Clinical Approach to Post-acute Sequelae After COVID-19 Infection and Vaccination
Nicolas Hulscher, Brian C Procter, Cade Wynn, Peter A Mccullough
Cureus, doi:10.7759/cureus.49204
The spike protein of SARS-CoV-2 has been found to exhibit pathogenic characteristics and be a possible cause of post-acute sequelae after SARS-CoV-2 infection or COVID-19 vaccination. COVID-19 vaccines utilize a modified, stabilized prefusion spike protein that may share similar toxic effects with its viral counterpart. The aim of this study is to investigate possible mechanisms of harm to biological systems from SARS-CoV-2 spike protein and vaccine-encoded spike protein and to propose possible mitigation strategies. We searched PubMed, Google Scholar, and 'grey literature' to find studies that (1) investigated the effects of the spike protein on biological systems, (2) helped differentiate between viral and vaccine-generated spike proteins, and (3) identified possible spike protein detoxification protocols and compounds that had signals of benefit and acceptable safety profiles. We found abundant evidence that SARS-CoV-2 spike protein may cause damage in the cardiovascular, hematological, neurological, respiratory, gastrointestinal, and immunological systems. Viral and vaccine-encoded spike proteins have been shown to play a direct role in cardiovascular and thrombotic injuries from both SARS-CoV-2 and vaccination. Detection of spike protein for at least 6-15 months after vaccination and infection in those with post-acute sequelae indicates spike protein as a possible primary contributing factor to long COVID. We rationalized that these findings give support to the potential benefit of spike protein detoxification protocols in those with long-term postinfection and/or vaccine-induced complications. We propose a base spike detoxification protocol, composed of oral nattokinase, bromelain, and curcumin. This approach holds immense promise as a base of clinical care, upon which additional therapeutic agents are applied with the goal of aiding in the resolution of postacute sequelae after SARS-CoV-2 infection and COVID-19 vaccination. Large-scale, prospective, randomized, double-blind, placebo-controlled trials are warranted in order to determine the relative risks and benefits of the base spike detoxification protocol.
Additional Information Author Contributions All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work.
Concept and design:
References
Ait-Belkacem, García, Millet-Wallisky, SARS-CoV-2 spike protein induces a differential monocyte activation that may contribute to age bias in COVID-19 severity, Sci Rep,
doi:10.1038/s41598-022-25259-2Akhter, Quéromès, Pillai, The combination of bromelain and acetylcysteine (Bromac) synergistically inactivates SARS-CoV-2, Viruses,
doi:10.3390/v13030425Almehdi, Khoder, Alchakee, Alsayyid, Sarg et al., SARS-CoV-2 spike protein: pathogenesis, vaccines, and potential therapies, Infection,
doi:10.1007/s15010-021-01677-8Avolio, Carrabba, Milligan, The SARS-CoV-2 spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease, Clin Sci (Lond),
doi:10.1042/CS20210735Barati, Motavallihaghi, Nikfar, Chaichian, Momtazi-Borojeni, Potential therapeutic effects of ivermectin in COVID-19, Exp Biol Med,
doi:10.1177/15353702221099579Baumeier, Aleshcheva, Harms, Intramyocardial Inflammation after COVID-19 vaccination: an endomyocardial biopsy-proven case series, Int J Mol Sci,
doi:10.3390/ijms23136940Brogna, Cristoni, Marino, Detection of recombinant Spike protein in the blood of individuals vaccinated against SARS-CoV-2: possible molecular mechanisms, Proteomics Clin Appl,
doi:10.1002/prca.202300048Chakraborty, Mitra, Tallei, Bromelain a potential bioactive compound: a comprehensive overview from a pharmacological perspective, Life,
doi:10.3390/life11040317Cheng, Hsu, Lin, Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions, Anticancer Res
Clemens, Ye, Zhou, SARS-CoV-2 spike protein-mediated cardiomyocyte fusion may contribute to increased arrhythmic risk in COVID-19, PLoS One,
doi:10.1371/journal.pone.0282151Craddock, Mahajan, Spikes, Persistent circulation of soluble and extracellular vesicle-linked Spike protein in individuals with postacute sequelae of COVID-19, J Med Virol,
doi:10.1002/jmv.28568De Michele, Amati, Leopizzi, Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients, J Hematol Oncol,
doi:10.1186/s13045-022-01329-wDebnath, Dewaker, Prabhakar, Bhattacharyya, Mandal, Conformational perturbation of SARS-CoV-2 spike protein using N-acetyl cysteine, a molecular scissor: a probable strategy to combat COVID-19, PREPRINT,
doi:10.26434/chemrxiv.12687923.v1Deore, Tran, Andrews, Ramirez, Galie, SARS-CoV-2 spike protein disrupts blood-brain barrier integrity via RhoA activation, J Neuroimmune Pharmacol,
doi:10.1007/s11481-021-10029-0Dormoy, Perotin, Gosset, Maskos, Polette et al., Nicotinic receptors as SARS-CoV-2 spike co-receptors?, Med Hypotheses,
doi:10.1016/j.mehy.2021.110741Engin, Engin, Engin, Two important controversial risk factors in SARS-CoV-2 infection: obesity and smoking, Environ Toxicol Pharmacol,
doi:10.1016/j.etap.2020.103411Espinoza, Emmady, Histology, monocytes
Finterer, Scorza, A retrospective analysis of clinically confirmed long post-COVID vaccination syndrome, J Clin Transl Res
Fiolet, Opstal, Mosterd, Efficacy and safety of low-dose colchicine in patients with coronary disease: a systematic review and meta-analysis of randomized trials, Eur Heart J,
doi:10.1093/eurheartj/ehab115Fontes-Dantas, Fernandes, Gutman, SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice, Cell Rep,
doi:10.1016/j.celrep.2023.112189Forsyth, Zhang, Bhushan, The SARS-CoV-2 S1 spike protein promotes MAPK and NF-kB activation in human lung cells and inflammatory cytokine production in human lung and intestinal epithelial cells, Microorganisms,
doi:10.3390/microorganisms10101996Grobbelaar, Venter, Vlok, SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: implications for microclot formation in COVID-19, Biosci Rep,
doi:10.1042/BSR20210611Hassaniazad, Eftekhar, Inchehsablagh, A triple-blind, placebo-controlled, randomized clinical trial to evaluate the effect of curcumin-containing nanomicelles on cellular immune responses subtypes and clinical outcome in COVID-19 patients, Phytother Res,
doi:10.1002/ptr.7294Hegde, Girisa, Bharathwajchetty, Vishwa, Kunnumakkara, Curcumin formulations for better bioavailability: what we learned from clinical trials thus far?, ACS Omega,
doi:10.1021/acsomega.2c07326Hulscher, Alexander, Amerling, A systematic review of autopsy findings in deaths after COVID-19 vaccination, PREPRINT,
doi:10.5281/zenodo.8120771Huynh, Rethi, Lee, Higa, Kao et al., Spike protein impairs mitochondrial function in human cardiomyocytes: mechanisms underlying cardiac injury in COVID-19, Cells,
doi:10.3390/cells12060877Karatza, Ismailos, Karalis, Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens, Xenobiotica,
doi:10.1080/00498254.2021.1909782Kim, Jeon, Kim, Lee, Kim et al., Spike proteins of SARS-CoV-2 induce pathological changes in molecular delivery and metabolic function in the brain endothelial cells, Viruses,
doi:10.3390/v13102021Kritis, Karampela, Kokoris, Dalamaga, The combination of bromelain and curcumin as an immuneboosting nutraceutical in the prevention of severe COVID-19, Metabol Open,
doi:10.1016/j.metop.2020.100066Kucia, Ratajczak, Bujko, An evidence that SARS-CoV-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner, Leukemia,
doi:10.1038/s41375-021-01332-zKurosawa, Nirengi, Homma, Esaki, Ohta et al., A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles, Sci Rep,
doi:10.1038/srep11601Lotz-Winter, On the pharmacology of bromelain: an update with special regard to animal studies on dosedependent effects, Planta Med,
doi:10.1055/s-2006-960949Mayordomo-Colunga, Vivanco-Allende, López-Alonso, López-Martínez, Vega et al., SARS-CoV-2 spike protein in intestinal cells of a patient with coronavirus disease 2019 multisystem inflammatory syndrome, J Pediatr,
doi:10.1016/j.jpeds.2021.11.058Mccullough, Wynn, Procter, Clinical rationale for SARS-CoV-2 base spike protein detoxification in post COVID-19 and vaccine injury syndromes, J Am Physicians Surg
Murae, Shimizu, Yamamoto, The function of SARS-CoV-2 spike protein is impaired by disulfide-bond disruption with mutation at cysteine-488 and by thiol-reactive N-acetyl-cysteine and glutathione, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2022.01.106Nag, Banerjee, Paul, Kundu, Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study, Comput Biol Med,
doi:10.1016/j.compbiomed.2022.105552Oba, Rongduo, Saito, Natto extract, a Japanese fermented soybean food, directly inhibits viral infections including SARS-CoV-2 in vitro, Biochem Biophys Res Commun,
doi:10.1016/j.bbrc.2021.07.034Oh, Cho, Barcelon, Kim, Hong et al., SARS-CoV-2 spike protein induces cognitive deficit and anxiety-like behavior in mouse via non-cell autonomous hippocampal neuronal death, Sci Rep,
doi:10.1038/s41598-022-09410-7Omoboyowa, Balogun, Chukwudozie, SARS-CoV-2 spike glycoprotein as inhibitory target for Insilico screening of natural compounds, Biointerface Res Appl Chem,
doi:10.33263/BRIAC116.1497414985Palestra, Poto, Ciardi, SARS-CoV-2 spike protein activates human lung macrophages, Int J Mol Sci,
doi:10.3390/ijms24033036Pandey, Rane, Chatterjee, Kumar, Khan et al., Targeting SARS-CoV-2 spike protein of COVID-19 with naturally occurring phytochemicals: an in silico study for drug development, J Biomol Struct Dyn,
doi:10.1080/07391102.2020.1796811Parry, Lefringhausen, Turni, Neil, Cosford et al., Spikeopathy': COVID-19 spike protein is pathogenic, from both virus and vaccine mRNA, Biomedicines,
doi:10.3390/biomedicines11082287Patel, Kaki, Potluri, Kahar, Khanna, A comprehensive review of SARS-CoV-2 vaccines: Pfizer, Moderna & Johnson & Johnson, Hum Vaccin Immunother,
doi:10.1080/21645515.2021.2002083Patterson, Francisco, Yogendra, Persistence of SARS CoV-2 S1 protein in CD16+ monocytes in post-acute sequelae of COVID-19 (PASC) up to 15 months post-infection, Front Immunol,
doi:10.3389/fimmu.2021.746021Perico, Morigi, Pezzotta, SARS-CoV-2 spike protein induces lung endothelial cell dysfunction and thrombo-inflammation depending on the C3a/C3a receptor signalling, Sci Rep,
doi:10.1038/s41598-023-38382-5Praditya, Kirchhoff, Brüning, Rachmawati, Steinmann et al., Anti-infective properties of the golden spice curcumin, Front Microbiol,
doi:10.3389/fmicb.2019.00912Rabbani, Parikh, Rafique, Colchicine for the treatment of myocardial injury in patients with coronavirus disease 2019 (COVID-19)-an old drug with new life?, JAMA Netw Open,
doi:10.1001/jamanetworkopen.2020.13556Robles, Zamora, Castro, Siqueiros-Marquez, De La Escalera et al., The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB signaling, J Biol Chem,
doi:10.1016/j.jbc.2022.101695Rowan, Buttle, Barrett, The cysteine proteinases of the pineapple plant, Biochem J
Sadeghizadeh, Asadollahi, Jahangiri, Promising clinical outcomes of nano-curcumin treatment as an adjunct therapy in hospitalized COVID-19 patients: a randomized, double-blinded, placebo-controlled trial, Phytother Res,
doi:10.1002/ptr.7844Said, Al-Otaibi, Aljaloud, Al-Anazi, Alsolami et al., The frequency and patterns of post-COVID-19 vaccination syndrome reveal initially mild and potentially Immunocytopenic signs in primarily young Saudi women, Vaccines,
doi:10.3390/vaccines10071015Schroeder, Bieneman, The S1 subunit of the SARS-CoV-2 spike protein activates human monocytes to produce cytokines linked to COVID-19: relevance to galectin-3, Front Immunol,
doi:10.3389/fimmu.2022.831763Sheng, Yang, Wang, Sun, Yan, Microbial nattokinase: from synthesis to potential application, Food Funct,
doi:10.1039/d2fo03389eShrestha, Venkataraman, The prevalence of post-COVID-19 vaccination syndrome and quality of life among COVID-19-vaccinated individuals, IN PRESS,
doi:10.1016/j.vacun.2023.10.002Sogut, Can, Guven, Safety and efficacy of hydroxychloroquine in 152 outpatients with confirmed COVID-19: a pilot observational study, Am J Emerg Med,
doi:10.1016/j.ajem.2020.12.014Speciale, Muscarà, Molonia, Cimino, Saija et al., Silibinin as potential tool against SARS-CoV-2: in silico spike receptor-binding domain and main protease molecular docking analysis, and in vitro endothelial protective effects, Phytother Res,
doi:10.1002/ptr.7107Tardif, Bouabdallaoui, Allier, Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial, Lancet Respir Med,
doi:10.1016/S2213-2600(21)00222-8Tenório, Graciliano, Moura, Oliveira, Goulart, N-acetylcysteine (NAC): impacts on human health, Antioxidants,
doi:10.3390/antiox10060967Tuli, Sood, Pundir, Molecular docking studies of apigenin, kaempferol, and quercetin as potential target against spike receptor protein of SARS CoV, J Exp Biol Agric Sci,
doi:10.18006/2022.10(1).144.149Turner, Khan, Putrino, Woodcock, Kell et al., Long COVID: pathophysiological factors and abnormalities of coagulation, Trends Endocrinol Metab,
doi:10.1016/j.tem.2023.03.002Vettori, Dima, Henry, Effects of different types of recombinant SARS-CoV-2 spike protein on circulating monocytes' structure, Int J Mol Sci,
doi:10.3390/ijms24119373Yasmin, Najeeb, Moeed, Safety and efficacy of colchicine in COVID-19 patients: a systematic review and meta-analysis of randomized control trials, PLoS One,
doi:10.1371/journal.pone.0266245Yuan, Pavel, Wang, Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Commun Biol,
doi:10.1038/s42003-022-03841-8Zeng, Li, Deng, SARS-CoV-2 spike spurs intestinal inflammation via VEGF production in enterocytes, EMBO Mol Med,
doi:10.15252/emmm.202114844Zheng, Zhao, Li, SARS-CoV-2 spike protein causes blood coagulation and thrombosis by competitive binding to heparan sulfate, Int J Biol Macromol,
doi:10.1016/j.ijbiomac.2021.10.112
