Persistent T‐cell exhaustion in relation to prolonged pulmonary pathology and death after severe COVID‐19: Results from two Norwegian cohort studies

Trøseid, Marius; Dahl, Tuva B.; Holter, Jan Cato; Kildal, Anders Benjamin; Murphy, Sarah; Yang, Kuan; Quiles‐Jiménez, Ana; Heggelund, Lars; Müller, Karl Erik; Tveita, Anders; Michelsen, Annika E.; Bøe, Simen; Holten, Aleksander Rygh; Hoel, Hedda; Mathiessen, Alexander; Aaløkken, Trond Mogens; Fevang, Børre; Granerud, Beathe Kiland; Tonby, Kristian; Nezvalová-Henriksen, Kateřina; Lerum, Tøri Vigeland; Müller, Fredrik; Skjønsberg, Ole Henning; Barratt‐Due, Andreas; Dyrhol‐Riise, Anne Ma; Aukrust, Pål; Halvorsen, Bente; Ueland, Thor

doi:10.1111/joim.13549

Cited by 5 publications

(8 citation statements)

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“…50 In line with this, we have recently suggested that persistent activation of check-point inhibitors may predispose to cellular exhaustion in Covid-19 patients. 51 The present study has several limitations such as low number of patients and lack of follow-up data after the first week of hospitalization. Moreover, measurements of other forms of DNA damage, including detection of DSBs are lacking and hampered the conclusion of the study.…”

Section: Discussionmentioning

confidence: 90%

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DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients

Olsen¹,

Huse²,

Sousa³

et al. 2022

JIR

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Purpose Reactive oxygen species (ROS) are an important part of the inflammatory response during infection but can also promote DNA damage. Due to the sustained inflammation in severe Covid-19, we hypothesized that hospitalized Covid-19 patients would be characterized by increased levels of oxidative DNA damage and dysregulation of the DNA repair machinery. Patients and Methods Levels of the oxidative DNA lesion 8-oxoG and levels of base excision repair (BER) proteins were measured in peripheral blood mononuclear cells (PBMC) from patients (8-oxoG, n = 22; BER, n = 17) and healthy controls (n = 10) (Cohort 1). Gene expression related to DNA repair was investigated in two independent cohorts of hospitalized Covid-19 patients (Cohort 1; 15 patents and 5 controls, Cohort 2; 15 patients and 6 controls), and by publicly available datasets. Results Patients and healthy controls showed comparable amounts of oxidative DNA damage as assessed by 8-oxoG while levels of several BER proteins were increased in Covid-19 patients, indicating enhanced DNA repair in acute Covid-19 disease. Furthermore, gene expression analysis demonstrated regulation of genes involved in BER and double strand break repair (DSBR) in PBMC of Covid-19 patients and expression level of several DSBR genes correlated with the degree of respiratory failure. Finally, by re-analyzing publicly available data, we found that the pathway Hallmark DNA repair was significantly more regulated in circulating immune cells during Covid-19 compared to influenza virus infection, bacterial pneumonia or acute respiratory infection due to seasonal coronavirus. Conclusion Although beneficial by protecting against DNA damage, long-term activation of the DNA repair machinery could also contribute to persistent inflammation, potentially through mechanisms such as the induction of cellular senescence. However, further studies that also include measurements of additional markers of DNA damage are required to determine the role and precise molecular mechanisms for DNA repair in SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 90%

“… 50 In line with this, we have recently suggested that persistent activation of check-point inhibitors may predispose to cellular exhaustion in Covid-19 patients. 51 …”

Section: Discussionmentioning

confidence: 99%

DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients

Olsen¹,

Huse²,

Sousa³

et al. 2022

JIR

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“…Some of the microbes being enriched in ICU patients, including Pyramidobacter and Olsenella, also had increased relative abundance in patients who died during the first 60 days. In a previous work, enhanced gut microbiota levels of Pyramidobacter correlated with circulating IL-6 levels, an upstream regulator of the pro-inflammatory response in severe COVID-19 disease, and predictor of disease progression in frail adults [ 14 ] while enriched Olsenella were detected in the lung microbiota of COVID-19 patients [ 15 ].…”

Section: Resultsmentioning

confidence: 99%

“…Study participants were recruited from the Norwegian SARS-CoV-2 study (NCT04381819), a multicentre cohort study of COVID-19 patients admitted to five Norwegian hospitals, conducted as part of an International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) WHO Clinical Characterization Protocol study, as previously described [ 14 ]. Participants aged ≥ 18 years and admitted to hospital with PCR-confirmed SARS-2-CoV-2 infection were eligible for inclusion and were included from March 9, 2020, until December 15, 2020.…”

Section: Methodsmentioning

confidence: 99%

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Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19

et al. 2023

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Background Gut microbiota alterations have been reported in hospitalized COVID-19 patients, with reduced alpha diversity and altered microbiota composition related to respiratory failure. However, data regarding gut microbiota and mortality are scarce. Methods Rectal swabs for gut microbiota analyses were collected within 48 h after hospital admission (baseline; n = 123) and three-month post-admission (n = 50) in a subset of patients included in the Norwegian SARS-CoV2 cohort study. Samples were analysed by sequencing the 16S rRNA gene. Gut microbiota diversity and composition at baseline were assessed in relation to need for intensive care unit (ICU) admission during hospitalization. The primary objective was to investigate whether the ICU-related gut microbiota was associated with 60-day mortality. Results Gut microbiota diversity (Shannon index) at baseline was lower in COVID-19 patients requiring ICU admission during hospitalization than in those managed in general wards. A dysbiosis index representing a balance of enriched and reduced taxa in ICU compared with ward patients, including decreased abundance of butyrate-producing microbes and enrichment of a partly oral bacterial flora, was associated with need of ICU admission independent of antibiotic use, dexamethasone use, chronic pulmonary disease, PO2/FiO2 ratio, C-reactive protein, neutrophil counts or creatinine levels (adjusted p < 0.001). The ICU-related dysbiosis index at baseline correlated with systemic inflammation and was associated with 60-day mortality in univariate analyses (Hazard ratio 3.70 [2.00–8.6], p < 0.001), as well as after separate adjustment for covariates. At the three-month follow-up, the dysbiosis index remained elevated in ICU patients compared with ward patients (adjusted p = 0.007). Conclusions Although our data should be regarded as exploratory due to low number of clinical end points, they suggest that gut microbiota alterations during hospitalization could be related to poor prognosis after severe COVID-19. Larger studies of gut involvement during COVID-19 in relation to long-term clinical outcome are warranted. Trial registrationNCT04381819. Retrospectively registered May 11, 2020.

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Humoral and cellular immune responses in fully vaccinated individuals with or without SARS‐CoV‐2 breakthrough infection: Results from the CoV‐ADAPT cohort

Hollstein,

Dierks,

Schön

et al. 2023

Journal of Medical Virology

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Despite recent advances in prophylactic vaccination, SARS‐CoV‐2 infections continue to cause significant morbidity. A better understanding of immune response differences between vaccinated individuals with and without later SARS‐CoV‐2 breakthrough infection is urgently needed. CoV‐ADAPT is a prospective long‐term study comparing humoral (anti‐spike‐RBD‐IgG, neutralization capacity, avidity) and cellular (spike‐induced T‐cell interferon‐γ [IFN‐γ] release) immune responses in individuals vaccinated against SARS‐CoV‐2 at four different time points (three before and one after third vaccination). In this cohort study, 62 fully vaccinated individuals presented with SARS‐CoV‐2 breakthrough infections vs 151 without infection 3–7 months following third vaccination. Breakthrough infections significantly increased anti‐spike‐RBD‐IgG (p < 0.01), but not spike‐directed T‐cell IFN‐γ release (TC) or antibody avidity. Despite comparable surrogate neutralization indices, the functional neutralization capacity against SARS‐CoV‐2—assessed via a tissue culture‐based assay—was significantly higher following breakthrough vs no breakthrough infection. Anti‐spike‐RBD‐IgG and antibody avidity decreased with age (p < 0.01) and females showed higher anti‐spike‐RBD‐IgG (p < 0.01), and a tendency towards higher antibody avidity (p = 0.051). The association between humoral and cellular immune responses previously reported at various time points was lost in subjects after breakthrough infections (p = 0.807). Finally, a machine‐learning approach based on our large immunological dataset (a total of 49 variables) from different time points was unable to predict breakthrough infections (area under the curve: 0.55). In conclusion, distinct differences in humoral vs cellular immune responses in fully vaccinated individuals with or without breakthrough infection could be demonstrated. Breakthrough infections predominantly drive the humoral response without boosting the cellular component. Breakthrough infections could not be predicted based on immunological data, which indicates a superior role of environmental factors (e.g., virus exposure) in individualized risk assessment.

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Persistent T‐cell exhaustion in relation to prolonged pulmonary pathology and death after severe COVID‐19: Results from two Norwegian cohort studies

Cited by 5 publications

References 29 publications

DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients

DNA Repair Mechanisms are Activated in Circulating Lymphocytes of Hospitalized Covid-19 Patients

Gut microbiota composition during hospitalization is associated with 60-day mortality after severe COVID-19

Humoral and cellular immune responses in fully vaccinated individuals with or without SARS‐CoV‐2 breakthrough infection: Results from the CoV‐ADAPT cohort

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