Persistence of respiratory deficits in post-COVID-19 patients: 36 months after hospital dischargeAbstract
Introduction: COVID-19, caused by SARS-CoV-2, is an acute respiratory infection with high transmissibility and multiple complications, particularly pulmonary. Patients who required invasive mechanical ventilation (IMV) are at increased risk of long-term respiratory sequelae.
Objective: To investigate the presence of respiratory deficits in post-COVID-19 individuals, 36 months after hospital discharge, who underwent IMV.
Methods: A cross-sectional study conducted between December 2023 and May 2024 with patients discharged from the intensive care unit between November 2020 and August 2021. Sociodemographic data, Maximum Inspiratory Pressure (MIP), Maximum Expiratory Pressure (MEP), and dyspnea using the Medical Research Council (mMRC) scale were collected. Statistical analysis was performed using R software, with paired Student's t-tests and Fisher's exact test (p < 0.05).
Results: Of the 149 eligible patients, 31 comprised the final sample. The mean age was 54.27 ± 14.59 years, and the mean body mass index was 32.52 ± 4.88 kg/m2. A significant reduction in MIP was observed in the age groups 20–29 years (53% of predicted), 30–39 years (86%), and 50–59 years (72%). MEP was higher among older adults aged 70–79 years (119% of predicted). There was an association between inspiratory muscle weakness and the duration of neuromuscular blocker (NMB) use (p = 0.047), as well as a correlation between dyspnea and comorbidities (p = 0.04).
Conclusion: The study identified a reduction in MIP among younger individuals, with an association between inspiratory muscle weakness and NMB duration, as well as between dyspnea and comorbidities. These findings highlight the importance of continuous respiratory rehabilitation and personalized clinical care.
Keywords:
COVID-19; Mechanical ventilation; Respiratory function tests; Rehabilitation; Acute post-COVID-19 syndrome
Resumo
Introdução: A COVID-19, causada pelo SARS-CoV-2, é uma infecção respiratória aguda com alta transmissibilidade e múltiplas complicações, especialmente pulmonares. Pacientes submetidos à ventilação mecânica invasiva (VMI) apresentam risco aumentado de sequelas respiratórias prolongadas.
Objetivo: Investigar a presença de déficits respiratórios em indivíduos pós-COVID-19, 36 meses após a alta hospitalar, que foram submetidos à VMI.
Métodos: Trata-se de um estudo transversal, realizado entre dezembro de 2023 e maio de 2024, com pacientes que receberam alta da unidade de terapia intensiva entre novembro de 2020 e agosto de 2021. Foram coletados dados sociodemográficos, pressão inspiratória máxima (PImáx), pressão expiratória máxima (PEmáx) e dispneia pela escala do Medical Research Council (mMRC). A análise estatística utilizou o software R, testes t de Student pareado e exato de Fisher (p < 0,05).
Resultados: Dos 149 pacientes elegíveis, 31 compuseram a amostra final. A média de idade foi 54,27 ± 14,59 anos e o índice de massa corporal médio foi de 32,52 ± 4,88 kg/m2. Observouse redução significativa da PImáx nas faixas etárias de 20-29 anos (53% do previsto), 30-39 anos (86%) e 50-59 anos (72%). A PEmáx foi maior em idosos de 70-79 anos (119% do previsto). Houve associação entre fraqueza inspiratória e tempo de uso de bloqueadores neuromusculares (BNM) (p = 0,047), além de correlação entre dispneia e comorbidades (p = 0,04).
Conclusão: O estudo identificou redução da PImáx em jovens, com associação entre fraqueza inspiratória e tempo de BNM, além de associação entre dispneia e presença de comorbidades. Esses achados indicam a importância de reabilitação respiratória contínua e cuidado clínico personalizado.
Palavras-chave:
COVID-19; Ventilação mecânica; Testes de função respiratória; Reabilitação; Síndrome de pós-COVID-19 aguda
Introduction
COVID-19, the disease caused by SARS-CoV-2 coronavirus, emerged as an acute respiratory infection of high transmissibility and global impact, responsible for millions of deaths since 2019.1-3 Its clinical spectrum ranges from mild presentations to severe forms with acute respiratory failure, frequently requiring admission to intensive care units (ICUs) and invasive ventilatory support.1,4-8
Follow-up studies demonstrate that COVID-19 survivors admitted to the ICU, particularly those who underwent invasive mechanical ventilation (IMV), may present persistent respiratory deficits, including dyspnea, reduced functional capacity, and exercise intolerance for up to 12 months after discharge.9-13 However, understanding of respiratory outcomes beyond 24 months remains limited, and in the Brazilian context there is a scarcity of longitudinal studies evaluating the persistence of these deficits in severely ill patients who underwent IMV, which compromises the planning of long-term follow-up and rehabilitation strategies.
Thus, a knowledge gap persists regarding the behavior of respiratory outcomes three years after hospital discharge. Investigating functional evolution at 36 months is fundamental to understanding the trajectory of recovery or persistence of sequelae, and to support policies for continued care. The present study therefore aimed to assess the persistence of respiratory deficits in individuals with severe post-COVID-19 who underwent IMV, 36 months after hospital discharge, contributing to the advancement of knowledge on late outcomes that remain underexplored in the national context.
Methods
A cross-sectional, descriptive, and quantitative study was conducted between December 2023 and May 2024, involving patients who were discharged from the ICU following SARS-CoV-2 infection between November 2020 and August 2021. The research was conducted at a hospital located in the metropolitan region of Curitiba, state of Paraná, Brazil. Participants were invited to join the study through telephone contact. No prior sample size calculation was performed; the sample was defined by convenience and comprised eligible patients who could be reached during the study period. This strategy was adopted considering the high inhospital mortality among patients initially admitted for COVID-19. During the analyzed period, 149 patients were hospitalized, of whom 98 died, resulting in 51 survivors eligible for follow-up.
The study received approval from the Research Ethics Committees of the Hospital de Clínicas - Universidade Federal do Paraná (HCU-FPR) and the Municipal Health Department of São José dos Pinhais (SEMS/SJP), under registration numbers CAEE 47158821.6.0000.0096 and 47158821.6.3001.9587, respectively. All participants signed a free and informed consent form.
Participants
The initial study sample comprised 149 hospitalized patients aged ≥18 years who underwent orotracheal intubation, regardless of sex, race, color, or ethnicity. Patients were excluded from the study if, after hospital discharge, they required readmission due to any clinical condition that could interfere with outcome assessment, such as reinfections, late respiratory complications, decompensations of chronic diseases, or other associated conditions.
Procedures
Participants were contacted by telephone and invited to join the study. After obtaining the free and informed consent, assessments were conducted in person at participants' homes. The evaluator responsible for data collection was the same professional who had accompanied the participants during hospitalization and home follow-up. Assessments were not conducted in a blinded manner with respect to participants' clinical history and prior conditions.
Collected data included sociodemographic, anthropometric, and respiratory assessments, as well as clinical data related to the hospital stay, including total hospitalization duration, IMV duration, duration of neuromuscular blockade, sedation, and vasoactive drug administration.
Respiratory muscle strength was assessed by manovacuometry using a VentCare analog manovacuometer calibrated in cmH2O with an operating range of −150 to +150 cmH2O. The procedure followed standardized guidelines for measuring maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP). For MIP measurement, participants were instructed to perform a maximum expiration to residual volume, followed by a maximum inspiration against the occluded mouthpiece of the device, maintaining the effort for at least one second. For MEP, participants performed a maximum inspiration to total lung capacity, followed by a forced expiration against the occluded mouthpiece, also sustained for one second. Each measurement was repeated three times, with a rest interval between attempts; the highest value was recorded, provided the variation between measurements did not exceed 10%. Measured values were compared to predicted values calculated from specific regression equations adjusted for age and sex.14,15
Dyspnea perception was assessed using the modified Medical Research Council (mMRC) scale. The scale comprises five categories ranging from 0 to 4, reflecting the degree of functional limitation caused by dyspnea: 0 corresponds to absence of dyspnea except during intense exertion, and 4 to dyspnea at rest, preventing the individual from leaving home or performing basic tasks. During data collection, participants were instructed to select the grade that best represented their current experience of breathlessness based on their functional limitations. The scale was administered individually, with prior explanation of the criteria for each category to ensure comprehension and reliability of responses.14
In this study, difficult weaning was defined as the condition in which the patient had three consecutive failures in spontaneous breathing trials (SBT) or when the weaning process extended for more than seven days after the first attempt to discontinue mechanical ventilation.16
For the purpose of age classification, participants aged 60 years or older were considered elderly, in accordance with guidelines established by the World Health Organization.17 Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE), a widely validated instrument in the scientific literature for its efficacy in screening cognitive changes in elderly populations.18
Statistical analysis was performed using R software (version 4.1.0). Continuous quantitative variables were characterized through descriptive statistics, including minimum and maximum values, arithmetic mean, and standard deviation, while categorical variables were expressed as absolute and relative frequencies. Normality of continuous variables was verified using the Shapiro-Wilk test. For comparison of means of continuous variables within the same group, the paired Student's t-test was applied, provided the normality assumption was met. Association between categorical variables was evaluated using Fisher's exact test. A significance level of 5% (p < 0.05) was adopted, and results with p-values below this threshold were considered statistically significant.
Results
The initial sample included 149 patients who underwent orotracheal intubation, of whom 98 died during hospitalization, leaving 51 eligible individuals. Twenty patients were excluded due to refusal (n = 7), inability tolocate (n = 3), post-discharge death (n = 3), residence in other states (n = 4), or readmission (n = 3), resulting in a final sample of 31 participants (Figure 1). Among these, 10 were elderly individuals, all cognitively capable as assessed by the MMSE.
The 31 participants presented in Table 1 had a mean age of 54.27 ± 14.59 years and a mean body mass index of 32.52 ± 4.88 kg/m2, indicating a predominance of overweight in the sample. The mean length of hospitalization was 25.61 ± 16.86 days, demonstrating wide clinical variability among cases. The data reveal a markedly vulnerable profile among post-COVID-19 individuals, with a predominance of low educational attainment and limited household income.
Analysis of predicted and observed MIP values in the age groups 20–29 (p = 0.0177), 30–39 (p = 0.0039), and 50–59 years (p = 0.0013) revealed a significant reduction in inspiratory muscle strength relative to predicted values. Regarding MEP, statistically significant differences were identified in the 60–69 (p = 0.0461) and 70–79 year age groups (p = 0.0427), suggesting an increase in expiratory muscle strength in older individuals (Table 2). In terms of the distribution of mean percentage values of maximum respiratory pressures by age group: among 20–29 year-olds, observed values were 53% for MIP and 53% for MEP. In the 30–39 year group, percentages increased to 86% and 98%, respectively. The 40–49 year group recorded the highest values, at 110% for MIP and 109% for MEP. In the 50–59 year group, values decreased to 72% (MIP) and 96% (MEP).
Comparison between predicted and measured values of maximumiInspiratory pressure (MIP) and maximum expiratory pressure (MEP) by age group (n = 31)
In the 60–69 and 70–79 year groups, percentages increased again to 93% and 96% for MIP, and 115% and 119% for MEP, respectively. Finally, in the 80–89 year group, values were 57% for MIP and 72% for MEP.
Table 3 shows a statistically significant association between inspiratory muscle weakness and the duration of neuromuscular blocker (NMB) use (p = 0.047), with shorter exposure duration to blockade observed among affected individuals.
Relationship between invasive mechanical ventilation, neuromuscular blocker use, and respiratory outcomes (n = 31)
Among the variables analyzed in Table 4, only dyspnea demonstrated a statistically significant association with the presence of comorbidities (p = 0.04). This result suggests that individuals with comorbidities tend to exhibit a higher occurrence of dyspnea, which may reflect a more pronounced clinical impact of these conditions on respiratory function.
Discussion
This study assessed persistent respiratory limitations in post-COVID-19 individuals 36 months after hospital discharge. To date, this is the only Brazilian study to specifically investigate the respiratory repercussions in patients who underwent orotracheal intubation due to COVID-19 three years after hospitalization. Although still scarce in the national context, international studies covering this follow-up period suggest that the effects of COVID-19 may persist for up to three years after infection, with potentially relevant clinical implications, especially in individuals who experienced severe forms of the disease.17-21 However, these findings should be interpreted as indicative of trends rather than established causal relationships.
The predominance of males observed in this sample (54.83%) is consistent with the literature, which indicates a higher frequency of men among severe COVID-19 cases, possibly associated with hormonal and immunological differences and a greater burden of comorbidities in this population.22,23 Similarly, the high prevalence of obesity, systemic arterial hypertension, and dyslipidemia reflects the clinical profile described in several studies, in which these conditions are associated with greater disease severity and worse clinical outcomes.23-27 These data reinforce that the studied sample represents a high-risk group, which should be considered when interpreting the results.
Regarding invasive ventilatory support, all participants in this study required IMV, demonstrating the severity of the clinical presentations — an aspect widely documented in the scientific literature. Furthermore, non-IMV was used in approximately 68% of cases, a proportion similar to that observed in prior studies, which report its use in approximately 65% of affected individuals, highlighting its role as an initial strategy in managing respiratory failure.12,22,28-33 These clinical aspects reinforce that the evaluated individuals underwent interventions typical of critical illness, potentially associated with late functional repercussions.
Prone positioning was used in 74.19% of intubated COVID-19 patients with the aim of optimizing oxygenation and improving the ventilation/perfusion ratio. The efficacy of this intervention is widely documented in the literature, with evidence demonstrating significant improvement in oxygenation and pulmonary ventilation distribution, especially in cases of acute respiratory distress syndrome associated with COVID-19.23,31,34,35
Regarding the clinical data of this study, a mean age of 54.27 ± 14.59 years was observed among the analyzed individuals. The mean length of hospitalization was 25.61 ± 16.86 days, while the mean IMV duration was 16.29 ± 13.32 days, demonstrating the high severity of cases. These findings are consistent with the literature, which describes prolonged periods of invasive ventilation and hospitalization in patients with severe COVID-19, corroborating the severity observed in this study and aligning with international trends.36-38
Respiratory data revealed reductions in respiratory muscle strength across different age groups, with greater impairment of MIP in elderly individuals. These findings are consistent with evidence demonstrating a progressive decline in respiratory muscle strength with aging, aggravated by factors such as sarcopenia, changes in ventilatory mechanics, and lower functional reserve.14,39 In the context of COVID-19, this impairment may be potentiated by additional mechanisms, such as residual lung damage, persistent inflammation, and physical deconditioning, especially in individuals with comorbidities.40,41 Furthermore, the possibility that unmeasured factors, such as prior physical activity level, adherence to rehabilitation, or functional status prior to infection, may have influenced the observed results cannot be excluded.
An unexpected finding of this study was the inverse association between the duration of NMB use and the presence of inspiratory muscle weakness, as patients with this outcome had shorter exposure to blockade. This result contrasts with the literature, which describes prolonged NMB use as a risk factor for ICU-acquired muscle weakness.42-45 However, this association should be interpreted with caution, as the influence of selection bias cannot be ruled out, given that only survivors who could be located 36 months later were evaluated. Furthermore, initial clinical severity may have acted as a confounding factor, simultaneously influencing NMB indication and duration and late respiratory outcomes. Additionally, the limited sample size increases the possibility of Type I error, that is, identifying a statistically significant association that may not reflect a true relationship, and may have contributed to unstable estimates, especially in unadjusted analyses. Accordingly, this finding should be understood as exploratory and not as an established causal relationship, requiring confirmation in prospective studies with greater statistical power and multivariate control.
The analysis revealed a statistically significant association between the presence of comorbidities and the occurrence of dyspnea (p = 0.04), suggesting that patients with pre-existing clinical conditions exhibit greater respiratory vulnerability following COVID-19 infection. Recent studies demonstrate that comorbidities such as systemic arterial hypertension, diabetes mellitus, obesity, and cardiovascular disease are strongly associated with greater disease severity and persistence of respiratory symptoms, including dyspnea, even months after recovery.46-48 Post-COVID dyspnea has been reported in up to 46% of patients 12 months after hospital discharge, with a negative impact on quality of life and association with factors such as systemic inflammation, cardiac dysfunction, and physical deconditioning.49,50 Moreover, even in mild cases, alterations in respiratory muscle strength and pulmonary function have been observed, with significant reductions in MEP and exercise capacity.51,52
On the other hand, no significant associations were observed between comorbidities and inspiratory (p = 0.99) or expiratory muscle weakness (p = 0.89), which may indicate that these dysfunctions are more closely related to acute hospitalization factors, such as mechanical ventilation, sedation, and prolonged immobilization, than to underlying clinical conditions. The literature reinforces that respiratory muscle weakness in post-COVID patients may occur independently of comorbidities, being influenced by mechanisms such as ventilation-induced diaphragmatic atrophy and structural muscle alterations.53,54
The results of the present study suggest that respiratory changes may persist for up to three years after hospitalization for COVID-19, with relevant repercussions on autonomy, selfcare, and social participation. Deficits in respiratory muscle strength and the presence of dyspnea may compromise activities of daily living, such as walking long distances, climbing stairs, performing house-hold tasks, and maintaining occupational performance. Such limitations may impact mobility, functional independence, and return to work, especially in clinically vulnerable individuals. These findings reinforce the importance of longitudinal follow-up and the implementation of structured physiotherapeutic strategies for respiratory and motor rehabilitation in late stages of recovery, both in outpatient and primary healthcare settings, aiming to minimize functional losses and promote social and occupational reintegration.
This study has limitations that must be considered when interpreting the results. The sample was defined by convenience and no prior sample size calculation was performed, which prevents a priori estimation of statistical power and may have limited the detection of smaller-magnitude associations. Additionally, the absence of a control group and the clinical heterogeneity of participants restrict the generalizability of the findings. Respiratory functional assessment was conducted at a single time point, preventing temporal analysis of muscle strength evolution throughout follow-up. Furthermore, variability in care protocols, length of hospital stay, and access to rehabilitation during the 36-month period may have influenced the observed outcomes.
The risk of measurement bias should also be considered, as measurements were performed by an evaluator who was not blinded to participants' prior clinical conditions. Knowledge of clinical history and the previously established relationship with participants may have unintentionally influenced outcome measurement. The absence of blinding and the observational nature of the study limit causal inference and reinforce the need for caution in interpreting the results. Future studies with prospective design, larger samples, serial assessments, blinded evaluators, and adjustment for clinical severity are necessary to elucidate the mechanisms underlying late respiratory sequelae of COVID-19 and to guide more precise interventions.
Conclusion
The results of this study indicate that patients who underwent IMV during COVID-19 may present persistent respiratory changes even three years after hospital discharge. The reduction in inspiratory strength across different age groups, combined with the presence of comorbidities and reported dyspnea, highlights the importance of continuous rehabilitation strategies and functional follow-up. These findings reinforce the need for multicenter studies with larger samples to consolidate these results and broaden understanding of the long-term respiratory impacts in post-COVID-19 individuals.
Data availability statement
The data that support the findings of this study are available upon reasonable request.
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Associate editor:
Ana Paula Cunha Loureiro
