If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department for BioMedical Research DBMR, Inselspital, Bern University Hospital, University of Bern, SwitzerlandDepartment of Pulmonary Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland
Some patients have persistent symptoms, lung function impairment, and radiological abnormalities post-severe acute respiratory syndrome coronavirus 2 infection.
•
Post-COVID-fibrotic changes have shown resolution at 12 months, however, in a cohort of patients, the changes persist.
•
The long-term impact of post-COVID fibrosis remains unknown and ongoing studies are aimed at assessing the frequency and consequences of this new disease entity.
•
Post-COVID interstitial lung disease may represent a significant burden on the health care systems.
Introduction
On the March 11, 2020, the World Health Organization (WHO) declared the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global pandemic, commonly referred to as coronavirus 2019 (COVID-19).
Ghebreyesus TA. WHO Director-General’s opening remarks at the media briefing on COVID-19. In: World Health Organization. 2020. Available at WHO Director-General's opening remarks at the media briefing on COVID-19-11 March 2020. Accessed September 9, 2022.
World Health Organization. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. In: World Health Organization 2022. Available at WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. Accessed September 9, 2022.
The spectrum of presentations and symptoms of COVID-19 can vary widely from asymptomatic carriers to life-threatening respiratory and multi-organ failure. The risk factors for the severity of COVID-19 are thought to correlate with increasing age, body mass index (BMI), and comorbidities such as diabetes, obesity, cardiovascular disease, hypertension, and chronic kidney disease.
The widespread collaborative efforts of governments, public health, pharmaceutical industry, and researchers have led to a wealth of expertise in tackling the pandemic over a relatively short time. We have effective therapies that can reduce the symptom burden and risk of hospitalization and in-hospital mortality with COVID-19. Antivirals, monoclonal antibodies, and immunomodulatory drugs have emerged through robust trials as treatments for SARS-CoV-2 infection.
Several therapies have been shown to reduce the risk of hospitalization in patients with mild to moderate disease. Treatment of symptomatic COVID-19 with Paxlovid, a SARS-CoV-2 protease inhibitor consisting of nirmatrelvir and ritonavir, has led to a reduction of severe COVID-19 by 89%, without evident safety concerns.
Coupled with the rollout of mass vaccination programs worldwide, we have seen the mortality from COVID-19 declining despite continued high rates of infection.
Office for National Statistics. Coronavirus (COVID-19) latest insights. In:Office for National Statistics 2022. Available at Coronavirus (COVID-19) latest insights - Office for National Statistics (ons.gov.uk). Accessed September 10, 2022.
Centers for Disease Control and Prevention. CDC COVID Data Tracker: Daily and Total Trends. In: Centers for Disease Control and Prevention 2022. Available at CDC COVID Data Tracker: Daily and Total Trends. Accessed August 25, 2022.
Although we are grappling with the changing nature of the virus and attempting to rebuild our lives and economies, we are now faced with an emerging yet unquantifiable health epidemic –post-COVID-19 condition (long COVID). This review will discuss the emerging evidence for the development of post-COVID interstitial lung disease (PC-ILD) focusing on the pathophysiological mechanisms, incidence, diagnosis, and impact of this potentially new and emerging respiratory disease.
Pathophysiology of post-COVID interstitial lung disease
Data from previous coronavirus outbreaks of Middle East respiratory syndrome (MERS) and SARS suggest that between 25% and 35% of survivors will experience long-term respiratory complications with lung function and radiographic abnormalities consistent with the development of pulmonary fibrosis, therefore, raising the suspicion that persistent respiratory symptoms post-SARS-CoV-2 infection may have similar pathophysiological mechanisms to MERS and SARS infections.
Several histopathological findings have been identified among COVID-19 cases. Gross examination of postmortem specimens revealed that tissue damage was more severe in the lung peripheries, where fibrous tissue proliferation in the alveolar septa and alveolar destruction was remarkably abundant. In the central areas, the alveolar structure was roughly preserved with only focal fibrosis.
The most commonly reported histological pattern of lung injury is diffuse alveolar damage (DAD) with two identifiable stages; an acute stage, defined by scattered or diffuse hyaline membranes, associated with alveolar edema, an alveolar eosinophil exudate, and few vacuolated macrophages, and a more organized stage of parenchymal collapse, enlargement of alveolar septa, alveolar fibrin deposits, hyperplasia of type-2 pneumocytes, sparse multinucleated giant cells, and minor fibroblast proliferation
A lung cryobiopsy study performed in patients with a mean disease duration of 31.3 days observed marked fibrotic lung parenchymal remodeling, characterized by fibroblast proliferation, airspace obliteration, and micro-honeycombing.
PC-ILD as a potential long-term outcome of COVID-19 is concerning. Distinct from the idiopathic form of PF or other progressive ILD, fibrosis resulting from ARDS is largely stable. However, whereas some patients with fibrosis post-ARDS may fully recover, some may have lasting symptoms of decreased lung function.
In postmortem studies of those with COVID-19 features suggestive of a fibrotic phase, such as mural fibrosis and microcystic honeycombing, these findings were observed to be focal, rather than widespread. This may be due to the short duration of the disease at the time of death.
In general, there is conflicting evidence regarding the possibility that viral infection may predispose one to the development of fibrosis. It is postulated that chronic viral infection may contribute to the fibrotic response through the promotion of a state of mild but chronic inflammation, which disrupts homeostasis and healing, thereby leading to increased susceptibility to a secondary insult. The coronavirus infection tends to have an acute duration; however, there is evidence from ARDS that even a duration of less than 1 week can lead to fibrosis.
Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies.
Viruses can upregulate the expression of critical host cell surface receptors, signaling pathways, and production of growth factors. The angiotensin-converting enzyme 2 (ACE2) receptor, which is engaged by the S1 subunit of the SARS-CoV-2 spike protein, acts as a regulator of the renin-angiotensin system (RAS), which activates a broad range of signaling pathways including proinflammatory and profibrotic effects. Inflammation promotes viral clearance, but excessive cytokine response can be damaging.
Cytokines such as transforming growth factor (TGF)-β, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and chemokines promote activation of immune populations that clear infection and promote immunity through T-cell and B-cell recruitment. They also activate macrophage populations that clear apoptotic cellular debris. In acute lung injury, activated macrophages also contribute to the induction of neutrophil recruitment and activation.
Neutrophilic infiltrate, in turn, contributes to the generation of reactive oxygen species (ROS) and both neutrophilic infiltrate and ROS may contribute to tissue injury.
In response to injury, the alveolar epithelial cells recruit fibroblast and inflammatory cells to initiate wound healing by reshaping the extracellular environment to restore tissue integrity and promote the replacement of parenchymal cells.
Usually, this pro-fibrotic process is turned off once the tissue heals. However, repeated damage and repair, such as that seen in SARS-CoV-2 infection, can lead to the imbalance of this process, resulting in excessive pathological deposition of extracellular matrix protein, accompanied by upregulation of myofibroblast activity, resulting in a chronic inflammatory environment of macrophage and immune cell infiltration. This is supported by a study on lung samples from individuals who succumbed to COVID-19 and control individuals using single-nucleus RNA sequencing. They noted a reduction in the epithelial cell compartment, of both alveolar type 1 and 2 cells, and an increase in monocytes/macrophages and fibroblasts in COVID-19 patients as compared with control lungs.
Furthermore, in a multi-omics study of postmortem COVID-19 patients, there was hyperinflammation, alveolar epithelial cell exhaustion, vascular changes and fibrosis, and parenchymal lung senescence as a molecular state of COVID-19 pathology. A forkhead transcription factor, FOXO3A suppression was implicated as a potential mechanism underlying the fibroblast-to-myofibroblast transition associated with PC-ILD.
In this cellular environment, massive proinflammatory and profibrotic cytokines are released, thus, activating fibrosis-related pathways including the TGF-β signal pathway, wingless/integrated (WNT), signal pathway and yes-associated protein/transcriptional cofactor with PDZ binding motif signal pathways.
Fig. 1 illustrates how viruses can upregulate the expression of critical host cell surface receptors, signaling pathways, and production of growth factors. The ACE2 receptor acts as a regulator of the RAS which activates a broad range of signaling pathways including proinflammatory and profibrotic effects.
A significant proportion of patients with severe COVID-19 required invasive mechanical ventilation (IMV). IMV can induce stretch force injury and alveolar injury and may contribute to ARDS. Increased lung stretch can induce oxidative injury, increase cytokine production, increase epithelial-mesenchymal transition (EMT),
and increase collagen deposition in the lungs which contributes to the development of PF. Careful ventilation of injured lungs, or lungs that may have increased stiffness, could potentially help to minimize ventilator-induced profibrotic signaling.
Although the majority of patients’ symptoms recover within 4 to 8 weeks of a SARS-CoV-2 infection, some find their symptoms will persist beyond 12 weeks, leading to the term “long COVID”.
National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19 (NG188). In:London: National Institute for Health and Care Excellence (NICE). 2021. Available at Overview | COVID-19 rapid guideline: managing the long-term effects of COVID-19 | Guidance | NICE. Accessed September 10, 2022.
The WHO has defined “post-COVID-19 (long COVID)” as a condition occurring in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis. Studies have shown up to 48.8% of individuals reporting not feeling fully recovered from COVID-19 with a median of nine persistent symptoms 1 year following the SARS-CoV-2 infection (Box 1) with the most reported symptoms being breathlessness and fatigue.
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.
Female gender, being middle age (40–59 years), having two or more self-reported comorbidities and experiencing a more severe form of COVID-19 at the time of diagnosis and resultant hospitalization had a lower rate of self-reported recovery
Persistent symptoms of COVID-19 have been reported in the early phases and late phases of follow-up (Table 1). As time has elapsed since the emergence of the novel SARS-CoV-2 infection, we are beginning to appreciate the long-term symptom burden. Two large prospective observational studies looking at long-term outcomes after SARS-CoV-2 infection, the Lung Injury COVID-19 study and the Post-Hospitalization COVID-19 study (PHOSP-COVID) have followed up 305 Spanish and 1077 UK patients, respectively.
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.
The Lung Injury COVID-19 study stratified patients according to the severity of SARS-CoV-2 infection as a moderate disease (features of pneumonia with oxygen saturations above 90% requiring supplemental oxygen, n = 162) or severe disease (patients who required either non-invasive ventilation, high flow oxygen, or intubation and IMV, n = 143). At medium term follow-up classed as less than 180 days from the initial symptoms, 55.5% of patients with severe disease and 44.1% of patients with moderate disease had persistent dyspnea with a modified Medical Research Council (mMRC) dyspnea scale of above 2. Dyspnea was significantly more prevalent in the severe group than in the moderate group (P = 0.042). At this time point, only 13.5% of patients had symptom resolution and other persistent symptoms included chest pain, fatigue, and cough with no differences in frequency between the moderate and severe groups.
Beyond 10 months, one-third of patients’ symptoms had resolved; however, breathlessness (mMRC>2) remained in 18.4 and 20% of the moderate and severe groups, respectively. Intriguingly, patients with moderate disease severity had a higher symptom burden at this later time point than those with severe disease, including cough (11.9% vs 3%; P = 0.03), chest pain (14% vs 4.4%; P = 0.025), and fatigue (20% vs 7.7%; P = 0.017). This suggests that the ongoing symptoms do not correlate with the severity of the acute COVID-19 illness.
In the PHOSP-COVID study only 239 of 830 (28.8%) individuals described themselves as fully recovered at a median of 5.9 months (interquartile range 4.9–6.5) post-hospital discharge; 632 of 855 (92.8%) individuals had at least one persistent symptom with a median of nine symptoms (see Table 1).
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.
A persistence of respiratory symptoms at 1-year follow-up in a subset of patients after acute COVID-19 highlights the potential for ongoing respiratory sequelae and the need for continued monitoring of this group of patients. With over 550 million people affected worldwide,
World Health Organization. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. In: World Health Organization 2022. Available at WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. Accessed September 9, 2022.
up to 20% may have continued respiratory symptoms in a year equating to a staggering 110 million people. This proportion of symptomatic patients with post-COVID-19 condition (long COVID) represents a significant burden on the individual as well as on the health care systems. A greater understanding of the natural evolution of symptoms over a longer period and the impacts of interventions will improve our understanding of the long-term impacts of the COVID-19 disease. Persistent respiratory symptoms have a complex etiology and are not always attributable to the underlying parenchymal disease. Although the natural assumption is that these symptomatic patients may have underlying structural changes such as PF, one needs to be mindful that deconditioning. overall well-being such as the presence of anxiety and depression and muscle weakness/fatigue may also be contributing to ongoing breathlessness. Objective evidence of pulmonary abnormalities with pulmonary physiology and advanced radiology is therefore paramount.
Pulmonary Function Impairment Post-COVID-19
Pulmonary function abnormalities are seen as early as 2 weeks post-discharge of an acute SARS-CoV-2 infection. In a retrospective observational study of 137 patients from China, 81% of patients demonstrated an inspiratory vital capacity of less than 80% predicted and 24.1% of patients had a forced vital capacity (FVC) of less than 80% predicted. The degree of restrictive ventilatory impairment correlates with the severity of acute SARS-CoV-2 infection
Lung function impairment had poor correlation with the presence of respiratory symptoms, however, a correlation between biomarkers involved in host defense reflecting neutrophil activation (lipocalin-2), fibrosis signaling (matrix metalloproteinase-7) and alveolar repair (hepatocyte growth factor), and reduction in FVC and diffusing capacity for carbon monoxide (DLCO) was found.
Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
(Tables 2). The principal study out of Wuhan, China, showed that in 83 patients who did not require IMV, 55% of patients had a DLCO less than 80% predicted and 23% had an FVC of less than 80% predicted at 3 months post-discharge.
The degree of restrictive ventilatory impairment correlated with the severity of acute SARS-CoV-2 infection. Evidence of small airway dysfunction at a much lower frequency
Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
Persistent health problems beyond pulmonary recovery up to 6 months after hospitalization for COVID-19: a longitudinal study of respiratory, physical, and psychological outcomes.
Annals of the American Thoracic Society.2022; 19: 551-561
However, even after a year post-COVID-19, a proportion of patients will continue to have lung function impairment, raising the suspicion of long-term pulmonary complications such as the development of PF. In a Chinese study of 83 patients, 33% of patients had a DLCO less than 80% predicted at 12 months compared with 55% at 3 months and 11% of patients had an FVC less than 80% predicted at 12 months compared with 23% at 3 months.
Similar improvements albeit persistent impairments in lung function parameters were observed in a Dutch study of 92 patients where the frequency of impaired FVC improved from 25% at 6 weeks to 11% at 6 months, and for DLCO, this percentage improved from 63% to 46%.
Persistent health problems beyond pulmonary recovery up to 6 months after hospitalization for COVID-19: a longitudinal study of respiratory, physical, and psychological outcomes.
Annals of the American Thoracic Society.2022; 19: 551-561
Larger multicenter prospective studies have corroborated these findings and have identified risk factors for persistent lung function impairment as having asthma as a comorbidity,
Persistent lung function abnormalities highlight underlying structural lung involvement as a mechanism of ongoing respiratory symptoms post-COVID and necessitate further radiological assessment.
Radiological features post-COVID-19
Radiology has been a very helpful tool in helping us understand the disease process
Thin-section computed tomography findings and longitudinal variations of the residual pulmonary sequelae after discharge in patients with COVID-19: a short-term follow-up study.
In a retrospective study out of the Lombardy region in Italy, the worst hit region in Europe, 90 consecutive hospitalized patients had computerized tomography (CT) performed on admission and 60 days post-discharge. On admission, 90% of patients had bilateral lung disease with an 80% peripheral and 63% mid-zone and lower-zone predominance; 54.4% demonstrated diffuse ground glass opacities (GGO) and 46.6% had both GGO and consolidation. CT images were reported as fibrotic based on the presence of reticulation, architectural distortion, traction bronchiectasis, and honeycombing. Twenty-three (25.5%) patients were defined as having a non-specific interstitial pneumonia (NSIP) pattern by two thoracic radiologists with over 30 years of experience. Patients with features of fibrosis on their imaging were older and had evidence of systemic inflammation with statistically higher lactate dehydrogenase (LDH), c-reactive protein, erythrocyte sedimentation rate (ESR), d-dimer, evidence of bone marrow suppression with reduced hemoglobin, white cell counts and platelets, and corresponding reductions in lung function parameters (FVC and DLCO) compared with individuals without features of fibrosis on their imaging
These findings were similar to studies out of Wuhan, China, where 46% of patients at a median of 56 days follow-up had CT evidence of fibrotic changes manifesting as parenchymal bands (76%), irregular interface (32%), traction bronchiectasis (38%), lung distortion (25%), and honeycombing (9%). The fibrosis was predominantly peripheral in distribution (89%), corresponding with the areas of acute COVID-19 changes, and the overall burden of fibrosis was minimal or mild in the majority (84%) of patients
In 50% of this cohort, initial features of lung distortion attributed to improved fibrosis, suggesting a reversible element to these changes. On multivariate analysis, fibrosis was associated with higher ESR, eosinophil counts, and advancing age. More patients in the fibrosis cohort required non-invasive ventilation and 77% of the overall cohort was defined as having severe SARS-CoV-2 infection.
A further study of 216 discharged patients found that 85.1% had CT abnormalities at 3 months and these were more frequent in patients defined as severe/critical or required IMV or high-flow oxygen. There was also a significant negative correlation between total lung capacity (TLC) and residual volume and a weaker correlation to DLCO on lung function testing (P < 0.05).
These early studies raised several questions as to whether features defined as fibrotic during early imaging are reversible over time and thus highlighted the need for longer follow-up studies, or whether the severity of COVID-19 or the need for IMV is driving the development of fibrosis. One such study found that at 4 months follow-up, 44.4% of patients had a multi-disciplinary diagnosis of ILD on CT imaging; 56% had evidence of architectural distortion and this correlated with reductions in DLCO. The majority of patients with ILD at 4 months were admitted to ICU (6.3% vs 93.8%; P = 0.001) and required IMV, high flow oxygen, or underwent prone ventilation, and also had more complications of venous thromboembolism (VTE) and ARDS during their acute illness.
Highlighting a potential role of severity of infection and IMV as risk factors and contributors to the development of fibrosis. Furthermore, in a study of 220 patients with 20% incomplete CT resolution at 6 months, predicators of persistent CT abnormalities were older age, prolonged hospital stay, a lower PaO2/FiO2 at hospital admission, a higher degree of support, and higher oxygen requirements.
Thin-section computed tomography findings and longitudinal variations of the residual pulmonary sequelae after discharge in patients with COVID-19: a short-term follow-up study.
Longitudinal serial CT studies over 3 and 6 months showed that fibrosis-like findings were more prominent with severe SARS-CoV-2 infection (24.3% (17/70) vs 52.0% (53/102)), and that even with severe disease, these findings could improve over time with 24% and 52% improvement seen in severe and moderate disease, respectively. Radiological abnormalities persisted and were slower to resolve in the severe group.
Thin-section computed tomography findings and longitudinal variations of the residual pulmonary sequelae after discharge in patients with COVID-19: a short-term follow-up study.
A further large retrospective Italian study of 405 patients with follow-up between 5 and 7 months showed CT resolution in 55.6% of patients. Residual non-fibrotic and fibrotic abnormalities were noted in 37.5% and 6.9% of patients, respectively. Non-fibrotic changes were described as overt GGO (4.9% of whole population) or barely visible GGO (27.2% of whole population), peripheral predominant bronchiectasis (12.8%), peri lobular opacities (7.9%), and peripheral parenchymal bands (2.7%), resembling an NSIP pattern with or without organizing pneumonia features. Residual fibrotic abnormalities were found in 6.9% of patients of which a third were attributed to post-ventilatory abnormalities. Fibrotic abnormalities included subpleural reticulation (3.7%), bronchiectasis (4%), and volume loss (2.2%).
A subset of 65 patients had further CT imaging at 12 months follow-up. Nine (13.8%) had complete resolution at 12 months, 46 had non-fibrotic residual abnormalities at 5 to 7 months, of which 26 (40%) completely resolved and 20 (30.8%) had improvement but with residual changes. The remaining 10 (15.4%) with fibrotic abnormalities remained unchanged at 12 months.
In multivariate analysis, length of hospital admission, smoking history, and obesity have been identified as risk factors for persistent radiological abnormalities.
The Emergence of Post-COVID Interstitial Lung Disease
Persistent symptoms, lung function, and radiological abnormalities have been reported post-COVID-19 (see Box 1, Table 1, Table 2, Table 3). Several studies have demonstrated the gradual resolution of these findings over time including improvements in lung function impairment and radiological abnormalities.
The COVID-FIBROTIC study of 448 patients demonstrated ongoing radiological abnormalities in 27.4% of the patients at 12 months, with GGO being the most common abnormality (15.8%) followed by reticular pattern (11.8%), traction bronchiectasis (10.7%), and parenchymal bands (11.6%). Overall residual fibrotic changes were noted at 12 months in 22.7% of the cohort. Residual fibrotic features have been noted at varying time points in studies extending out to a year.
Risk factors for developing PC-ILD include increasing age (mean age 59 in fibrotic group vs 48.5 non-fibrotic group), chronic obstructive pulmonary disease (HR 2.88; 95% CI 1.27, 6.52), and severity of COVID-19 stratified according to baseline CT, a requirement for non-invasive or IMV and prolonged length of stay.
A systematic review and meta-analysis of 46 studies assessing radiological features in 2811 CT images within 12 months found great heterogeneity in fibrotic findings between studies with a mean estimate of 29% (95% CI 22–37%).
There remain several unanswered questions regarding PC-ILD. There is little doubt that a cohort of individuals have residual fibrotic changes at 12 months ranging from 1 to 29% in studies,
however, pathologically whether that is related to fibrosis promoted by coronavirus itself or sequelae of severe infection and IMV remains to be determined. Certainly, studies have shown the presence of fibrosis being highest among those mechanically ventilated.
Long-term studies are also needed to ascertain whether the fibrotic changes observed at a year, and consequently pulmonary function impairment and symptoms, continue to improve or remain static (similar to that seen in ARDS) over time. One such study, The UK Interstitial Lung Disease Long COVID study (UKILD-Long COVID) aims to investigate the prevalence and risk factors for PC-ILD looking at clinical, functional, and imaging parameters over time.
A greater understanding of the pathophysiological mechanisms by which COVID-19 contributes to the development of lung fibrosis is key to our understanding of the natural history and development of PC-ILD. This, in turn, may lead us to the development of therapies that could ameliorate or hasten resolution.
The beneficial role of Dexamethasone in acutely unwell COVID-19 patients has been demonstrated in a randomized controlled trial.
There is limited trial evidence of therapy for PC-ILD. The majority of data are from observational cohorts. In a study of 837 patients followed up 4 weeks after discharge, 325 had ongoing symptoms and were offered further investigations and assessment; 35 (4.8%) patients were given the diagnosis of PC-ILD–predominantly an organizing pneumonia pattern; 30 patients were treated with corticosteroid therapy at day 61 ( ± 19) post-COVID which was weaned over a period of 3 weeks. Patients reported symptomatic (median MRC improved from 3 (±2) to 2 (±1); P = 0.002), physiological (mean relative increase in FVC of 9.6% (±13.6); P = 0.004 and mean increase in TlCO of 31.49% (±27.7); P < 0.001), and radiological improvements. There was no observation of the progression of CT findings or change to fibrosis after treatment with corticosteroids. This study was limited due to the lack of randomization and control arm.
Furthermore, the potential role of antifibrotics has been studied in a small retrospective, matched case-control study of 21 patients who received nintedanib therapy. There were improvements in SpO2/FiO2 ratio (P = 0.006) with no differences in chest imaging or oxygenation between the nintedanib and the control group.
To date, only a few observational studies have investigated the role of immunomodulatory and antifibrotic therapies highlighting the great need for randomized control trials.
Molina M. Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19. In: ClinicalTrials.gov. 2021. Available at Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19-Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
Novel therapies targeting histone deacetylase 88 and hepatocyte growth factor secreted by mesenchymal stem cells have been proposed due to their antifibrotic effects.
A phase 1 clinical trial in 27 patients with COVID-19 PF using human embryonic stem cell-derived immunity and matrix-regulatory cells during the SARS-CoV-2 outbreak in Wuhan City showed improvements in exercise capacity and resolution of fibrotic changes on CT.
Molina M. Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19. In: ClinicalTrials.gov. 2021. Available at Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19-Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
University of Chicago. Assessing the Efficacy of Sirolimus in Patients with COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis. In:ClinicalTrials.gov. 2021, Available at Assessing the Efficacy of Sirolimus in Patients With COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis - Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
Issak ER. Colchicine and Post-COVID-19 Pulmonary Fibrosis. In: ClinicalTrials.gov, 2021. Available at Colchicine and Post-COVID-19 Pulmonary Fibrosis - Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
and we eagerly await robust trials investigating therapies in PC-ILD.
Summary
The long-term impact of the COVID-19 pandemic remains to be elucidated. The SARS-CoV-2 virus triggers a significant inflammatory and immune response, which causes lung damage. Though the majority of patients will improve and recover fully, some have persistent symptoms, reduced lung function, and radiological abnormalities at 12 months. With over 550 million people affected worldwide, the significance of persistent pulmonary abnormalities in the form of PF cannot be underestimated in terms of ongoing morbidity. The incidence of PC-ILD is very heterogenous and varies from study to study, according to varied factors including the duration of follow-up, severity of SARS-CoV-2 infection, and need for IMV. as well as other potential risk factors. Further studies are eagerly awaited that will glean more light on the risk factors for developing PC-ILD, the role of therapies in preventing or treating PC-ILD, and give a greater understanding of the clinical significance of this new disease.
Clinics care points
•
Persistent pulmonary symptoms are commonly reported post-SARS-CoV-2 infection and risk factors include increased length of stay in hospital with COVID-19, severe COVID-19 pneumonitis on initial CT, the need for higher respiratory support, female gender, and increasing age.
•
Lung function impairment improves over time, however, can persist in a proportion of patients post-SARS-CoV-2 infection.
•
CT abnormalities at 1 year include mostly non-fibrotic changes (like GGO, bronchiectasis, peri lobular opacities, and parenchymal bands), and less commonly, peripheral fibrotic changes.
•
The long-term consequences of persistent fibrotic changes post-COVID-19 remain to be elucidated and studies need to assess the significance of these findings.
Disclosure
N. Kewalramani reports grant and nonfinancial support from CSL Behring, Bern (Switzerland) outside the submitted work. K.-M. Heenan has nothing to disclose. D. McKeegan has nothing to disclose. N. Chaudhuri has nothing to disclose.
References
Ghebreyesus TA. WHO Director-General’s opening remarks at the media briefing on COVID-19. In: World Health Organization. 2020. Available at WHO Director-General's opening remarks at the media briefing on COVID-19-11 March 2020. Accessed September 9, 2022.
World Health Organization. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. In: World Health Organization 2022. Available at WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. Accessed September 9, 2022.
Office for National Statistics. Coronavirus (COVID-19) latest insights. In:Office for National Statistics 2022. Available at Coronavirus (COVID-19) latest insights - Office for National Statistics (ons.gov.uk). Accessed September 10, 2022.
Centers for Disease Control and Prevention. CDC COVID Data Tracker: Daily and Total Trends. In: Centers for Disease Control and Prevention 2022. Available at CDC COVID Data Tracker: Daily and Total Trends. Accessed August 25, 2022.
Chronology of histological lesions in acute respiratory distress syndrome with diffuse alveolar damage: a prospective cohort study of clinical autopsies.
National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19 (NG188). In:London: National Institute for Health and Care Excellence (NICE). 2021. Available at Overview | COVID-19 rapid guideline: managing the long-term effects of COVID-19 | Guidance | NICE. Accessed September 10, 2022.
Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study.
Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
Persistent health problems beyond pulmonary recovery up to 6 months after hospitalization for COVID-19: a longitudinal study of respiratory, physical, and psychological outcomes.
Annals of the American Thoracic Society.2022; 19: 551-561
Thin-section computed tomography findings and longitudinal variations of the residual pulmonary sequelae after discharge in patients with COVID-19: a short-term follow-up study.
Molina M. Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19. In: ClinicalTrials.gov. 2021. Available at Pirfenidone Compared to Placebo in Post-COVID19 Pulmonary Fibrosis COVID-19-Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
University of Chicago. Assessing the Efficacy of Sirolimus in Patients with COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis. In:ClinicalTrials.gov. 2021, Available at Assessing the Efficacy of Sirolimus in Patients With COVID-19 Pneumonia for Prevention of Post-COVID Fibrosis - Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
Issak ER. Colchicine and Post-COVID-19 Pulmonary Fibrosis. In: ClinicalTrials.gov, 2021. Available at Colchicine and Post-COVID-19 Pulmonary Fibrosis - Full Text View - ClinicalTrials.gov. Accessed October 10, 2022.
00004-8&id=gr1.jpg){kind=link}