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Effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in patients with moderate to severe COVID-19.
Fernandes, AL, Murai, IH, Reis, BZ, Sales, LP, Santos, MD, Pinto, AJ, Goessler, KF, Duran, CSC, Silva, CBR, Franco, AS, et al
The American journal of clinical nutrition. 2022;(3):790-798
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Abstract
BACKGROUND The modulating effect of vitamin D on cytokine concentrations in severe coronavirus disease 2019 (COVID-19) remains unknown. OBJECTIVES We aimed to investigate the effect of a single high dose of vitamin D3 on cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19. METHODS This is a post hoc, ancillary, and exploratory analysis from a multicenter, double-blind, placebo-controlled, randomized clinical trial. Patients with moderate to severe COVID-19 were recruited from 2 hospitals in São Paulo, Brazil. Of 240 randomly assigned patients, 200 were assessed in this study and randomly assigned to receive a single oral dose of 200,000 IU vitamin D3 (n = 101) or placebo (n = 99). The primary outcome was hospital length of stay, which has been published in our previous study. The prespecified secondary outcomes were serum concentrations of IL-1β, IL-6, IL-10, TNF-α, and 25-hydroxyvitamin D. The post hoc exploratory secondary outcomes were IL-4, IL-12p70, IL-17A, IFN-γ, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IFN-inducible protein-10 (IP-10), macrophage inflammatory protein-1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and leukocyte count. Generalized estimating equations for repeated measures, with Bonferroni's adjustment, were used for testing all outcomes. RESULTS The study included 200 patients with a mean ± SD age of 55.5 ± 14.3 y and BMI of 32.2 ± 7.1 kg/m2, of which 109 (54.5%) were male. GM-CSF concentrations showed a significant group-by-time interaction effect (P = 0.04), although the between-group difference at postintervention after Bonferroni's adjustment was not significant. No significant effects were observed for the other outcomes. CONCLUSIONS The findings do not support the use of a single dose of 200,000 IU vitamin D3, compared with placebo, for the improvement of cytokines, chemokines, and growth factor in hospitalized patients with moderate to severe COVID-19.This trial was registered at clinicaltrials.gov as NCT04449718.
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Vitamin D attenuates COVID-19 complications via modulation of proinflammatory cytokines, antiviral proteins, and autophagy.
Gilani, SJ, Bin-Jumah, MN, Nadeem, MS, Kazmi, I
Expert review of anti-infective therapy. 2022;(2):231-241
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INTRODUCTION Global emergence of coronavirus disease-19 (COVID-19) has clearly shown variable severity, mortality, and frequency between and within populations worldwide. These striking differences have made many biological variables attractive for future investigations. One of these variables, vitamin D, has been implicated in COVID-19 with rapidly growing scientific evidence. AREAS COVERED The review intended to systematically explore the sources, and immunomodulatory role of vitamin D in COVID-19. Search engines and data sources including Google Scholar, PubMed, NCBI, Scopus, and Web of Science were used for data collection. The search terms used were Vitamin D, COVID-19, immune system, and antiviral mechanism. Overall, 232 sources of information were collected and 188 were included in this review. EXPERT OPINION Interaction of vitamin D and vitamin D receptor (VDR) triggers the cellular events to modulate the immune system by regulation of many genes. Vitamin D operates as a double-edged sword against COVID-19. First, in macrophages, it promotes the production of antimicrobial and antiviral proteins like β-defensin 2 and cathelicidin, and these proteins inhibit the replication of viral particles and promote the clearance of virus from the cells by autophagy. Second, it suppresses cytokine storm and inflammatory processes in COVID-19.
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Elderberry for prevention and treatment of viral respiratory illnesses: a systematic review.
Wieland, LS, Piechotta, V, Feinberg, T, Ludeman, E, Hutton, B, Kanji, S, Seely, D, Garritty, C
BMC complementary medicine and therapies. 2021;(1):112
Abstract
BACKGROUND Elderberry has traditionally been used to prevent and treat respiratory problems. During the COVID-19 pandemic, there has been interest in elderberry supplements to treat or prevent illness, but also concern that elderberry might overstimulate the immune system and increase the risk of 'cytokine storm'. We aimed to determine benefits and harms of elderberry for the prevention and treatment of viral respiratory infections, and to assess the relationship between elderberry supplements and negative health impacts associated with overproduction of pro-inflammatory cytokines. METHODS We conducted a systematic review and searched six databases, four research registers, and two preprint sites for studies. Two reviewers independently assessed studies for inclusion, extracted data from studies, assessed risk of bias using Cochrane tools, and evaluated certainty of estimates using GRADE. Outcomes included new illnesses and the severity and duration of illness. RESULTS We screened 1187 records and included five randomized trials on elderberry for the treatment or prevention of viral respiratory illness. We did not find any studies linking elderberry to clinical inflammatory outcomes. However, we found three studies measuring production of cytokines ex vivo after ingestion of elderberry. Elderberry may not reduce the risk of developing the common cold; it may reduce the duration and severity of colds, but the evidence is uncertain. Elderberry may reduce the duration of influenza but the evidence is uncertain. Compared to oseltamivir, an elderberry-containing product may be associated with a lower risk of influenza complications and adverse events. We did not find evidence on elderberry and clinical outcomes related to inflammation. However, we found evidence that elderberry has some effect on inflammatory markers, although this effect may decline with ongoing supplementation. One small study compared elderberry to diclofenac (a nonsteroidal anti-inflammatory drug) and provided some evidence that elderberry is as effective or less effective than diclofenac in cytokine reduction over time. CONCLUSIONS Elderberry may be a safe option for treating viral respiratory illness, and there is no evidence that it overstimulates the immune system. However, the evidence on both benefits and harms is uncertain and information from recent and ongoing studies is necessary to make firm conclusions.
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Conditions Favoring Increased COVID-19 Morbidity and Mortality: Their Common Denominator and its Early Treatment.
Shevel, E
Missouri medicine. 2021;(2):113-115
Abstract
The factors contributing to increased morbidity and mortality in SARS-CoV-2 infection are diverse, and include diabetes, obesity, Chronic Obstructive Pulmonary Disease (COPD), advanced age, and male sex. Although there is no obvious connection between these, they do have one common denominator-they all have a tendency towards lower urine pH, which may indicate a lower-than-normal tissue pH. Furthermore, it has been shown that lower pH has two important negative influences: 1) it enhances viral fusion via the endosomal route, thereby facilitating viral multiplication; and 2) it facilitates increased production of inflammatory cytokines, thereby exacerbating the cytokine storm. This paper discusses published literature on lower tissue/interstitial pH in those diseases/co-morbidities that are known risk factors of severe COVID-19, and hypothesize that small doses of baking soda could be a simple, cost-effective, and rapid method of reducing both morbidity and mortality in COVID-19 patients.
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Cascade of immune mechanism and consequences of inflammatory disorders.
Megha, KB, Joseph, X, Akhil, V, Mohanan, PV
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2021;:153712
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Inflammatory responses arise as an outcome of tissues or organs exposure towards harmful stimuli like injury, toxic chemicals or pathogenic microorganism. It is a complex cascade of immune mechanism to overcome from tissue injury and to initiate the healing process by recruiting various immune cells, chemical mediators such as the vasoactive peptides and amines, pro-inflammatory cytokines, eicosanoids and acute-phase proteins to prevent tissue damage and ultimately complete restoration of the tissue function. The cytokines exhibits a central function in communication between the cells, inflammatory response initiation, amplification and their regulation. This review covers the importance of inflammatory responses; the significance of cytokines in inflammation and numerous inflammatory disorders/ailments due to the abrupt expression of cytokines and the hyper-inflammatory response or cytokine storm associated with poor prognosis in COVID-19 pandemic. Also highlighting the importance of naturally derived anti-inflammatory metabolites to overcome the side-effects of currently prevailing anti-inflammatory drugs.
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COVID-19, cytokines, inflammation, and spices: How are they related?
Kunnumakkara, AB, Rana, V, Parama, D, Banik, K, Girisa, S, Henamayee, S, Thakur, KK, Dutta, U, Garodia, P, Gupta, SC, et al
Life sciences. 2021;:119201
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BACKGROUND Cytokine storm is the exaggerated immune response often observed in viral infections. It is also intimately linked with the progression of COVID-19 disease as well as associated complications and mortality. Therefore, targeting the cytokine storm might help in reducing COVID-19-associated health complications. The number of COVID-19 associated deaths (as of January 15, 2021; https://www.worldometers.info/coronavirus/) in the USA is high (1199/million) as compared to countries like India (110/million). Although the reason behind this is not clear, spices may have some role in explaining this difference. Spices and herbs are used in different traditional medicines, especially in countries such as India to treat various chronic diseases due to their potent antioxidant and anti-inflammatory properties. AIM: To evaluate the literature available on the anti-inflammatory properties of spices which might prove beneficial in the prevention and treatment of COVID-19 associated cytokine storm. METHOD A detailed literature search has been conducted on PubMed for collecting information pertaining to the COVID-19; the history, origin, key structural features, and mechanism of infection of SARS-CoV-2; the repurposed drugs in use for the management of COVID-19, and the anti-inflammatory role of spices to combat COVID-19 associated cytokine storm. KEY FINDINGS The literature search resulted in numerous in vitro, in vivo and clinical trials that have reported the potency of spices to exert anti-inflammatory effects by regulating crucial molecular targets for inflammation. SIGNIFICANCE As spices are derived from Mother Nature and are inexpensive, they are relatively safer to consume. Therefore, their anti-inflammatory property can be exploited to combat the cytokine storm in COVID-19 patients. This review thus focuses on the current knowledge on the role of spices for the treatment of COVID-19 through suppression of inflammation-linked cytokine storm.
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SARS-CoV-2 infection as a trigger of humoral response against apolipoprotein A-1.
Pagano, S, Yerly, S, Meyer, B, Juillard, C, Suh, N, Le Terrier, C, Daguer, JP, Farrera-Soler, L, Barluenga, S, Piumatti, G, et al
European journal of clinical investigation. 2021;(11):e13661
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BACKGROUND Unravelling autoimmune targets triggered by SARS-CoV-2 infection may provide crucial insights into the physiopathology of the disease and foster the development of potential therapeutic candidate targets and prognostic tools. We aimed at determining (a) the association between anti-SARS-CoV-2 and anti-apoA-1 humoral response and (b) the degree of linear homology between SARS-CoV-2, apoA-1 and Toll-like receptor 2 (TLR2) epitopes. DESIGN Bioinformatics modelling coupled with mimic peptides engineering and competition experiments were used to assess epitopes sequence homologies. Anti-SARS-CoV-2 and anti-apoA-1 IgG as well as cytokines were assessed by immunoassays on a case-control (n = 101), an intensive care unit (ICU; n = 126) and a general population cohort (n = 663) with available samples in the pre and post-pandemic period. RESULTS Using bioinformatics modelling, linear sequence homologies between apoA-1, TLR2 and Spike epitopes were identified but without experimental evidence of cross-reactivity. Overall, anti-apoA-1 IgG levels were higher in COVID-19 patients or anti-SARS-CoV-2 seropositive individuals than in healthy donors or anti-SARS-CoV-2 seronegative individuals (P < .0001). Significant and similar associations were noted between anti-apoA-1, anti-SARS-CoV-2 IgG, cytokines and lipid profile. In ICU patients, anti-SARS-CoV-2 and anti-apoA-1 seroconversion rates displayed similar 7-day kinetics, reaching 82% for anti-apoA-1 seropositivity. In the general population, SARS-CoV-2-exposed individuals displayed higher anti-apoA-1 IgG seropositivity rates than nonexposed ones (34% vs 16.8%; P = .004). CONCLUSION COVID-19 induces a marked humoral response against the major protein of high-density lipoproteins. As a correlate of poorer prognosis in other clinical settings, such autoimmunity signatures may relate to long-term COVID-19 prognosis assessment and warrant further scrutiny in the current COVID-19 pandemic.
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Distinct cytokine profiles associated with COVID-19 severity and mortality.
Dorgham, K, Quentric, P, Gökkaya, M, Marot, S, Parizot, C, Sauce, D, Guihot, A, Luyt, CE, Schmidt, M, Mayaux, J, et al
The Journal of allergy and clinical immunology. 2021;(6):2098-2107
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BACKGROUND Markedly elevated levels of proinflammatory cytokines and defective type-I interferon responses were reported in patients with coronavirus disease 2019 (COVID-19). OBJECTIVE We sought to determine whether particular cytokine profiles are associated with COVID-19 severity and mortality. METHODS Cytokine concentrations and severe acute respiratory syndrome coronavirus 2 antigen were measured at hospital admission in serum of symptomatic patients with COVID-19 (N = 115), classified at hospitalization into 3 respiratory severity groups: no need for mechanical ventilatory support (No-MVS), intermediate severity requiring mechanical ventilatory support (MVS), and critical severity requiring extracorporeal membrane oxygenation (ECMO). Principal-component analysis was used to characterize cytokine profiles associated with severity and mortality. The results were thereafter confirmed in an independent validation cohort (N = 86). RESULTS At time of hospitalization, ECMO patients presented a dominant proinflammatory response with elevated levels of TNF-α, IL-6, IL-8, and IL-10. In contrast, an elevated type-I interferon response involving IFN-α and IFN-β was characteristic of No-MVS patients, whereas MVS patients exhibited both profiles. Mortality at 1 month was associated with higher levels of proinflammatory cytokines in ECMO patients, higher levels of type-I interferons in No-MVS patients, and their combination in MVS patients, resulting in a combined mortality prediction accuracy of 88.5% (risk ratio, 24.3; P < .0001). Severe acute respiratory syndrome coronavirus 2 antigen levels correlated with type-I interferon levels and were associated with mortality, but not with proinflammatory response or severity. CONCLUSIONS Distinct cytokine profiles are observed in association with COVID-19 severity and are differentially predictive of mortality according to oxygen support modalities. These results warrant personalized treatment of COVID-19 patients based on cytokine profiling.
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Blood purification therapy with a hemodiafilter featuring enhanced adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study.
Villa, G, Romagnoli, S, De Rosa, S, Greco, M, Resta, M, Pomarè Montin, D, Prato, F, Patera, F, Ferrari, F, Rotondo, G, et al
Critical care (London, England). 2020;(1):605
Abstract
BACKGROUND Systemic inflammation in COVID-19 often leads to multiple organ failure, including acute kidney injury (AKI). Renal replacement therapy (RRT) in combination with sequential extracorporeal blood purification therapies (EBP) might support renal function, attenuate systemic inflammation, and prevent or mitigate multiple organ dysfunctions in COVID-19. AIM: Describe overtime variations of clinical and biochemical features of critically ill patients with COVID-19 treated with EBP with a hemodiafilter characterized by enhanced cytokine adsorption properties. METHODS An observational prospective study assessing the outcome of patients with COVID-19 admitted to the ICU (February to April 2020) treated with EBP according to local practice. Main endpoints included overtime variation of IL-6 and multiorgan function-scores, mortality, and occurrence of technical complications or adverse events. RESULTS The study evaluated 37 patients. Median baseline IL-6 was 1230 pg/ml (IQR 895) and decreased overtime (p < 0.001 Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 24 h (p = 0.001). The reduction in serum IL-6 concentrations correlated with the improvement in organ function, as measured in the decrease of SOFA score (rho = 0.48, p = 0.0003). Median baseline SOFA was 13 (IQR 6) and decreased significantly overtime (p < 0.001 at Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 48 h (median 8 IQR 5, p = 0.001). Compared to the expected mortality rates, as calculated by APACHE IV, the mean observed rates were 8.3% lower after treatment. The best improvement in mortality rate was observed in patients receiving EBP early on during the ICU stay. Premature clotting (running < 24 h) occurred in patients (18.9% of total) which featured higher effluent dose (median 33.6 ml/kg/h, IQR 9) and higher filtration fraction (median 31%, IQR 7.4). No electrolyte disorders, catheter displacement, circuit disconnection, unexpected bleeding, air, or thromboembolisms due to venous cannulation of EBP were recorded during the treatment. In one case, infection of vascular access occurred during RRT, requiring replacement. CONCLUSIONS EBP with heparin-coated hemodiafilter featuring cytokine adsorption properties administered to patients with COVID-19 showed to be feasible and with no adverse events. During the treatment, patients experienced serum IL-6 level reduction, attenuation of systemic inflammation, multiorgan dysfunction improvement, and reduction in expected ICU mortality rate.
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Does intestinal dysbiosis contribute to an aberrant inflammatory response to severe acute respiratory syndrome coronavirus 2 in frail patients?
Terruzzi, I, Senesi, P
Nutrition (Burbank, Los Angeles County, Calif.). 2020;:110996
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In a few months, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become the main health problem worldwide. Epidemiologic studies revealed that populations have different vulnerabilities to SARS-CoV-2. Severe outcomes of the coronavirus disease 2019 (COVID-19) with an increased risk of death are observed in patients with metabolic syndrome, as well as diabetic and heart conditions (frail population). Excessive proinflammatory cytokine storm could be the main cause of increased vulnerability in this frail population. In patients with diabetes and/or heart disease, a low inflammatory state is often associated with gut dysbiosis. The increase amount of microbial metabolites (i.e., trimethylamine N-oxide and lipopolysaccharide), which generate an inflammatory microenvironment, is probably associated with an improved risk of severe illness from COVID-19. Nutritional interventions aimed at restoring the gut microbial balance could represent preventive strategies to protect the frail population from COVID-19. This narrative review presents the possible molecular mechanisms by which intestinal dysbiosis that enhances the inflammatory state could promote the spread of SARS-CoV-2 infection. Some nutritional strategies to counteract inflammation in frail patients are also analyzed.
