European Respiratory Society Statement on Long COVID-19 Follow-Up

Evidence overview

Few data are available on predictors of long-term consequences of COVID-19. They mainly include pulmonary fibrosis (PF), as described by reduced single breath carbon monoxide lung diffusing capacity (DL_CO), restrictive syndrome, and persistent ground glass, and fatigue and/or anxiety one to eight months post-COVID-19. Initially, 4524 records were identified. Twelve eligible studies were included (1 retrospective cohort study and 11 prospective) [8, 19–29], focusing directly on predicting factors of PF and/or persistent symptoms after COVID-19 episode (Appendix C). Of the 12 studies, the majority reported on hospitalised patients and three reported on both hospitalised and non-hospitalised. No studies included non-hospitalised patients only.

The main persistent symptoms reported in the included studies were fatigue (50–65% of patients) and anxiety/depression (20–40%). Risk factors for COVID-19 persistent symptoms, especially fatigue, were not associated with initial severity [19], but with age, female gender and the number of symptoms during the first week of infection [19]. These results were not found in all studies [20]. Few studies focused on olfactory and gustatory late resolution. The initial grade of dysfunction (total or partial), gender, and presence of nasal congestion appeared as potential predictive factors [21].

The vast majority of the studies included in this analysis focused on PF and reduced DL_CO. The size of the cohorts and/or the design does not permit the calculation or estimation of the PF risk. Han reported (in 114 hospitalised patients) that one third of patients had fibrotic like lesions on a Computed Tomography (CT) scan done six months after discharge [22].

Age among all possible factors, was the most frequent predictor of long-term consequences [8, 22], possibly because the aging lung is more susceptible to development of fibrotic response or elderly people may have a subclinical interstitial lung disease exacerbated by acute infection [30]. Presence of acute respiratory distress syndrome (ARDS, OR: 13; 95% CI: 3.3, 55) at the acute phase of the SARS-CoV-2, and the severity of the initial disease [8, 22, 23] were two predictive factors of PF, but these data are also demonstrated in other causes of ARDS. According to these studies, COVID-19 severity, as a predictor of PF, is evaluated by need of mechanical ventilation, ventilation duration, opacity score at discharge and hospitalisation duration [8, 22]. Some biological parameters have been found to be associated with higher risk of PF: high LDH level on admission, low level of T-cells and, prolonged elevation of interleukin-6 [24]. These parameters again reflect disease severity and indicate the dysregulated immune response [25]. LDH has already been considered as a marker of pulmonary injury [26].

In the studies focusing on DL_CO decrease, the time to evaluate pulmonary function was variable between one to eight months, and so the long-term outcome of these abnormalities remains unknown. As for PF, initial disease severity [23, 27, 28] often evaluated by oxygenation modalities, sometimes by intensive care severity score and/or by other organ failure (for instance renal failure), appeared as the main risk factor. High flow oxygen therapy, and mechanical ventilation (invasive and non-invasive ventilation) are associated to a higher risk of diffusion impairment (OR 4.6 in Huang study) [16]. Biologically, a higher level of D-Dimer at admission in a small cohort of 55 patients, was an independent predictor of abnormal DL_CO at three months [29].

Concluding remarks

Age, severity of COVID-19 (evaluated by a range of variables: oxygenation and ventilator modalities, ARDS, radiological data, and some biological parameters; D Dimers, T cell count, LDH, Interleukin-6) appeared to be the best predictors of abnormal DL_CO and PF occurrence. On the contrary, severity of initial disease was not associated with the persistence of symptoms, factors which appeared to be linked to gender, age and to the number of symptoms during the first week. These data are based on a few small studies and will need to be confirmed in new larger studies.

Evidence overview

Hypercoagulability is a frequent haematological alteration in hospitalised patients with COVID-19. Clinical manifestations include venous thromboembolism (VTE), disseminated intravascular coagulation (DIC), thrombosis of the lung microvascular circulation, and arterial thrombosis. The systematic literature search identified 1181 studies on long-term consequences and patient follow-up. Six eligible studies (3 prospective, 2 retrospective, 1 strategy proposition) were included (Appendix C) [31–36].

Four studies examined the rate of thrombosis after discharge. In an Italian follow-up study of 767 patients with COVID-19, 51% still reported symptoms at a median time of 81 days after discharge, with 38% of those having an elevated D-dimer level [31]including two asymptomatic pulmonary thrombosis discovered by investigating striking D-dimer elevation. In a retrospective cohort study of 163 post-discharge patients with confirmed COVID-19 not receiving anticoagulation, the cumulative incidence of thrombosis (including arterial and venous events) at day 30 following discharge was 2.5% (95% CI, 0.8–7.6); the cumulative incidence of VTE alone was 0.6% (95% CI, 0.1–4.6). As the rate of haemorrhage appeared to be of the same magnitude, universal post discharge thromboprophylaxis was not recommended [32]. Similar figures were demonstrated at 42 days follow-up in a 152-patient cohort [33]. In a six week follow-up study of 33 patients discharged without anticoagulation, all patients with elevated D-dimer levels underwent ultrasound duplex scanning and ventilation/perfusion (V/Q) scan to rule out VTE [34]. There were no thromboembolic complications and no echocardiographic impairments. Consequently, in the absence of other thrombotic risk factors, patients with COVID-19 are mostly discharged without prophylactic anticoagulation. If diagnosed with pulmonary embolism (PE) de novo during follow-up, patients should be treated in line with PE guidelines [37].

Only one of the identified studies reported on the long-term outcomes of patients with COVID-19 and VTE. This prospective observational study evaluated a composite of major bleeding and death at 90 days in 100 consecutive patients with VTE in the setting of COVID-19 (2/3 hospitalised, 1/4 in ICU; 64% PE) [35]. Mortality (24%) and major bleeding (11%) were high. The majority of complications occurred in the first 30 days. Most patients received Direct Oral Anticoagulants (DOACs) (52%) or Low Molecular Weight Heparin (LMWH) (28%) at discharge. There were no VTE recurrences. The follow-up evaluation of patients with PE during acute COVID-19 draws from PE guidelines [37].

Concluding remarks

At this stage, it is still unclear if pulmonary thromboembolism and inflammatory pulmonary microangiopathy [36]demonstrated in patients with severe COVID-19 will lead to sequelae such as chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). In patients with persistent exertional dyspnoea without evidence of parenchymal lung opacities on high resolution CT three to six months after discharge and with pulmonary function tests documenting preserved lung volumes and normal or reduced DL_CO, follow-up evaluation should include echocardiogram and contrast enhanced CT to identify significant pulmonary vascular involvement, as per proposed guidance [18]. As contrast enhanced CT cannot exclude CTEPH [38], lung perfusion studies with single-photon emission computed tomography (SPECT) or dual-energy CT (DECT) are proposed to exclude vascular involvement in symptomatic post-COVID patients, even in absence of PE history during the acute illness [39]. As suggested by previous guidelines, if there is evidence of significant Pulmonary Hypertension (PH), patients should be considered for referral to a specialist PH centre [40, 41].

Evidence overview

Although SARS-CoV-2 can theoretically infect various organs after binding to the ubiquitous ACE-2 cell membrane receptor, the respiratory system is the most frequently impacted due to the airborne nature of the infective agent. Regarding pulmonary function tests (PFTs) after the acute phase, 1578 records were identified (Appendix C). Thirty-nine eligible studies (1 Randomized Controlled Trial (RCT), 3 systematic reviews, 11 prospective cohort studies, 7 retrospective studies, 15 cross-sectional, 2 case series) were included [8, 23, 27–29, 34, 42–74]. Two studies were longitudinal [56, 57], 11 were prospective [23, 44–48, 56, 57, 59, 60, 74], including four multicenter [23, 45, 46, 56] .

When measuring PFTs at rest, all investigators sought three main features, i.e. the existence of 1) obstructive pattern, 2) restrictive pattern, and 3) lung gas exchange impairment [27, 42, 43, 52–54, 29, 55–57, 28, 58–60, 44–46, 23, 47, 48, 34, 8, 49–51, 66–68, 73, 74]. Some investigators also looked at more integrative responses to physical exercise, either using six-minute walking test (6 MWT) [8, 23, 34, 42–51, 61, 62, 73, 74] or cardiopulmonary exercise testing (CPET) [51, 63–65]. The main parameter used to define bronchial obstructive pattern is the ratio of Forced Expiratory Volume in one second (FEV₁) over Forced Vital Capacity (FVC). Restrictive pattern was deemed to be present based on either reduction of Total Lung Capacity (TLC) or the combination of low FVC and high FEV₁/FVC ratio when TLC could not be measured. In some studies, reduced Residual Volume (RV) was also considered as part of the restrictive pattern. Lung gas exchange was mostly assessed using the DL_CO [27, 73, 42, 43, 74, 52–54, 29, 55–57, 28, 58–60, 44–46, 23, 47, 48, 34, 8, 49, 50]. Only one study examined nitric oxide lung diffusing capacity (DL_NO) combined with DL_CO [69]. The earliest time point after the acute phase of the disease is one month [27, 42, 73], with a majority of the studies reporting PFTs from six weeks to four months [42, 43, 53, 54, 29, 55–57, 28, 58–60, 44–46, 23, 47–51, 66, 67], with very few at six months [8, 52, 64] post discharge or onset of disease. Patient inclusion criteria were inconsistent between studies. The majority of the studies included hospitalised patients, while two studies involved both hospitalised and non hospitalised, and only one has been performed on non hospitalised patients. Patients with pre-existing chronic lung disease were not differentiated, thus making it difficult to relate abnormal PFTs results to either COVID-19 lung injury or possible pre-existing disease. There were disparities in reporting data either as absolute values, percentage of predicted values, with only a few reporting both absolute and percentage. Few studies adopted the Global Lung Initiative (GLI) approach using the lower limits of normal (LLN) threshold to distinguish abnormal values, whilst the majority retained 80% of predicted values for TLC, FVC and DL_CO. Correcting DL_CO for hemoglobin was not consistent. All studies reported a relatively high prevalence of reduced DL_CO in 40–65% of patients as compared with the medium to high prevalence of restrictive pattern and the exceptionally low prevalence, if not absence, of obstructive pattern. If the high prevalence of altered DL_CO found at one month after discharge, or the onset of the disease partly result from ongoing residual inflammation related to the initial lung injury, the persistent low values of DL_CO at three and six months, even in patients with normalised chest CT, raise the need for further discussion [75]. DL_CO is the product of the accessible alveolar volume (V_A) and the transfer coefficient K_CO; altered DL_CO can theoretically occur when either V_A or K_CO, or both, are reduced [76]. Deciphering between V_A and K_CO as the causal factor for reduced DL_CO is therefore critical to infer the underlying lung structural changes with either interstitial abnormalities or pulmonary vascular abnormalities. If DL_CO had been measured in all studies assessing PFTs, V_A and K_CO were seldom reported, thus compromising key messages regarding the pathological nature of impaired lung gas transfer. Another way to dissect the underlying mechanisms of reduced DL_CO could be the simultaneous measurement of DL_NO and DL_CO. This test is only available in a small number of centers, which may explain the scarcity of DL_NO papers in patients with COVID-19.

Concluding remarks

From the currently available literature [70–72], PFT's were performed on average three months after onset of COVID-19. PFT measurement including at least static lung volumes with ideally TLC measurement, expiratory flow rates and DL_CO assessment are regarded as useful tools to assess long-term lung function sequelae in patients with COVID-19 by most investigators. An effort of global harmonisation to 1) express results, 2) choose criteria defining anomaly, 3) refine patients’ inclusion criteria, 4) prospectively investigate lung function in 5) multiple centers is still insufficient. There is agreement in all studies on the high prevalence of altered lung gas exchange in patients with COVID-19 as the main feature of PFTs anomalies. Most TF members provide DL_CO results after correction for hemoglobin, and together with V_A and K_CO, it helps the readers to decipher the underlying causes of altered lung gas exchange. A large, international multicenter trial using DL_NO and DL_CO simultaneous measurement could provide more useful information.

Evidence overview

Fourteen eligible studies (9 prospective cohort studies, 4 retrospective, and 1 cross-sectional) [22, 43, 45, 47, 77–84, 52, 19] were included on imaging follow-up of patients with COVID-19, following a search of 1300 initial records (Appendix C). A small number of studies reported high rates of persisting abnormalities on radiology at discharge, despite absence of symptoms [52, 77–80, 19]. Indeed, we know that radiological healing of pneumonitis is slower than clinical conversion. Further studies aimed to report the frequency of pulmonary abnormalities at three and six-month CT scan [22, 43, 45, 52, 81, 82]. Studies of radiological abnormalities on CT at three to six months may overestimate the true frequency of persistent abnormalities as studies without systematic follow-up will be biased towards patients with severe disease and persistent symptoms. Only four of the studies included also non-hospitalised patients. In fact, residual lung lesions are more frequently observed in CT scans of patients who had extensive imaging abnormalities as well as severely altered clinical-laboratory markers of disease severity (including ICU admission, longer hospitalisation) during the acute phase [22, 52, 83].

The longitudinal behavior of CT abnormalities mostly reflects the temporal evolution of diffuse alveolar damage and organising pneumonia, namely the main pathologic patterns underlying COVID-19 pneumonia [84]. Ground-glass opacity (GGO) is the most frequent finding at three-month CT, followed by parenchymal bands, peri-lobular opacities, and scant interlobular septal thickening. It was observed that these CT abnormalities diminish with time [22], while complete waning is still under investigation as more longitudinal data accumulates. Intriguingly, GGO may gradually increase in extent and reduce in density [22]. Terms such as “fibrosis” or "fibrotic-like" changes entered the literature, yet are still not justified for practical use and interpretation of the patient management. CT features of lung fibrosis were interpreted in up to 47.1% at the three-month follow-up [47]. Han et al. reported a prospective cohort of 114 patients undergoing a six-month follow-up CT scan [22]. This included 35% of the total cohort with “fibrotic-like” features (e.g. parenchymal bands, traction bronchiectasis etc.). Indeed, it is unlikely that lung fibrosis occurs in such a large proportion of subjects who have had COVID-19 pneumonia, and most of those "fibrotic-like" changes might be reversible at later follow-up.

Concluding remarks

Despite the current data, it is unclear if “fibrotic-like” CT features represent irreversible disease (e.g. post-ARDS), or slowly regressive infiltrate secondary to organising pneumonia, also seen with mild distortion mimicking actual fibrosis. The risk of over-calling lung fibrosis in follow-up CT scan seems more frequent in the presence of bronchial distortion within the areas of organising pneumonia features. TF members do not call such bronchial distortion traction bronchiectasis, which, by definition, represents an established CT feature of irreversible lung fibrosis. Therefore, most TF members are cautious when calling out fibrosis, especially in the early follow-up CT where parenchymal changes are encountered frequently and are more prone to resolve. Given the high proportion of subjects who either develop ARDS or undergo mechanical ventilation, the development of lung fibrosis remains a concern. More imaging data are needed to clearly distinguish between COVID-pneumonia sequelae and ventilator-induced lung injury. Guidelines are awaited to inform when and how imaging should be referred. TF members consider imaging follow-up in patients that were hospitalised and/or showed a more severe clinical disease course, or in patients presenting with new or progressive respiratory symptoms in the mid-long-term after acute COVID-19 syndrome. There are recommendations to repeat CT scan at 12 weeks post-discharge in patients with persistent symptoms, to complement clinical assessment [18].

CT is the most utilised imaging technique to follow-up subjects who had COVID-19 pneumonia. In fact, it is undisputed that fine residual abnormalities such as GGO are best depicted with CT, rather than chest X-ray or lung ultrasound. As this disease involves a sizeable proportion of younger subjects who might need repeated follow-up, it is worth underscoring that low-dose thin-section CT protocol is used by the TF members.

Evidence overview

A large number of reports on COVID-19 have been published within the past 17 months, yet evidence regarding the dynamics of SARS-CoV-2 shedding in patients with COVID-19 in general and in specific patient subgroups in particular, is scarce. Five eligible studies were included (2 retrospective studies, 2 case studies, 1 guideline) [85–89] following a search of 815 initial studies (Appendix C). A further systematic review and meta-analysis identified by the authors after completion of the literature searches is also included in this review [90].

In susceptible individuals, viral replication starts to increase rapidly only a few days after SARS-CoV-2 exposure. Viral load usually peaks about a week after infection, in most patients approximately 24-hours before COVID-19 symptoms commence. In immune-competent patients, replication-competent SARS-CoV-2 can be isolated from the respiratory tract for one to several weeks after the onset of symptoms. More specifically, a recent meta-analysis of 79 reports on SARS-CoV-2 found that mean duration of SARS-CoV-2 RNA shedding was 17.0 days (95% CI 15.5–18.6) in upper respiratory tract, 14.6 days (9.3–20.0) in lower respiratory tract, 17.2 days (14.4–20.1) in stool, and 16.6 days (3.6–29.7) in serum samples [90]. SARS-CoV-2 shedding duration was positively associated with age and COVID-19 severity. While these numbers suggest that after three weeks viral shedding usually concludes, it is noteworthy that the same meta-analysis reports maximum shedding duration of 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stools, and 60 days in serum [90]. Importantly, viral shedding does not necessarily provide active infectious virus. Many studies did not detect live virus beyond day nine of illness despite persistently high viral mRNA loads. One study observed shedding of infectious SARS-CoV-2 up to 70 days after initial diagnosis from an asymptomatic immunocompromised patient with cancer [85]. Other conditions of constitutive or acquired immunosuppression may predispose to prolonged shedding of live SARS-CoV-2 or reactivation of infection, such as cancer-directed therapies [86]. Further, time to SARS-CoV-2 clearance among cancer patients varies substantially depending on the criteria used [87]. Most evidence has been derived from other virus variants than the currently wide-spread delta-variant, however, there is no evidence available for significant differences in the time course of viral load between SARS-CoV-2 variants.

Of note, positive SARS-CoV-2 PCR tests following temporary PCR negativity have been described in recovered patients with COVID-19. Several causes of recurrent positive tests for SARS-CoV-2 are suggested, including false-negative, and false-positive PCR tests, detection of viral particles rather than replication-competent virus, reactivation, and re-infection with SARS-CoV-2, the latter two being more likely in immunocompromised patients than in healthy individuals. Depending on the specific healthcare setting, recurrent SARS-CoV-2 test positivity may preclude patients from treatment of underlying diseases over a longer time period. Considering the risk of increased morbidity and mortality of the underlying disease resulting from treatment delay, the TF members advocate for interpretation of the Cycle Threshold (Ct) value of Real Time-PCR in the clinical context. This will enable treatment of high risk underlying disease, despite ongoing positive SARS-CoV-2 testing [88, 89].

Concluding remarks

The majority of TF members perform recurrent PCR testing after acute COVID-19 in specific subgroups of patients, on a case-by-case decision, given the lack of scientific evidence and universally agreed follow-up strategies for infection control in COVID-19. Particularly immunodeficient patients including, but not restricted to, hematologic, oncologic, T- or B-cell incompetent patients is useful to undergo repetitive testing with individual frequency (e.g., once weekly) due to protracted high risk status or recurrent viral shedding.

Evidence overview

Published studies attempt to measure a range of symptoms occurring as a consequence of COVID-19, the impact of long COVID and evaluate outcome measures used. One thousand, four hundred and two studies were screened (Appendix C) and 19 studies were included [8, 34, 49, 61, 74, 91–104] (2 reviews; 1 systematic, 9 prospective cohort studies, 3 survey design, 3 retrospective studies, 1 ambi-directional cohort study/1 cross-sectional) reporting on symptom burden and QOL. All studies included hospitalised patients. The survey conducted by Machado et al. [98]extended to non-hospitalised patients and a small RCT (n=72) investigating the impact of rehabilitation on the elderly post-COVID did not differentiation hospitalisation status [74].

The spectrum of symptoms reported include fatigue [8, 61, 92–94]; dyspnoea; cough [34, 92, 94]; dysphagia [96]; frailty [97]; loss of memory [93]; concentration [93]; sleep disorders [8, 93, 98]; anxiety, and/or depression [8, 34, 74, 92, 99, 100]; pandemic-related stress factors (PRSF) [92, 95, 99]; with several studies reporting on HRQOL [34, 49, 74, 94, 95, 100–102], specifically functional status [98, 103] or level of independence with activities of daily living (ADLs) [96]. A prospective cohort study of 183 patients (median age 57 years; 61.5% male, 54.1% white) reported older participants (65 to 75 years) (OR 8.666 [95% CI: 2.216, 33.884], p=0.0019), and women (male versus female [OR 0.462 {0.225, 0.949}, p=0.0356]), had statistically significant higher odds of experiencing persistent symptoms at 5 weeks post discharge [94].

At six months post-acute COVID-19 survivors continued to experience fatigue, muscle weakness, sleep difficulties, and anxiety or depression. A cross-sectional study of 1696 consecutive patients, age 71.8±13.0 years-old; 56.1% of females; 82.3% with comorbidities reported that independence for ADLs was lower in those admitted to the ICU than the ward group (61.1% [95%CI 55.8–66.2%] versus 72.7% [95%CI 70.3–75.1], p<0.001). Conversely dependence for ADLs was also more frequent in the ICU group (84.6%, 95%CI [80.4–88.2%], versus 74.5%, [95%CI 72.0–76.8%], p<0.001) [96]. Patients who were more severely ill during hospital stay had more impaired DL_CO and were the main target population for interventions of long-term recovery [8]. Those admitted to ICU required more oxygen therapy (25.5% versus 12.6%, p<0.001), and experienced more dyspnoea during routine (45.2% versus 34.5%, p<0.001) and non-routine activities (66.3% versus 48.2%, p<0.001) [96].

Persistent symptoms of fatigue and sleep disturbance following severe COVID-19 pneumonia impacted HRQOL, productivity, physical activity and mental ill-health, associated with high rates of positive screening tests for anxiety, depression and Post-Traumatic Stress Disorder (PTSD) [92, 95, 99]. A systematic review and narrative synthesis recommended a prompt “general clinical” evaluation and risk assessment of patients presenting with neurological symptoms to minimise cognitive impairment and mental health thereby improving prognosis and outcomes [104]. Causative mechanisms for adverse mental health outcomes following COVID-19 infection have not yet been established. Biological pathophysiological mechanisms, relating to cerebral vascular inflammation and thrombosis, survivor guilt and isolation in COVID-19 survivors are cited as contributory factors of adverse mental health outcomes [92].

There is a lack of consistency in the selection of instruments to measure symptom burden, cognitive impairment, psychological well-being and QOL. A systematic review identified 33 outcome measures from 36 studies [70]. Most commonly used were the Hospital Anxiety and Depression Scale (HADS); Short Form-36 (SF-36) and St George's Respiratory Questionnaire (SGRQ). A summary of broad range of instruments reported on in this review is summarised in supplementary Table 2. According to standardised questionnaires, patients experienced reduced QOL mainly due to decreased mobility (SGRQ activity score: 54 [19–78]) [34].

The battery of outcome measures implemented in some studies is recognised as being impractical for routine clinical use. Focussed patient interviews were suggested as an alternative substitute for questionnaires [92]. Further, recommendations included a call to rationalise the approach to the selection of / combination of outcome measures to capture all elements of COVID-19 to better understand the impact on survivors and to plan timely and appropriate interventions to maximise functional return [70].

Few differences were observed between HRQOL for patients cared for on the ward and ICU [93]. Hospitalised individuals presented high levels of disability, dyspnoea, dysphagia, and dependence [96]. Social disconnect appeared to predict the presence of Post Trauma Stress Syndrome (PTSS) (beta 0.59, 95% CI 0.37–0.81, p<0.001) a month after hospitalisation but the severity of COVID symptoms was not predicative for PTSS [99]. Depressive and anxiety symptoms decreased one-month following hospitalisation. However, higher levels of anxiety (standardised beta 1.15, 95% CI 0.81–1.49, p<0.001) and depression (beta 0.97, 95% CI 0.63–1.31 p<0.001) during the first week of hospitalisation, feelings of social disconnected and longer hospitalisation period (beta 0.25, 95% CI0.03–0.47 p=0.026) predicted higher PTSS scores one month post-hospitalisation [106]. The need for social support during hospitalisation with a more robust approach to managing uncertainty regarding health status and family concerns is identified. Few studies explored the cognitive, psychological and QOL consequences of long COVID in non-hospitalised patients.

Concluding remarks

Few differences were observed between HRQOL for patients cared for on the ward and ICU, more in depth exploration in larger cohorts of patients including more severe ICU patients is needed. A need was identified to target the reduction and avoidance of PTSD. The long-term psychosocial effects (e.g. depression, anxiety, psychosomatic preoccupations, insomnia) and an awareness of symptoms indicative of PTSD, require prompt clinical follow up as suggested by earlier guidelines [95]. Early rehabilitation helps to reduce PTSD and mitigates the long-term sequelae [103]. To date Pulmonary Rehabilitation has been informed by experiences in other chronic respiratory conditions. Further studies and consensus on the approach are needed. Consensus is also needed on the selection of outcome measures to minimise clinical burden and standardise research.

Psychosocial implications should not be ignored and particular attention paid to the caregiver burden, family support and impact of recurrent and cross infection.

HRQOL captures symptom experience and disease impacts that may result in disability. Further discussions on symptoms associated with disability are reviewed in Q8.

Evidence overview

One thousand one hundred and twenty-one studies were screened (Appendix C) and 15 eligible studies [23, 28, 43, 45, 47, 56, 74, 92, 105–111] were included (1 RCT, 1 systematic review, 12 prospective studies, and 1 retrospective). Nine studies included hospitalised patients, two included non-hospitalised patients, and four both hospitalised and non-hospitalised. All studies report on disability (a physical or mental condition that limits a person's movements, senses, or activities) due to persistent symptoms after recovering from acute COVID-19 infection, including fatigue and dyspnoea. Evidence is emerging of patients experiencing more than one symptom resulting in disability with psychological and cognitive symptoms reported to affect functional abilities in the long-term [23, 28, 43, 45, 47, 56, 74, 92, 105–111].

In COVID-19 survivors, dyspnoea and associated disability is the most frequent persistent respiratory symptom regardless of the need for hospitalisation ranging from 5.5% to 54% at one to four months [28, 45, 47, 56, 92, 106–108]. Tenforde [109]reported shortness of breath at three weeks in 29% of patients never hospitalised. The most used measure to assess dyspnoea was the modified Medical Research Council (mMRC) scale [19, 23, 43, 45, 47, 56] followed by the modified Borg dyspnoea scale (MBS) [19]and the Borg category dyspnoea scale [92, 107].

Follow-up and management of COVID-19 survivors presenting symptoms and subsequent disability is an urgent priority. There is emerging evidence of debilitating disability months after COVID-19 infection. Disability with limited physical performance due to dyspnoea, fatigue or both was measured with at least one of the following tests: the Short Physical Performance Battery (SPPB) score, 2-minute walking test or 1-minute sit-to-stand test (1 MSTST) was found in 35% of COVID-19 survivors at six weeks [92], in 14% at three months [106], in 53.8% at four months [28], in 32% at six months [110]. Six-MWD was within normal values at 75 days with only 3% of patients experiencing documented oxygen saturation below 90% (median [IQR] MBS 3[2–5]) [105]. At three months follow-up, 6 MWD was within normal values [45]and only one out of 62 patients had oxygen saturation below 90% [47]. Six-MWT showed a significant reduction in distance walked and oxygen saturation levels in severely impaired COVID-19 patients compared to those with mild/moderate disease [23]. In a prospective observational study at three months after discharge [43]22% of patients had 6 MWD <80% of predicted and 16% de-saturated on exertion.

Disability persisted after a multidisciplinary rehabilitation programme:1 MSTST below normal value in 33.3% and SPPB in 53.3%. Barthel Index showed poor performance in ADLs in 47.5% of COVID-19 survivors [111]. In a RCT [74], exercise capacity (6 MWD) and ADLs (assessed with Functional Independence Measure [FIM] scale) were evaluated six months after the COVID-19 infection: patients undergoing a six-week rehabilitation programme (including respiratory muscle training, cough exercise, diaphragmatic training, stretching exercise and home exercise but without specific training and whole body exercises) showed improvement in 6 MWD when compared to the control group. Results on ADLs have been also reported in a prospective follow-up study [107]on 116 post-COVID ICU patients which documented no limitations after two months from infection.

Concluding remarks

Evidence on follow-up of COVID-19 survivors suggests that patients recovering after the acute phase may present with prolonged symptoms for more than four weeks causing disability with reduced functional performance and ADLs. This impacts some if not all aspects of HRQOL. Most TF members evaluate and systematically follow-up COVID survivors with unresolved or new or progressive symptoms with related disability. Decline in exercise tolerance, weakness, or reduced mobility define the assistance needed for ADLs (e.g., feeding, dressing, bathing, toileting, driving, housekeeping, and grocery shopping) and help clinicians to develop appropriate disability management strategies of pulmonary sequelae. Rehabilitation programmes including exercise training could mitigate longer term disability. Long COVID clinics offer a one stop shop for assessment and monitoring disability. Longitudinal cohort studies are needed to determine the most effective interventions.

Evidence overview

Patients with post-acute COVID-19 are at risk of long-term functional impairment, and the rehabilitation community is calling for action preparing for a large increase of rehabilitation needs in this patient population [95]. We screened 2057 records that were initially identified (Appendix C). According to the 29 eligible studies included (4 systematic reviews, 15 prospective cohort studies, 8 retrospective, and 2 suggestion documents) [95, 96, 112–138], tele-health, often used a broad term to include tele-visit, telemedicine, tele-coaching, tele-nursing and tele-rehabilitation offers an opportunity to follow-up patients whilst reducing the burden of travel for those patients affected by COVID-19, those with positive COVID tests and those with COVID sequelae. Virtual services may include: asynchronous clinical communications, real-time virtual care, messaging, telephony or video conferencing, virtual health assessments, and medication review. The COVID-19 pandemic forced a rapid adoption of tele/digital approaches over traditional in-person visits although uptake is reported to be lower in communities with higher rates of poverty [112]. Telemedicine and tele-rehabilitation have been proposed in COVID patients who suffer from exercise dyspnea, adequate stable condition, residual disability, displaced or isolated [113]provided they can ambulate independently, use technology, require minimal supplemental oxygen, and were cognitively intact [114]. Tele-health may improve access and reduce barriers to healthcare access, overcome financial costs, increase medical care and follow-ups, and, most importantly, reduces the risk of COVID-19 transmission [115]. Approaches can monitor vital parameters (SpO2, heart rate, blood pressure, respiratory rate). Specifically pocket oximeters and smart phone-based systems need particular accuracy to avoid error in pulse oximetry [116]. In selected cases, breath sounds can be analysed using advanced signal processing and analysis in tandem with new deep/machine learning [117]. Tele-health implemented in response to the COVID-19 pandemic in general resulted in high patient and provider satisfaction [115, 118–125]. Telemedicine/tele-rehabilitation acceptance is related to increased accessibility, enhanced care, usefulness, ease of use, and privacy/discomfort, whereas anxiety about COVID-19 is not [126]. Being male, having a history of both depression and anxiety, lower patient activation [121]technical and administrative challenges [122]were significantly associated with a poor telehealth experience.

Mobile apps have been proposed for citizens, health professionals and decision-makers to reduce the burden on hospitals, provide access to credible information, track the symptoms and mental health of individuals [127–129], help patients to improve their emotional resilience and subsequently their ability to cope with the trauma of their COVID-19 experiences [130]. During the pandemic the percentage of visits via telemedicine increased twenty-three-fold compared with the pre-pandemic period [112, 131]. As a majority of chronic respiratory patients are elderly and have multiple co-morbidities, they are notably susceptible to severe complications of COVID-19 and as such, have been advised to minimise social contact. This increased patients’ vulnerability to physical deconditioning, depression, and social isolation. To address this major gap in care, some clinic-centered Pulmonary Rehabilitation programs converted some or all of their educational packages to home-based tele-rehabilitation [132]. Tele-rehabilitation offers positive clinical results, even comparable to conventional face-to-face rehabilitation approaches [133]with general guides prepared in some countries [134]. In post ICU patients tele-rehabilitation consisted mostly of second opinions of psychologists (11.8%), physical therapists (8.0%), dietitians (6.8%), and speech-language pathologists (4.6%) [96]. Tele-health has been used for patients experiencing depression and isolation to maintain sufficient relationships [135]. Barriers to medicine at distance have been described as: advanced age, poor confidence with technology, lack of communication, reduced confidence in doctors, additional burden for complex care, ethical issues, and skepticism [121] [115, 136–138]. Several obstacles must be overcome for a wide use of tele-health: 1) the technology must be usable by the largest possible number of patients, 2) clarity on medico-legal liability and data privacy, 3) lack of the economic reimbursement, 4) proper training of health professionals involved, 5) adequate caregiver support, 6) infrastructure, operational challenges, regulatory, communication and legislative barriers [113, 119, 132].

Concluding remarks

Telehealth appointment experiences were often comparable to traditional in-person medical appointment experiences. Although telemedicine/tele-rehabilitation appear to be acceptable, the level of agreement on standardisation remains unclear in particular the ratio of cost- effectiveness. Telehealth was effective as a mode of health care delivery during the pandemic and may be sustainable [113, 121]. Careful attention will be needed to integrate these services into current health care delivery systems whilst preserving patient-centered and quality care [123]. Further high-quality studies to enable the successful implementation of these modalities are needed [132].