signals of disproportionate reporting for oxycodone (ATC: N02AA05; 847 cases of "Accidental overdose", 35%), risperidone (ATC: N05AX08; 469 cases "Inappropriate schedule of product administration", 22.3%) and rivaroxaban (ATC: B01AF01; 1,377 cases of "Incorrect dose administered", 34.6%) stood out with higher magnitude SDRs for the age group 2 months to 2 years, with an reporting odds ratio range between 8.2 and 10.7, while for the entire EudraVigilance the reporting odds ratio ranged between 1.3 and 1.6 for the same drugs. CONCLUSIONS: This exploratory research provides an overview of characterised ME individual case safety reports and SDRs from the EudraVigilance database. Most conspicuous SDRs were identified in specific age groups. Signals of disproportionate reporting, not described in the literature, were found for vaccines, oxycodone, rivaroxaban and risperidone, and may prompt further examination by stakeholders. Top-reported MEs ("Inappropriate schedule of product administration", "Incorrect dose administered" and "Wrong technique in product usage process") emerged as a general priority focus to perform a further root-cause analysis involving healthcare providers, manufacturers and regulatory bodies, to improve the understanding and prevention of MEs.

Descriptive analysis on disproportionate medication errors and associated patient characteristics in the Food and Drug Administration's Adverse Event Reporting System.

BACKGROUND: Medication errors (MEs) are a major public health concern which can cause harm and financial burden within the healthcare system. Characterizing MEs is crucial to develop strategies to mitigate MEs in the future. OBJECTIVES: To characterize ME-associated reports, and investigate signals of disproportionate reporting (SDRs) on MEs in the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: FAERS data from 2004 to 2020 was used. ME reports were identified with the narrow Standardised Medical Dictionary for Regulatory Activities® (MedDRA®) Query (SMQ) for MEs. Drug names were converted to the Anatomical Therapeutic Chemical (ATC) classification. SDRs were investigated using the reporting odds ratio (ROR). RESULTS: In total 488 470 ME reports were identified, mostly (59%) submitted by consumers and mainly (55%) associated with females. Median age at time of ME was 57 years (interquartile range: 37-70 years). Approximately 1 out of 3 reports stated a serious health outcome. The most prevalent reported drug class was "antineoplastic and immunomodulating agents" (25%). The most common ME type was "incorrect dose administered" (9%). Of the 1659 SDRs obtained, adalimumab was the most common drug associated with MEs, noting a ROR of 1.22 (95% confidence interval: 1.21-1.24). CONCLUSION: This study offers a first of its kind characterization of MEs as reported to FAERS. Reported MEs are frequent and may be associated with serious health outcomes. This FAERS data provides insights on ME prevention and offers possibilities for additional in-depth analyses.

Parasitic infections related to anti-type 2 immunity monoclonal antibodies: a disproportionality analysis in the food and drug administration's adverse event reporting system (FAERS).

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab. Methods: Spontaneous reports were used from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities® (MedDRA®). Safety signal strength was assessed by the Reporting Odds Ratio (ROR). Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was 55 years (interquartile range 24-63 years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4-29.3). Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation.

Drug Utilisation Patterns of Alternatives to Ranitidine-Containing Medicines in Patients Treated with Ranitidine: A Network Analysis of Data from Six European National Databases.

INTRODUCTION: Ranitidine, a histamine H2-receptor antagonist (H2RA), is indicated in the management of gastric acid-related disorders. In 2020, the European Medicines Agency (EMA) recommended suspension of all ranitidine-containing medicines in the European Union (EU) due to the presence of N-nitrosodimethylamine (NDMA) impurities, which were considered to be carcinogenic. The aim of this study was to investigate the impact of regulatory intervention on use patterns of ranitidine-containing medicines and their therapeutic alternatives. OBJECTIVES: The aim was to study drug utilisation patterns of ranitidine and report discernible trends in treatment discontinuation and switching to alternative medications. METHODS: This retrospective, population-based cohort study was conducted using primary care records from six European countries between 2017 and 2023. To explore drug utilisation patterns, we calculated (1) incident use of ranitidine, other H2RAs, and other alternative drugs for the treatment of gastric ulcer and/or gastric bleeding; (2) ranitidine discontinuation; and (3) switching from ranitidine to alternative drugs (H2RAs, proton-pump inhibitors [PPIs], and other medicinal products for acid-related disorders). RESULTS: During the study period, 385,273 new ranitidine users were observed, with most users being female and aged 18-74 years. Ranitidine was the most commonly prescribed H2RA in the pre-referral period (September 2017-August 2019), with incidence rates between 0.8 and 9.0/1000 person years (PY). A steep decline to 0.3-3.8/1000 PY was observed in the referral period (September 2019-March 2020), eventually dropping to 0.0-0.4/1000 PY in the post-referral period (April 2020-March 2022). Switching from ranitidine to alternative drugs increased in the post-referral period, with the majority of patients switching to PPIs. Discontinuation of ranitidine use ranged from 270 to 380/1000 users in 2017 and decreased over time. CONCLUSIONS: Ranitidine was commonly used prior to referral, but it was subsequently discontinued and replaced primarily with PPIs.

Drug utilization analysis of osteoporosis medications in seven European electronic health databases.

We studied the characteristics of patients prescribed osteoporosis medication and patterns of use in European databases. Patients were mostly female, older, had hypertension. There was suboptimal persistence particularly for oral medications. Our findings would be useful to healthcare providers to focus their resources on improving persistence to specific osteoporosis treatments. PURPOSE: To characterise the patients prescribed osteoporosis therapy and describe the drug utilization patterns. METHODS: We investigated the treatment patterns of bisphosphonates, denosumab, teriparatide, and selective estrogen receptor modulators (SERMs) in seven European databases in the United Kingdom, Italy, the Netherlands, Denmark, Spain, and Germany. In this cohort study, we included adults aged ≥ 18 years, with ≥ 1 year of registration in the respective databases, who were new users of the osteoporosis medications. The study period was between 01 January 2018 to 31 January 2022. RESULTS: Overall, patients were most commonly initiated on alendronate. Persistence decreased over time across all medications and databases, ranging from 52-73% at 6 months to 29-53% at 12 months for alendronate. For other oral bisphosphonates, the proportion of persistent users was 50-66% at 6 months and decreased to 30-44% at 12 months. For SERMs, the proportion of persistent users at 6 months was 40-73% and decreased to 25-59% at 12 months. For parenteral treatment groups, the proportions of persistence with denosumab were 50-85% (6 month), 30-63% (12 month) and with teriparatide 40-75% (6 month) decreasing to 21-54% (12 month). Switching occurred most frequently in the alendronate group (2.8-5.8%) and in the teriparatide group (7.1-14%). Switching typically occurred in the first 6 months and decreased over time. Patients in the alendronate group most often switched to other oral or intravenous bisphosphonates and denosumab. CONCLUSION: Our results show suboptimal persistence to medications that varied across different databases and treatment switching was relatively rare.

Liver Injury Following Isoniazid Preventive Therapy in HIV Patients Attending Halibet National Referral Hospital, Eritrea: A Prospective Cohort Study.

INTRODUCTION: A 6-month course of isoniazid, 300 mg daily, was programmatically introduced in Eritrea in 2014 as tuberculosis preventive therapy in people living with human immunodeficiency virus (PLHIV). The rollout of isoniazid preventive therapy (IPT) in PLHIV was successful in the first 2-3 years. After 2016, rumours based on rare but real incidents of liver injuries following use of IPT spread widely across the country and created concerns amongst healthcare professionals and consumers, that ultimately caused dramatic decline in the rollout of the intervention. Decision makers have been demanding better evidence as previously conducted local studies had inherent methodological limitations. This real-world observational study was conducted to evaluate the risk of liver injury associated with IPT among PLHIV attending Halibet national referral hospital, Asmara, Eritrea. METHODS: A prospective cohort study, that consecutively enrolled PLHIV attending Halibet hospital, was conducted between 1 March and 30 October 2021. Those exposed to anti-retroviral therapy (ART) plus IPT were considered as exposed and those taking only ART were considered as unexposed. Both groups were prospectively followed up for 4-5 months with monthly liver function tests (LFTs). A Cox proportional hazard model was used to explore whether there was increased risk of drug-induced liver injury (DILI) associated with IPT. Probability of survival without DILI was also estimated using Kaplan-Meier curves. RESULTS: A total of 552 patients, 284 exposed and 268 unexposed, completed the study, with a mean follow-up time of 3.97 (SD 0.675) months for the exposed and 4.06 (SD 0.675) months for the unexposed. Twelve patients developed drug-induced liver injury (DILI), with a median time-to-onset of 35 days (interquartile range: 26.8, 60 days). All cases were from the exposed group and all except two cases were asymptomatic. The incidence rate of DILI in the exposed group was 10.6 cases per 1000 person-months and zero for the unexposed group (p = 0.002). CONCLUSION: DILI in PLHIV taking IPT was common; therefore, liver function should be closely monitored to safely administer the product. Despite high levels of deranged liver enzymes, the majority had no symptoms of DILI, emphasising the importance of close laboratory monitoring, especially during the first 3 months of treatment.

Challenges of Estimating Global Feature Importance in Real-World Health Care Data.

Feature importance is often used to explain clinical prediction models. In this work, we examine three challenges using experiments with electronic health record data: computational feasibility, choosing between methods, and interpretation of the resulting explanation. This work aims to create awareness of the disagreement between feature importance methods and underscores the need for guidance to practitioners how to deal with these discrepancies.

Epidemiology of unexplained chronic cough in adults: a population-based study.

Unexplained chronic cough accounts for a significant proportion of chronic cough cases in adults, and its persistent phenotype shows female preponderance that is demographically similar to individuals with cough hypersensitivity https://bit.ly/3EwjWVo.

Characterising the treatment of thromboembolic events after COVID-19 vaccination in 4 European countries and the US: An international network cohort study.

Background: Thrombosis with thrombocytopenia syndrome (TTS) has been identified as a rare adverse event following some COVID-19 vaccines. Various guidelines have been issued on the treatment of TTS. We aimed to characterize the treatment of TTS and other thromboembolic events (venous thromboembolism (VTE), and arterial thromboembolism (ATE) after COVID-19 vaccination and compared to historical (pre-vaccination) data in Europe and the US. Methods: We conducted an international network cohort study using 8 primary care, outpatient, and inpatient databases from France, Germany, Netherlands, Spain, The United Kingdom, and The United States. We investigated treatment pathways after the diagnosis of TTS, VTE, or ATE for a pre-vaccination (background) cohort (01/2017-11/2020), and a vaccinated cohort of people followed for 28 days after a dose of any COVID-19 vaccine recorded from 12/2020 onwards). Results: Great variability was observed in the proportion of people treated (with any recommended therapy) across databases, both before and after vaccination. Most patients with TTS received heparins, platelet aggregation inhibitors, or direct Xa inhibitors. The majority of VTE patients (before and after vaccination) were first treated with heparins in inpatient settings and direct Xa inhibitors in outpatient settings. In ATE patients, treatments were also similar before and after vaccinations, with platelet aggregation inhibitors prescribed most frequently. Inpatient and claims data also showed substantial heparin use. Conclusion: TTS, VTE, and ATE after COVID-19 vaccination were treated similarly to background events. Heparin use post-vaccine TTS suggests most events were not identified as vaccine-induced thrombosis with thrombocytopenia by the treating clinicians.

Global Epidemiology of Hip Fractures: Secular Trends in Incidence Rate, Post-Fracture Treatment, and All-Cause Mortality.

In this international study, we examined the incidence of hip fractures, postfracture treatment, and all-cause mortality following hip fractures, based on demographics, geography, and calendar year. We used patient-level healthcare data from 19 countries and regions to identify patients aged 50 years and older hospitalized with a hip fracture from 2005 to 2018. The age- and sex-standardized incidence rates of hip fractures, post-hip fracture treatment (defined as the proportion of patients receiving anti-osteoporosis medication with various mechanisms of action [bisphosphonates, denosumab, raloxifene, strontium ranelate, or teriparatide] following a hip fracture), and the all-cause mortality rates after hip fractures were estimated using a standardized protocol and common data model. The number of hip fractures in 2050 was projected based on trends in the incidence and estimated future population demographics. In total, 4,115,046 hip fractures were identified from 20 databases. The reported age- and sex-standardized incidence rates of hip fractures ranged from 95.1 (95% confidence interval [CI] 94.8-95.4) in Brazil to 315.9 (95% CI 314.0-317.7) in Denmark per 100,000 population. Incidence rates decreased over the study period in most countries; however, the estimated total annual number of hip fractures nearly doubled from 2018 to 2050. Within 1 year following a hip fracture, post-hip fracture treatment ranged from 11.5% (95% CI 11.1% to 11.9%) in Germany to 50.3% (95% CI 50.0% to 50.7%) in the United Kingdom, and all-cause mortality rates ranged from 14.4% (95% CI 14.0% to 14.8%) in Singapore to 28.3% (95% CI 28.0% to 28.6%) in the United Kingdom. Males had lower use of anti-osteoporosis medication than females, higher rates of all-cause mortality, and a larger increase in the projected number of hip fractures by 2050. Substantial variations exist in the global epidemiology of hip fractures and postfracture outcomes. Our findings inform possible actions to reduce the projected public health burden of osteoporotic fractures among the aging population. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Chronic Cough-Related Differences in Brain Morphometry in Adults: A Population-Based Study.

BACKGROUND: Individuals with cough hypersensitivity have increased central neural responses to tussive stimuli, which may result in maladaptive morphometric changes in the central cough processing systems. RESEARCH QUESTION: Are the volumes of the brain regions implicated in cough hypersensitivity different in adults with chronic cough compared with adults without chronic cough? STUDY DESIGN AND METHODS: Between 2009 and 2014, participants in the Rotterdam Study, a population-based cohort, underwent brain MRI and were interviewed for chronic cough, which was defined as daily coughing for at least 3 months. Regional brain volumes were quantified with the use of parcellation software. Based on literature review, we identified and studied seven brain regions that previously had been associated with altered functional brain activity in chronic cough. The relationship between chronic cough and regional brain volumes was investigated with the use of multivariable regression models. RESULTS: Chronic cough was prevalent in 9.6% (No. = 349) of the 3,620 study participants (mean age, 68.5 ± 9.0 years; 54.6% female). Participants with chronic cough had significantly smaller anterior cingulate cortex volume than participants without chronic cough (mean difference, -126.16 mm3; 95% CI, -245.67 to -6.66; P = .039). Except for anterior cingulate cortex, there were no significant difference in the volume of other brain regions based on chronic cough status. The volume difference in the anterior cingulate cortex was more pronounced in the left hemisphere (mean difference, -88.11 mm3; 95% CI, -165.16 to -11.06; P = .025) and in male participants (mean difference, -242.58 mm3; 95% CI, -428.60 to -56.55; P = .011). INTERPRETATION: Individuals with chronic cough have a smaller volume of the anterior cingulate cortex, which is a brain region involved in cough suppression. CLINICAL TRIAL REGISTRATION: The Netherlands National Trial Registry (NTR; www.trialregister.nl) and the World Health Organization's International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under the joint catalogue number NTR6831.

Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom.

Population-based studies can provide important evidence on the safety of COVID-19 vaccines. Using data from the United Kingdom, here we compare observed rates of thrombosis and thrombocytopenia following vaccination against SARS-CoV-2 and infection with SARS-CoV-2 with background (expected) rates in the general population. First and second dose cohorts for ChAdOx1 or BNT162b2 between 8 December 2020 and 2 May 2021 in the United Kingdom were identified. A further cohort consisted of people with no prior COVID-19 vaccination who were infected with SARS-Cov-2 identified by a first positive PCR test between 1 September 2020 and 2 May 2021. The fourth general population cohort for background rates included those people in the database as of 1 January 2017. In total, we included 3,768,517 ChAdOx1 and 1,832,841 BNT162b2 vaccinees, 401,691 people infected with SARS-CoV-2, and 9,414,403 people from the general population. An increased risk of venous thromboembolism was seen after first dose of ChAdOx1 (standardized incidence ratio: 1.12 [95% CI: 1.05 to 1.20]), BNT162b2 (1.12 [1.03 to 1.21]), and positive PCR test (7.27 [6.86 to 7.72]). Rates of cerebral venous sinus thrombosis were higher than otherwise expected after first dose of ChAdOx1 (4.14 [2.54 to 6.76]) and a SARS-CoV-2 PCR positive test (3.74 [1.56 to 8.98]). Rates of arterial thromboembolism after vaccination were no higher than expected but were increased after a SARS-CoV-2 PCR positive test (1.39 [1.21 to 1.61]). Rates of venous thromboembolism with thrombocytopenia were higher than expected after a SARS-CoV-2 PCR positive test (5.76 [3.19 to 10.40]).

TreatmentPatterns: An R package to facilitate the standardized development and analysis of treatment patterns across disease domains.

BACKGROUND AND OBJECTIVES: There is an increasing interest to use real-world data to illustrate how patients with specific medical conditions are treated in real life. Insight in the current treatment practices helps to improve and tailor patient care, but is often held back by a lack of data interoperability and a high-level of required resources. We aimed to provide an easy tool that overcomes these barriers to support the standardized development and analysis of treatment patterns for a wide variety of medical conditions. METHODS: We formally defined the process of constructing treatment pathways and implemented this in an open-source R package TreatmentPatterns (https://github.com/mi-erasmusmc/TreatmentPatterns) to enable a reproducible and timely analysis of treatment patterns. RESULTS: The developed package supports the analysis of treatment patterns of a study population of interest. We demonstrate the functionality of the package by analyzing the treatment patterns of three common chronic diseases (type II diabetes mellitus, hypertension, and depression) in the Dutch Integrated Primary Care Information (IPCI) database. CONCLUSION: TreatmentPatterns is a tool to make the analysis of treatment patterns more accessible, more standardized, and more interpretation friendly. We hope it thereby contributes to the accumulation of knowledge on real-world treatment patterns across disease domains. We encourage researchers to further adjust and add custom analysis to the R package based on their research needs.

Epidemiology of chronic inflammatory demyelinating polyradiculoneuropathy in The Netherlands.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare but disabling disorder that often requires long-term immunomodulatory treatment. Background incidence rates and prevalence and risk factors for developing CIDP are still poorly defined. In the current study, we used a longitudinal population-based cohort study in The Netherlands to assess these rates and demographic factors and comorbidity associated with CIDP. We determined the incidence rate and prevalence of CIDP between 2008 and 2017 and the occurrence of potential risk factors in a retrospective Dutch cohort study using the Integrated Primary Care Information (IPCI) database. Cases were defined as CIDP if the diagnosis of CIDP was described in the electronic medical file. In a source population of 928 030 persons with a contributing follow-up of 3 525 686 person-years, we identified 65 patients diagnosed with CIDP. The overall incidence rate was 0.68 per 100 000 person-years (95% CI 0.45-0.99). The overall prevalence was 7.00 per 100 000 individuals (95% CI 5.41-8.93). The overall incidence rate was higher in men compared to woman (IRR 3.00, 95% CI 1.27-7.11), and higher in elderly of 50 years or older compared with people <50 years of age (IRR 17 95% CI 4-73). Twenty percent of CIDP cases had DM and 9% a co-existing other auto-immune disease. These background rates are important to monitor changes in the frequency of CIDP following infectious disease outbreaks, identify potential risk factors, and to estimate the social and economic burden of CIDP.

The interrelationship of chronic cough and depression: a prospective population-based study.

Background: Chronic cough is a debilitating medical condition that is often complicated by psychomorbidities such as depressive symptoms. Nevertheless, little is known about the impact of chronic cough on the risk of developing depression. Therefore, we investigated the association between chronic cough and prevalent, incident and recurrent depression in a population-based sample of middle-aged and older persons. Methods: Within the Rotterdam Study, a population-based cohort, we defined chronic cough as reporting daily coughing for ⩾3 months. Depression was assessed using the Center for Epidemiologic Studies Depression scale, clinical interviews and medical records. Associations between chronic cough and depression were determined with linear, logistic and Cox regression analyses. Results: The study included 5877 participants (mean±sd age 72±8 years, 59% female) who contributed 37 287 person-years of follow-up. At baseline, participants with chronic cough reported more depressive symptoms (adjusted standardised mean difference 0.15, 95% CI 0.07-0.22) compared to those without chronic cough. Over time, chronic cough was associated with an increased risk of depression in participants with a history of depression (hazard ratio (HR) 1.45, 95% CI 1.13-1.84), but not in those without a history of depression (HR 0.91, 95% CI 0.68-1.22). Conclusions: Adults with chronic cough have a disproportionate burden of depressive symptoms and an increased risk of recurrent depression. This highlights the importance of screening for depression in patients with chronic cough.

Characterization of Asthma by Age of Onset: A Multi-Database Cohort Study.

BACKGROUND: Asthma can occur at any age but the differences in patient characteristics between childhood-, adult-, and late-onset asthma are not well understood. OBJECTIVE: To investigate differences in patients' characteristics by age at asthma onset. METHODS: From 5 European electronic databases, we created a cohort encompassing adult patients with doctor-diagnosed asthma in 2008 to 2013. Patients were categorized based on their age at asthma onset: childhood-onset (age at onset < 18 y), adult-onset (age at onset 18-40 y), and late-onset asthma (age at onset ≥ 40 y). Comorbidities were assessed at study entry. For each characteristic and comorbidity, odds ratios and age- and sex-adjusted odds ratios (ORadj) comparing asthma-onset categories were estimated per database and combined in a meta-analysis using a random effect model. RESULTS: In total, 586,436 adult asthma patients were included, 81,691 had childhood-onset, 218,184 adult-onset, and 286,561 late-onset asthma. Overall, 7.3% had severe asthma. Subjects with adult-onset compared with childhood-asthma had higher risks for overweight/obesity (ORadj 1.4; 95% CI 1.1-1.8) and lower risks for atopic disorders (ORadj 0.8; 95% CI 0.7-0.95). Patients with late-onset compared with adult-onset asthma had higher risks for nasal polyposis (ORadj 1.8; 95% CI 1.2-2.6), overweight/obesity (ORadj 1.3; 95% CI 1.2-1.4), gastroesophageal reflux disease (ORadj 1.4; 95% CI 1.2-1.7), and diabetes (ORadj 2.3; 95% CI 1.8-2.9). A significant association between late-onset asthma and uncontrolled asthma was observed (ORadj 2.8; 95% CI 1.7-4.5). CONCLUSIONS: This international study demonstrates clear differences in comorbidities between childhood-, adult-, and late-onset asthma phenotypes in adults. Furthermore, patients with late-onset asthma had more frequent uncontrolled asthma.

Sarcopenia, systemic immune-inflammation index and all-cause mortality in middle-aged and older people with COPD and asthma: a population-based study.

BACKGROUND: Increasing evidence suggests that sarcopenia and a higher systemic immune-inflammation index (SII) are linked with morbidity in patients with COPD. However, whether these two conditions contribute to all-cause mortality in middle-aged and older patients with COPD or asthma is unclear. Therefore, we investigated the association between sarcopenia, SII, COPD or asthma and all-cause mortality in a large-scale population-based setting. METHODS: Between 2009 and 2014, 4482 participants (aged >55 years; 57.3% female) from the population-based Rotterdam Study were included. COPD and asthma patients were diagnosed clinically and based on spirometry. Six study groups were defined according to the presence or absence of COPD or asthma and sarcopenia. Cox regression models were used to assess all-cause mortality in the study groups, adjusted for sex, age, body mass index, SII, smoking, oral corticosteroid use and comorbidities. In addition, all participants were categorised into sex-specific quartiles of SII, and mortality in these groups was compared. RESULTS: Over a median follow-up of 6.1 years (interquartile range 5.0-7.2 years), 466 (10.4%) persons died. Independent of the presence of sarcopenia, participants with COPD had a higher risk of all-cause mortality (hazard ratio (HR) 2.13, 95% CI 1.46-3.12 and HR 1.70, 95% CI 1.32-2.18 for those with and without sarcopenia, respectively). Compared to lower SII levels, higher SII levels increased mortality risk even in people without sarcopenia, COPD or asthma. CONCLUSION: Middle-aged and older people with COPD, higher SII levels or sarcopenia had an independently increased mortality risk. Our study suggests prognostic usefulness of routinely evaluating sarcopenia and SII in older people with COPD or asthma.

Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. OBJECTIVE: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. METHODS: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. RESULTS: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. CONCLUSION: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.

Identification of ROBO2 as a Potential Locus Associated with Inhaled Corticosteroid Response in Childhood Asthma.

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10-6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29-14.93, p = 4.61 × 10-7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10-5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.