Restrictive Lung Disease in Patients With Subclinical Coronavirus Infection: Are We Bracing Ourselves for Devastating Sequelae?

Dadhwal, Rahul; Sharma, Munish; Surani, Salim

doi:10.7759/cureus.12501

Cited by 10 publications

(12 citation statements)

References 17 publications

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“…Thus, post-COVID de novo interstitial lung disease was found in a case study of five patients 92who were either asymptomatic or had very mild symptoms. These patients had symptoms of dyspnea, intermittent cough, and lingering fatigue 4–8 weeks after COVID diagnosis, consistent with the lung disease patterns observed on CT scans [ 19 ].…”

Section: Introductionsupporting

confidence: 62%

Lung Fibrosis after COVID-19: Treatment Prospects

et al. 2021

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At the end of 2019, a highly contagious infection began its ominous conquest of the world. It was soon discovered that the disease was caused by a novel coronavirus designated as SARS-CoV-2, and the disease was thus abbreviated to COVID-19 (COVID). The global medical community has directed its efforts not only to find effective therapies against the deadly pathogen but also to combat the concomitant complications. Two of the most common respiratory manifestations of COVID are a significant reduction in the diffusing capacity of the lungs (DLCO) and the associated pulmonary interstitial damage. One year after moderate COVID, the incidence rate of impaired DLCO and persistent lung damage still exceeds 30%, and one-third of the patients have severe DLCO impairment and fibrotic lung damage. The persistent respiratory complications may cause substantial population morbidity, long-term disability, and even death due to the lung fibrosis progression. The incidence of COVID-induced pulmonary fibrosis caused by COVID can be estimated based on a 15-year observational study of lung pathology after SARS. Most SARS patients with fibrotic lung damage recovered within the first year and then remained healthy; however, in 20% of the cases, significant fibrosis progression was found in 5–10 years. Based on these data, the incidence rate of post-COVID lung fibrosis can be estimated at 2–6% after moderate illness. What is worse, there are reasons to believe that fibrosis may become one of the major long-term complications of COVID, even in asymptomatic individuals. Currently, despite the best efforts of the global medical community, there are no treatments for COVID-induced pulmonary fibrosis. In this review, we analyze the latest data from ongoing clinical trials aimed at treating post-COVID lung fibrosis and analyze the rationale for the current drug candidates. We discuss the use of antifibrotic therapy for idiopathic pulmonary fibrosis, the IN01 vaccine, glucocorticosteroids as well as the stromal vascular fraction for the treatment and rehabilitation of patients with COVID-associated pulmonary damage.

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Section: Introductionsupporting

confidence: 62%

Lung Fibrosis after COVID-19: Treatment Prospects

et al. 2021

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“…As the acute phase of the COVID-19 pandemic winds down, the chronic diseases in its aftermath have begun to emerge. For example, many survivors are suffering from a mysterious long-haul form of the disease which culminates in a fibrotic form of interstitial lung disease (post-COVID-19 ILD) (1)(2)(3)(4)(5)(6)(7)(8)(9) . The actual prevalence of post-COVID-19 ILD (henceforth, PCLD) is still emerging; early analysis indicates that more than a third of the survivors develop fibrotic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

Sinha

Castillo

Espinoza

et al. 2021

Preprint

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STRUCTURED ABSTRACTBackgroundIn the aftermath of Covid-19, a long-haul form of mysterious and progressive fibrotic lung disease has emerged, i.e., post-COVID-19 lung disease (PCLD), for which we currently lack insights into pathogenesis, disease models, or treatment options.MethodUsing an AI-guided approach, we analyzed > 1000 human lung transcriptomic datasets associated with various lung conditions using two viral pandemic (ViP and sViP) and one covid lung gene signatures. Upon identifying similarities between COVID-19 and idiopathic pulmonary fibrosis (IPF), we subsequently dissected the basis for such similarity from molecular, cytopathic, and immunologic perspectives using a panel of IPF-specific gene signatures, alongside signatures of alveolar type II (AT2) cytopathies and of prognostic monocyte-driven processes that are known drivers of IPF. To pinpoint the AT2 processes that are shared points of convergence between COVID-19 and IPF, transcriptome-derived findings were used to construct protein – protein interaction (PPI) network. Key findings were validated in hamster and human adult lung organoid (ALO) pre-clinical models of COVID-19 using immunohistochemistry and qPCR.FindingsWe found that COVID-19 resembles IPF at a fundamental level; it recapitulates the gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric) and the AT2 cytopathic changes, e.g., injury, DNA damage, arrest in a transient, damage-induced progenitor state, and senescence-associated secretory phenotype (SASP). These immunocytopathic features were induced in pre-clinical COVID models (ALO and hamster) and reversed with effective anti-CoV-2 therapeutics in hamsters. PPI-network analyses pinpointed ER stress as one of the shared early triggers of both diseases, and IHC studies validated the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2-challenged hamster lungs. Lungs from tg-mice, in which ER stress is induced specifically in the AT2 cells, faithfully recapitulate the host immune response and alveolar cytopathic changes that are induced by SARS-CoV-2.InterpretationLike IPF, COVID-19 may be driven by injury-induced ER stress that culminates into progenitor state arrest and SASP in AT2 cells. The ViP signatures in monocytes may be key determinants of prognosis. The insights, signatures, disease models identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease.FundingThis work was supported by the National Institutes for Health grants R01-GM138385 and AI155696 and funding from the Tobacco-Related disease Research Program (R01RG3780).One Sentence SummarySevere COVID-19 triggers cellular processes seen in fibrosing Interstitial Lung DiseasePANEL: RESEARCH IN CONTEXTEvidence before this studyIn its aftermath, the COVID-19 pandemic has left many survivors, almost a third of those who recovered, with a mysterious long-haul form of the disease which culminates in a fibrotic form of interstitial lung disease (post-COVID-19 ILD). Post-COVID-19 ILD remains a largely unknown entity. Currently we lack insights into the core cytopathic features that drives this condition.Added value of this studyUsing an AI-guided approach, which involves the use of a sets of gene signatures, protein-protein network analysis, and a hamster model of COVID-19, we have revealed here that COVID-19 -lung fibrosis resembles IPF, the most common form of ILD, at a fundamental level—showing similar gene expression patterns in the lungs and blood, and dysfunctional AT2 processes (ER stress, telomere instability, progenitor cell arrest and senescence). These findings are insightful because AT2 cells are known to contain an elegant quality control network to respond to intrinsic or extrinsic stress; a failure of such quality control results in diverse cellular phenotypes, of which ER stress appears to be a point of convergence, which appears to be sufficient to drive downstream fibrotic remodeling in the lung.Implications of all the available evidenceBecause unbiased computational methods identified the shared fundamental aspects of gene expression and cellular processes between COVID-19 and IPF, the impact of our findings is likely to go beyond COVID-19 or any viral pandemic. The insights, tools (disease models, gene signatures, and biomarkers), and mechanisms identified here are likely to spur the development of therapies for patients with IPF and other fibrotic interstitial lung disease, all of whom have limited or no treatment options. to dissect the validate prognostic biomarkers to assess and track the risk of pulmonary fibrosis and develop therapeutics to halt fibrogenic progression.

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“…Similarly, a study in Italy found that patients with nonsevere manifestations displaying pulmonary opacities showed complete remission of such lesions and no fibrosis during follow-up. In contrast, Dadhwal and Surani ( 2021 ) reported 5 cases of asymptomatic or mild symptomatic COVID-19 patients who presented shortness of breath and thorax images suggestive of resolving ground-glass opacities and later developed fibrosis 4–8 weeks after diagnosis (Rogliani and others 2020 ).…”

Section: Postinfection Pf: the Case Of Covid-19mentioning

confidence: 99%

Possible Role of Matrix Metalloproteinases and TGF-β in COVID-19 Severity and Sequelae

Ramírez-Martínez

Jiménez-Álvarez

Cruz‐Lagunas

et al. 2022

Journal of Interferon & Cytokine Research

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The costs of coronavirus disease 2019 (COVID-19) are devastating. With millions of deaths worldwide, specific serological biomarkers, antiviral agents, and novel therapies are urgently required to reduce the disease burden. For these purposes, a profound understanding of the pathobiology of COVID-19 is mandatory. Notably, the study of immunity against other respiratory infections has generated reference knowledge to comprehend the paradox of the COVID-19 pathogenesis. Past studies point to a complex interplay between cytokines and other factors mediating wound healing and extracellular matrix (ECM) remodeling that results in exacerbated inflammation, tissue injury, severe manifestations, and a sequela of respiratory infections. This review provides an overview of the immunological process elicited after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Also, we analyzed available data about the participation of matrix metalloproteinases (MMPs) and transforming growth factor-beta (TGF-β) in immune responses of the lungs. Furthermore, we discuss their possible implications in severe COVID-19 and sequela, including pulmonary fibrosis, and remark on the potential of these molecules as biomarkers for diagnosis, prognosis, and treatment of convalescent COVID-19 patients. Our review provides a theoretical framework for future research aimed to discover molecular hallmarks that, combined with clinical features, could serve as therapeutic targets and reliable biomarkers of the different clinical forms of COVID-19, including convalescence.

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Restrictive Lung Disease in Patients With Subclinical Coronavirus Infection: Are We Bracing Ourselves for Devastating Sequelae?

Cited by 10 publications

References 17 publications

Lung Fibrosis after COVID-19: Treatment Prospects

Lung Fibrosis after COVID-19: Treatment Prospects

COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

Possible Role of Matrix Metalloproteinases and TGF-β in COVID-19 Severity and Sequelae

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