Dr. Khalid is a health researcher and science writer with a Ph.D. in clinical research.
The long-term sustenance of coronavirus disease 2019 (COVID-19) complications increases the risk of critical illnesses and reduces the quality-adjusted life years of the treated patients. The multifactorial systems biology approaches utilize computational simulations to predict the complex pathophysiological pathways of the SARS-CoV-2 virus based on its interactions with the host cell lines.
An extensive literature search via CINAHL, Web of Science, Cochrane library, Google Scholar, JSTOR, and PubMed/Medline revealed Long COVID virulence, pathophysiology, and deleterious complications that require multifactorial management via systems biology approaches.
The findings signified the role of pharmacotherapies, diagnostic modalities, immunoinformatic strategies, genomics, metabolomics, transcriptomics, proteomics, immunomics, and lipid identification techniques in improving the recovery and post-recovery experiences of patients with COVID-19 infection.
Keywords: SARS-CoV-2, COVID-19, Systems Biology, Long COVID Treatment, Multi-omics
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is the predominant cause of coronavirus disease 2019 (COVID-19) whose adversities continue to disrupt human life across multiple dimensions . The World Health Organization declared COVID-19 a pandemic situation on 11th March 2020, while its rapid progression followed by global lockdowns challenged human survival to an unprecedented scale . The global health emergency potentiated by COVID-19 resulted in profound clinical complications and cardiovascular mortality in the infected patients.
The progressive worsening of the lower respiratory tract manifestations after rapid replication of SARS-CoV-2 occurs due to inflammatory cell infiltrates, chemokine responses, and pro-inflammatory cytokines . The contemporary literature demonstrates the progressive worsening of the immune system responses in patients with COVID-19 infection. In addition, the post-acute sequelae in immunocompromised patients add to their risk of morbidity and mortality . The Long COVID condition develops due to the prolonged persistence of COVID-19 symptoms or potential complications that reduce the quality-adjusted life years and recovery paradigm. The frequently reported complications in Long COVID cases include inattention, trouble focusing, myalgia, palpitations, breathlessness, chest tightness, hoarse voice, cough, and fatigue. The deleterious morbidities include post-critical syndrome, post-viral syndrome, and multiple organ failure .
The epidemic progression of COVID-19 continues to increase the risk and incidence of sudden cardiac death, life-threatening arrhythmias, cardiac failure, myocardial infarction, microvascular injury, myocardial flow reserve impairment, pericarditis, myocarditis, blood pressure fluctuations, and labile heart rate . The neuropsychiatric complications of Long COVID include cognitive blunting, tremors, headache, posttraumatic stress disorder, depression, anxiety, and peripheral nerve dysfunction. The patients with Long COVID who received prone ventilation experience a high risk of multifocal peripheral nerve injury. Young patients experience a risk of encephalitis or encephalopathy. The prolonged mechanical ventilation in critically ill COVID-19 patients predisposes them to delirium, neuropathies, myopathies, deconditioning, and ICU-acquired weakness . Other long-term complications include arteriovenous thrombosis, coagulopathy, autoreactivity against self-antigens, and inflammatory arthralgia . These conditions substantially increase the disability-adjusted life years of patients and reduce their life expectancy and treatment satisfaction.
The post-COVID syndromes warrant systematic medical management through multidisciplinary systems biology approaches to minimize the incidence of cardiovascular, metabolic, neuromuscular, cerebrovascular, and pulmonary complications . The recent investigations aim to unravel multi-level systems pathology in COVID-19 patients by exploring their general metabolism, genetics, immune responses, endocrine system, and neurophysiology . The primary goal of these assessments is to improve the survival rate, prognostic outcomes, recovery patterns, and quality of life in patients with a known history of COVID-19 infection. This perspective paper critically examines the evidence-based systems biology approaches and their implications in the therapeutic management of Long COVID complications.
Virulence and Pathophysiology of Long COVID
SARS-CoV-2 is a positive-sense single-stranded RNA virus that utilizes angiotensin-converting enzyme 2 (ACE2) for invading the host defense mechanisms . The virus antigen is identified by cytotoxic T lymphocytes and major histocompatibility complex. Thorough knowledge of the antigen presentation of the SARS-CoV-2 virus is paramount to understanding its virulence and pathophysiology. The cytokine production and hyper-inflammation in Long COVID cases are the outcomes of an elevated HLA-DR expression potentiated by IL-6 accumulation. SARS-CoV-2 virus disrupts the renin-angiotensin-aldosterone system (RAAS) and deteriorates the host immune responses in the infected patients . The hyper inflammation and RAAS imbalance often result in coagulopathy and acute lung injury in patients with COVID-19 infection. These abnormalities deteriorate the fluid balance and blood pressure regulation, thereby increasing the risk of immunothrombosis and fibrinolysis. The persistence of COVID-19 symptoms for a longer term in COVID-19 patients predisposes them to acute respiratory distress syndrome and multiple organ failure. The high adaptability of the SARS-CoV-2 virus in the host cells is a predominant cause of Long COVID manifestations in the infected patients. The infection of macrophages and pneumocytes by SARS-CoV-2 and virus-induced dysregulation of angiotensin-converting enzyme (ACE2) receptor on the extra-pulmonary surface leads to a substantial loss of pulmonary function . The virus-infected cells undergo furin-mediated S1/S2 cleavage potentiated by the vital host factor TMPRSS2. The currently developed treatments aim to deactivate the TMPRSS2 function to restrict the survival of the SARS-CoV-2 virus in the host cell lines . However, SARS-CoV-2-specific virulence is noticeably higher in patients with pre-existing cardiometabolic diseases and respiratory conditions. The SARS-CoV-2 variants reported to date include Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron (B.1.1.529), Epsilon (B.1.429/B.1.427), Zeta (P.2), Iota (B.1.526), Theta (P.3), Kappa (B.1.617.1), Lambda (C.37), and Mu (B.1.621) lineages . Figure-1 effectively summarizes Long COVID causes and their deleterious complications.
Long COVID Treatment
The clinical studies indicate the therapeutic effectiveness of interferon (IFN)-α, peptide (EK1), ganciclovir, ritonavir, lopinavir, oseltamivir, RNA synthesis inhibitors, and neuraminidase inhibitors in COVID-19 infection . The antiviral drugs including chloroquine and remdesivir align with RNA-dependent RNA polymerase for restricting the viral RNA synthesis. The nucleoside analogs including galidesivir, ribavirin, and favipiravir also restrict the pathogenesis of COVID-19 and help minimize its long-term complications . The host immune response inhibition via papain-like protease, chymotrypsin, and other non-structural proteins facilitates the replication of the SARS-CoV-2 virus in the host cell lines. The drugs including PLP inhibitors, flavonoids, and cinanserin potentially challenge COVID-19 infection progression by actively inhibiting these protein molecules . The recent evidence also substantiates the role of other drugs including methylprednisolone, mycophenolate mofetil, hexamethylene-amiloride, chlorpromazine, amodiaquine-dihydrochloride, lycorine, emetine, mycophenolic acid, and pyrvinium-pamoate in blocking viral activity and reducing the incidence of Long COVID complications . In addition, expectorants and paracetamol administration is the first-line approach to manage cough, fever, and other preliminary symptoms. The complex conditions, including hypoxemia and respiratory conditions, require oxygen management to reduce the risk of morbidity and mortality. Long COVID also develops due to the coexisting fungal and bacterial infections that require systematic management through evidence-based treatments. Glucocorticoid therapy is the preferred treatment option to manage the immunosuppressed status of COVID-19 infected patients . The prophylactic management through DNA vaccines, viral vector vaccines, attenuated viruses, and subunit vaccines also aims to minimize long COVID manifestations in the predisposed patients. The existing therapies aiming at the therapeutic management of Long COVID help improve its cardiorespiratory, gastrointestinal, hepatobiliary, thromboembolic, neuropsychiatric, and skin manifestations. They also assist in minimizing treatment side-effects and improving the lived experiences and quality of life of patients with critical illnesses. The treatment algorithms for Long COVID management depend on laboratory findings and patient-reported outcomes. The rapid expansion of telehealth applications continues to improve long-term treatment follow-ups and prognostic outcomes in COVID-19 scenarios .
The diagnostic assessment of COVID-19 biomarkers is the key to managing Long COVID outcomes . These biomarkers include hemoglobin, lactate dehydrogenase, C-reactive protein (CRP), interleukin-6, CD4+/CD8+ cells, neutrophils, cytokines, chemokines, procalcitonin, prothrombin time, activated partial thromboplastin time, D-dimer, fibrinogen, cardiac troponin, brain natriuretic peptide, aspartate/alanine aminotransferase, albumin, bilirubin, myoglobin, creatine kinase, serum creatinine, and electrolytes. The requirement of mechanical ventilation and ICU admission is determined by ferritin/transferrin ratio, while hemoglobin assessment predicts the mortality risk by ruling out altered iron homeostasis and anemia . The lymphocyte, CD8+, CD4+, and peripheral blood leukocyte assessment in Long COVID cases is paramount to evaluating cytokine storm, inflammatory mediators, and lymphocytopenia . The neutrophil count provides an estimate of the risk and incidence of ICU admissions in patients with COVID-19 complications. COVID pneumonia assessment depends on evaluating serum eosinophil-derived neurotoxin and eosinophil levels . The evaluation of platelets is paramount to ruling out the risk of thrombocytosis and thrombocytopenia. In addition, a marked reduction in the lymphocyte count and increase in TNF-α, IL-10, IL-8, IL-6, IL-2r, procalcitonin, ferritin, CRP, neutrophils, and leukocytes predicts the Long COVID adversities in the infected patients . The high levels of NT-proBNP, Mb, cTnI, and CK-MB prognosticate myocardial injury and cardiovascular mortality in Long COVID scenarios . The vascular endothelial growth factor expression and reduction in serum albumin total mass predict hypoalbuminemia in patients with Long COVID. The intensive care requirement and worsening of acute respiratory distress syndrome clinically correlate with high LDH levels. The Long COVID symptoms also correlate with elevated protein and urine/blood glucose levels . The decision of evaluating specific biomarkers in Long COVID patients reciprocates with their symptomatology, treatment course, clinical history, and demographic variables.
Systems Biology Applications in Long COVID Management
The systems biology approaches utilize outcomes from in silico studies, databases, and multi-omics to evaluate COVID-19 pathophysiology and prognoses . Computational biology guides the assessment of protein-protein interactions to understand the possible Long COVID complications in the infected patients. The epigenomic concepts help predict heritable phenotypic alterations and their impact on COVID-19 complications . They also determine phenotypic and genetic modulations by unraveling covalent modifications in lysine ubiquitination, threonine/serine phosphorylation, and lysine methylation/acetylation. The extrapulmonary ACE2 alterations and immune responses in Long COVID patients require a computational assessment to determine the transmissibility and virulence of the SARS-CoV-2 virus. The computational interventions also determine the possible drug designs, diagnostic interventions, and treatment algorithms to improve the health, wellness, and recovery of patients based on their Long COVID predisposition . Computational biology and bioinformatics approaches predict host-virus interactions in a variety of patients. They also determine viral replication processes across mucous and oral surfaces and their impact on innate and acquired immunity. The computational simulations predict cytokine storm, macrophage fluctuations, reactive oxygen species, and their impact on blood pressure, breathing patterns, and immune responses in Long COVID cases . In addition, the Ramachandran plot and SWISS-MODEL determine amino acid patterns of the host cells and SARS-CoV-2 virus and their influence on ACE-2 activity .
Systems Biology Approach to COVID-19 Vaccines
The development of novel vaccines for COVID-19 prophylaxis and medical management relies on structural vaccinology, rational vaccinology, epitope prediction, reverse vaccinology, and other immunoinformatic strategies . The in-silico tools like GLIMMER, GS FINDER, ORF-FINDER, RAPER, RAMBLE, SCAP, and SCWRL help optimize the design, structure, and function of potential vaccine candidates for COVID-19 management . A variety of machine learning approaches facilitate the analysis of SARS-CoV-2 T-cell and B-cell epitopes to develop viable vaccines. The procedures and techniques based on antibodyomics, codon optimization, multivalent scaffolding, and multi-grafting help achieve significant milestones in the vaccine development process . In addition, assessment of pSTAT1, pSTAT3, IFN- y, CD16+/CD14+ inflammatory monocytes, and innate immune responses of the patients who receive COVID-19 vaccines helps determine their long-term outcomes .
The Role of Multi-omics in Long COVID Treatment
The assessment of gene expressions in the SARS-CoV-2 virus via high throughput DNA microarrays, RNA sequencing, and ribosome profiling guides the development of dose-response models for Long COVID management . The transcriptomics approaches also help analyze infection progression and long-term outcomes by analyzing viral mRNA expression and responsiveness in the host cell lines . The diagnostic modalities including mass spectrometry, high-performance liquid chromatography, and nuclear magnetic resonance help evaluate metabolic profiles of patients with Long COVID. The metabolomics interventions determine novel drug development pathways that aim to counter the progressive worsening of COVID-19 infections in patient populations .
The assessment of genome sequences of the coronaviridae family by comparative genomic approaches helps determine the virulence and progression of SARS-CoV-2 variants . The genomic strategies also predict the role of secondary bacterial infection, kidney injury, liver complications, myocardial injury, coagulation cascade, and cellular immune deficiency in deteriorating COVID-19 prognosis. They also guide the development of prodrugs and monoclonal antibodies to counter the ACE2 receptor structure and configuration for minimizing its interaction with the SARS-CoV-2 virus . They help improve disease containment strategies that aim to minimize virus replication and reduce the incidence of human-to-human transmission.
The immunomics approaches help determine the etiology of lethal pneumonia in patients with Long COVID . The assessment of T1-IFN, monocyte-macrophage interactions, inflammatory processes, and their role in immune system dysregulation determines the fate of SARS-CoV-2 variants in the host cell lines. The formulation of potential vaccine candidates against COVID-19 depends on exploring potential immune targets via sequence homology . The immune response modulation by targeting viral and host carbohydrates/proteins is another potential strategy to reduce the risk and incidence of Long COVID outcomes.
The protein identification technique like mass spectrometry unravels the structure and function of complex viral peptides . The specificity and sensitivity assessment of the replicase polyprotein 1 ab and spike glycoprotein helps analyze viral progression in RT-PCR negative patients. The proteome analysis via chemical labeling techniques helps explore virus replication pathway and their interactions with carbon metabolism, splicing, translation, nucleic acid metabolism, and proteostasis. The protein microarrays effectively facilitate drug-drug identification, DNA–protein interactions, and protein-protein interactions in patients at high risk of Long COVID complications . The tissue microarrays guide the tissue expression profiling and cDNA assessment in patients with COVID-19 and life-threatening comorbidities. The X-ray crystallography and nuclear magnetic resonance are robust techniques that unravel the structure and function of viral glycoproteins in host cell lines .
The lipid identification techniques determine changes in arachidonic and linoleic acid metabolisms in COVID-19 scenarios . They also predict virus replication by examining its double-membrane vesicles and their impact on cytosolic phospholipase A2α and primary lipid processing enzymes. The lipid assessment also predicts the replication, transmission, assemblage, and trafficking of the viral protein. The public health omics approaches further unravel host-antigen interactions and their long-term impact on host genes [13, 27]. They also guide the development of novel therapeutic approaches to improve the long-term management of COVID-19 infection.
The systems biology approaches to Long COVID management utilize multifactorial strategies guided by computational methods to understand the molecular interactions between virus particles and host cell lines. The development of novel treatment algorithms against Long COVID via multi-omics methods aims to improve the treatment outcomes and reduce the risk of preventable complications. The computational simulations effectively unravel intricate molecular pathways of SARS-CoV-2 variants to help enhance robust treatment algorithms for Long COVID management. Future studies should expand the assessment of systems biology algorithms and validate omics methods that claim to minimize post-recovery complications in patients with COVID-19 infection.
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© 2022 Dr Khalid Rahman