Long-Term Disabilities in ICU Survivors of COVID-19

Abstract

BACKGROUND:

COVID-19 is associated with prolonged disability, particularly after critical illness. This study aimed to assess and compare disability post–hospital discharge of subjects who were invasively ventilated versus those who were not, following ICU admission due to COVID-19. This study also explored variables associated with long-term disability.

METHODS:

In this prospective cohort study, subjects with COVID-19 who received invasive ventilation, noninvasive ventilation, or high-flow nasal cannula during ICU stay were assessed with the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 at 3 and 6 months post–hospital discharge. Data were analyzed collectively and stratified as subjects with and without invasive mechanical ventilation. Analysis of variance and multiple regression analyses were applied.

RESULTS:

The subjects (N = 43) were mainly male, middle age, and overweight. Subjects who were invasively ventilated (n = 21) had decreased physical function compared to those who were not during hospital assessments. From 3–6 months after discharge, all WHODAS domains and the overall score decreased in both groups (P < .001), indicating disability recovery. The participation domain, which assesses joining in society, was the only domain that remained worse in the ventilation group compared to the no ventilation group (P = .01). No interaction was found between time and the study groups, suggesting that the recovery trajectory was similar. At 6 months, considering the entire cohort, 70% and 56% had no disability in self-care and getting along domains, respectively, while 42% exhibited moderate to severe disability in the participation domain. According to the overall WHODAS score, 86% of subjects still had some level of disability at 6 months. In multivariate analyses, the overall WHODAS score along with the household and participation domains showed significant positive correlations, indicating higher disability, with corticosteroid use.

CONCLUSIONS:

Disability persisted at 6 month post–hospital discharge for ICU survivors of COVID-19, regardless of the need for invasive mechanical ventilation. Participation was the only domain that showed higher disability among those who received invasive ventilation.

Introduction

Post–COVID-19 condition is characterized by continuation or emergence of new symptoms 3 months following the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months and having no other cause.¹ Common manifestations are fatigue, breathlessness, and cognitive dysfunction.^1,2 This condition often results in disability, which manifests as difficulties in any area of functioning, including environmental and personal factors,³ significantly disrupting social relationships and daily activities such as household tasks.^2,4-6

Although post–COVID-19 condition can affect individuals who did not have severe forms of COVID-19, patients who had acute respiratory failure requiring invasive mechanical ventilation are anticipated to have a higher risk of developing greater severity of disability.^7,8 This phenomenon may be attributed to the combined impact of the COVID-19 infection itself, the severity of the critical illness, and the treatment requirements for patients undergoing invasive ventilation.^2,9,10 However, evidence suggests that disability among ICU survivors due to COVID-19 may not significantly differ from those unrelated to COVID-19.^11-13 In a follow-up cohort study of 256 ICU survivors, no significant differences were found in the incidence or severity of new disability at 6 months post–ICU admission between subjects requiring invasive ventilation for ARDS caused by COVID-19 and those unrelated to COVID-19.¹¹ Additionally, 2 other studies found no differences in self-reported physical symptoms¹² or in predicted distances during the 6-min walk test¹³ between ICU survivors of COVID-19 and those with other conditions.

Although there is existing literature on ICU survivors of COVID-19,^7,11,14-18 most studies have focused on the changes in body functions and structure, with very few addressing a more comprehensive approach that includes daily activities and social engagement, and they are mainly from high-income countries.¹⁹ A more comprehensive approach could aid in guiding caregivers and policy makers to develop more targeted recovery strategies, focusing beyond the physical function and giving more priority to quality of life and social re-engagement.^20-22 Furthermore, insights from long-term studies on disability among survivors of critical COVID-19 illnesses could potentially be extrapolated to critical illnesses related to other causes.

The primary objective of this study was to assess and compare disability at 3 and 6 months post hospital discharge in adult subjects who recovered from critical COVID-19 illness, specifically comparing those who received invasive ventilation to those who did not following ICU admission. As a secondary aim, this study sought to explore variables associated with long-term disability.

QUICK LOOK.

Current knowledge

COVID-19 can cause prolonged symptoms and disability. Individuals who experienced acute respiratory failure necessitating invasive mechanical ventilation are anticipated to exhibit a heightened frequency and severity of disability. The WHO Disability Assessment Schedule (WHODAS) 2.0 represents a standardized, cross-cultural assessment tool designed to evaluate health and disability.

What this paper contributes to our knowledge

This study shows that, despite improvements over time, disability remained highly prevalent among survivors of critical COVID-19 illness 6 months after hospital discharge, regardless of whether they received invasive mechanical ventilation or not. The participation domain, which assesses joining in social activities, was the only WHODAS domain that remained worse in subjects who were invasively ventilated.

Methods

This study is part of prospective cohort research among adults hospitalized for COVID-19 in 2 public teaching hospitals, Instituto do Coração - Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo and Hospital São Paulo - Universidade Federal de São Paulo, both in São Paulo, Brazil. The results of the hospital cohort were published elsewhere.²³ Herein, a preplanned analysis of 3- and 6-month follow-up data are reported.

This study was approved by the committees for medical research ethics and the data protection officials at both hospitals (HC-FMUSP, number 4.711.382, and UNIFESP, number 4.870.812). Informed consent was obtained from all subjects. No sample size calculation was performed due to the exploratory nature of the study, and a convenience, consecutive sample was used. Recruitment occurred between July 2021–February 2022, with follow-up occurring through October 2022.

The inclusion criteria were subjects admitted to the ICU due to laboratory-confirmed COVID-19 infection, age ≥ 18 y, need for invasive mechanical ventilation for > 24 h, noninvasive ventilation (NIV) or high-flow nasal cannula (HFNC) for > 8 h/d, and hospital discharge. The exclusion criteria were history of amputation of the hand of the dominant upper limb and previous and permanent cognitive disorders or neuromusculoskeletal deficits with inability to consent to participate in the study and/or to execute the proposed physical evaluations.

Subject-Reported Disability: 36-Item World Health Organization Disability Assessment Schedule 2.0

World Health Organization Disability Assessment Schedule (WHODAS) 2.0 represents a standardized, cross-cultural assessment tool designed to evaluate health and disability.²⁴ Its applicability extends to assessing disability in both post–COVID-19 condition and critical illness subjects, demonstrating reliability and sensitivity in tracking disability changes over time.^11,24 This instrument evaluates the level of functioning in 6 domains of life: domain 1, cognition (understanding and communicating); domain 2, mobility (moving and getting around); domain 3, self-care (hygiene, dressing, eating, and staying alone); domain 4, getting along (interacting with other people); domain 5, life activities (domestic responsibilities, leisure, work, and school); and domain 6, participation (joining in community activities, participating in society).²⁴

In this study, the questionnaire was administered by telephone by 2 researchers to subjects at 3 and 6 months after hospital discharge. The study data were collected within a secure, web-based software platform, Research Electronic Data Capture (REDCap), hosted at both universities. The full version with 36 questions was used. The participants were asked to answer the questions related to difficulties experienced during the previous 30 d. Each question was scored from 1 (no difficulty) to 5 (extreme difficulty or cannot do) with the possibility of answering not applicable if the participant did not have the opportunity to complete the task in the last 30 d. The complex method of scoring was applied resulting in the conversion of the summary score into a metric ranging from 0–100 (where 0 = no disability, 100 = full disability) for all the 6 domains and the overall score. Missing data for questions from the same respondent at 3- or 6-month follow-up were imputed based on the instructions outlined in the WHODAS 2.0 training manual.²⁴

The WHODAS total score was calculated using complex scoring, and subjects were classified according to the total score, as follows: no disability (WHODAS < 5%), mild (WHODAS 5–24%), moderate (WHODAS 25–49%), severe (WHODAS 50–95%), and very severe (WHODAS 96–100%).¹⁸

Data from the hospital assessments.

During hospital stay, the subjects underwent a comprehensive physical functional assessment after ICU discharge and on the seventh day on the ward (or earlier if the subject would be discharged from the hospital).²³ Herein the results of the Medical Research Council sum score (MRC-SS)²⁵ and Short Physical Performance Battery (SPPB)²⁶ test are shown to illustrate physical functioning early in the recovery. The MRC-SS was used to evaluate upper- and lower-body muscle strength according to a standardized protocol.²⁵ The SPPB represents the sum of results from 3 functional tests, standing balance, 3-m gait speed, and 5-repetition sit-to-stand maneuver.²⁶ Each component is scored based on a subscale, and the 3 subscores are added to obtain a summary score. Scores between 0–3 denote severe physical function impairment, 4–6 low function, 7–9 intermediate function, and 10–12 normal function.²⁶

Demographic and hospital data were extracted from medical records. These data included age, sex, weight, height, comorbid conditions, Sequential Organ Failure Assessment (SOFA) score, need for hemodialysis, use of neuromuscular blockers, corticosteroids usage, duration of mechanical ventilation support, and ICU and hospital length of stay.

In both hospitals, all subjects received physiotherapy according to the institutional protocol, and no study intervention was performed. After hospital discharge, no rehabilitation program was provided to the subjects.

Statistical analysis.

Categorical variables were reported as counts and percentages. Continuous variables were reported as mean and SD or medians and interquartile ranges, according to the distribution. Categorical variables were compared using the chi-square test or Fisher exact test, as appropriate. Continuous variables were compared using t tests, Mann-Whitney test, or analysis of variance (ANOVA) for repeated measures, as recommended. The ANOVA model was built with one within factor (time: 3 months vs 6 months), one between factor (groups: invasive ventilation vs no invasive ventilation), and one interaction factor (time vs group). Spearman correlation analysis among all hospital variables and the WHODAS domains and overall score were performed, and only correlations with P < .01 were reported. The correlations with P < .01 were subsequently included in multiple regression analysis models to explore predictors of the domains within the WHODAS questionnaire and the overall score. Statistical analysis was performed using SPSS Statistics for Windows (Version 22.0, IBM, Armonk, New York). A 2-sided P < .05 was considered statistically significant.

Missing data from 5 subjects that did not respond to the questionnaire at 6-month follow-up were imputed using the missing at random pattern, a technique where the probability of an observation being missing depends on observed values but not on unobserved values.²⁷ The multivariate imputation by chained equations package in R software (version 4.3.2 (R Foundation for Statistical Computing, Vienna, Austria) was employed for this purpose, involving 10 iterations to create an imputed database. The predictive mean matching method was selected to impute missing values in all response variables. This method was chosen for its ability to constrain imputations to observed values, providing a more accurate representation of the data.²⁸

Results

Subjects and Hospital Data

Sixty-four patients were included in the hospital cohort. Seventeen were unable or not willing to be contacted, and 4 died; thus, 43 subjects were included in this study. Of these, 21 (48.8%) subjects received invasive mechanical ventilation. All 43 completed the survey at 3 months and 38 (90.7%) at 6 months (Fig. 1).

Fig. 1.

Flow chart.

Demographic and hospital data are described in Table 1. Overall, the subjects were mainly male, middle age, overweight, and most had at least one comorbidity. Subjects requiring invasive mechanical ventilation were a median of 9 y younger than those not invasively ventilated (P = .043). The duration of invasive ventilation was 12.0 [8.5–31.5] d; 7 subjects (33.3%) needed tracheostomy, and the median use of neuromuscular blockers was 6.0 [2.5–14.5] d. In subjects without invasive ventilation, half (50.0%) used HFNC, followed by HFNC interspersed with NIV (45.5%), and a minority (4.5%) used only NIV. Subjects who were invasively ventilated had significantly reduced physical function compared to those who were not, as indicated by the SPPB and MRC-SS scores on days 1 and 7 after ICU discharge (Table 1).

Table 1.

Demographic and Hospital Data for Overall Population and Subjects With and Without Invasive Mechanical Ventilation

Disability Outcomes at 3 and 6 Months After Hospital Discharge

The WHODAS overall score at 3 and 6 months were 35.5 [30.8–51.0] and 21.0 [9.5–25.0] for the no invasive ventilation group and 55.0 [37.0–62.5] and 26.0 [15.5–35.5] for the invasive ventilation group, respectively. Since 53.5% (n = 23) of the subjects did not work or study, their life activities domain was composed only of the household chores results.

All 6 domains and the overall WHODAS score decreased significantly across time in both groups (P < .001) (Fig. 2 and Table 2). Only the participation domain remained worse in invasively ventilated subjects compared to subjects without invasive ventilation (P = .01) (Fig. 2 and Table 2). No interaction was found between time and the study groups, suggesting the recovery trajectory was similar regardless of the need for invasive ventilation (Table 2).

Fig. 2.

Levels of disability for subjects with and without invasive mechanical ventilation at 3- and 6-month post–hospital discharge. Levels of disability were classified as follow: 0 = no disability (World Health Organization Disability Assessment Schedule [WHODAS] < 5%), 1 = mild (5% ≤ WHODAS < 25%), 2 = moderate (25% ≤ WHODAS < 50%), 3 = severe (50% ≤ WHODAS < 96%), and 4 = very severe (96% ≤ WHODAS ≤ 100%). Blue and red represent median levels of disability, while lines in gray show individuals’ levels of disability. *Analysis of variance within factor (time: 3 months vs 6 months), P ≤ .001. ^†Analysis of variance between factor (groups: invasive ventilation vs no invasive ventilation), P ≤ .001. A: Cognition, B: mobility, C: self-care, D: getting along, E: household, F: participation, and G: overall score.

Table 2.

World Health Organization Disability Assessment Schedule Domains Data for Overall Population and Subjects With and Without Invasive Mechanical Ventilation

Figure 3 illustrates the distribution of all subjects according to their levels of disability. At 6 months, the domains with higher percentage of subjects (> 50%) with no disability were self-care and getting along. The participation domain was the most affected with 28% and 14% of the subjects presenting moderate and severe disability, respectively. The WHODAS overall score at 6 months revealed that only 14% of the participants had no disability, while 7% still had severe disability.

Fig. 3.

Distribution of subjects according to levels of disability 3 and 6 months post–hospital discharge. Levels of disability were classified as follow: none (World Health Organization Disability Assessment Schedule [WHODAS] < 5%), mild (WHODAS 5–24%), moderate (WHODAS 25–49%), severe (WHODAS 50–95%), and very severe (WHODAS 96–100%). A: Cognition, B: mobility, C: self-care, D: getting along, E: household, F: participation, and G: overall score.

Table 3 displays the significant correlations, with P < .01, observed between hospital data and the WHODAS score. Household activities domain, participation domain, and the overall score exhibited positive associations, indicating higher disability, with corticosteroid use. Conversely, these domains and the overall score showed negative associations with the SPPB score, signifying higher disability with lower physical functioning. Notably, the duration of invasive mechanical ventilation, ICU length of stay, and the use of neuromuscular blockers exhibited associations solely with the participation domain.

Table 3.

Spearman Correlation Analyses on the Hospital Data and the World Health Organization Disability Assessment Schedule 2.0

In the multivariate analysis, using all variables with P < .01 entered into the regression model, only corticosteroid usage showed significant correlation with household activities (r = 0.434, P = .004), participation (r = 0.530, P < .001), and the overall WHODAS score (r = 0.448, P = .003) assessed at 6 months.

Discussion

The primary findings of this study can be summarized as follows. First, after 6 months of hospital discharge, survivors of critical COVID-19 illness who were submitted to invasive mechanical ventilation only exhibited a higher degree of disability within the participation domain when compared to those who were not invasively ventilated. Second, all domains improved across time in both groups, with no interaction between time and groups, suggesting a similar recovery trajectory, regardless of the need for invasive ventilation. Third, it is notable that 86% of the subjects persisted in experiencing some degree of disability after 6 months, with 42% of them falling into the classification of moderate to severe disability. Last, the variables most correlated with the WHODAS domains were the duration of corticosteroids use and the SPPB test score; however, only the use of corticosteroids remained significant after multivariate analyses.

The percentages of disability observed in the present study at 6 months appear higher when compared to other studies that used the WHODAS questionnaire.^17,18 In a cohort study of COVID-19 critical illness, Hodgson et al¹⁸ reported that 61% of the study subjects exhibited some degree of disability, with 23% presenting moderate to complete disability at 6-month follow-up. In a study by Higgins et al,¹⁷ 40% of the participants presented moderate to complete disability at 3 months following hospital discharge for COVID-19. Several factors may account for the elevated disability rates observed in the current study. Our participants likely had a higher severity of illness, indicated by significantly longer median ICU and hospital lengths of stay (approximately 8 d longer) compared to the study by Hodgson et al.¹⁸ In contrast to the Higgins et al study,¹⁷ the present cohort had a larger proportion of mechanically ventilated subjects (51% vs 29%). Moreover, it is important to consider the WHODAS questionnaire version utilized. Whereas both the Hodgson et al¹⁸ and the Higgins et al¹⁷ studies employed the 12-item questionnaire, this present study employed the more comprehensive 36-item version. The 12-item questionnaire captures 81% of the variance present in the 36-item version, indicating the latter’s greater sensitivity and capacity to provide a more thorough assessment of disability.²⁴

The participation domain evaluates an individual’s engagement in communal activities, reflecting their integration into society.^24,29 Effective social participation necessitates physical, psychological, and cognitive capabilities, as well as favorable environmental factors. Thus, the participation domain may depict a more energy-demanding functioning condition than the other domains, as it encompasses a broader spectrum of capabilities. Whereas lacking statistical significance, it is noteworthy that the mechanically ventilated subjects displayed marginally higher continuous scores in the mobility domain at both 3 months and 6 months, as well as in the cognition domain at 6 months. These findings converge to support the hypothesis that the participation domain, by covering a wider range of functioning competences, may expose underlying disability more prominently. Although the 12-item WHODAS does not display the results for each domain, the questions regarding “community activities” and “being emotionally affected by health problems” can be extrapolated to the participation domain. In agreement with our findings, studies by Fernandes et al¹⁴ and Hodgson et al¹⁸ also indicated that the highest proportion of disability among survivors of critical COVID-19 illness after hospital discharge was associated with the question about “being emotionally affected by health problems.”

It is well known that corticosteroids can increase protein breakdown and decrease protein synthesis, potentially leading to muscle atrophy and weakness.³⁰ This mechanism could explain the positive association between corticosteroids usage and long-term disability observed in our study. However, the existing literature on the effects of corticosteroids on the development of myopathies in critically ill subjects presents conflicting findings.^30-33 One possible explanation is that, whereas corticosteroids have a catabolic effect, they may simultaneously improve outcomes in cases of organ failure and downregulate inflammatory processes involved in myopathies/neuropathies, ultimately benefiting patients’ clinical progress.³⁰ Yet, in a recent retrospective cohort study of 1,539 hospitalized adults with COVID-19, prolonged corticosteroids treatment (> 10 d) was associated with higher in-hospital mortality. Although the authors mentioned the absence of data on subjects who may have used corticosteroids for longer periods due to chronic conditions, potentially leading to worse outcomes, their findings may also align with our results.³⁴ Still, it is important to underscore that, based on the results of this present study, it is not possible to conclude whether corticosteroids usage during hospitalization is a marker or mediator of long-term disability.

Notably, there was no significant difference in the mobility domain between subjects who received invasive ventilation and those who did not 6 months after hospital discharge. This is in apparent contradiction with the worse score of physical functioning during hospital assessments, especially pronounced among those invasively ventilated. Furthermore, despite the decreased physical functioning and greater severity of critical illness during hospital stay, subjects who were invasively ventilated presented a similar disability recovery trajectory, as no interaction between time and the groups was observed. This unexpected finding may be partially explained by the fact that invasively ventilated subjects were, on average, 9 years younger. However, further investigation is needed to confirm this result.

The strengths of this study lie in its prospective design and dual-center approach, providing detailed functional outcomes assessed with the 36-item WHODAS. However, several limitations should be acknowledged. A portion of patients from the hospital cohort was unavailable for follow-up assessments, resulting in a reduced final sample size. Functional assessments conducted during hospitalization were not repeated in the follow-up, limiting our understanding of post–COVID-19 condition. Due to a significant number of subjects not engaged in work or study, the assessment of these activities was not feasible. An important limitation is the lack of information on functional status before hospital admission, marital status, family support, and mental health, all known to be contributors to functioning and disability.³⁵

Conclusions

Despite improvements over time, disability remained highly prevalent among ICU survivors of COVID-19 6 months after hospital discharge, regardless of whether they received invasive mechanical ventilation or not. Intriguingly, the participation domain emerged as the sole WHODAS domain exhibiting higher disability in subjects who were invasively ventilated. The participation domain, by embracing a broader spectrum of capabilities, may expose underlying disability more clearly. However, given the limited sample size of this study, these findings warrant the need for larger cohorts to validate them.