Clinical, Imaging, and Histopathological Features of Pulmonary Sequelae after Mild COVID-19

Gagiannis, Daniel; Hackenbroch, Carsten; Bloch, Wilhelm; Zech, Fabian; Kirchhoff, Frank; Djudjaj, Sonja; Stillfried, Saskia von; Bülow, Roman David; Steinestel, Konrad

doi:10.1164/rccm.202302-0285le

Cited by 6 publications

(18 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7 ). Consistent with the observed improvement in outcomes and a recent study identifying increased BAL IL-1β levels in respiratory PASC (7), we found that circulating IL-1β levels were elevated in individuals exhibiting persistent abnormal pulmonary function compared to those that had fully recovered (Fig. 6n), suggesting that chronic IL-1β activity may impede the restoration of normal lung function after acute SARS-CoV-2 infection.…”

Section: Resultssupporting

confidence: 90%

“…Some individuals also develop a non-resolving fibroproliferative response – PASC pulmonary fibrosis (PASC-PF) and typically require persistent oxygen supplementation and eventual lung transplantation (4–8). Despite progress in identifying dysregulated immune signatures associated with respiratory PASC (3, 7, 9–16), little is known regarding their mechanistic roles in driving pathological tissue sequelae, in part due to the lack of studies adopting “clinically relevant” animal models of respiratory PASC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Narasimhan,

Cheon,

Qian

et al. 2023

Preprint

View full text Add to dashboard Cite

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear. In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

show abstract

Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Narasimhan,

Cheon,

Qian

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…1 C summarize clinical, serological, imaging and histopathology data for the complete cohort. 51/54 patients from the unvaccinated cohort have been published previously [7]. No patient had been hospitalized for COVID-19, 61/99 patients were soldiers (61.6%).…”

Section: Resultsmentioning

confidence: 99%

“…We performed immunohistochemistry for Spike and Nucleocapsid proteins of SARS-CoV-2 using the following antibodies: anti-SARS-CoV-2 spike antibody, clone 1A9, mouse monoclonal, 1:400 (GeneTex, Irvine, CA, USA); anti-SARS-CoV-2 nucleocapsid antibody, rabbit monoclonal, 1:20000 (SinoBiological, Bejing, China). Tissue-based RT-PCR in a subset of cases was performed as previously described [7].…”

Section: Methodsmentioning

confidence: 99%

“…Evaluation of PASC can be hampered by preexisting lung disease or severe COVID-19 with scarring or post-ventilaton change [5]. In a a prospective cohort of 51 previously healthy pulmonary PASC patients after mild COVID-19, we have previously shown pulmonary function impairment in a subset of patients, including a reduction in maximal expiratory flow at 50% of FVC (MEF50) and a reduction in FEV1 together with CD4+T cell-mediated bronchiolitis, indicating obstructive change [6, 7]. To our best knowledge, this was the first study to use verifiable tissue-based criteria to assess lung involvement in PASC in previously healthy patients after mild COVID-19.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of mRNA vaccination on pulmonary sequelae after mild COVID-19

Gagiannis,

Hackenbroch,

Zech

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundPrevious studies indicate a protective role for SARS-CoV-2 vaccination against development of pulmonary post-acute sequelae of COVID (PASC). We compared clinical, imaging, histopathology and ultrastructural features of pulmonary PASC with and without prior vaccination in a consecutive cohort of 54 unvaccinated, 17 partially vaccinated and 28 fully vaccinated patients who presented with dyspnea on exertion after mild COVID-19 (without hospitalization).MethodsPatients underwent full clinical evaluation including autoantibody (ANA/ENA) serology, high-resolution computed tomography (HRCT), bronchioloalveolar lavage fluid (BAL) analysis and transbronchial biopsy followed by histopathological and ultrastructural analysis and SARS-CoV-2 immunohistochemistry.ResultsWhile vaccinated patients were younger (p=0.0056), included more active smokers (p=0.0135) and a longer interval since infection (35 vs. 17 weeks, p=0.0002), dyspnea on exertion and impaired lung function were not different between vaccinated and unvaccinated patients. Ground glass opacities in HRCT and centrilobular fibrosis were more frequent in unvaccinated patients (p=0.0154 and p=0.0353), but presence of autoantibodies, BAL lymphocytosis and bronchiolitis were common findings in all groups. While vaccination against SARS-CoV-2 is associated with a longer time span between infection and consultation along with a reduced frequency of ground glass opacities and centrilobular fibrosis, impaired lung function, bronchiolitis and presence of autoantibodies are comparable between vaccinated and unvaccinated patients. Residual virus was not detected in lung tissue in all but 1 patient.ConclusionWhile differences between the investigated groups with regard to age, smoking status and SARS-CoV-2 variants have to be taken into account, a proposed protective role of SARS-CoV-2 vaccination against pulmonary PASC is so far not fully explained by clinical and histopathology findings.KEY MESSAGESThe role of SARS-CoV-2 vaccination in the protection against pulmonary post-acute sequelae of COVID-19 (PASC) is unclear. Using a multidimensional approach integrating clinical, serological, imaging and histopathology data as well as ultrastructural analyses, we show here that previous vaccination has no impact on lung function, bronchiolitis or the detection of autoantibodies or residual virus in a previously healthy cohort of 99 PASC patients after mild COVID-19. While a higher frequency of ground glass opacities in unvaccinated patients might be due to the longer interval between infection and consultation, the observed fibrotic remodeling should prompt further investigation of a possible pro-fibrotic role of SARS-CoV-2 infection in the lung.

show abstract

Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease

Mehta

Estrada

Denneny

et al. 2023

Preprint

View full text Add to dashboard Cite

Rationale: Persistent pulmonary sequelae are evident in many survivors of acute coronavirus disease 2019 (COVID-19) but the molecular mechanisms responsible are incompletely understood. Post-COVID radiological lung abnormalities comprise two broad categories, organising pneumonia and reticulation, interpreted as indicative of subacute inflammation and fibrosis, respectively. Whether these two patterns represent distinct pathologies, likely to require different treatment strategies is not known. Objectives: We sought to identify differences at molecular and cellular level, in the local immunopathology of post-COVID inflammation and fibrosis. Methods: We compared single-cell transcriptomic profiles and T cell receptor (TCR) repertoires of bronchoalveolar cells obtained from convalescent individuals with each radiological pattern of post-COVID lung disease (PCLD). Measurements and Main Results: Inflammatory and fibrotic PCLD single-cell transcriptomes closely resembled each other across all cell types. However, CD4 central memory T cells (TCM) and CD8 effector memory T cells (TEM) were significantly more abundant in inflammatory PCLD. A greater proportion of CD4 TCM also exhibited clonal expansion in inflammatory PCLD. High levels of clustering of similar TCRs from multiple donors was a striking feature of both PCLD phenotypes, consistent with tissue localised antigen-specific immune responses, but there was no enrichment for known SARS-CoV-2 reactive TCRs. Conclusions: There is no evidence that radiographic organising pneumonia and reticulation in PCLD are associated with differential immmunopathological pathways. Inflammatory radiology is characterised by greater bronchoalveolar T cell accumulation. Both groups show evidence of shared antigen-specific T cell responses, but the antigenic target for these T cells remains to be identified.

show abstract

Clinical, Imaging, and Histopathological Features of Pulmonary Sequelae after Mild COVID-19

Cited by 6 publications

References 15 publications

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

Effect of mRNA vaccination on pulmonary sequelae after mild COVID-19

Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease

Contact Info

Product

Resources

About