Biomarker Profiles Associated with COVID-19 Severity and Mortality

Introduction: The aim of this study was to analyze biomarkers that might predict the severity and progression of the SARS-CoV-2 infection, both in the acute phase and after recovery. Methods: Unvaccinated patients infected with the original strain of COVID-19 requiring ward (Group 1, n = 48) or ICU (Group 2, n = 41) admission were included. At the time of admission (visit 1), a clinical history was acquired, and blood samples were obtained. One and six months after discharge from the hospital (visits 2 and 3, respectively), a clinical history, lung function tests, and blood samples were carried out. At visit 2, patients also underwent a chest CT scan. Different cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, G-CSF, GM-CSF, IFN-ɣ, MCP-1, MIP-1β, and TNF-α) and lung fibrosis biomarkers (YKL-40 and KL-6) were measured in blood samples obtained at visits 1, 2, and 3. Results: At visit 1, IL-4, IL-5, and IL-6 levels were higher in Group 2 (p = 0.039, 0.011, and 0.045, respectively), and IL-17 and IL-8 levels were higher in Group 1 (p = 0.026 and 0.001, respectively). The number of patients in Groups 1 and 2 who died during hospitalization was 8 and 11, respectively. YKL-40 and KL-6 levels were higher in patients who died. Serum YKL-40 and KL-6 levels determined at visit 2 correlated negatively with FVC (p = 0.022 and p = 0.024, respectively) and FEV1 (p = 0.012 and p = 0.032, respectively) measured at visit 3. KL-6 levels also correlated negatively with the diffusing capacity of the lungs for carbon monoxide (DLCO, p = 0.001). Conclusions: Patients who required ICU admission had higher levels of Th2 cytokines, while patients admitted to the ward showed an innate immune response activation, with IL-8 release and Th1/Th17 lymphocyte contribution. Increased levels of YKL-40 and KL-6 were associated with mortality in COVID-19 patients.

[1]  A. Sette,et al.  Humoral and cellular immune responses to CoronaVac assessed up to one year after vaccination , 2022, medRxiv.

[2]  V. Poletti,et al.  European Respiratory Society statement on long COVID follow-up , 2022, European Respiratory Journal.

[3]  C. De Molo,et al.  Spontaneous Evolution of COVID-19 Lung Sequelae: Results from a Double-Step Follow-Up , 2022, Respiration.

[4]  X. Chen,et al.  The Investigation of Pulmonary Function Changes of COVID-19 Patients in Three Months , 2022, Journal of healthcare engineering.

[5]  S. Luzzi,et al.  Cytokine profiles in the detection of severe lung involvement in hospitalized patients with COVID-19: The IL-8/IL-32 axis , 2021, Cytokine.

[6]  Ramezan Jafari,et al.  Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective. , 2021, Viral immunology.

[7]  H. Rui,et al.  Cytotoxic CD8-positive T-lymphocyte infiltration in the lungs as a histological pattern of SARS-CoV-2 pneumonitis , 2021, Pathology.

[8]  T. Yin,et al.  ACE2 and Innate Immunity in the Regulation of SARS-CoV-2-Induced Acute Lung Injury: A Review , 2021, International journal of molecular sciences.

[9]  R. Singh,et al.  Role of toll‐like receptors in modulation of cytokine storm signaling in SARS‐CoV‐2‐induced COVID‐19 , 2021, Journal of medical virology.

[10]  D. Eksombatchai,et al.  Pulmonary function and six-minute-walk test in patients after recovery from COVID-19: A prospective cohort study , 2021, PloS one.

[11]  S. Avdeev,et al.  Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: A pilot study , 2021, Cytokine.

[12]  G. Jenkins,et al.  COVID‐19 and pulmonary fibrosis: A potential role for lung epithelial cells and fibroblasts , 2021, Immunological reviews.

[13]  R. Okuda,et al.  Serum Krebs von den Lungen-6 levels are associated with mortality and severity in patients with coronavirus disease 2019 , 2021, Respiratory Investigation.

[14]  I. Efremova,et al.  Interleukin 17 antagonist netakimab is effective and safe in the new coronavirus infection (COVID-19) , 2021, European Cytokine Network.

[15]  O. Malaise,et al.  YKL-40 as a new promising prognostic marker of severity in COVID infection , 2021, Critical Care.

[16]  M. Bocchino,et al.  Serum KL-6 Could Represent a Reliable Indicator of Unfavourable Outcome in Patients with COVID-19 Pneumonia , 2021, International journal of environmental research and public health.

[17]  C. Ranasinghe,et al.  Interleukin-13 as a target to alleviate severe coronavirus disease 2019 and restore lung homeostasis , 2021, Journal of clinical and translational research.

[18]  R. Heads,et al.  COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation , 2021, Mediators of inflammation.

[19]  R. Preissner,et al.  IL-13 is a driver of COVID-19 severity , 2020, medRxiv : the preprint server for health sciences.

[20]  L. Notarangelo,et al.  An immune-based biomarker signature is associated with mortality in COVID-19 patients , 2020, JCI insight.

[21]  R. Kream,et al.  Long-Term Respiratory and Neurological Sequelae of COVID-19 , 2020, Medical science monitor : international medical journal of experimental and clinical research.

[22]  Keith Sigel,et al.  An inflammatory cytokine signature predicts COVID-19 severity and survival , 2020, Nature Medicine.

[23]  N. Laura,et al.  Interleukin-6-based mortality risk model for hospitalised COVID-19 patients , 2020, Journal of Allergy and Clinical Immunology.

[24]  Hedayat Sahraei,et al.  The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging” , 2020, Inflammation Research.

[25]  J. Knight,et al.  Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease. , 2020, JCI insight.

[26]  D. Bennett,et al.  Serum KL‐6 concentrations as a novel biomarker of severe COVID‐19 , 2020, Journal of medical virology.

[27]  K. Subbarao,et al.  Respiratory Virus Infections: Understanding COVID-19 , 2020, Immunity.

[28]  M. Rotondi,et al.  The cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system , 2020, Cytokine & Growth Factor Reviews.

[29]  L. Roncati,et al.  Signals of Th2 immune response from COVID-19 patients requiring intensive care , 2020, Annals of Hematology.

[30]  Georg Schett,et al.  COVID-19: risk for cytokine targeting in chronic inflammatory diseases? , 2020, Nature Reviews Immunology.

[31]  Robert J. Mason,et al.  Pathogenesis of COVID-19 from a cell biologic perspective , 2020, European Respiratory Journal.

[32]  Quanyi Wang,et al.  Viral load of SARS-CoV-2 in clinical samples , 2020, The Lancet Infectious Diseases.

[33]  Chuan Qin,et al.  Dysregulation of immune response in patients with COVID-19 in Wuhan, China , 2020, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  Y. Hu,et al.  Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China , 2020, The Lancet.

[35]  R. Liu,et al.  Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors , 2020, Emerging microbes & infections.

[36]  Kevin McCarthy,et al.  Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement , 2019, American journal of respiratory and critical care medicine.

[37]  J. Barata,et al.  Flip the coin: IL-7 and IL-7R in health and disease , 2019, Nature Immunology.

[38]  K. Zorena,et al.  Chitinases and immunity: Ancestral molecules with new functions. , 2016, Immunobiology.

[39]  S. Stanojevic,et al.  Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations , 2012, European Respiratory Journal.

[40]  T. Fry,et al.  Harnessing the biology of IL-7 for therapeutic application , 2011, Nature Reviews Immunology.

[41]  B. Ma,et al.  Role of chitin and chitinase/chitinase-like proteins in inflammation, tissue remodeling, and injury. , 2011, Annual review of physiology.

[42]  R. Flavell,et al.  Role of breast regression protein 39 (BRP-39)/chitinase 3-like-1 in Th2 and IL-13–induced tissue responses and apoptosis , 2009, The Journal of experimental medicine.

[43]  L. Ware Pathophysiology of acute lung injury and the acute respiratory distress syndrome. , 2006, Seminars in respiratory and critical care medicine.

[44]  N. Kohno,et al.  KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. , 2005, Biochemical and biophysical research communications.

[45]  N. Kohno,et al.  KL-6, a human MUC1 mucin, is chemotactic for human fibroblasts. , 1997, American journal of respiratory cell and molecular biology.