Result of one-year, prospective follow-up of intensive care unit survivors after SARS-CoV-2 pneumonia

In late December 2019, an outbreak of pneumonia started in Wuhan, China, caused by a novel coronavirus, which was named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1], due to the occurrence of severe acute respiratory distress syndrome (ARDS) in 29% of hospitalized patients.

Although data to accurately estimate the extent of post-SARS-CoV-2 sequelae are lacking, survivors of viral ARDS are at risk of long-term physical, functional and neuropsychological complications resulting from the lung injury itself, but also from potential multiorgan dysfunction, and the long stay in the intensive care unit (ICU) [2‐4]. Post-viral syndromes are well documented following other viral infections, including previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). SARS resulted in significant repercussions on pulmonary function, chronic musculoskeletal pain, and long-term mental disorders in survivors [5]. Chen et al. followed up 56 patients with H7N9 avian influenza to analyze pulmonary function and imaging changes up to 2 years after infection. Their results showed that despite interstitial changes and fibrosis on imaging, ventilation and diffusion dysfunction improved during the first 3 months and the improvement was associated with the sequelae observed at 2 years [6]. Wu et al. recently reported serial pulmonary function, exercise capacity, and chest high-resolution computed tomography (HRCT) changes in non-intubated patients hospitalized in Wuhan with severe SARS-CoV-2 pneumonia at 3, 6, 9, and 12 months following hospital discharge. They found evidence of persistent physiological and radiographic changes in a subgroup of patients [7]. To the best of our knowledge, there is no European report focusing exclusively on the most severe patients, as defined by the World Health Organization (WHO) categories. The long-term effect of SARS-CoV-2 on lung parenchyma and pulmonary function remains an open question.

With 295 patients hospitalized in the ICU at the peak of the epidemic in April, the region of Bourgogne-Franche-Comté in Eastern France was one of the regions with the highest incidence rates and ICU admissions for SARS-CoV-2 in France [8]. The goal of this study was to describe one-year recovery profiles, defined by repeated respiratory and exercise function, and quality of life evaluations, in a prospectively identified cohort of ICU patients who survived severe pneumonia.

In this study, we report the results of a longitudinal evaluation of 85 patients admitted to the ICU for SARS-CoV-2, with a follow-up of one year. To the best of our knowledge, no reports have described such a large European cohort of SARS-CoV-2 survivors after ICU, with systematic comprehensive evaluation including lung function testing, 6MWT, incremental CPET, thoracic CT-Scan, polygraphy and HRQoL, with an excellent compliance of 86% at 1 year. A strength of our study is the complete longitudinal follow-up with repeated measures, making it possible to qualify the recovery of our patients as a function of time.

The most interesting findings were that only 8 patients (11%) having persistent impairment of DLCO at 1 year. Among these 8 patients, due to pre-existing, undiagnosed respiratory comorbidities in 7 patients, only 1 patient was likely to actually have COVID-19-related DLCO alteration at 1 year. The proportion of patients with abnormal DLCO in our study is lower than that reported by Wu et al., which was 32.5% [7]. This might be explained by the use of different reference values compared than in Wu’s cohort who used the American Thoracic Society guidelines of 1994 [14]. Compared with their DLCO reference values for adults, the most recent GLI DLCO reference values are notably lower [15]. Another explanation for this difference may consist in the fact that none of the patient in Wu’s cohort have received mechanical ventilation likewise in the cohort of Huang (< 1%) [7, 16]. This may be a message in favor of the implementation of lung protective ventilation in COVID-19 related ARDS. Compared to the population with all-cause ARDS followed by Herridge et al., in whom 3-month DLCO was 63% of predicted (IQR: 54–77) [2], respiratory function recovered more quickly in our cohort of patients with severe SARS-CoV-2.

Although the 6MWT showed significant recovery between 3 and 12 months in most patients, the walked distance remained below the predicted distance in 18 patients (27.3%), and 37.9% of patients had a drop of 4% or more in SpO₂ at 12 months. Our results are concordant with the cohort of Wu et al. who reported around 14% of patients with 6MWT distance below the predicted value.

SARS-Cov-2 infection may have caused myopathic changes, also represented by the MIP (% of pred) or MEP (% of pred), which showed a constant improvement over the 12 months of follow-up [17].

Creatinine increased at the time of ICU hospitalization was shown as a predictive of low DLCO in the cohort follow-up. The association between creatinine and DLCO can be explained by the high prevalence of thromboembolic events. Reinforcing this hypothesis, the median level of D-dimers was high at the time of hospitalization with a frequency of pulmonary embolisms of 24%. We believe that these patients may have abnormal tiny blood vessels or microthrombus formation, which can be implicated in the reduction of DLCO over time or kidney injury. Other studies have demonstrated a higher rate of thromboembolic events in survivors of COVID-19 at 6 months follow-up, raising the question of the number of undiagnosed cases of segmental or subsegmental pulmonary embolism [18, 19]. The endothelial inflammation classically described in COVID-19 remains a good hypothesis for the increased incidence of pulmonary embolism, and potentially the leading cause of the persistent reduction in DLCO and kidney function over time with a specific increase in D-dimer levels [20]. In our study, D-dimer at the time of hospitalization was not showed to be correlated with KCO measurement at 3 months. Thus, other hypotheses can be put forward on the initial reduction of DLCO with normal KCO apart from microthrombus formation. Considering the number of patients with a history of chronic lung disease and obesity in our cohort, a re-distribution of the regional ventilation/perfusion ratio might have partially compensated the gas transfer efficiency, maintaining satisfactory KCO levels in some patients. Moreover, KCO may have been overestimated due to a functional restrictive pattern [21] that may have masked the possible persistence of damage to the vascular component [22].

Our analyses showed a slight-to-moderate deterioration in HRQoL in all domains except for the role-emotional domain. The most altered domains were vitality and role-physical, with a median score of 55 for vitality at 3 months. The only domain that improved over time was the role-physical domain. In an observational cohort by Vlake et al., 118 COVID-19 ICU survivors were evaluated using the same questionnaire [23]. These authors observed that mental HRQOL increased between 6 weeks and 3 months, and remained stable thereafter. Only the role-physical domain improved constantly over time, as in our cohort. A possible explanation might be that for all components except for the physical domain, improvements occur before 3 months, with a ceiling effect already reached by the time the study questionnaires were administered [24]. Compared to the population with all-cause ARDS followed by Herridge et al., HRQoL increased over time for each domain, and particularly the role physical domain, as in our cohort. At the 3-month evaluation, HRQoL scores were lower in the cohort of all-cause ARDS followed by Herridge et al. [2]. These results suggest, as in the paper by Vlake et al. comparing HRQOL results with those of a historical non-COVID-19 post-ICU population, that HRQOL is less deteriorated after an ICU stay for SARS-COV2 than after other causes of ARDS. When we investigated the relation between HRQoL and objective parameters, such as the 6MWT or CT scan findings, there were no significant relations, suggesting a discrepancy between the patient's perception and the functional parameters measured in our study. At 3 months, among the 50 patients (63.3%) who had walk distances below their age-adjusted predicted values, the median (min–max) score in the vitality domain was 55 (5–100), which was the same score as in patients with no alteration on the 6MWT. Vaes et al. reported survey results of post-discharge SARS-CoV-2 patients and they showed significant improvements in work productivity and functional status, although a proportion of patients had persistent symptom, moderate-to-poor health and impaired quality of life, as in our data [25]. No explanation was given for the persistence of an alteration in these domains, and some authors have characterized these patients with the term "long COVID" [26].

The last point to highlight from our cohort is that there were few indicators of psychological disorders, such as depression or anxiety, according to the self-reported HADS score. Using the HADS score at 3 months after hospital discharge, the results reported by Vlake et al. in their cohort of 118 post-ICU patients showed a higher frequency of depression and anxiety [23]. However, in our study, patients had early psychological follow-up and were encouraged to use new technologies to interact with their loved ones, as suggested by Kennedy et al. [27]. It has been reported that survivors of infectious diseases, such as SARS-CoV-2, are exposed to psychological risk, due to contagiousness, extensive isolation measures and public fear of the disease [28]. PTSD would have been interesting to evaluate. Indeed, in the cohort by Vlake et al., 23% of the 57 patients who responded to the IES-R questionnaire had psychological distress, including probable posttraumatic stress disorder (PTSD) in 7% of cases at 6 weeks after hospital discharge.

Our prospective study has some limitations. The severity of the epidemic and the significant mobilization of medical teams made it impossible to consider the constitution of a multicenter cohort at such short notice. Furthermore, some practices have changed based on the lessons learned from the epidemic. For example, the role of dexamethasone in hospitalized patients with COVID-19 has been established [29]. No effects of steroid use, ventilation supports, neuromuscular blocking agents, or prone position on DLCO could be demonstrated but this may be due to the too small size of our cohort. It is recommended to perform contrast-enhanced chest CT scan. Another potential bias is the lack of data regarding the patients’ respiratory function or existence of possible obstructive sleep apnea before contracting SARS-CoV-2. To minimize this potential bias, patients known to have chronic respiratory insufficiency, those on long-term oxygen therapy or those followed for interstitial lung disease were excluded from the cohort.

In this large cohort of ICU survivors of SARS-CoV-2 infection, systematic multidimensional evaluation up to one year after symptom onset showed that most patients had an improvement in DLCO at 3, 6, and 12 months, and patients who normalized their DLCO did not subsequently deteriorate.