Severe COVID-19: How are these patients today

The coronavirus disease 2019 (COVID-19) pandemic infected over 700 million people, causing >6 million deaths worldwide (1).

COVID-19, caused by the SARS-CoV-2 virus, is a multiorgan disease, mostly affects the respiratory system. Viral pneumonia and respiratory failure are the leading causes of hospitalisation (2), with a high admission rate to both hospital wards (20%) and Intensive Care Units (ICUs) (6%) (3).

The natural history of COVID-19, as well as its long-term sequelae that are estimated to occur in about 10% of infected individuals (4), are not fully understood (5). The National Institute for Health and Care Excellence, the Scottish Intercollegiate Guidelines Network, and the Royal College of General Practitioners proposed a definition for long COVID syndrome as ‘signs and symptoms that develop during or after an infection consistent with COVID-19 and persist for >12 weeks and are not explained by an alternative diagnosis’ (6). Common symptoms are dyspnoea (7), fatigue, anxiety, depression, and sleep problems, which can significantly impair health-related quality of life (8). To identify these patients, the British Thoracic Society has suggested algorithms for assessing survivors of COVID-19 in the first 3 months after hospital discharge based on the severity of acute COVID-19 (9). The European Respiratory Society (ERS) Task Force has also concurred with the recommendation (2). Pulmonary fibrosis (PF), persistent ground-glass opacities (GGOs), reduced carbon monoxide diffusion capacity, restrictive ventilatory impairment, and fatigue 1–8 months after infection are predictors of the long-term consequences of COVID-19 (2). Patients with SARS-CoV-2 may experience a range of clinical presentations, from asymptomatic infection to critical illness (10).

The aim of this study is to evaluate patients who had severe COVID-19 requiring admission to ICU in three different periods after infection: up to 6 months, between 7 months and 12 months, and after 12 months.

According to COVID-19 Treatment Guidelines, severe illness corresponds to ‘individuals who have peripheral oxygen saturation (SpO₂) <94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO₂/FiO₂) <300 mmHg, a respiratory rate >30 breaths/min, or lung infiltrates >50%’; critical illness relates to ‘individuals who have respiratory failure, septic shock, and/or multiple organ dysfunction’ (10).

This is a retrospective, observational, and descriptive study including patients with severe SARS-CoV-2 infection admitted to ICU 1 at Unidade Local de Saúde de Lisboa Ocidental from January to September 2021. Patients with respiratory symptoms or functional limitations (≥1 point on the modified Medical Research Council Dyspnoea Scale (11) or ≥2 points on the Post-COVID Functional Status Scale (12)) 3 months post-discharge were included.

Symptoms were assessed at two points: 4 months post-discharge and three to 6 months after the first evaluation. Functional and imaging assessments were performed up to 6 months, between 7–12 months and beyond 12 months post-discharge.

Respiratory function was assessed through spirometry, plethysmography, diffusing capacity of the lung for carbon monoxide (DLCO) by single breath, and assessment of muscle strength through maximal respiratory pressures. Patients were classified according to ERS/American Thoracic Society (ATS) 2005 and ACCP 2000–2002 criteria, as having restrictive ventilatory impairment (forced vital capacity [FVC] <80% of predicted and total lung capacity [TLC] <80% of predicted) or obstructive impairment (forced expiratory volume in 1 s [FEV₁/FVC] <lower limit of normal), reduced DLCO (<80% of predicted), and decreased maximal respiratory pressures (maximal inspiratory pressure [MIP] and maximal expiratory pressure [MEP] <60% of predicted). Acceptability criteria followed ERS/ATS 2005 guidelines.

Imaging changes were also assessed using chest computed tomography (CT). Patients were categorised as having inflammatory changes (GGOs) and fibrotic changes (PF manifested through traction bronchiectasis or honeycomb pattern and residual lung fibrosis with fibrotic cicatricial changes), organising pneumonia (OP), or coexisting inflammatory and fibrotic changes.

Data were collected from clinical records, chest CT reports, and respiratory functional studies. Descriptive analysis of all variables was performed. Categorical variables are presented as frequencies (absolute count and percentage); continuous variables are presented as mean and standard deviation (SD) or median and interquartile range, depending on the empirical distribution of the variables. The Kolmogorov-Smirnov test was used to analyse the normality of the distribution of each continuous variable.

This study was approved by the Unidade Local de Saúde de Lisboa Ocidental Ethics Committee.

This study included 34 patients, with 50.0% (n = 17) being female and 50.0% (n = 17) male, with a mean age of 66.6 ± 9.9 years (range 40–84 years). Regarding smoking habits, 58.8% (n = 20) of patients had no prior smoking habits, and 41.2% (n = 14) of patients were former smokers with an average smoking history of 32.0 ± 19.8 pack-years. Thirty patients had at least one comorbidity, with the most frequent being: arterial hypertension (n = 22; 64.7%), obesity (n = 14; 41.2%), dyslipidaemia (n = 13; 38.2%), type 2 diabetes mellitus (n = 11; 32.4%), and depression (n = 5; 14.7%). Regarding respiratory pathology, 14.7% (n = 5) of patients had obstructive sleep apnoea, 8.8% (n = 3) had asthma, and 2.9% (n = 1) had chronic obstructive pulmonary disease.

During ICU stay, most patients (n = 26; 76.5%) required invasive mechanical ventilation with a median duration of 8 days (6–11), range 2–93 days; eight patients (23.5%) required only non-invasive ventilation with a mean duration of 4.8 ± 1.6 days (range 2–6 days). The median length of stay in the ICU was 9 days (6–12), range 4–93 days.

All ICU patients with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection received systemic corticosteroids treatment according to ICU’s protocol. Patients with SARS-CoV-2 infection and acute respiratory distress syndrome (ARDS) received 1 mg/kg/day of methylprednisolone, and the other patients received dexamethasone 6 mg once daily up to 10 days plus standard of care.

Post-discharge, only four patients (11.8%) still had respiratory insufficiency requiring oxygen therapy, which was discontinued 3 months later, at a post-discharge assessment conducted by the Intensive Care Team. None of the patients required long-term oxygen therapy.

These patients were assessed in their first pulmonology appointment with a median time of 4 months ((4, 5), range 2–11 months) after discharge.

The main purpose of this study was to evaluate patients with severe SARS-CoV-2 infection, who had been admitted to ICU, for a follow-up period up to 18 months post-discharge. Our study show that persistent symptoms and physiologic and radiologic abnormalities are common at 3-month follow-up. Dyspnoea was the primary symptom reported by patients after SARS-CoV-2 infection, followed by dry cough and asthenia/fatigue. There was a progressive improvement in this symptomatology in the second assessment. In line with our results, dyspnoea was the most frequent respiratory symptom 1–4 months after infection in some reports (13, 14); however, these studies assessed patients with different severity levels of COVID. In a study involving patients with ICU admission, dyspnoea was also the most frequently reported symptom (15). Previously, significant improvements in dyspnoea were also observed in assessments conducted between 6 months and 1 year after SARS-CoV-2 infection in ICU-admitted patients (16, 17).

Regarding the main respiratory functional changes between 3 months and 12 months post-COVID infection, some studies showed a persistently decrease in DLCO, as well as a restrictive ventilatory impairment and obstructive ventilatory impairment (16, 18). In a 6-month evaluation study, in addition to the reduction in DLCO, a decrease in MIP was one of the most frequent alterations (19).

In our evaluation up to the first 6 months post-discharge, the main lung function abnormalities observed were a decrease in DLCO, followed by a decrease in MIP and MEP, and restrictive ventilatory impairment. A decrease in MIP was present in 10.0% of our patients. Longitudinal analysis between 7 months and 12 months after SARS-Cov-2 infection also showed us that the main alterations were a decrease in DLCO, restrictive ventilatory impairment, and a decrease in MEP. After 12 months post-discharge, the only lung function impairment that persisted was a decrease in DLCO. Our results are in line with other study of Wu and colleagues that showed that approximately one-third of COVID-19 patients had persistently impaired DLCO at 12 months after COVID-19 (20). Among patients who underwent two respiratory functional assessments, five (83.3%) had some impairment in their function, with improvement observed in 50.0% (n = 3) of the patients. The literature also demonstrated a gradual improvement in respiratory function in critically ill COVID patients throughout the period from discharge to 6 months (21) and 12 months (22).

In terms of average values of respiratory function tests, severe abnormalities were not observed, being a decrease in DLCO the most pronounced impairment. These are in line with findings in the literature, as demonstrated in a study of 18 patients who survived COVID-19 and required mechanical ventilation, where lung function tests at 6 months postdischarge did not show significant limitations (FVC: 92 ± 16%; FEV₁: 92 ± 20%; and DLCO/VA: 81 ± 16%) (23).

We evaluated MIP and MEP as indicators of inspiratory and expiratory muscle strength, respectively (24), useful for assessing muscle function in lower respiratory tract infections (25), including severe SARS-CoV-2 infection, which can cause lung damage leading to limitations in respiratory muscle strength (26). MIP and MEP can be influenced by ICU-related myopathy and corticosteroid-induced myopathy (27). Over half of the patients in this study required invasive mechanical ventilation, likely contributing to observed abnormalities and complicating interpretation. The prevalence of respiratory muscle weakness post-SARS-CoV-2 remains unclear, as these assessments are rarely reported. Small studies suggest that inspiratory muscle training offers physiological benefits during recovery (28).

Regarding pulmonary radiological abnormalities, up to the first 6 months after SARS-CoV-2 infection, the main radiological findings were GGOs, OP, fibrosis, and ground-glass opacities with fibrosis (GGO-F). Between 7 months and 12 months, the more frequent CT pattern findings were GGO, fibrosis, or both simultaneously. After 12 months, the CT findings observed were the same: GGO, PF, or both. Over time, there was a decrease in GGOs (consistent with inflammatory changes) and persistence of fibrotic changes. Two patients initially described as having marked PF transitioned to residual fibrosis in the re-evaluation. This chest CT longitudinal evaluation reveals persistent abnormality in the lung interstitium and may suggest an explanation for the observed reduction of the diffusion capacity of the lung physiologically. Several studies assessing patients after hospitalisation for COVID-19 show that fibrotic sequelae were present four to 12 months post-discharge in 20 to 33.3% of patients (29, 30). In this study, fibrotic changes were present in 37.5% of patients 4–26 months after infection. Therefore, it is evident that fibrosis occurs in a significant proportion of individuals who had COVID-19 pneumonia. Some authors also found that abnormalities present in chest CT eventually decrease over time (17, 30). Our results support this, since in 45.5% of the patients, there was an improvement of CT abnormalities after 12 months of follow-up. Thus, in some patients, these sequelae may represent a regressive interstitial syndrome (2) and not a diffuse progressive interstitial lung disease. However, more long-term studies are needed to evaluate these patients.

A main limitation of our study was the small sample size, preventing us from correlating PFT changes with radiological abnormalities. However, according to the literature, respiratory functional impairment after COVID-19 pneumonia is associated with persistent pulmonary radiological abnormalities (13, 18, 20).

Another limitation is the study’s retrospective nature, which hindered the collection of certain variables within specific time frames, complicating analysis. Additionally, the evaluation of CT scans by different radiologists and machines introduced subjectivity and potential bias.

Our study shows that patients with severe COVID-19 requiring ICU admission can fully recover. However, some patients may experience persistent symptoms, commonly referred to as long COVID, which can last beyond 12 months after hospitalisation. This persistent symptomatology with respiratory functional changes (particularly a reduction in DLCO) and imaging findings (most frequently residual PF) tends to improve over time.

Nevertheless, further studies are required to assess the long-term consequences of this disease in patients requiring ICU admission.