Respiratory consequences after COVID-19: outcome and treatment.

The SARS-CoV-2 (COVID-19) pandemic represents the infection with the highest lethality, but also the one that has caused the most sequelae and multi-organ consequences, especially respiratory, in the last century. Several actions have been required in the field of respiratory and intensive care medicine to reduce mortality and chronicity. The consequences of COVID-19 are multiple and encompass different physical, emotional, organizing, and economic aspects, which will require a multidisciplinary, transversal, and collaborative approach. This review includes the observations and results of published retrospective and prospective studies on post-COVID19 respiratory sequelae, especially after severe pneumonia with associated adult respiratory distress syndrome (ARDS).

INTRODUCTION

The SARS-CoV2 viral infection (COVID-19) is a global threat with hundreds of millions of affected patients worldwide [1]. As global rates for COVID-19 survival have increased, many are wrestling with the long-term sequelae and more interest has grown concerning the prevalence and appropriate management of residual lung disease in survivors of COVID-19. Post-covid19 lung syndrome would be considered if persistent radiological infiltrates and the consequent physiological respiratory deterioration are present for more than 12 weeks after the acute phase, envisioning post-covid lung sequelae if not resolved after 12 months [2,3].

The major cause of death in COVID-19 is the respiratory failure due to adult respiratory distress syndrome (ARDS) after the cytokine storm, with frequent microvascular thrombotic events and multi-organ system failure [1,2]. Around 60% of patients with ARDS induced by the SARS-CoV-2 viral infection improve clinically and radiologically after 2-3 weeks of treatment [4-6]. However, lung recovery is often slow, sometimes with supplemental oxygen required upon returning home [4-6]. In a minority of cases, clinical-radiological signs of pulmonary fibrosis have been observed in the first chest computed tomography (CT) performed after surviving the acute phase [6,7]. The induced lung fibrotic changes usually improve but in a minority of cases progress, which may associate worsening quality of life and increasing mortality risk [7-11]. Persistent inflammatory abnormalities on chest images beyond the acute illness period have been reported in several cohorts, and observational studies have suggested development of pulmonary fibrosis in a subset of patients [2,5,12-16].

Increasing evidence based on prospective post-covid19 follow-up protocols or retrospective cohorts has suggested different forms of post-COVID-19 lung sequelae that require a multidisciplinary approach [9,13]. Dyspnea, anxiety-depression, fatigue, or muscle weakness are frequent post-covid clinical problems that require an individual approach, including rehabilitation, psychological support, neurological and/or respiratory management, depending on patient features [9] (Table 1). The type of predominant post-covid dysfunction the patient may have depends on different factors, such as disease severity and in-hospital complications, age, gender, and patient comorbidities [12]. While most mild to moderate COVID-19 cases improve and present lung recovery over time, those survivors from severe covid19 that required high-flux nasal cannula (HFNC), non-invasive ventilation (NIV) or intubation and mechanical ventilation (IMV) frequently show interstitial lung abnormalities and pulmonary functional impairment over 6 and 12 months [12-15] (Figure 1). In fact, persistent interstitial changes with respiratory physiological impairment have been described as the most frequent sequela in severe COVID-19 pneumonia survivors [12] (Figure 1). Like other types of lung response after ARDS, different factors and mechanisms could be involved in the devel- opment of post-acute interstitial lung changes and the capacity of repairing ad integrum [17,18]. On the other hand, increased risk of pulmonary vascular disease during or after COVID-19 has been also described [19].

Table 1

Most frequent persistent symptoms after COVID-19 infection

Organ or system	Persistent post-COVID-19 symptoms
Respiratory system	DyspneaAnosmia and/or ageusiaCoughDifficulties for deep breathingChest pain
Muscle deconditioning	Muscle weaknessMuscle pain
Neurocognitive	Difficulties to pay attentionLoss of short-term memoryPoor quality of sleepInsomniaNightmares
Psychological	AnxietyDepression
Digestive	ChockingFeeling of stomach bloatingDiarrhea
Cardiovascular	High arterial pressureTachycardia
Others	Weight lostAutoimmune disorders/signs

Figure 1

Different radiological features of post-covid short-term post-covid lung patients. Here we present two real post-covid cases after 2 months from hospital discharge to differentiate what would be considered “predominant ground glass opacities” versus “predominant fibrotic-like changes”.

Therefore, post- COVID-19 respiratory dysfunction frequently involves muscle, vascular and parenchymal components. Long-term outcomes in different populations are likely to vary.

POST-COVID-19 LUNG SYNDROME: PATIENT FEATURES AND PREDICTIVE FACTORS

Several studies are currently ongoing worldwide to better define what the post-COVID-19 lung syndrome represent. However, to identify those patients with respiratory dysfunction due to persistent lung abnormalities after suffering covid19 pneumonia, optimization of patient follow-up and treatment is necessary [9].

Evidence from previous coronavirus outbreaks - severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) - suggested that persistent respiratory abnormalities were present after severe acute infection [20]. Although long-term studies for SARS and MERS lung sequela were scarce and included a limited number of cases, persistent interstitial changes and pulmonary function deterioration correlated with disease severity, illness duration and age of the patient [20]. Interstitial lung disease (ILD) was reported in 28% at one-year post-SARS and 1.8% at 15-years post-SARS [2,20].

Although several reports analyzing hospitalized COVID-19 cohorts have demonstrated a high incidence of short-term lung interstitial changes with respiratory functional impairment after recovery from the acute phase [2,5,10,11,12-15,21-29], longer follow-up studies on these patients are limited and provide analyzes of no more than one-year [5,21-29]. The proportion of patients with some residual CT abnormality at 2-4 months after hospital discharge ranges from 52% to 85% [5,21-29]. This variability depends in part on the number of patients with severe or critical COVID-19 included in each cohort [2,5,21-29]. Sonnweber, et al showed that post-covid19 survivors improved the mean CT severity score at 3 months follow-up in all cases, but higher score of residual CT changes was present in those severe and critical COVID-19 cases [5]. Furthermore, prospective long-term studies have shown radiological normalization at 1-year CT in most cases that didn’t require ventilatory support (IMV, NIV or HFNC) during hospitalization [5,21-29]. Despite the low proportion of cases with interstitial CT abnormalities at 12 months (5-24%), most of them had presented severe or critical COVID-19 that required ventilatory support [21,27-29]. Therefore, the incidence and type of residual interstitial CT abnormalities seems to depend on the severity of the COVID-19 acute phase.

Understanding the post-COVID-19 lung syndrome is complicated due to the varying interpretation of radiological CT findings among the studies, the limited number of longitudinal cohorts analyzing data over time, and the scant information concerning histologic correlation in the different time-points of post-acute COVID-19 lung remodeling. Furthermore, the methodology for analyzing the type and extension of inter-stitial CT abnormalities is extremely variable depending on the study, especially for identifying interstitial fibrosis [30]. A recent classification of radiological CT post-covid19 interstitial persistent changes has been proposed: 1) predominantly ground glass; 2) mixed ground glass and fibrotic; 3) predominantly fibrotic [30] (Figure 1). This differentiation could help in the clinical practice to better analyze the long-term predictive factors and setting the potential differences in the initial treatment strategies of post-acute persistent interstitial changes [15]. Predominant ground glass opacities are more frequent than fibrotic signs during the initial months after discharge [2,5,10-14,21-30]. Other frequent post-covid CT abnormalities are decreased attenuation areas attributed to small airways disease or hypoperfusion [31]. Identified predictive factors of persistent fibrotic changes at six and twelve months include age and severity of acute phase [13,22,25,27,29].

Through the inflammatory response, SARS-CoV-2 could activate different mediators of the coagulation cascade as well as cause an endothelial dysfunction after targeting the ACE-2 positive endothelial cells [19,32]. On the chest-CT pulmonary vascular alterations can be seen such as vascular thickening, which is not seen in pneumonia of other etiologies different than covid19 [19]. As we have previously mentioned, decreased DLCO can be observed in many patients which suffered from covid19 pneumonia. However, it is possible that this impairment is not only explained by a restriction mechanism but because of vascular changes [32]. Mejia-Renteria et al performed an observational prospective study in which they showed that patients after the acute phase (>100 days) presented a reduced vascular function compared to control patients as well as compared to patients with acute covid19 pneumonia [33]. Therefore, they suggest that changes in the endothelial cells could lead to vascular dysfunction, contributing to chronic complications of the infection and potential long term-vascular post-covid effects [33].

Although several uncertainties remain to be clarified, prospective ongoing longitudinal studies and multidisciplinary expert consensus will be crucial to better define the post-covid lung patterns and outcomes [17].

POST-COVID LUNG DYSFUNCTION: CLINICAL FOLLOW-UP AND TREATMENT APPROACH

Persistent respiratory symptoms after COVID-19 are investigated by pulmonary follow-up after hospital discharge including forced spirometry, plethysmography, diffusion lung capacity of carbon monoxide (DLCO), and the 6-minutes walking test (6MWT) for measuring exercise capacity and oxygen saturation [9,34-36]. The current statements on post-covid19 recommend a pulmonary follow-up in all hospitalized COVID-19 cases, especially those that required some non-invasive or invasive respiratory supportive therapy during admission [9,34-36]. Most data indicate that the extent of residual abnormal pulmonary parenchymal involvement significantly correlates with DLCO [5,10,12-15,21-29]. Decrease in forced vital capacity (FVC) at 3-months after discharge has been primarily described in those cases that suffered more severe COVID-19 but didn’t significantly correlate with the residual CT abnormalities [27]. FVC and DLCO impairment may be due to different post-covid abnormalities, including not only the interstitial changes but also the muscle weakness or endothelial-vascular dysfunction [9]. However, FVC, DLCO and the 6MWT have been useful for monitoring patients with post-covid interstitial syndrome [27]. Radiologically, low-dose CT performed supinely should be sufficient in the majority of post-COVID patients on follow-up [30]. Expiratory CT would be used for those cases with suspicion of distal airflow obstruction [31]. Single or dual energy contrast enhanced (DECT) studies should be performed on those patients with suspicion of vascular involvement, depending on clinical and functional evaluation, for instance those cases with persisting abnormal gas exchange despite normalization of lung parenchyma on CT [30].

Breathlessness and cough are the most common respiratory symptoms in patients with post-covid interstitial or/and vascular persistent abnormalities after severe-critical COVID-19 [5,26-29]. Other frequently associated symptoms are fatigue, neurocognitive dysfunction, psychological and sleep disorders, join pain and muscle weakness [5,13,27-29] (Table 1). Therefore, the initial required therapeutic approach should be multidisciplinary and individualized depending on the patient’s needs, but always including functional rehabilitation, symptoms relief and psychological support in a holistic way [9,34-37]. Muscle deconditioning is usually present in COVID-19 survivors, with limited capacity for exercise [37]. Respiratory physiotherapy has demonstrated to be a crucial factor for improving pulmonary function [3,37].

Due to scarcity of published evidence, no agreement exists about the pharmacological treatment of patients after COVID-19 who present with persistent interstitial abnormalities [9,34,35]. However, those symptomatic patients that present respiratory dysfunction and CT predominant ground glass opacities are frequently treated with an empiric systemic steroid treatment [15,34]. Strategies to reduce the severity and progression of post-COVID-19 are unclear. An observational prospective study with no placebo-control arm suggested that low-dose corticosteroid treatment in post-covid patients that presented persistent interstitial changes and symptoms at 6 weeks after discharge was well tolerated and associated a rapid significant improvement [15]. No agreement exists for the treatment approach of post-covid patients that present predominant fibrotic persistent CT abnormalities [34]. Initially, considering the potential pro-fibrotic pathways that COVID-19 could trigger by acting on ACE-2 enzyme and inducing alveolar epithelial cell damage (among other pathways), the potential benefit of anti-fibrotic medications was suggested [8,15]. Currently, clinical trials with antifibrotic drugs, nintedanib (NCT04619680,NCT04541680) and pirfenidone (NCT04607928), including patients with predominant pulmonary fibrotic changes after covid are ongoing. The results of these studies will clarify it the anti-fibrotic approach in these specific cases could be beneficial. Finally, lung transplantation has been a treatment option for patients with progressive pulmonary fibrosis and severe respiratory failure after weeks or months from the onset of infection [38].

CONCLUSIONS

Respiratory consequences after COVID-19 infection are common, especially in those cases that required hospitalization and respiratory support during the acute phase and involves muscle and parenchymal dysfunction. The systematic follow-up of severe COVID-19 patients has enabled to identify different types of post-covid respiratory cases that require a patient-centered integral approach, including rehabilitation, respiratory physiotherapy, emotional and nutritional support, as well as an individual evaluation of parenchymal distortion regarding interstitial changes for the potential need of medication (usually low-dose corticosteroids) and thrombotic vascular events (anticoagulant approach). The frequency of post-covid lung sequela will depend on the severity of the acute infection. Therefore, since the severity of the acute infection is decreasing with the advent of covid-vaccination and the last less-severe covid strains, probably the proportion of patients with post-covid lung consequences will decline in the future. However, patients with post-COVID-19 respiratory dysfunction exist and the optimization of their treatment for reducing the potential chronicity remains a challenge. Increasing research evidence is giving us more and better information about how to better manage these patients. But first, the recognition of this healthcare problem by the healthcare authorities is crucial for working together to mitigate the future consequences and also to support the current post-covid patients.