Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9

Lerum, Tøri Vigeland; Maltzahn, Niklas; Aukrust, Pål; Trøseid, Marius; Nezvalová-Henriksen, Kateřina; Kåsine, Trine; Dyrhol-Riise, Anne Margarita; Stiksrud, Birgitte; Haugli, Mette; Blomberg, Björn; Kittang, Bård Reiakvam; Johannessen, Asgeir; Hannula, Raisa; Aballi, Saad; Kildal, Anders Benjamin; Eiken, Ragnhild; Dahl, Tuva B.; Lund‐Johansen, Fridtjof; Müller, Fredrik; Rodriguez, Jezabel Rivero; Meltzer, Carin; Einvik, Gunnar; Ueland, Thor; Olsen, Inge Christoffer; Pettersen, Frank Olav; Holten, Aleksander Rygh; Tonby, Kristian; Reikvam, Dag Henrik; Røstad, Kjerstin; Jenum, Synne; Hesstvedt, Liv; Vaage, Eline Brenno; Kolderup, Anette; Tran, Trung; Andersen, Jan Terje; Holberg-Petersen, Mona; Johal, Simreen Kaur; Berg, Åse; Tveita, Anders; Ernst, Gernot; Heggelund, Lars; Thoresen, Lars; Müller, Karl Erik; Hoff, Dag Arne Lihaug; Olsen, Roy Bjørkholt; Finbråten, Ane-Krisitne; Hoel, Hedda; Mathiessen, Alexander; Vinge, Leif Erik; Nordberg, L.B.; Manotheepan, Ravinea; Stenvik, Grethe-Elisabeth; Rasmussen, Hans Schmidt; Thorkildsen, Ruth Foseide; Mielnik, Paweł; Le, Lan Ai Kieu; Ystrøm, Carl Magnus; Molvik, Richard Alexander; Skei, Nina Vibeche; Dalgård, Olav; Åsheim-Hansen, Bjørn; Halstensen, Anne Marie; Brynhildsen, Jorunn; Ghanima, Waleed; Skogen, Vegard; Mohn, Krisine Greve Isdahl; Kvåle, Reidar; Langeland, Nina; Gustad, Lise Tuset; Saxhaug, Lars Mølgaard; Fladeby, Cathrine; Dudman, Susanne; Steffensen, Anne Katrine; Barratt‐Due, Andreas; Aaløkken, Trond Mogens; Skjønsberg, Ole Henning

doi:10.1038/s41598-021-02547-x

Cited by 29 publications

(27 citation statements)

References 39 publications

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“…Studies have shown that DL CO is the pulmonary measure most frequently affected after hospitalization for COVID‐19 [ 14 , 15 ]. For the purpose of this study, we chose DL CO as a measure of pulmonary function, as previously reported from the NOR‐Solidarity cohort [ 16 ]. The DL CO, in per cent of predicted and the LLN, was calculated according to the Global Lung Function Initiative Network (GLI) [ 17 ], as previously described [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

Respiratory dysfunction three months after severe COVID‐19 is associated with gut microbiota alterations

et al. 2022

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Background Although coronavirus disease 2019 (COVID‐19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long‐term respiratory dysfunction remains unknown. Methods Plasma was collected during hospital admission and after 3 months from the NOR‐Solidarity trial (n = 181) and analyzed for markers of gut barrier dysfunction and inflammation. At the 3‐month follow‐up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO). Rectal swabs for gut microbiota analyses were collected (n = 97) and analyzed by sequencing the 16S rRNA gene. Results Gut microbiota diversity was reduced in COVID‐19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal 3 months after hospitalization. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalization, increased plasma levels of lipopolysaccharide‐binding protein (LBP) were strongly associated with respiratory failure, defined as pO2/fiO2 (P/F ratio) <26.6 kPa. LBP levels remained elevated during and after hospitalization and were associated with low‐grade inflammation and respiratory dysfunction after 3 months. Conclusion Respiratory dysfunction after COVID‐19 is associated with altered gut microbiota and persistently elevated LBP levels. Our results should be regarded as hypothesis generating, pointing to a potential gut–lung axis that should be further investigated in relation to long‐term pulmonary dysfunction and long COVID.

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Section: Methodsmentioning

confidence: 99%

Respiratory dysfunction three months after severe COVID‐19 is associated with gut microbiota alterations

et al. 2022

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“…The timing of this 3-month follow-up was different in the 2 cohorts, defined by inclusion date in cohort 1, and date of hospital discharge in cohort 2. In cohort 1, lung function testing (n = 90), consisting of spirometry, and diffusing capacity of the lungs ( Dlco ) was also performed [ 24 ]. The predicted percentage of Dlco and the lower limit of normal were calculated according to the Global Lung Function Initiative Network guidelines [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

“…In cohort 1, lung function testing (n = 90), consisting of spirometry, and diffusing capacity of the lungs ( Dlco ) was also performed [ 24 ]. The predicted percentage of Dlco and the lower limit of normal were calculated according to the Global Lung Function Initiative Network guidelines [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

Tveita

Murphy

Holter

et al. 2022

The Journal of Infectious Diseases

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Background Immune dysregulation is a major factor in the development of severe Covid-19. The homeostatic chemokines CCL19 and CCL21 have been implicated as mediators of tissue inflammation, but data on their regulation in SARS-CoV-2 infection is limited. We thus investigated the levels of these chemokines in Covid-19 patients. Methods Serial blood samples were obtained from patients hospitalized with Covid-19 (n = 414). Circulating CCL19 and CCL21 levels during hospitalization and three-month follow-up were analyzed. In vitro assays and analysis of RNAseq data from public repositories were performed to further explore possible regulatory mechanisms. Results A consistent increase in circulating levels of CCL19 and CCL21 was observed, with high levels correlating with disease severity measures, including respiratory failure, need for intensive care, and 60-day all-cause mortality. High levels of CCL21 at admission were associated with persisting impairment of pulmonary function at the three-month follow-up. Conclusions Our findings highlight CCL19 and CCL21 as markers of immune dysregulation in Covid-19. This may reflect aberrant regulation triggered by tissue inflammation, as observed in other chronic inflammatory and autoimmune conditions. Determination of the source and regulation of these chemokines and their effects on lung tissue is warranted to further clarify their role in Covid-19.

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“…Some researchers observed a higher concentration of MMP-2, 3, and 9 in the blood of COVID-19 patients on admission to the hospital compared to healthy people. The severity of the disease was related to the concentrations of examined MMPs [ 40 , 41 , 42 , 43 , 44 ]. MMP-3 activity is also elevated in ARDS patients, according to Kadry et al [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

The Mortality Risk and Pulmonary Fibrosis Investigated by Time-Resolved Fluorescence Spectroscopy from Plasma in COVID-19 Patients

Wybranowski

Pyskir

Bosek

et al. 2022

JCM

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A method of rapidly pointing out the risk of developing persistent pulmonary fibrosis from a sample of blood is extraordinarily needed for diagnosis, prediction of death, and post-infection prognosis assessment. Collagen scar formation has been found to play an important role in the lung remodeling following SARS-CoV-2 infection. For this reason, the concentration of collagen degradation products in plasma may reflect the process of lung remodeling and determine the extent of fibrosis. According to our previously published results of an in vitro study, an increase in the concentration of type III collagen degradation products in plasma resulted in a decrease in the fluorescence lifetime of plasma at a wavelength of 450 nm. The aim of this study was to use time-resolved fluorescence spectroscopy to assess pulmonary fibrosis, and to find out if the lifetime of plasma fluorescence is shortened in patients with COVID-19. The presented study is thus far the only one to explore the fluorescence lifetime of plasma in patients with COVID-19 and pulmonary fibrosis. The time-resolved spectrometer Life Spec II with the sub-nanosecond pulsed 360 nm EPLED® diode was used in order to measure the fluorescence lifetime of plasma. The survival analysis showed that COVID-19 mortality was associated with a decreased mean fluorescence lifetime of plasma. The AUC of mean fluorescence lifetime in predicting death was 0.853 (95% CI 0.735–0.972, p < 0.001) with a cut-off value of 7 ns, and with 62% sensitivity and 100% specificity. We observed a significant decrease in the mean fluorescence lifetime in COVID-19 non-survivors (p < 0.001), in bacterial pneumonia patients without COVID-19 (p < 0.001), and in patients diagnosed with idiopathic pulmonary fibrosis (p < 0.001), relative to healthy subjects. Furthermore, these results suggest that the development of pulmonary fibrosis may be a real and serious problem in former COVID-19 patients in the future. A reduction in the mean fluorescence lifetime of plasma was observed in many patients 6 months after discharge. On the basis of these data, it can be concluded that a decrease in the mean fluorescence lifetime of plasma at 450 nm may be a risk factor for mortality, and probably also for pulmonary fibrosis in hospitalized COVID-19 patients.

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Persistent pulmonary pathology after COVID-19 is associated with high viral load, weak antibody response, and high levels of matrix metalloproteinase-9

Cited by 29 publications

References 39 publications

Respiratory dysfunction three months after severe COVID‐19 is associated with gut microbiota alterations

Respiratory dysfunction three months after severe COVID‐19 is associated with gut microbiota alterations

High Circulating Levels of the Homeostatic Chemokines CCL19 and CCL21 Predict Mortality and Disease Severity in COVID-19

The Mortality Risk and Pulmonary Fibrosis Investigated by Time-Resolved Fluorescence Spectroscopy from Plasma in COVID-19 Patients

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