Table of Contents
Introduction
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which is increasingly appreciated as a major global challenge.
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Various case definitions are currently in use—long COVID refers to symptoms that continue or develop beyond 4 weeks after the start of acute COVID-19,
whereas post-COVID condition refers to symptoms 3 months from initial infection and lasting at least 2 months.
Long COVID is a heterogeneous condition that can involve multiple organs, resulting in numerous, often debilitating symptoms.
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People with long COVID commonly have breathlessness, anxiety, and reduced quality of life.
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At least 10% of people who develop COVID-19 have one or more symptoms for 12 weeks or longer,
with some estimates considerably higher.
Currently, approximately 1·3 million people in the UK (2% of the population), are estimated to have long COVID.
Evidence before this study
We searched PubMed using the search terms “post-COVID-19 syndrome”, “long COVID” and “trial” or “treatment”, from inception to Feb 20, 2022, with no limits on language, and found no randomised clinical trial data addressing interventions or treatments in people with ongoing symptoms following COVID-19. Previous research has demonstrated large numbers of people experience long-term illness and disability due to COVID-19, with breathlessness being a common symptom. Individualised holistic approaches to rehabilitation have been widely advocated given potentially relevant research in other conditions.
Added value of this study
To our knowledge, this is the first randomised controlled trial to evaluate an intervention for people with long COVID. We found that participation in an online breathing and wellbeing programme resulted in improvements in the mental component of health-related quality of life, and elements of breathlessness, in people with persisting breathlessness after COVID-19.
Implications of all the available evidence
Our findings suggest that mind–body and music-based approaches, including practical, enjoyable symptom-management techniques, might have a role supporting recovery for people with persisting breathlessness following COVID-19. Research into other related approaches would be valuable, as would better characterisation of long COVID subgroups to identify those most likely to benefit. Further randomised controlled trials of interventions targeting both symptoms and underlying pathology are required to create a portfolio of evidence-based management options adaptable to the specific needs of individual patients.
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Long COVID management guidelines have so far largely been based on expert opinion, and advocate personalised, holistic approaches to support recovery.
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Arts-in-health interventions can promote health and wellbeing for people with long-term health conditions.
Music and singing based activities have been shown to improve health related quality of life (HRQoL)
and are popular for people with long-term respiratory conditions and breathlessness.
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Additionally, the pandemic has seen successful online adaptation and delivery of many activities, including dance and Singing for Lung Health programmes,
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because singing is an activity associated with increased aerosol generation.
The English National Opera (ENO) created ENO Breathe in collaboration with health-care professionals, as part of its long-standing commitment to social prescribing. ENO Breathe is an online breathing retraining and wellbeing programme, which aims to support people recovering from COVID-19 with persistent breathlessness, with or without anxiety. Since the programme started on Oct 1, 2020, more than 500 people have taken part in ENO Breathe, and many other organisations and individuals globally have begun developing related programmes. The primary aim of this study was to test the hypothesis that ENO Breathe would improve mental and physical HRQoL, and breathlessness, in people with long COVID.
Methods
Study design and participants
) despite the investigation and management steps taken, could be considered for referral to ENO Breathe. Patients were given a unique login code by the clinic team. The exact proportion of codes that were used from those given out was not monitored during the trial period itself. However, during the subsequent 3 months as the clinical programme has continued, the rate has been stable at 43–44%.
and was made by the collaborating specialist clinic using a combination of laboratory investigations and comprehensive clinical assessment. Recruitment continued until the target sample size was met. All participants provided written informed consent.
Ethics approval was granted by the National Health Service Health Research Authority, Stanmore Research Ethics Committee (19/LO/0418). The study was conducted in accordance with the 1975 Declaration of Helsinki.
Randomisation and masking
Participants were randomly assigned (1:1) to immediate participation in ENO Breathe or to usual care (in effect a 6-week delay to participation in ENO Breathe until after they had exited the trial) using computer-generated block randomisation lists, with block size 10 (using SealedEnvelope). Randomisation by the research team took place when the potential participant used their individual code to log in to the ENO online system, which in practice resulted in five random assignments of individuals who then did not consent to participate in the research study, although two went on to participate in the programme after the research was completed. These individuals were not allocated to a study group or told which group they would have been allocated to.
Masking of participants was not possible given the nature of the intervention. However, outcome measures were collected using a self-completion online form, with the researcher responsible for randomisation masked to responses.
Procedures
Table 1Overview of the components of the ENO Breathe programme
ENO=English National Opera.
At the time the study commenced, 192 people with long COVID had taken part in the ENO Breathe programme, including continuous evaluation by an external independent evaluator (THH), which suggested the intervention was acceptable and safe. Adherence to, and potential adaptations from, the standard format are monitored and discussed in reflective programme provider discussions facilitated by a health psychologist (AMA) focused on clinical issues and potential emotional and relational pitfalls emerging from the group's dynamics. Fortnightly meetings involving ENO Breathe session leaders and clinicians at ICHT (respiratory physiotherapists and speech and language therapists) were scheduled to continue discussion of exercises delivered during sessions. Every 2 months, ENO Breathe Steering Group meetings also took place and involved a range of relevant stakeholders, including participant representatives. No substantial changes to the intervention took place during the study period, or since, at the time of writing.
Adherence to the programme is monitored with a register, with reasons for non-attendance recorded when possible. Participants are informed that full attendance at sessions is strongly recommended to get the full benefits of the programme, with additional adherence support including emails and phone calls to individuals who missed sessions, with support from either the ENO or clinical teams as appropriate.
People in the usual care group continued their clinical management as directed by their COVID-19 clinic and any other clinical services, going on to take part in the ENO Breathe programme once they had exited the trial. Given the current absence of randomised controlled trials in people with long COVID, usual care is not standardised; rather, current guidelines suggest holistic, individualised, multidisciplinary approaches, responsive to varied symptoms experienced by this group. For example, participants reported varied components of physiotherapy, including breathing exercises, physical rehabilitative exercises, balance training, and fatigue management.
All data collection was via an online form, which required a response to each question to progress through the form, resulting in no data missing for people who completed data collection. Participants started ENO Breathe or usual care within 1 week of baseline data collection and completed the follow-up data collection within 1 week of completion of the intervention period.
Qualitative results and interpretation were reviewed by all co-authors and patient experts. Full qualitative methods are shown in the appendix (pp 5–11).
Outcomes
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comparing the ENO Breathe and usual care groups. Secondary outcome measures were the chronic obstructive pulmonary disease (COPD) assessment test score (CAT), visual analogue scales (VAS) for breathlessness (scored 0–100; participants asked to “rate the following levels of your breathlessness over the past 2 weeks: [1] at rest, [2] walking around the house, [3] climbing stairs, and [4] running”), and scores on the dyspnoea-12 (its two subscales), the generalised anxiety disorder 7-item (GAD-7) scale, the eight RAND SF-36 subscales to support interpretation of the MHC and PHC, and the short form-6D (SF-6D), which can be useful for economic evaluations. The qualitative component was prespecified, aiming to explore participant experience in the programme.
Participants were actively asked about any adverse events, experiences, and reasons for non-attendance or engagement.
Statistical analysis
Subsequently, evaluation data from previous ENO Breathe participants became available, which was used to revise the recruitment target before any research participant follow-up data were collected. The revised sample calculation indicated that 108 participants were required to have a 90% chance of detecting as significant, at the 5% level, a difference of 5 points in the SF-36 MHC or PHC, between the control group and the experimental group. Allowing for 30% dropout, the revised recruitment target was 158 participants. This change was prospectively documented on the ClinicalTrials.gov record.
Baseline RAND MHC and PHC scores for ENO Breathe participants before the trial started were in the 30–50 range, corresponding with the 10% improvement responder threshold used. An additional, post-hoc responder analysis using a 5-point threshold
was also conducted. Given the differential withdrawal rate between study groups, an additional post-hoc sensitivity analysis was conducted imputing missing data using the baseline observation carried forward method.
The control group participants went on to take part in open-label ENO Breathe immediately after the conclusion of the study. This allowed us to do a post-hoc modified per-protocol analysis. We compared only those participants in ENO Breathe who participated in all intervention sessions, with only those in the control group who had gone on to participate in all the intervention sessions when offered the programme subsequently. This allowed us to assess effectiveness of the intervention in groups likely to be better matched in terms of programme suitability, health status, and engagement.
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
Table 2Baseline characteristics
Data are mean (SD), n (%), or median (IQR). CAT=chronic obstructive pulmonary disease assessment test. ENO=English National Opera. GAD-7=generalised anxiety disorder-7 questionnaire. MHC=mental health composite. PHC=physical health composite. RAND SF-36=RAND 36-item short form survey instrument. VAS=visual analogue scale.
All ENO Breathe participants who consented to study participation attended their initial one-to-one session. Mean attendance at group sessions was 4·5 (SD 2·3) of 6 sessions. 16 (22%) participants in the ENO Breathe group withdrew due to being unable to attend the session times offered (n=4); levels of fatigue being deemed excessive during one-to-one session (n=7; after discussion with the clinical team it was felt that participation risked exacerbating symptoms); new acute COVID-19 (n=1); and becoming uncontactable without providing a reason (n=3). In the ENO Breathe group, one self-limiting minor adverse event attributable to the intervention resulting in study withdrawal was reported, which was dizziness due to looking at the computer screen. There were five (7%) withdrawals from the usual care group due to work commitments (n=1); moving abroad (n=1); feeling too symptomatic to participate (n=1); and becoming uncontactable without providing a reason (n=2).
Figure 2Change in RAND SF-36 scores from baseline to week 6 follow-up
(A) Change in RAND SF-36 MHC score. (B) Change in RAND SF-36 PHC score. Boxes indicate 25th to 75th percentile, central line is the median, whiskers are upper and lower adjacent values, outliers are values beyond the upper and lower adjacent values. ENO=English National Opera. MHC=mental health composite. PHC=physical health composite. SF-36=36-item short form survey instrument.
Table 3Comparison of outcomes between study groups in the intention-to-treat population
Data are mean (SD). CAT=chronic obstructive pulmonary disease assessment test. ENO=English National Opera. GAD-7=generalised anxiety disorder-7 questionnaire. MHC=mental health composite. PHC=physical health composite. RAND SF-36=RAND 36-item short form survey instrument. SF-6D=short form-6D. VAS=visual analogue scale.
Table 4Numbers of participants with an improvement in the RAND SF-36 MHC score
ENO=English National Opera. MHC=mental health composite. PHC=physical health composite. RAND SF-36=RAND 36-item short form survey instrument.
Table 5Comparison of outcomes between study groups in the modified per-protocol population
Data are mean (SD). CAT=chronic obstructive pulmonary disease assessment test. ENO=English National Opera. GAD-7=generalised anxiety disorder-7 questionnaire. MHC=mental health composite. PHC=physical health composite. RAND SF-36=RAND 36-item short form survey instrument. SF-6D=short form-6D. VAS=visual analogue scale.
Categorised under the theme of improvements in symptoms, the improvements experienced were most commonly related to breathlessness on exertion and anxiety, although sleep, concentration, and voice abnormalities were noted to improve by some. Improvements were attributed to (1) learning practical and effective techniques for acute symptom management that could be applied in daily life (subtheme 1a); (2) providing calming and enjoyable experiences during the sessions; and (3) changing the way participants experienced their condition. A 32-year-old woman from the ENO Breathe group stated “It has given me the confidence outside of these sessions to remember that I can breathe and rely on the techniques that we're taught.”
The second theme, that the programme was considered complementary to standard health care, related primarily to addressing gaps in the type of care, or the way it is delivered. These strengths were perceived as resulting from the programme being specifically designed for people with long COVID, providing continuity over time, and facilitating interpersonal connections. A 44-year-old woman from the ENO Breathe group stated “there has been so little treatment for so many of us, and I really like that it's a programme designed for us … I'm so glad that someone cares that I have long COVID.”
Under the third theme, participants considered the use of music and song to be a particularly suitable approach to support recovery, even for those who were hesitant or dubious about singing or music-based approaches initially. Underpinning this were interrelated experiences of enjoyment, emotional engagement, and the ability to engage with the breath without consciously focusing on breathlessness. A 60-year-old man from the ENO Breathe group stated “the singing helps—it's like you're breathing without thinking.'
Discussion
We assessed the effect of ENO Breathe on HRQoL for people with long COVID who had breathlessness, with or without anxiety. The intervention appears safe and was effective at improving the mental component of HRQoL and elements of breathlessness. Participants reported symptomatic improvements, felt the programme was complementary to usual care, and that the use of singing and music was particularly suitable for their needs even if initially unsure about this type of activity.
and this study is one of the first randomised controlled trials to evaluate such an intervention, addressing an important evidence gap for this patient group.
There is considerable interest in developing singing based approaches to address long COVID—68 attendees from 12 countries (including Latin America, Canada, the USA, and Europe) attended an international webinar in June, 2021, hosted by the ENO Breathe team to share information about the programme. All attendees expressed the intention of setting up a similar service in their country in the near future or were already in the active process of doing so.
The ENO Breathe programme was accessed via review and suitability assessment by an NHS long COVID clinic, demonstrating a potential point of integration for these types of approaches into clinical services, and our qualitative findings suggest participants felt the integration in this format was appropriate. It is important to ensure that patients, clinicians, and those delivering this type of intervention can be confident that cardiorespiratory or other problems that require specific therapy have been identified.
and yoga,
that have been developed for other conditions. Individualised participant selection would be required, particularly given the potential for other approaches to be physiologically demanding,
which might lead to worsening of symptoms in some individuals. Comparisons of approaches would also help identify which individual and combinations of intervention components are most beneficial. Future research should consider that, although progress is slow, for many people with long COVID, there is a general trajectory towards improvement.
This trajectory might influence the way in which intervention impacts are interpreted, and emphasises the importance of having comparator groups whenever possible. Interestingly, the CAT score, GAD-7, dyspnoea-12, and VAS breathlessness scores for walking, stairs, and running all improved more in the ENO Breathe group than in the usual care group, with many close to the predefined statistical significance threshold of p
The post-hoc modified per-protocol analysis extends our findings. It showed a greater effect on a range of outcomes compared with the main analysis, comparing individuals in each treatment group who actually completed, or went on to complete, the ENO Breathe programme. This analysis provides useful insights to guide future research identifying specific responder phenotypes, as has been done in rehabilitation research more broadly. Interestingly, the affective, but not the physical component, of the dyspnoea-12 improved, suggesting moderation of how breathlessness was experienced and the emotional impact it had. This impact was possibly through increased confidence and changes in mood, rather than if breathlessness occurred or not, which aligns with qualitative analysis of participant experience regarding changes to how participants experienced their condition. Future research is required to clarify mechanisms of impact.
Participants with excessive fatigue were withdrawn at the end of their one-to-one session, before the more participatory components of the intervention took place, as such the shared decision to withdraw was proactive to avoid causing potential harm. Reassuringly, the SF-36 energy (vitality) subscale did not show worsening of this symptom in either the intention-to-treat or modified per-protocol analysis, with both numerically favouring the treatment group. The difference in withdrawal rate between groups is notable, although perhaps not unexpected given the absence of an active intervention to withdraw from in the usual care group, who were randomly assigned to delayed treatment. Differential withdrawal rates might have contributed slightly to the findings as suggested by the post-hoc sensitivity analyses using the baseline observation carried forward method described. However, this approach might, in this situation, be a cautious one given the trend towards improvement seen in outcome measures of the control group. Overall, the differential withdrawal rate is unlikely to explain the results when considered as a whole, particularly given the findings of the qualitative component and modified per-protocol analysis, which suggest that between-group differences are related to intervention participation.
Of note, a systematic review assessing the responsiveness of the SF-36 in randomised controlled trials involving treatments that are otherwise established to be effective in COPD, found that none of the identified studies achieved PHC or MHC score improvements exceeding that MCID.
It might be the case that a lower threshold for the MCID in long COVID is appropriate too. The particulars of this and other conditions might not be captured by this more generic health status measure. Absolute MCID thresholds also need to be considered in the context of the type of intervention involved. Qualitative data suggest many participants had improvements that were meaningful to them, and even a small improvement in measured HRQoL might be considered to represent a good value intervention if the health system or participant cost is low enough.
MCIDs for VAS breathlessness scales are generally in the range of 10 to 20,
indicating our study identified a between-group difference of important magnitude for the VAS breathlessness (running) scale, but not on other dyspnoea measures. VAS breathlessness measures were based on participants' perception over the preceding 2 weeks. Some participants might have estimated what their experience would have been like rather than drawing on a specific recollection. The VAS results are in keeping with the qualitative findings regarding participant experience, which suggested improvements in breathlessness on exertion, rather than at rest or minimal exertion, and might relate to breathing pattern disorder, which appears prevalent post-COVID-19.
ENO Breathe includes a focus on breathing retraining, which might have been particularly helpful in individuals with breathing pattern disorder, and future research should assess whether formal assessment of the presence of this disorder should be used to guide referral into this kind of programme. The improvements observed could be influenced by the measures selected, the amount of time spent participating in the intervention, or heterogeneity of the participant group. Regarding the last point, the modified per-protocol analysis suggests that in people who fully participate in ENO Breathe, the effect of the intervention was substantially greater than usual care.
However, a higher proportion of minority ethnic participants might have been expected, which might suggest barriers to participation in research, or the intervention. Fifth, given the nature of the intervention, establishing intervention fidelity in practice could present challenges, as with other established non-pharmacological interventions. Clear guidance, training, and auditing or monitoring are likely to be important. Last, although there was limited discussion of barriers to participation in the patient experience component, barriers might exist that were not identified because individuals experiencing the most substantial barriers would have been less likely to participate in the trial or, if they did, they would have been more likely to withdraw before qualitative data collection.
The ENO Breathe online wellbeing programme appears safe and effective at improving the mental component of HRQoL, and elements of breathlessness, for people with long COVID with breathlessness, with or without anxiety. Participants reported symptomatic improvements, felt the programme was complementary to standard care, and felt that the use of singing and music were particularly suitable for their needs. This study suggests mind–body interventions targeting HRQoL could have a potential role as complementary additional elements of long COVID management, particularly in patients who participate most in the intervention. Research into other related approaches would be valuable, as would better characterisation of long COVID subgroups to identify those most likely to benefit.
NSH, KEJP, ALe, HO, and SE designed the study. KEJP and NSH wrote the protocol and obtained ethics approval and authorisation for the study. HO and SE provided clinical input and support for the study. The ENO Breathe programme was devised by the English National Opera in collaboration with Imperial College Healthcare Trust. Scope and content were designed by SZ, JM, TP, SE, HO, VP, and ALo. TP, SM, and KB coordinated delivery of ENO Breathe and data collection. KEJP randomly assigned participants. KEJP analysed the data and wrote the first draft of the manuscript. WB provided statistical advice and support for quantitative components. KEJP, NSH, and WB have directly accessed and verified the underlying data reported in the manuscript. All authors contributed to the study design, study conduct, interpretation, revising the manuscript, and agreeing on the final version. No authors were precluded from accessing data in the study, and all authors accept final responsibility to submit for publication.
Acknowledgments
KEJP was supported by the Imperial College Clinician Investigator Scholarship. KEJP would like to acknowledge the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London for their support. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The ENO Breathe programme is generously supported by ENO's patrons and donors. We the authors thank the participants for their time and effort, with particular thanks to Sharon Sullivan, Umut Esmer, and Jen Shepherd for contributing to the steering group meetings and providing participant feedback and perspectives on the qualitative aspects of the research. We also thank Laura Moth, Phillip Crisp, Georgina Russell, Boon Lim, Michelle Maguire, Anna Wallin, Helena Klinge, Abi Simpson, Stuart Murphy, Beth Warnock, Emily Smith, Anya Chomacki, Poppy Harrison, Amy Powell, Lea Cornthwaite, and Edmund Jeffery for their expertise, advice, and support in the creation, development, and delivery of the programme. Thanks also to all original SHIELD Trial team members for contribution to the study design.
