Persistence of dysfunctional immune response 12 months after SARS-CoV-2 infection and their relationship with pulmonary sequelae and long COVID

Abstract

Introduction: Most patients recover fully after an acute infection by SARS-CoV-2. Some, however, may develop pulmonary sequelae (PS) and/or long COVID (LC). However, whether these two clinical conditions have similar or different pathogenic mechanisms is unknown.

Methods: The levels of autoantibodies and 184 inflammatory and organ damage associated proteins in plasma were determined (by immunofluorescence and Olink panels, respectively) 1 year after an acute infection by SARS-CoV-2 in 51 patients with PS (DLCO < 80% ref), 31 patients with LC and 31 patients fully recovered (Rec). PS was defined by the presence of reduced carbon monoxide diffusing capacity (DLCO) lower than 80% ref. LC was defined by the presence of chronic symptoms in the absence of an alternative diagnosis.

Results: We found that patients with PS or LC both showed increased levels than Rec of anti-microbial, immune cell activation and recruitment related proteins. Patients with PS showed higher levels of anti-nuclear autoantibodies, whereas LC patients had increased levels of organ-damage associated proteins. In patients with PS most of the elevated proteins correlate with the impairment of lung function (DLCO). Finally, in PS we additionally performed the determinations at an earlier time point (6 months) and showed that the expression of CCL20 and IFN-ɣ was already higher at 6 months, while CCL3 and CCL19 increase from 6 to 12 months, suggesting a pathogenic role in PS persistence.

Conclusions: Patients with PS or LC have abnormal but different persistent circulatory immune and organ damage biomarkers, suggesting different underlying biology of both post-COVID conditions.

Keywords: 1 year of convalescence; Autoantibodies; Biomarkers; COVID-19; Long COVID; Organ-damage markers; Persistence of viral reservoirs; Pulmonary Sequelae.

Fig. 1

Inflammatory markers are increased in PS and LC while organ-damage proteins are only increased in LC. A Venn diagram showing the plasma inflammatory markers with different levels in the comparison between the three studied groups and B Venn diagram for the organ-damage related proteins

Fig. 2

The inflammatory markers increased with severity of the PS and changes over time post-acute episode. A The levels of plasma inflammatory markers correlate with the severity of the PS by DLCO. B At 6 months post-infection PS patients had increased levels of CCL20 and IFN-ɣ. C There is an increased in the plasma inflammatory markers at 12 months post-discharge

Fig. 3

Biological pathways altered in patients with PS and LC. The percentage of plasma elevated proteins in PS or LC is represented for each KEGG pathway

Fig. 4

PS patients had increased levels of chronic lung disease associated proteins. A Boxplot of the plasma levels of GDF-15 and WFDC2. B Correlation plots of the levels of GDF-15 and WFDC2 and the 12 months DLCO