In this study, a 6-week outpatient pulmonary rehabilitation significantly improved exercise capacity of patients with long COVID. On average, we observed a lowering of one grade on the PCFS scale. Notably, we saw an increase in pulmonary function (i.e., FEV1 and DLCO) and inspiratory muscle strength. Furthermore, significant improvements were also observed in secondary endpoints, including dyspnea, fatigue, and quality of life.

In this cohort, most patients suffered from mild to moderate COVID-19 but had substantial limitations in form of persistent symptoms including reduced exercise capacity, dyspnea, fatigue, and functional impairment. In the baseline evaluation, these complaints were substantiated, with patients on average reaching only 88% of their predicted 6MWD and a median impairment grade of 2 on the PCFS scale. Such findings are well-known in survivors of critical illness, who face the risk of substantial impairment due to the post-intensive care syndrome [22]. This condition includes ICU-acquired weakness, critical illness polyneuropathy, and myopathy [23]. Often, recovery is slow and incomplete. In a 5-year follow-up study on 109 ARDS survivors, the 6MWD was at 76% of the predicted capacity with patients reporting physical and psychological sequelae [24]. Predominantly, restrictive pulmonary alterations and decreased diffusion capacity after acute lung injury contribute to long-term functional limitations and lead to a decreased health-related quality of life [25]. Taken together, these aspects might explain the long-term sequelae of COVID-19 associated ARDS patients and provide reasonable evidence to support rehabilitation for this patient group [26]. However, there is also extensive data on the dismal long-term health impact on patients with COVID-19 with only mild to moderate disease and without COVID-19-related hospitalization [8, 27, 28]. Similarities to the severe acute respiratory syndrome coronavirus (SARS) epidemic of 2003 and the Middle East respiratory syndrome coronavirus outbreak of 2012 could be recognized [29-31]. In a study on 97 SARS survivors at 1-year, 6MWD and DLCO were lowered compared to normal healthy subjects [32]. The complexity and severity of the sequelae led to the definition of the post-SARS syndrome, to which the long COVID/post-acute COVID-19 syndrome shows similarities [33]. Lessons learned from those 2 outbreaks may now guide health care strategies including exercise training and rehabilitation programs in patients at risk for long-term sequelae [34-36].

Despite their young age and rather high baseline 6MWD, participants improved their 6MWD by twice the MCID, which is substantially higher compared to rehabilitation data in other respiratory diseases [37, 38]. Similar improvements in exercise capacity were observed in maximal workload and the 1-MSTST. Functional status improved as indicated by an NNT of 1.26 to lower the PCFS by 1 grade. Further, patients improved their level of dyspnea during daily activities (mMRC scale) and at maximal exertion (Borg scale). We observed a 14.9 percent point increase in quality of life on the EuroQol Group 5-dimension visual analog scale. The impact on quality of life was not statistically significant when measured with the EQ-5D index score, which is likely due to the lower number of patients completing this questionnaire. Furthermore, we noted a clinically significant reduction in fatigue (i.e., change in FAS) between baseline and end of rehabilitation. In line with previous data on post-CO-VID-19, patients showed a reduced FEV1 and DLCO of 82.6% and 84.6% at baseline [39-41]. Of note, both parameters (i.e., DLCO and FEV1) significantly improved over the 6-week-rehabilitation period, which is reassuring as impaired diffusion capacity was the most common anomaly reported at discharge in a study on noncritical COVID-19 cases [41].

Beneficial effects of rehabilitation have been clearly demonstrated in a broad range of health conditions. In patients with pulmonary diseases (e.g., chronic obstructive pulmonary disease, interstitial lung disease, pulmonary hypertension), rehabilitation reduces dyspnea, increases exercise, and improves health-related quality of life [42]. Thus and based on our and previous findings, rehabilitation might be a valuable treatment option in patients with persistent symptoms after COVID-19 [13-15, 43]. Two previous studies investigated acute or post-acute inpatient rehabilitation in patients with COVID-19. The first study retrospectively analyzed rehabilitation after acute care and provided feasibility data on 28 COVID-19 survivors [39]. The second study prospectively followed up 24 mild to moderate and 26 severe to critical cases [40]. To the best of our knowledge, our study provides the first results on outpatient rehabilitation on patients with long COVID. The patients in our study were substantially younger compared to the inpatient rehabilitation population described in the previous study but had a fairly similar age distribution when compared to a prior study of our outpatient rehabilitation center [38]. A possible explanation here is that older patients are more likely to choose inpatient rehabilitation, while younger patients attend outpatient rehabilitation likely due to better compatibility of outpatient rehabilitation with duties at home or work. Taken together, pulmonary rehabilitation was found to have short-term benefits in exercise capacity and patient-reported outcomes and no adverse events in all 3 studies. To ensure long-term effects, maintenance of physical activity and healthy lifestyles should be enforced by generating personalized home-based rehabilitation plans or transition patients into phases of long-term rehabilitation at an outpatient center.

Several limiting aspects need to be considered when interpreting our study findings. First, no causal role of rehabilitation can be assumed with certainty due to our observational study design. However, the conduct of a randomized controlled study on the effect of rehabilitation was considered unethical due to the lack of clinical equipoise as highlighted in the corresponding guidance statements [13-15]. Therefore, the observed improvement in the primary and secondary endpoints might also be due to the normal recovery process or regression to the mean. However, given that patients went through outpatient rehabilitation in mean 4.4 months after the infection, causal beneficial effects of this 6-weeks individualized rehabilitation program seem to be a reasonable assumption. Second, our study is limited by missing values for some of the secondary outcomes. Third, our results cannot be generalized to the total population of COVID-19 survivors, as the study population was relatively young and had a high proportion of highly educated people who likely had a good health care provider network that referred them to outpatient rehabilitation without clear guidelines at that time. Fourth, the limited number of patients hindered subgroup analysis to examine differences in outcome and course of the disease stratified by patient characteristics (e.g., severity of COVID-19 or primary symptom of long COVID). However, in conjunction with prior reports on acute and post-acute inpatient rehabilitation [39, 40, 43], multi-professional individualized pulmonary rehabilitation appears to be an important treatment strategy for COVID-19 survivors with persistent or progressive symptoms.

The cause of long-term sequelae in COVID-19 is currently unknown. However, it is evident now that not only the majority of COVID-19 survivors discharged from hospital but also patients with home treatment need an integrated model of care to recognize and treat long-term consequences of this multi-organ disease. Therefore, clinicians should monitor COVID-19 patients and evaluate a potential need for rehabilitation. Rehabilitation service providers should be aware of deconditioning as seen in chronic fatigue syndrome and should focus on individualized rehabilitation plans in contrast to a one-model-fits-all approach. As more patients accrue, identification of specific subgroups would be of high relevance to tailor specific therapies to each subgroup. Future rehabilitation studies may shed more light on the optimal treatment of patients with long COVID and evaluate cost-effectiveness (NCT04649918, NCT04365738, NCT04406532, NCT04642040).