Respiratory sequelae of COVID-19: pulmonary and extrapulmonary origins, and approaches to clinical care and rehabilitation

Abstract

Although the exact prevalence of post-COVID-19 condition (also known as long COVID) is unknown, more than a third of patients with COVID-19 develop symptoms that persist for more than 3 months after SARS-CoV-2 infection. These sequelae are highly heterogeneous in nature and adversely affect multiple biological systems, although breathlessness is a frequently cited symptom. Specific pulmonary sequelae, including pulmonary fibrosis and thromboembolic disease, need careful assessment and might require particular investigations and treatments. COVID-19 outcomes in people with pre-existing respiratory conditions vary according to the nature and severity of the respiratory disease and how well it is controlled. Extrapulmonary complications such as reduced exercise tolerance and frailty might contribute to breathlessness in post-COVID-19 condition. Non-pharmacological therapeutic options, including adapted pulmonary rehabilitation programmes and physiotherapy techniques for breathing management, might help to attenuate breathlessness in people with post-COVID-19 condition. Further research is needed to understand the origins and course of respiratory symptoms and to develop effective therapeutic and rehabilitative strategies.

Figure 1

Shared risk factors and mechanisms in IPF and post-COVID-19 ILD COVID-19 and IPF share several risk factors, including demographic and genetic factors and comorbidities. Furthermore, severe COVID-19 causes alveolar injury and activates profibrotic pathways similar to those observed in IPF. In IPF, resident cell populations are changed, with loss of AEC type I and development of a new subpopulation of aberrant transitional cells. In both IPF and post-COVID-19 ILD, apoptosis of AEC type I and type II occurs. In post-COVID-19 ILD, SARS-CoV-2 can directly infect AEC type II, leading to macrophage activation and recruitment of immune cells, causing sustained production of proinflammatory cytokines (ie, a cytokine storm). This proinflammatory response causes AEC and endothelial cell damage, resulting in fibroblast activation and the incorporation of collagen-rich extracellular matrix in the interstitial space. In genetically susceptible individuals, COVID-19 induction of profibrotic pathways has the potential to lead to pulmonary fibrosis. Treatments that reduce COVID-19-induced lung injury are likely to mitigate these effects, but long-term outcomes are yet to be determined. AEC=alveolar epithelial cells. DPP9=dipeptidyl peptidase 9. IFN=interferon. ILD=interstitial lung disease. IPF=idiopathic pulmonary fibrosis. mTOR=mammalian target of rapamycin. MUC5B=mucin 5B, oligomeric mucus/gel-forming. OAS1=2'-5'-oligoadenylate synthetase 1. TERT=telomerase reverse transcriptase. TYK2=tyrosine kinase 2. Adapted from Mehta and colleagues, by permission of Springer-Verlag. Figure originally created using BioRender.com.

Figure 2

Thoracic CT changes following hospital admission for acute COVID-19 COVID-19 is associated with a range of changes on acute and follow-up thoracic CT scans. Thoracic CT scans shown here were acquired after discharge from three patients who had been admitted to hospital with COVID-19 (WHO Clinical Progression Scale ≥5). (A) CT scan from a 66-year-old man acquired 2 weeks after discharge shows initially diffuse ground-glass opacification with consolidation and interlobular septal thickening (left panel), with resolution of changes on CT imaging 7 months after discharge (right panel). (B) CT scan from a 55-year-old woman acquired 2 months after discharge shows predominantly peripheral bilateral ground-glass opacification (left panel), with resolution of changes on CT imaging 9 months after discharge (right panel). (C) CT scan from a 71-year-old man acquired 3 months after discharge shows initially diffuse ground-glass opacification and fibrosis (left panel), with partial resolution of changes and persistent fibrosis on CT imaging 8 months after discharge (right panel).

Figure 3

Potential origins of persistent breathlessness and proposed rehabilitation and care approaches ARDS=acute respiratory distress syndrome. BPAT=Breathing Pattern Assessment Tool. CPET=cardiopulmonary exercise test. ICU=intensive care unit. PICS=post-intensive care syndrome. PICUPS=Post-ICU Presentation Screen.