Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients
Agostino Di Ciaula
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorLuca Liberale
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorCorresponding Author
Piero Portincasa
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Correspondence
Piero Portincasa, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, Policlinico Hospital, Piazza G. Cesare 11, 70124 Bari, Italy.
Email: [email protected]
Search for more papers by this authorMohamad Khalil
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorIlaria Galerati
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorIlaria Farella
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorAntonino Noto
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorStephy JohnBritto
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorMargherita Moriero
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorCristina Michelauz
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorFederica Frè
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorChiara Olivero
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorMaria Bertolotto
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorFabrizio Montecucco
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorFederico Carbone
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorLeonilde Bonfrate
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorAgostino Di Ciaula
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorLuca Liberale
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorCorresponding Author
Piero Portincasa
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Correspondence
Piero Portincasa, Department of Precision and Regenerative Medicine and Ionian Area (DiMePre-J), University of Bari Aldo Moro, Policlinico Hospital, Piazza G. Cesare 11, 70124 Bari, Italy.
Email: [email protected]
Search for more papers by this authorMohamad Khalil
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorIlaria Galerati
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorIlaria Farella
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorAntonino Noto
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorStephy JohnBritto
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorMargherita Moriero
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorCristina Michelauz
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorFederica Frè
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorChiara Olivero
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorMaria Bertolotto
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
Search for more papers by this authorFabrizio Montecucco
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorFederico Carbone
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
IRCCS Ospedale Policlinico San Martino Genoa—Italian Cardiovascular Network, Genoa, Italy
Search for more papers by this authorLeonilde Bonfrate
Clinica Medica “A. Murri”, Division of Internal Medicine, Department of Preventive and Regenerative Medicine and Ionian Area (DiMePrev-J), University of Bari Aldo Moro, Bari, Italy
Search for more papers by this authorAgostino Di Ciaula and Luca Liberale equally contributed as first authors to this work.
Federico Carbone and Leonilde Bonfrate equally contributed as last authors to this work.
Abstract
Background
Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.
Materials and Methods
A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.
Results
The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.
Conclusion
In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.
CONFLICT OF INTEREST STATEMENT
None to declare.
REFERENCES
- 1Thaweethai T, Jolley SE, Karlson EW, et al. Development of a definition of Postacute sequelae of SARS-CoV-2 infection. Jama. 2023; 329: 1934-1946.
- 2Huang L, Li X, Gu X, et al. Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study. Lancet Respir Med. 2022; 10: 863-876.
- 3Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Sci Rep. 2021; 11: 16144.
- 4Rahmati M, Udeh R, Yon DK, et al. A systematic review and meta-analysis of long-term sequelae of COVID-19 2-year after SARS-CoV-2 infection: a call to action for neurological, physical, and psychological sciences. J Med Virol. 2023; 95:e28852.
- 5Carfi A, Bernabei R, Landi F, Gemelli Against C-P-ACSG. Persistent symptoms in patients after acute COVID-19. JAMA. 2020; 324: 603-605.
- 6Xiong Q, Xu M, Li J, et al. Clinical sequelae of COVID-19 survivors in Wuhan, China: a single-centre longitudinal study. Clin Microbiol Infec. 2021; 27: 89-95.
- 7Goertz YMJ, Van Herck M, Delbressine JM, et al. Persistent symptoms 3 months after a SARS-CoV-2 infection: the post-COVID-19 syndrome. ERJ Open Res. 2020; 6:00542–2020.
- 8Hopkins C, Surda P, Whitehead E, Kumar BN. Early recovery following new onset anosmia during the COVID-19 pandemic—an observational cohort study. J Otolaryngol Head Neck Surg. 2020; 49: 26.
- 9Halpin SJ, McIvor C, Whyatt G, et al. Postdischarge symptoms and rehabilitation needs in survivors of COVID-19 infection: a cross-sectional evaluation. J Med Virol. 2021; 93: 1013-1022.
- 10Bowles KH, McDonald M, Barron Y, Kennedy E, O'Connor M, Mikkelsen M. Surviving COVID-19 after hospital discharge: symptom, functional, and adverse outcomes of home health recipients. Ann Intern Med. 2020; 174: 316-325.
- 11Wong AW, Shah AS, Johnston JC, Carlsten C, Ryerson CJ. Patient-reported outcome measures after COVID-19: a prospective cohort study. Eur Respir J. 2020; 56:2003276.
- 12Han Q, Zheng B, Daines L, Sheikh A. Long-term sequelae of COVID-19: a systematic review and meta-analysis of one-year follow-up studies on post-COVID symptoms. Pathogens. 2022; 11: 11.
- 13Fernandez-de-Las-Penas C, Rodriguez-Jimenez J, Cancela-Cilleruelo I, et al. Post-COVID-19 symptoms 2 years after SARS-CoV-2 infection among hospitalized vs nonhospitalized patients. JAMA Netw Open. 2022; 5:e2242106.
- 14Zanza C, Romenskaya T, Manetti AC, et al. Cytokine Storm in COVID-19: immunopathogenesis and Therapy. Medicina (Kaunas). 2022; 58: 144.
- 15Phetsouphanh C, Darley DR, Wilson DB, et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat Immunol. 2022; 23: 210-216.
- 16Muralidharan A, Wyatt TA, Reid SP. SARS-CoV-2 dysregulates neutrophil degranulation and reduces lymphocyte counts. Biomedicine. 2022; 10: 10.
- 17Bankar R, Suvarna K, Ghantasala S, et al. Proteomic investigation reveals dominant alterations of neutrophil degranulation and mRNA translation pathways in patients with COVID-19. iScience. 2021; 24:102135.
- 18Akgun E, Tuzuner MB, Sahin B, et al. Proteins associated with neutrophil degranulation are upregulated in nasopharyngeal swabs from SARS-CoV-2 patients. PloS One. 2020; 15:e0240012.
- 19Mohebbi A, Haybar H, Nakhaei Moghaddam F, Rasti Z, Vahid MA, Saki N. Biomarkers of endothelial dysfunction are associated with poor outcome in COVID-19 patients: a systematic review and meta-analysis. Rev Med Virol. 2023; 33:e2442.
- 20Kozlowski P, Smiarowski M, Przyborska W, et al. Mild-to-moderate COVID-19 convalescents may present pro-longed endothelium injury. J Clin Med. 2022; 11: 11.
- 21Orea-Tejada A, Sanchez-Moreno C, Aztatzi-Aguilar OG, et al. Plasma endothelial and oxidative stress biomarkers associated with late mortality in hospitalized COVID-19 patients. J Clin Med. 2022; 11: 6461.
- 22Grewal T, Buechler C. Adipokines as diagnostic and prognostic markers for the severity of COVID-19. Biomedicine. 2023; 11: 11.
- 23Perrotta F, Scialo F, Mallardo M, et al. Adiponectin, leptin, and resistin are dysregulated in patients infected by SARS-CoV-2. Int J Mol Sci. 2023; 24: 1131.
- 24Flikweert AW, Kobold ACM, van der Brugge S, et al. Circulating adipokine levels and COVID-19 severity in hospitalized patients. Int J Obes (Lond). 2023; 47: 126-137.
- 25de Nooijer AH, Kooistra EJ, Grondman I, et al. Adipocytokine plasma concentrations reflect influence of inflammation but not body mass index (BMI) on clinical outcomes of COVID-19 patients: a prospective observational study from The Netherlands. Clin Obes. 2023; 13:e12568.
- 26Byambasuren O, Stehlik P, Clark J, Alcorn K, Glasziou P. Effect of covid-19 vaccination on long covid: systematic review. BMJ Med. 2023; 2:e000385.
- 27Watanabe A, Iwagami M, Yasuhara J, Takagi H, Kuno T. Protective effect of COVID-19 vaccination against long COVID syndrome: a systematic review and meta-analysis. Vaccine. 2023; 41: 1783-1790.
- 28Zhu X, Gebo KA, Abraham AG, et al. Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study. Lancet Microbe. 2023; 4: e692-e703.
- 29 Center for Disease Control and Prevention (CDC). Long COVID or Post-COVID Conditions. 2023.
- 30Carbone F, Ministrini S, Bonaventura A, et al. Serum levels of VCAM-1 are associated with survival in patients treated with nivolumab for NSCLC. Eur J Clin Invest. 2022; 52:e13668.
- 31Zeng N, Zhao YM, Yan W, et al. A systematic review and meta-analysis of long term physical and mental sequelae of COVID-19 pandemic: call for research priority and action. Mol Psychiatry. 2023; 28: 423-433.
- 32Quaranta VN, Portacci A, Dragonieri S, et al. The predictors of Long COVID in southeastern Italy. J Clin Med. 2023; 12: 12.
- 33Wang Y, Zhao D, Xiao W, et al. Paxlovid reduces the risk of Long COVID in patients six months after hospital discharge. J Med Virol. 2023; 95:e29014.
- 34Ndrepepa G. Myeloperoxidase—a bridge linking inflammation and oxidative stress with cardiovascular disease. Clin Chim Acta. 2019; 493: 36-51.
- 35Al-Hakeim HK, Al-Rubaye HT, Almulla AF, Al-Hadrawi DS, Maes M. Chronic fatigue, depression and anxiety symptoms in Long COVID are strongly predicted by Neuroimmune and neuro-oxidative pathways which are caused by the inflammation during acute infection. J Clin Med. 2023; 12: 12.
- 36Al-Hakeim HK, Al-Rubaye HT, Al-Hadrawi DS, Almulla AF, Maes M. Long-COVID post-viral chronic fatigue and affective symptoms are associated with oxidative damage, lowered antioxidant defenses and inflammation: a proof of concept and mechanism study. Mol Psychiatry. 2023; 28: 564-578.
- 37Fang Y, Doyle MF, Chen J, et al. Association between inflammatory biomarkers and cognitive aging. PloS One. 2022; 17:e0274350.
- 38Smyth LCD, Murray HC, Hill M, et al. Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer's disease. Acta Neuropathol Commun. 2022; 10: 38.
- 39da Silva-Neto PV, de Carvalho JCS, Pimentel VE, et al. sTREM-1 predicts disease severity and mortality in COVID-19 patients: involvement of peripheral blood leukocytes and MMP-8 activity. Viruses. 2021; 13: 13.
- 40Kimura N, Aikawa M, Etou K, Aso Y, Matsubara E. Association between matrix metalloproteinases, their tissue inhibitor and white matter lesions in mild cognitive impairment. Curr Alzheimer Res. 2020; 17: 547-555.
- 41Watany MM, Abdou S, Elkolaly R, Elgharbawy N, Hodeib H. Evaluation of admission levels of P, E and L selectins as predictors for thrombosis in hospitalized COVID-19 patients. Clin Exp Med. 2022; 22: 567-575.
- 42Mohammed RN, Watson HA, Vigar M, et al. L-selectin is essential for delivery of activated CD8(+) T cells to virus-infected organs for protective immunity. Cell Rep. 2016; 14: 760-771.
- 43Antar AAR, Yu T, Demko ZO, et al. Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection. Front Immunol. 2023; 14:1147549.
- 44de Leeuw FE, de Kleine M, Frijns CJ, Fijnheer R, van Gijn J, Kappelle LJ. Endothelial cell activation is associated with cerebral white matter lesions in patients with cerebrovascular disease. Ann N Y Acad Sci. 2002; 977: 306-314.
- 45Jaremo P, Milovanovic M, Buller C, Nilsson S, Winblad B. P-selectin paradox and dementia of the Alzheimer type: circulating P-selectin is increased but platelet-bound P-selectin after agonist provocation is compromised. Scand J Clin lab Invest. 2013; 73: 170-174.
- 46Liu N, Long H, Sun J, et al. New laboratory evidence for the association between endothelial dysfunction and COVID-19 disease progression. J Med Virol. 2022; 94: 3112-3120.
- 47Patel MA, Knauer MJ, Nicholson M, et al. Elevated vascular transformation blood biomarkers in Long-COVID indicate angiogenesis as a key pathophysiological mechanism. Mol Med. 2022; 28: 122.
- 48Tong M, Yan X, Jiang Y, et al. Endothelial biomarkers in patients recovered from COVID-19 one year after hospital discharge: a cross-sectional study. Mediterr J Hematol Infect Dis. 2022; 14:e2022033.
- 49Kuliczkowska-Plaksej J, Jawiarczyk-Przybylowska A, Zembska A, et al. Ghrelin and leptin concentrations in patients after SARS-CoV2 infection. J Clin Med. 2023; 12: 12.
10.3390/jcm12103551 Google Scholar
- 50Ceban F, Ling S, Lui LMW, et al. Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis. Brain Behav Immun. 2022; 101: 93-135.
- 51Kurajoh M, Kadoya M, Morimoto A, et al. Plasma leptin concentration is associated with fatigue severity in patients with cardiovascular risk factors—HSCAA study. Psychoneuroendocrinology. 2016; 74: 7-12.
- 52Piche T, Huet PM, Gelsi E, et al. Fatigue in irritable bowel syndrome: characterization and putative role of leptin. Eur J Gastroenterol Hepatol. 2007; 19: 237-243.
- 53Piche T, Gelsi E, Schneider SM, et al. Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut. 2002; 51: 434-439.
- 54Stringer EA, Baker KS, Carroll IR, et al. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013; 11: 93.
- 55Toh YL, Tan CJ, Yeo AHL, et al. Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: a prospective cohort study. J Cell Mol Med. 2019; 23: 4281-4289.
- 56Qiu C, Frederick IO, Sorensen TK, Enquobahrie DA, Williams MA. Sleep duration and plasma leptin concentrations in early pregnancy among lean and overweight/obese women: a cross sectional study. BMC Res Notes. 2014; 7: 20.
- 57Hodgin KS, Jones CL, Younger JW. Fatigue and pain severity in gulf war illness is associated with changes in inflammatory cytokines and positive acute phase proteins. J Occup Environ Med. 2022; 64: 905-911.
- 58Cernea S, Both E, Hutanu A, Sular FL, Roiban AL. Correlations of serum leptin and leptin resistance with depression and anxiety in patients with type 2 diabetes. Psychiatry Clin Neurosci. 2019; 73: 745-753.
