Development and Validation of the Indian Asthma Care Bundle for Reducing Readmission and Improving Post-hospitalisation Care After Discharge From Hospital Due to an Acute Asthma Exacerbation (I-ACB)

BACKGROUND AND RATIONALE Asthma is a chronic inflammatory airway disease characterised by variable airflow obstruction, bronchial hyperresponsiveness, and recurrent respiratory symptoms, affecting an estimated 290 million people worldwide. Approximately 2.9% Indians suffer from asthma, accounting for nearly 42 million people. Not only the prevalence, but also the Disability-Adjusted Life Years (DALYs) from asthma are double, while the mortality is as much as three times the global proportion. According to a report, nearly 25% of all asthma patients are hospitalised at least once every year due to exacerbations, which might be triggered by several factors, such as exposure to air pollution, poor treatment adherence, or any concomitant allergic reactions, which may lead to reduced lung function, increased risk of cardiopulmonary events, and mortality. Such a high number of asthma-related hospitalisations is not just due to poor treatment compliance or environmental triggers, but includes a fundamental gap in the infrastructure of asthma care. India spends nearly USD 9.5 billion on asthma care every year, most of which is out-of-pocket expenditure. Improper asthma care can play a significant role in perpetuating the vicious cycle of asthma management fallacy, ultimately resulting in a substantial economic burden. Although Indian data are not available, some reports have shown that >75% patients who were hospitalised due to an asthma exacerbation required oxygen, while nearly 38% asthma patients showed up in the emergency department (ED) or were re-hospitalised within 30 days of discharge. Hospital readmission or ED visit is associated with increased morbidity and utilisation of healthcare resources, and thus, contributes significantly to the economic burden of asthma. Therefore, continuous care and an optimised treatment plan must be in place for asthma patients during discharge from the hospital after an acute exacerbation to reduce morbidity and mortality.

International guidelines, such as the Global Initiative for Asthma (GINA), recommend a well-structured asthma care plan, particularly after hospital discharge. These structured care approaches, known as "Care Bundles", are a small, evidence-based set of recommendations, embedded in usual care or applied as a part of post-discharge management. Studies have shown that implementing predischarge care bundles significantly reduced ED visits and readmissions due to asthma exacerbations, and improved post-hospitalisation care. A current knowledge gap, particularly in the Indian setting, is whether a comprehensive care predischarge plan for patients with asthma reduces readmissions and ED visits, maintains symptom control, and improves quality of life. Despite its clinical and public health importance, no attention has been paid to developing a consensus care plan for asthma treatment and management in India.

To address this knowledge gap, the investigators aim to develop a hospital-initiated asthma care bundle and examine its effectiveness on post-hospitalisation asthma care and clinical outcomes through a prospective, multicentre cohort study of adult asthma patients hospitalised for asthma exacerbation. The investigators hypothesise that implementing a bundle to screen for and educate patients about asthma exacerbations will reduce post-discharge readmissions and ED visits and significantly improve treatment adherence, lung function, symptom control, and quality of life.

OBJECTIVES Our primary objective is to develop a hospital-initiated asthma care bundle (I-ACB), a contextual and India-specific post-discharge care bundle tailored for adult asthma patients hospitalised for asthma exacerbations and examine the effectiveness of I-ACB on post-discharge clinical outcomes, including the rate of readmissions or emergency department visits in 30, 60, and 90 days post-discharge.

Our secondary objectives are to evaluate the effectiveness of the care bundle on 1) treatment adherence, 2) lung function, 3) symptom control, and 4) quality of life for asthma patients in 30, 60, and 90 days post-discharge compared to usual care.

METHODS This is a multicentre prospective cohort study, conducted in accordance with the Indian Council of Medical Research (ICMR) National Ethical Guidelines for Biomedical and Health Research involving Human Participants. The study comprises three sequential phases: (i) Phase I - development of the care bundle through evidence synthesis and expert consensus, (ii) Phase II - pilot feasibility testing in tertiary healthcare settings, and (iii) Phase III - evaluation of its clinical effectiveness in a multicentre, parallel-group randomised controlled trial. The protocol has been developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statement, and the randomised trial will be reported in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. An infographic of the study design is presented in Figure 1.

Phase I: Development of the I-ACB Design and methods In this phase, the investigators aim to develop the I-ACB through a comprehensive synthesis of the available evidence on discharge interventions and management plans following acute exacerbations of asthma and other chronic respiratory diseases.

i) At first, the investigators will systematically review all available literature that has demonstrated evidence of post-discharge outcomes in asthma, including hospital readmission, emergency department attendance and recurrent exacerbations. The investigators will also assess the currently available national and international asthma management guidelines published by major respiratory societies, including GINA, the British Thoracic Society (BTS), the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), the Canadian Thoracic Society (CTS), and the Indian Chest Society - National College of Chest Physicians (India) (ICS/NCCP (I)) to identify areas of agreement and divergence, and to develop context-specific recommendations relevant to the Indian healthcare system.

ii) In the next step, the investigators will integrate the evidence obtained from the previous step into the formation of a preliminary version of the I-ACB, which will be particularly relevant to the Indian context. Apart from the general recommendations emanating from the international guidelines, the investigators will focus particularly on components that are particularly relevant to the Indian context, such as inhaler technique, patient education, identification of exacerbation triggers, treatment adherence, and post-discharge follow-up. The investigators will validate the contents of the I-ACB using a modified Delphi process involving a multidisciplinary panel of experts comprising respiratory physicians, emergency physicians, internists, epidemiologists, public health specialists, nurses and patient representatives. The panellists of the Delphi group will independently and anonymously evaluate each proposed bundle component with respect to its clinical relevance, clarity and feasibility using structured questionnaires. The investigators will score each item on a Likert scale from 1 to 10, with 1 being least relevant and 10 most relevant; a median cut-off of ≥ 6 was considered relevant.

Statistical analysis The investigators will first calculate the Content Validity Index (CVI) to assess the content validity of the items. CVI assesses the degree to which the content of an instrument is relevant to and representative of the construct it is intended to measure. Item-level CVI (I-CVI) and scale-level CVI (S-CVI) values > 0.8 indicate high agreement among the experts. Further to this, the investigators will also analyse the responses quantitatively using Cronbach's α coefficient, exploratory factor analysis following assessment of sampling adequacy using the Kaiser-Meyer-Olkin statistic and Bartlett's test of sphericity, and, where appropriate, Item Response Theory (IRT) modelling. These analyses will inform iterative refinement of the intervention until a final consensus-based version of the I-ACB is established.

Phase II: Pilot study Design and participants In this phase, the investigators will evaluate the feasibility and acceptability of the intervention in routine clinical practice, enabling refinement of both the intervention and implementation strategy before large-scale evaluation. Adult patients admitted with acute asthma exacerbation will receive the preliminary intervention before hospital discharge and will be followed for 90 days after discharge. The pilot study is intended primarily to evaluate the practicality of intervention delivery, patient comprehension, language appropriateness, acceptability among healthcare professionals and patients, and the logistics of follow-up procedures. A total of 40 participants will be recruited for the feasibility pilot study. As the primary purpose is feasibility assessment, the sample size is not powered to detect differences in clinical outcomes. No usual-care comparator will be included. Information obtained during this phase will be used to identify implementation barriers, optimise study procedures and refine the intervention before commencement of the definitive randomised controlled trial.

Statistical analyses The analysis of the pilot study will primarily focus on the feasibility, acceptability, comprehensibility and implementation of the Indian Asthma Care Bundle (I-ACB), rather than on testing its clinical effectiveness. The investigators will assess recruitment feasibility using the proportion of eligible patients who consent to participate and the recruitment rate during the pilot period. The proportion of participants who will complete the intervention at each scheduled follow-up assessment at 30, 60 and 90 days will be recorded, and compliance will be calculated. Any withdrawal or loss to follow-up will also be documented for qualitative assessments. The comprehensibility and acceptability of individual I-ACB components will be assessed quantitatively using a 5-point Likert scale (1: least comprehensible, 5: fully comprehensible), and the distributions will be reported as medians and interquartile ranges (IQR). Language suitability, in terms of terminology, wording, cultural appropriateness, and comprehension, will be evaluated qualitatively. In the exploratory analysis of the clinical outcomes collected in this phase, including asthma-related hospital readmissions, emergency department visits, treatment adherence, symptom control, lung function, and health-related quality of life, will be assessed using appropriate paired or repeated-measures methods. Nevertheless, these analyses will not be interpreted as evidence of intervention effectiveness.

Phase III: Randomised Controlled Trial Study design and participants The effectiveness of I-ACB will be evaluated through a prospective, multicentre, parallel-group, randomised controlled trial. Adult participants (≥18 years) admitted to any participating tertiary care hospital with an acute asthma exacerbation will be screened for eligibility. Participants who have i) a diagnosed co-pulmonary condition, such as chronic obstructive pulmonary disease, bronchiectasis, interstitial lung disease or other chronic respiratory disorders, ii) a recent (in the past 6 months) history of hospitalisation due to influenza, pneumonia, or any respiratory tract infections, iii) a recent (in the past 6 months) hospital admission due to cardiologic condition or under medications such as statins, beta-blockers, blood thinners, etc., and iv) a significant cognitive impairment, will be excluded. Additionally, participants with very low educational attainment (≤ primary school education), who transferred to another healthcare facility before discharge, or who are discharged against medical advice, will also be excluded. Participants will be randomly allocated in a 1:1 ratio to receive either the I-ACB intervention or usual care alone using a computer-generated randomisation sequence. Figure 2 presents a schematic layout of Phase III.

Participants allocated to the usual care group will receive discharge care plans in accordance with the standard clinical practices of the attending physicians at the participating institution. Despite anticipated variability in usual discharge care plans, the investigators will not further standardise discharge procedures. However, the investigators will prospectively document those usual care plans using a structured checklist.

Sample size calculation Although there is no available data on 30-day hospital readmission rates among asthma patients in India, the investigators estimated the sample size using a prior report indicating a 12% prevalence of hospital readmission due to asthma exacerbation within 30 days post-discharge in the US. To achieve the goal of a 60% relative reduction in these readmission rates, the investigators plan to recruit 254 asthma patients (rounded up to 260), with 130 participants in each treatment arm. This calculation is based on existing evidence, assuming an α level of 0.05, a β of 0.20, and a 10% expected dropout rate over 3 months.

Demographic and outcome measures A demographic questionnaire will be administered at recruitment to capture age, sex, height, weight, educational qualification, employment status, marital status, family size, smoking history, and regular physical activity. The investigators will assess comorbidity by the Elixhauser comorbidity index (-19: less likely in-hospital death to 89: more likely in-hospital death), and medication adherence by the Medication Adherence Rating Scale (MARS) (0: worse compliance to 10: better compliance) will be used to assess compliance. The investigators will use PROMIS® (Patient-Reported Outcomes Measurement Information System) tools to assess social, psychological, and behavioural attributes such as companionship, emotional support, instrumental support, social isolation, anxiety, depression, sleep disturbances, and alcohol abuse as described previously. Routine haematological tests, including total and differential blood cell counts (including eosinophils), are usually performed at the time of hospitalisation. Information about allergen sensitivity to house dust mites, cockroach allergens, fungal spores (Aspergillus sp. and Alternaria sp.), and grass pollen will be collected from the case record forms of the participants. If allergy information is unavailable, participants will be tested for allergic sensitisation before discharge.

The main outcome will be hospital readmissions or emergency department visits related to asthma happening within 30, 60, and 90 days post-discharge. The secondary outcomes will include treatment adherence, lung function, symptom management, and quality of life, assessed at follow-up visits at 30, 60, and 90 days after discharge.

Information about hospital admissions or ED visits, such as any incident of readmission/ED visit (yes/no), duration of stay (days), and any significant events at the hospitals during readmission (ventilation, oxygenation, etc.), will be obtained from participants during each follow-up and triangulated with their medical records. All participants will be asked to record their daily medications at discharge, and any changes in their medication history will be obtained from their prescriptions.

Lung function tests using spirometry and oscillometry will be performed according to the American Thoracic Society/European Respiratory Society (ATS/ERS) criteria at the time of discharge from the hospital. The tests will be administered again at home during the 30, 60, and 90-day follow-ups by trained technicians.

The investigators will measure symptom control and quality of life at each follow-up using the asthma control questionnaire (ACQ) and the asthma quality of life questionnaire AQLQ.

Other environmental measures A separate environmental questionnaire containing items on the quality of the indoor environment at home (indoor moulds, exposure to second-hand smoke, adequacy of sunlight and air movement, presence of dampness, proximity to green, blue, and grey spaces, ambient noise, exposure to pets, cooking medium used in the house, exposure to second-hand smoke at home, proximity to an industry that emits fumes/gases), and information about food allergies and occupational exposures will be compiled from the European Community Respiratory Health Survey (ECRHS Main-II) questionnaires, and will be administered to the participants at discharge.

Statistical analysis All analyses will follow the intention-to-treat principle, with participants analysed according to their randomised allocation. Baseline characteristics will be summarised descriptively by treatment group, with standardised mean differences for covariate balance. Descriptive statistics will be presented as mean (SD), median (IQR), or frequency (percentage) for continuous, count, and categorical variables, respectively. The primary outcome, defined as the occurrence of an asthma-related hospital readmission or emergency department (ED) visit within 30 days of discharge (either as yes/no or number of occurrences), will be compared between the I-ACB and usual-care groups using mixed-effects logistic (for dichotomised outcome, yes/no) or Poisson (for number of occurrences) regression models, incorporating participant-level random effects to account for within-person correlation. Adjustment for demographic, clinical, lifestyle, and environmental factors will be prespecified using a directed acyclic graph (DAG). A similar approach will be used to evaluate the composite outcome at 60 and 90 days as secondary time horizons. Based on the distribution nature of the secondary outcome variables, i.e., treatment adherence, symptom control, lung function, and health-related quality of life, the investigators will apply mixed-effects Poisson, negative binomial, or linear models to compare the I-ACB and usual care groups.

In additional analyses, the investigators will stratify by sex, age group, allergic sensitisation, and region, including interaction terms to formally assess heterogeneity of treatment effects. Additional exploratory analyses will examine whether improvements in treatment adherence or symptom control mediate the effect of I-ACB on subsequent healthcare utilisation. The investigators will not perform any imputation for the missing data.

Ethics and informed consent As per the latest guidelines of the Indian Council of Medical Research, multicentre studies in India will no longer require ethics approval from all participating institutes; a single ethics approval will suffice. The study is awaiting approval from the Institutional Ethics Committee of Ahmedabad University. Any significant changes to the protocol will be submitted to the ethics committees and regulatory bodies. Once these modifications are approved, they will be shared with both investigators and trial participants as necessary. Signed informed consent from participants will be obtained before they are recruited into Phase II or Phase III trial-related procedures.

DISCUSSION Hospitalisation, particularly re-hospitalisation due to asthma exacerbations, imposes a significant burden on healthcare in India, as most of these events incur out-of-pocket expenditure. Despite the substantial burden of asthma in India, a uniform post-discharge management remains lacking, and a structured, contextually appropriate care pathway may lower recurrent exacerbations, ED visits and hospital readmissions. The I-ACB study aims to address this gap, and the intervention is designed to standardise key elements of discharge care, taking into account India's cultural diversity, multilingualism, and healthcare contexts.

One of the major strengths of this study is its multi-phased development process. Instead of adapting a care plan developed elsewhere, the I-ACB will first integrate evidence from multiple sources, and the Delphi process will involve a wide range of specialists and patient representatives to build a consensus by incorporating clinical and patient perspectives. This approach will also help ensure that the final intervention addresses clinically important, potentially modifiable aspects of post-discharge care and ongoing follow-up. India is a large country with a wide spectrum of languages, social statuses, and cultures, and the feasibility phase provides an additional strength to this study by allowing the intervention to be tested for contextual, linguistic, and cultural appropriateness before undertaking the definitive trial. This iterative process will also allow us to identify potential practical barriers to implementation. The primary outcome of interest for asthma-related hospital readmissions or ED visits within 30 days post-discharge in Phase III of the study has been deliberately selected because it is a major preventable healthcare utilisation metric, with the aim of enhancing patient outcomes and reducing the overall burden on healthcare systems. Assessment at 60 and 90 days will provide information on whether this discharge bundle also provides long-term benefits. Treatment adherence, lung function, symptom control, and health-related quality of life will help us determine whether the intervention also impacts patient-centred outcomes.

The investigators also anticipate some challenges. First, because the attending healthcare provider will be directly responsible for delivering the care bundles (I-ACB or usual care), blinding will not be feasible, which could introduce selection and reporting bias. However, the investigators will conduct sessions before the trial phases to educate healthcare providers and minimise bias. Second, the varying nature of usual care may make the comparator heterogeneous. The investigators expect that the multilevel nature of the analysis, i.e., centre-level variations, can be accounted for. Third, despite standardised training and fidelity monitoring, the delivery of individual bundle components may vary across healthcare providers. However, our feasibility study will help us examine this potential issue, and the investigators will also perform regular monitoring of the study centres to ensure uniformity in the administration of the discharge plans. Finally, the estimated sample size is powered for the 30-day outcome and may provide limited power for other secondary analyses; however, the investigators will consider those analyses exploratory.

If effective, the I-ACB may provide India with its first scalable and adaptable framework for strengthening post-discharge asthma care. Its evidence-based and context-specific nature may be helpful for adapting to routine care across the country. More broadly, the study addresses a pivotal gap in current hospital-based management and long-term asthma care in this country and aims to provide a pragmatic model to reduce preventable healthcare utilisation and improve post-discharge asthma management.