key: cord-0871220-prl4yh3p authors: Middleton, S.; Chalitsios, C.; McKeever, T.; Jenkins, A.; Bolton, C. title: Patient-reported respiratory outcome measures in the recovery of adults hospitalised with COVID-19: A systematic review and meta-analysis date: 2022-03-18 journal: nan DOI: 10.1101/2022.03.16.22272509 sha: bef0df1be13ed1e38c411deee16a1fce667c3e2c doc_id: 871220 cord_uid: prl4yh3p Background Acute COVID-19 clinical symptoms have been clearly documented, but long-term functional and symptomatic recovery from COVID -19 is less well described. Methods A systematic review and meta-analysis were conducted to describe patient-reported outcome measures (PROMs) in adults at least 8 weeks post hospital discharge for COVID-19. Comprehensive database searches in accordance with the PRISMA statement were carried out up till 31/05/2021. Data were narratively synthesized, and a series of meta-analyses were performed using the random-effects inverse variance method. Results From 49 studies, across 14 countries with between 2-12 months follow up, the most common persisting symptom reported was fatigue with meta-analysis finding 36.6% (95 % CI 27.6 to 46.6, n=14) reporting it at 2-4 months, decreasing slightly to 32.5% still reporting it at >4 months (95% CI 22.6 to 44.2, n=15). This was followed by dyspnoea. Modified MRC score (mMRC) [≥]1 was reported in 48% (95% CI 30 to 37, n=5) at 2-4months reducing to 32% (95% CI 22 to 43, n=7) at 4 months. Quality of life (QOL) as assessed by the EQ-5D-5L VAS remained reduced at >4 months (73.6 95% CI 68.1 to 79.1, n=6). Hospitalisation with COVID-19 also resulted in persisting sick leave, change in scope of work, and continued use of primary and secondary healthcare. Conclusion The symptomatic and functional impact of COVID-19 continues to be felt by patients months after discharge from hospital. This widespread morbidity points towards a multi-disciplinary approach to aid functional recovery. Since emerging in December 2019, COVID-19 has impacted people, society and healthcare worldwide. As of 15 th March 2022 there has been over 450 million reported confirmed cases and 6 million deaths. [1] Although there is a significant acute mortality the majority of patients with COVID-19 infection will survive. [2] Attention then shifts to consideration of long-term morbidity and its effects on society, the economy and healthcare. Previous coronavirus outbreak survivors have shown continued fatigue, persistent shortness of breath and reduced quality of life up to 12 months post illness. [3] Hospitalised pneumonia patients experience fatigue, cough, and dyspnoea during recovery with adverse impacts on functioning and healthcare utilisation. [4] Studies of early recovery have shown similar ongoing morbidity [5, 6] with continuing abnormal respiratory function in COVID- 19 survivors. [7] Often there is a mismatch between patients and clinicians on when recovery has been reached. A negative COVID-PCR test, discharge from hospital and resolution of pneumonia on thoracic imaging can all occur with a person experiencing ongoing symptoms and reduced functioning. [8] Patient reported outcomes (PROMs) are measurement tools that are a useful way for patients to provide relevant information on their health, including quality of life, symptoms, and day-to-day functioning to help provide information on their recovery. [9] This systematic review and meta-analysis aimed to investigate the respiratory symptomatic and functional recovery of patients hospitalised with COVID-19 more than 8 weeks after hospitalisation using PROMs. This systematic review was registered with PROSPERO (CRD42021242134) [10] and followed PRISMA guidelines for reporting systematic reviews. [11] Search strategy The following databases were searched on 31/05/2021 for relevant studies: Embase, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The search strategy included synonyms for COVID-19, respiratory outcomes and relevant terms related to quality of life and functioning and was not subject to language restrictions (Supplementary table 1) . Following collation of search results and removal of duplicate citations, title and abstract screening was undertaken by one reviewer to eliminate obviously irrelevant papers. Full papers were reviewed in duplicate for selection by four reviewers (SM, CC, TM, AJ). Papers were included if they contained participants over 18 years old, had a sample size of at least 30 patients who had been hospitalised in the acute phase, incorporated patients that had a clinical or PCR diagnosis of COVID-19 and had a minimum follow up time of 8 weeks post hospital discharge. A cut off sample size of 30 patients was used to avoid the inclusion of low powered studies and case reports. Studies were excluded if their primary outcome measures were focussed solely on non-respiratory or functional outcomes such as olfactory, gustatory, or neurological outcomes of COVID-19. Studies that included both hospitalised and non-hospitalised patients were included if they reported the hospitalised cohort separately. Studies that recorded follow-up from symptom onset were included if follow-up occurred at least 10 weeks following symptom onset as average time to admission to hospital is 5-6 days and average length of hospital stay is 5-15 days depending on age. [12] Data extraction was undertaken using a proforma by four reviewers (SM, CC, TM, AR) and data agreed for each paper by two reviewers. Where disagreement remained, a third reviewer was included (CEB or TM). The proforma included patient selection, sample size, demographics, and study design. Main outcomes collected were patient reported symptoms, quality of life scores, breathlessness scales, functional testing, return to work and use of healthcare since discharge. The quality of the included studies was determined using the Newcastle-Ottawa score and Downs and Blacks checklist. [13, 14] Statistical analysis Narrative synthesis of evidence was conducted for all included studies. Extracted results were analysed for adequate numbers of each outcome reported to perform a meta-analysis. Studies were split into separate groups where participant subgroups had been reported separately and it was not possible to combine the data. Meta-analysis using random effects models was performed to allow for apparent heterogeneity among studies given the different population characteristics. When looking at the chronology of follow up there were 2 peaks around 3 and 6 months. To capture this the studies were grouped considering the time after discharge (2-4 months and > 4 months) and is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 18, 2022. ; https://doi.org/10.1101/2022.03.16.22272509 doi: medRxiv preprint meta-analyses were performed for each group. The generic inverse variance method was used for pooling. Pooled estimates were calculated using proportions with 95% CI for symptoms, modified medical research council dyspnoea score (mMRC) and mean difference with 95% CI for 6 minute walk test (6MWT), Short physical performance battery (SPPB), and EQ5D-5L. The Dersimonian-Laird method was used to estimate the between-study variance 2 . The percentage of variability in the effect sizes not caused by sampling error was tested by using the Higgins' 2 test, with estimates of 25%, 50% and 75% indicating low, moderate, and high heterogeneity respectively. If a study reported follow-up at multiple time-points with the same cohort, only the first follow-up timepoint was used in the meta-analysis to avoid bias. All meta-analyses were conducted in R v4.0.3 using the "meta" _and "metafor" packages and all statistical tests were two sided and used a significance level of p < 0.05. The search strategy identified 7331 papers of which 49 studies were included in the study (Figure 1 ). . CC-BY-ND 4.0 International license It is made available under a perpetuity. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint All studies were observational studies with follow-up time ranging from 2 to 12 months and originating from countries worldwide including Italy (11) Thirty-one papers reported on at least one respiratory or functional symptom and results from meta-analyses are reported in Table 1 (Forest plots Supplementary Figures 1 to 10) . [15-17, 23, 24, is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint Thirty-three studies reported respiratory and functional outcomes across 18 different outcome measures. [15, 16, 20-25, 27, 28, 30-38, 40-43, 45, 47, 51-53, 55, 56, 59, 60, 63] The most common outcome measure reported was the mMRC breathlessness score (2 to 4 months; 48%; 95% CI 30 TO 67) reducing to 32% (95% CI 22 to 43) at >4 months (Table 2 ) (Forrest plots Online supplement Figure 11 to 21). The six-minute walk test(6MWT) was around 500 metres for both patients in 2 to 4 months and >4 months after discharge. [20, 30-35, 41, 45, 55, 60, 63] Three studies measured breathlessness according to the Borg scale at 9 weeks (51%) [20] , 6 months (40%) [40] and 6 months (11%) [59] The full summary of outcomes not included in the meta-analysis can be seen in Supplementary Table 5 to 7. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint This comprehensive systematic review and meta-analysis investigating the respiratory and functional recovery of hospitalised adult patients with COVID-19 demonstrates over a third of participants continued to experience fatigue and 32% had an abnormal dyspnoea score over 4 months following hospital discharge. After 4 months the quality of life was below population average. [64] . Hospitalisation with COVID-19 resulted in persisting sick leave, change in scope of work and impairment at work up to 6 months post discharge and continued use of primary and secondary healthcare. Other respiratory infections have shown similar ongoing respiratory and functional sequalae after discharge. [4, 65, 66] In a systematic review of community acquired pneumonia (CAP) at 6 weeks post infection, fatigue was seen in 42% (95% CI 10 to 74) and dyspnoea in 39% (95% CI 21 to 58). is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint [38, 50] . Up to 6 months after testing positive for COVID-19, 73% of nonhospitalised patients had visited their GP, a hospital outpatient clinic or been admitted to hospital. Healthcare usage was increased compared to matched COVID-19 negative patients. To the best of our knowledge this is the first meta-analysis looking at PROMs during prolonged is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint The copyright holder for this this version posted March 18, 2022. ; https://doi.org/10.1101/2022.03. 16.22272509 doi: medRxiv preprint this. There is a potential bias due to uncontrolled confounders and heterogeneity in observational studies. Due to insufficient data reporting in the original publications, we could not assess the effects of other factors, such as sex, age, and comorbidities in the proportion of symptoms. For future research, standardising PROMs used as well as classification of COVID-19 severity would aid translative research and collaborative work. We have shown that beyond 2 months since discharge respiratory symptoms, functional deficits and reduced quality of life are experienced by survivors of COVID-19 hospital admission. 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