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Respiratory medicine
Original research
Clinical–functional characteristics and risk of exacerbation and mortality among more symptomatic patients with chronic obstructive pulmonary disease: a retrospective cohort study
  1. Qing Song1,2,3,
  2. Ling Lin1,2,3,
  3. Wei Cheng1,2,3,
  4. Xue-Shan Li1,2,3,
  5. Yu-Qin Zeng1,2,3,
  6. Cong Liu1,2,3,
  7. Min-Hua Deng4,
  8. Dan Liu5,
  9. Zhi-Ping Yu6,
  10. Xin Li7,
  11. Li-Bing Ma8,
  12. Yan Chen1,2,3,
  13. Shan Cai1,2,3,
  14. Ping Chen1,2,3
  1. 1Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University, Changsha, Hunan, China
  2. 2Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, China
  3. 3Diagnosis and Treatment Center of Respiratory Disease, Central South University, Changsha, Hunan, China
  4. 4Department of Respiratory, PLA Rocket Force Characteristic Medical Center, Beijing, China
  5. 5Department of Respiratory, The Eighth Hospital in Changsha, Hunan, China
  6. 6Department of Respiratory, Longshan Hospital of Traditional Chinese Medicine, Hunan, China
  7. 7Division 4 of Occupational Disease, Hunan Occupational Disease Prevention and Treatment Hospital, Changsha, Hunan, China
  8. 8Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Guilin Medical University, Guilin, China
  1. Correspondence to Dr Ping Chen; pingchen0731{at}csu.edu.cn

Abstract

Objectives The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 classified chronic obstructive pulmonary disease (COPD) patients into more and less symptomatic groups. This study aimed to analyze the clinical characteristics, risk of future exacerbation and mortality among patients in more symptomatic group.

Design A retrospective cohort study.

Setting Data were obtained from patients enrolled in a database setup by Second Xiangya Hospital of Central South University.

Participants 1729 stable COPD patients listed from September 2017 to December 2019 in the database. The patients were classified into more and less symptomatic groups based on GOLD 2017 report.

Outcomes All patients were followed up for 18 months. We collected baseline data and recorded the number of exacerbations and mortality during follow-up.

Results The more symptomatic patients were older, had higher Clinical COPD Questionnaire (CCQ) scores, more severe airflow limitation and higher number of exacerbations and hospitalizations in the past year (P < 0.05). Logistic regression showed that having more symptoms correlated with the CCQ scores and exacerbations in the past year (P < 0.05). After patients were followed up, there were higher numbers of exacerbations, hospitalizations and mortality rates in more symptomatic patients (P < 0.05). The multivariate model showed that age more than 65 years (OR = 2.047, 95% CI = 1.020-4.107) and COPD assessment test scores more than 30 (OR = 2.609, 95% CI = 1.339-5.085) were independent risk factors for mortality, whereas current smoker (OR = 1.565, 95% CI = 1.052-2.328), modified Medical Research Council scores (OR = 1.274, 95% CI = 1.073-1.512) and exacerbations in the past year (OR = 1.061, 95% CI = 1.013-1.112) were independent risk factors for exacerbation in more symptomatic patients (P < 0.05).

Conclusions More symptomatic COPD patients have worse outcomes. In addition, several independent risk factors for exacerbation and mortality were identified. Therefore, clinicians should be aware of these risk factors and take them into account during interventions.

  • respiratory medicine (see thoracic medicine)
  • risk management
  • respiratory physiology

Data availability statement

Data are available upon reasonable request. The datasets are available in the Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital repository (http://120.77.177.175:9007/a/login). The data that support the findings of this study are available upon reasonable request from the corresponding author Ping Chen.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

http://dx.doi.org/10.1136/bmjopen-2022-065625

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • This is a multicentre study and the data derived from outpatient chronic obstructive pulmonary disease (COPD) database, which included several hospitals.

    • This study is the first to explore the independent risk factors for future exacerbation and mortality among more symptomatic patients with COPD according to Global Initiative for Chronic Obstructive Lung Disease report.

    • A key limitation is that 281 of the more symptomatic patients were lost to follow-up.

    • This study did not discuss the comorbidities that might place a symptom burden on patients with COPD.

    Introduction

    Chronic obstructive pulmonary disease (COPD) is a serious chronic respiratory disease that typically features persistent respiratory symptoms, such as cough, expectoration and dyspnoea. This disease has brought a huge burden of mortality to humanity1 2; therefore, prevention and treatment are urgent.

    Breathlessness, cough and sputum production are common symptoms of COPD, bringing a huge burden to patients. Some may experience deterioration of their symptoms and need additional treatment.3 The COPD Assessment Test (CAT) and modified Medical Research Council (mMRC) scales cover several dimensions, such as dyspnoea, cough, expectoration, confidence, limitation of daily activities and chest tightness, and are used as indicators to measure the effect of symptoms on the health of patients with COPD.4 5 The higher the CAT and mMRC scores, the more symptoms the patients have and the greater the impact on patients’ health.6 Ding et al7 found that as the CAT scores increased, the frequency of primary care physician visits also increased. Kim et al8 found that patients with COPD with increased mMRC scores had a higher risk of exacerbation, more severe airflow limitation and respiratory symptoms when compared with patients with unchanged mMRC scores after 1 year of follow-up. In addition, one study showed that the BODE (body mass index (BMI), airflow obstruction, dyspnoea, exercise capacity) index includes dyspnoea as a meaningful marker of future exacerbation risk.9 In fact, some patients with COPD only experience cough or breathlessness, whereas others have multiple respiratory symptoms, including cough, expectoration, chest tightness and dyspnoea.

    The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 evaluated patients with COPD based on the CAT/mMRC scores and exacerbation risk to better guide the treatment, dividing patients into more symptomatic and less symptomatic groups.10 A Japanese study found that the patients with COPD in the more symptomatic group were older and had more severe airflow limitation and higher exacerbation rates according to the GOLD 2017 classification; however, the number of more symptomatic patients in this study was small.11 Several studies have shown that more symptomatic patients with COPD account for the majority.12–15 In addition, Cabrera López et al16 found that the risk of mortality was higher in groups B and D than in groups A and C according to the GOLD 2017 classification. However, the clinical characteristics and outcomes among more symptomatic patients with COPD remained unclear. Therefore, our purpose was to analyse the clinical characteristics and related risk factors, as well as the risk of future exacerbation and mortality, among patients in more symptomatic group.

    Methods

    Study participants

    We conducted a retrospective cohort study that captured the patients listed from September 2017 to December 2019 in the outpatient COPD database (register number: ChiCTR-POC-17010431; http://120.77.177.175:9007/a/login), which includes the Second Xiangya Hospital of Central South University, the Zhuzhou Central Hospital, the Hunan Prevention and Treatment Institute for Occupational Diseases, the First Affiliated Hospital of Shaoyang University, the Eighth Hospital in Changsha and the Longshan Hospital of Traditional Chinese Medicine (Hunan, China). The inclusion criterion for patients with COPD was a ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) of <0.70 after bronchodilator administration. Patients with interstitial lung disease, bronchiectasis, pneumonia, asthma, pleural effusion, lung cancer or active tuberculosis were excluded from the study.

    Patient and public involvement

    Patients and the public were not involved in the conception of this study, development of the research question, interpretation of the results or manuscript writing.

    Study procedures

    All included patients with COPD underwent 18 months of follow-up. Furthermore, at 6, 12 and 18 months, we recorded the number of exacerbation, hospitalisation and deaths among these patients. According to the GOLD 2017 report, the patients with COPD were assigned to more and less symptomatic groups. Briefly, the more symptomatic group was defined by mMRC scores ≥2 and CAT scores ≥10, with or without a history of exacerbation and hospitalisation. The less symptomatic group was defined by mMRC scores <2 and/or CAT scores <10, with or without a history of exacerbation and hospitalisation.10

    Data collection and definitions

    The baseline clinical characteristics included demographics, smoking history, biofuel and occupational exposure history, pulmonary function results, symptoms scores (including CAT and mMRC), Clinical COPD Questionnaire (CCQ) scores, treatment regimens and number of exacerbation and hospitalisation in the past year. Furthermore, we recorded mortality, and the number of exacerbation and hospitalisation during follow-up.

    A current smoker was defined as having a smoking exposure of more than 10 packs/year, whereas a former smoker was defined as having a smoking exposure of at least 10 packs/year, but with smoking cessation for more than half a year.17 Exacerbation was defined as disease progression that requires antibiotics, oral corticosteroids or hospitalisation for treatment or was determined by a sputum colour change (to green or yellow).18 Biofuel exposure was defined as continuous exposure to biofuels for at least 2 hours a day for at least 1 year. Occupational exposure was defined as exposure to dust, metals, chemical substances or other environmental agents for at least 8 hours a day for at least 1 year.19 According to the GOLD 2017 report, GOLD stage 1=FEV1 ≥80%pred; GOLD stage 2=FEV1 50%–79%pred); GOLD stage 3=FEV1 30%–49%pred and GOLD stage 4=FEV1 <30%pred.10 Oxygen therapy included home oxygen therapy and non-invasive positive pressure ventilation in this study.20

    The pulmonary function test was measured by a spirometer (MasterScreen-Body/Diff, CareFusion, Germany) according to the American Thoracic Society guidelines. FEV1 was defined as the time in seconds, measured from time 0 to 1, of the expiration after maximal forced inspiration. FVC was defined as the largest expiration volume immediately after maximal forced inspiration. Peak expiratory flow (PEF) was defined as the highest flow achieved from a maximum forced expiratory manoeuvre that started without hesitation from a position of maximal lung inflation.21

    Statistical analysis

    Continuous variables were presented as the mean±SD. The Χ2 and Fisher’s tests were used to analyse categorical variables. An independent-sample Student’s t-test was used to analyse continuous variables. For variables with non-normal distribution or uneven variance, we used non-parametric tests. The variously adjusted OR was calculated using multivariate logistic regression. Two-sided p values of <0.05 were considered to be statistically significant. SPSS V.26.0 (IBM) was used to perform all statistical analyses.

    Results

    Baseline characteristics

    A total of 1729 patients with COPD were included (figure 1). The mean age was 65.1±8.2 years, 89.1% were male and more than half of the patients were current smokers. Most of the patients were in GOLD stages 2–3 and on treatment with a long-acting muscarinic antagonist (LAMA), LAMA+long-acting β2-agonist (LABA)+inhaled corticosteroid (ICS). The mean CAT and CCQ scores were 15.4±6.6 and 21.9±7.2, respectively. Most patients suffered from exacerbation and hospitalisation less than once per year (table 1).

    View this table:
    Table 1

    The baseline characteristics of the patients with COPD

    Figure 1
    Figure 1

    Flow chart. COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease.

    According to the GOLD 2017 report, 1388 (80.3%) were more symptomatic patients. These patients were older (65.5±8.0 vs 63.4±8.8 years, p<0.001) and had lower education level, BMI, FEV1, FEV1 %pred, FVC, FEV1/FVC and PEF (p<0.001). In addition, a higher proportion of biofuel exposure history, GOLD stages 3–4 patients, treatment with LAMA+LABA+ICS and oxygen therapy were found in the more symptomatic group (p<0.05). Furthermore, more symptomatic patients with COPD had higher CCQ scores and a higher number of exacerbation and hospitalisation in the past year (p<0.001) (table 2).

    View this table:
    Table 2

    The clinical characteristics of more symptomatic patients with COPD

    Multivariate analysis of risk factors associated with more symptomatic patients with COPD

    Results were adjusted for age, education level, biofuel exposure, FEV1, FEV1 %pred, FVC, GOLD stages and BMI. Logistic regression analysis showed that FEV1/FVC and PEF were negatively correlated with the more symptomatic, with ORs of 0.980 (95% CI=0.964–0.995) and 0.774 (95% CI=0.688–0.872), respectively (p<0.05). However, CCQ scores and exacerbation in the past year were positively correlated with the more symptomatic, with ORs of 1.200 (95% CI=1.169–1.232) and 1.114 (95% CI=1.025–1.211), respectively (p<0.05) (table 3).

    View this table:
    Table 3

    Multivariate analysis of risk factors associated with more symptomatic patients with COPD

    Exacerbation and mortality after 18 months of follow-up

    As shown in table 4, after 18 months of follow-up, a total of 1407 patients were included. The mean values for exacerbation and hospitalisation were 0.7±1.3 and 0.4±0.8, respectively. Most of the patients suffered exacerbation and hospitalisation less than once per year and the mortality rate was 4.6%.

    View this table:
    Table 4

    Exacerbation and mortality after 18 months of follow-up in more symptomatic patients with COPD

    After 18 months of follow-up, 1107 more symptomatic patients with COPD were analysed for future exacerbation and mortality. The results show that the more symptomatic patients with COPD suffered from a higher number of exacerbation and hospitalisation (p<0.001). The proportion of more symptomatic patients who suffered from exacerbation and hospitalisation at least once per year was higher (p<0.001), with rates of 40.8% and 27.4%, respectively. Comparison of the exacerbation-free proportion using a Kaplan-Meier curve revealed that there was a significant difference between the more and less symptomatic patients (p<0.001) (figure 2). In addition, 58 (5.2%) more symptomatic patients with COPD died during the 18 months of follow-up, which is a higher number than in the less symptomatic group (p<0.001). Comparison of overall survival using the Kaplan-Meier curve revealed that survival was significantly different between the more and less symptomatic patients (p=0.013) (figure 3).

    Figure 2
    Figure 2

    Kaplan-Meier curves of the exacerbation-free proportion between more and less symptomatic patients with COPD; p<0.05 was considered to be statistically significant. COPD, chronic obstructive pulmonary disease.

    Figure 3
    Figure 3

    Kaplan-Meier curves of the overall survival between more and less symptomatic patients with COPD; p<0.05 was considered to be statistically significant. COPD, chronic obstructive pulmonary disease.

    Univariate and stepwise multivariate analyses of risk factors for mortality in more symptomatic patients with COPD

    Of the 1107 more symptomatic patients with COPD, 58 died during follow-up. Univariate analysis showed that there were several risk factors for mortality, including age more than 65 years (OR=2.925, 95% CI=1.532–5.586, p=0.001), smoking (packs/year) (OR=1.012, 95% CI=1.003–1.020, p=0.005), CAT scores more than 30 (OR=3.341, 95% CI=1.923–5.805, p<0.001), mMRC scores (OR=1.490, 95% CI=1.107–2.006, p=0.009), CCQ scores (OR=1.091, 95% CI=1.048–1.137, p<0.001), exacerbation in the past year (OR=1.057, 95% CI=1.001–1.117, p=0.049) and hospitalisation in the past year (OR=1.143, 95% CI=1.014–1.289, p=0.029). The multivariate model showed that age more than 65 years (OR=2.047, 95% CI=1.020–4.107, p=0.044), smoking (packs/year) (OR=1.014, 95% CI=1.005–1.023, p=0.002) and CAT scores more than 30 (OR=2.609, 95% CI=1.339–5.085, p=0.005) were independent risk factors for mortality in more symptomatic patients with COPD (table 5).

    View this table:
    Table 5

    Univariate and stepwise multivariate analyses of risk factors for mortality in more symptomatic patients with COPD

    Univariate and stepwise multivariate analyses of risk factors for future exacerbation in more symptomatic patients with COPD

    In total, 428 of 1107 more symptomatic patients with COPD suffered from exacerbation during follow-up. Univariate analysis showed that there were several risk factors for future exacerbation, including being a current smoker (OR=1.480, 95% CI=1.125–1.948, p=0.005), CAT scores 20–29 (OR=1.428, 95% CI=1.087–1.877, p=0.011) and CAT scores more than 30 (OR=3.225, 95% CI=1.531–6.793, p=0.002), mMRC scores (OR=1.375, 95% CI=1.199–1.576, p<0.001), CCQ scores (OR=1.025, 95% CI=1.006–1.045, p=0.012), exacerbation in the past year (OR=1.098, 95% CI=1.049–1.149, p<0.001) and hospitalisation in the past year (OR=1.208, 95% CI=1.094–1.335, p<0.001). The multivariate model showed that being a current smoker (OR=1.565, 95% CI=1.052–2.328, p=0.027), mMRC scores (OR=1.274, 95% CI=1.073–1.512, p=0.006) and exacerbation in the past year (OR=1.061, 95% CI=1.013–1.112, p=0.013) were independent risk factors for future exacerbation in more symptomatic patients with COPD (table 6).

    View this table:
    Table 6

    Univariate and stepwise multivariate analyses of risk factors for future exacerbation in more symptomatic patients with COPD

    Discussion

    In this study, we found that the more symptomatic patients accounted for the majority, and several studies have yielded the same results.12–15 In addition, patients with COPD in China typically do not go to the hospital until they have severe respiratory symptoms. We also found that the more symptomatic patients were older, and a similar result was observed by Han et al.22 Biofuel exposure is one of the main risk factors of COPD.23 24 A study showed that compared with smoking, patients with COPD with biofuel exposure experienced more dyspnoea.25 In addition, Dutt et al26 found that people exposed to biofuel may suffer from more respiratory symptoms. The results of our research confirmed that more symptomatic patients with COPD had a higher biofuel exposure rate. Maintenance of inhaled bronchodilators and ICS could reduce respiratory symptoms and exacerbation, and improve pulmonary function in patients with COPD. Our research results showed that more symptomatic patients were more likely to use triple inhalers and less likely to use monotherapy with LAMA. This was consistent with the results of a study done by Kobayashi et al.11

    Pulmonary function is used to evaluate airflow limitation and severity of patients with COPD. Our research also found that more symptomatic patients with COPD had worse pulmonary function, and that deterioration of pulmonary function was significantly associated with respiratory symptoms. This was consistent with a study by Boezen et al,27 which showed that both FEV1 and PEF decreased as the number of symptoms increased, and that the risk of having a FEV1 or PEF value of <70% increased with increasing symptoms. Brodkin et al28 also found that cough, phlegm, wheeze and dyspnoea were inversely related to pulmonary function. Another study found that initial FEV1 level was lower in patients with dyspnoea appearing during follow-up than in the group without symptoms.29 The GOLD 2013 report also recommends the CCQ as a symptom measure30 and states that it is predictive of mortality in patients with COPD.31 Our study showed that more symptomatic patients had higher CCQ scores, which were positively correlated with more symptoms.

    Exacerbation is an important risk factor for stable COPD, leading to pulmonary function decline and poor prognosis.32 Our study found that more symptomatic patients suffered from a higher number of exacerbation in the past year. Moreover, the higher the number of exacerbation, the more symptoms the patients experienced. Miravitlles et al33 also found that more exacerbation in the past year was associated with variability in symptom number. In addition, Kobayashi et al11 found that more symptomatic patients suffered a higher number of exacerbation in the past year, which is consistent with our research. However, it is unclear whether more symptomatic patients have worse outcomes. Therefore, we performed 18 months of follow-up to observe the patients’ future exacerbation and mortality. The results showed that there were higher exacerbation and hospitalisation rates in more symptomatic patients, along with higher mortality rates. In addition, Kim et al34 found that the more symptomatic patients had significantly higher future exacerbation risk among patients with FEV1 ≥50%. A study by Cabrera López et al16 also found a similar result, with more symptomatic patients showing a higher mortality rate at 5 years of follow-up. In addition, our research results show that more symptomatic patients had a lower BMI but a higher risk of future exacerbation and mortality. This was consistent with a study by Putcha et al,35 which showed that underweight participants had a significantly higher risk of death and severe exacerbation.

    Death is the most serious malignant event associated with COPD,36 and it is vital to analyse the risk factors for death in patients with COPD. Our results showed that age, smoking (packs/year) and CAT scores were positively correlated with mortality. Age and smoking are important risk factors associated with COPD development,37 38 and our study also found the same result. At the same time, it implied that improved pulmonary function, reduced respiratory symptoms and quitting smoking are important interventions to reduce the occurrence of malignant events in COPD.

    Acute exacerbation is an important deterioration event in patients with COPD during follow-up. Therefore, it is necessary to analyse the independent risk factors of the more symptomatic patients who suffered from exacerbation during the 18 months of follow-up in order to better guide the prevention and treatment. In this study, we found that the mMRC scores, being a current smoker and the number of exacerbation in the past year were positively correlated with future exacerbation. It is implied that the higher the mMRC scores and number of exacerbation in the past year, the higher the future exacerbation risk.

    Smoking is an important risk factor for COPD development,38 and it is important to demonstrate the effects of smoking on COPD exacerbation. Therefore, we further analysed the exacerbation and mortality after 18 months of follow-up in patients with COPD with different smoking histories. We found that current smokers had higher exacerbation and hospitalisation rates than former smokers and never smokers (online supplemental table 1). Furthermore, patients with COPD who smoked more than 10 packs/year had higher mortality (online supplemental table 2). This implies that smoking cessation may decrease the risk of exacerbation and mortality in patients with COPD. A study by Pezzuto and Carico39 had a similar result, showing that smoking cessation notably improved pulmonary functional parameters, oxygen desaturation and the walking test, as well as decreasing the CAT scores.

    This study has some limitations. First, 281 of the more symptomatic patients with COPD were lost to follow-up. However, we found that the characteristics of the patients who were lost to follow-up and those who remained in the study were not significantly different (online supplemental table 3). Also, the number of female patients in this study was small. In fact, the prevalence of COPD differed significantly between males and females in China, with the prevalence being higher in males, mainly because smoking was the main risk factor for COPD and because there were relatively few female patients who smoked.40 41 Furthermore, several studies showed that the proportion of female patients was relatively small in China.42–44 In addition, the number of patients with a low education level was higher. In fact, China is a developing country and the overall level of education is not high in early time. Finally, the comorbidities including interstitial lung disease, bronchiectasis, asthma and lung cancer were excluded from this study, which placed a symptom burden on patients with COPD and would have an impact on future exacerbation and mortality.

    In summary, our study revealed that the majority of patients with COPD have more symptoms, which is associated with worse pulmonary function. More symptomatic patients also have worse outcomes. Reducing respiratory symptoms might improve patients’ pulmonary function and outcomes. In addition, several independent risk factors for exacerbation and mortality in more symptomatic patients with COPD were identified, including age, smoking, mMRC scores, CAT scores and exacerbation in the past year. Therefore, clinicians should be aware of the risk factors and take them into account for interventions in more symptomatic patients with COPD.

    Data availability statement

    Data are available upon reasonable request. The datasets are available in the Department of Pulmonary and Critical Care Medicine, the Second Xiangya Hospital repository (http://120.77.177.175:9007/a/login). The data that support the findings of this study are available upon reasonable request from the corresponding author Ping Chen.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study was approved by an institutional review board from the Second Xiangya Hospital of Central South University and conducted in accordance with the Declaration of Helsinki. All patients in this study provided written informed consent.

    Acknowledgments

    We would like to thank the staff of the hospitals for their cooperation in collecting the study data.

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    Footnotes

    • Contributors PC is the guarantor. QS performed the data collection and statistical analyses, and drafted the manuscript. LL, WC, XuL, Y-QZ and CL performed the data collection and statistical analyses. M-HD, DL, Z-PY, XiL and L-BM performed the data collection. PC, YC and SC designed, coordinated the research and helped with editing of the paper. All authors revised the article critically for important intellectual content, agreed to submit to the current journal and gave final approval of the version to be published.

    • Funding This work was supported by the National Natural Science Foundation of China (NSFC, grants 81970044) and Xiangya Mingyi grant (2013).

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.