Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial
Abstract
:1. Introduction
2. Materials and Methods
2.1. Subject Selection
2.2. Trial Design and Supervision
- (1)
- B-complex: 10 mg of cyanocobalamin, 100 mg of thiamin, and 100 mg of pyridoxine administered intramuscularly every 24 h for the first 5 days.
- (2)
- NSS powder: one envelope orally after morning meals and another after evening meals, diluted in 400 mL of water each, during the whole intervention for a maximum of 21 days. Each envelope contained: Spirulina Maxima 2.5 g, folic acid 5 mg, glutamine 5 g, vegetable protein 10 g, constituted by two foods without processing or fragmenting in amino acids, brewer’s yeast, and amaranth, ascorbic acid 1 g, zinc 20 mg, selenium 100 mcg, cholecalciferol 2000 IU, resveratrol 200 mg, Omega-3 fatty acids 1 g, L-Arginine 750 mg, inulin 20 g, and magnesium 400 mg.
- (3)
- Probiotics: Saccharomyces boulardii (SB) 500 mg daily for 6 days orally.
2.3. Clinical and Laboratory Monitoring
2.4. Statistical Analysis
2.5. Sample Size
2.6. Ethical Aspects
3. Results
3.1. Baseline Results
3.2. Survival and Mortality of the Studied Patients
3.3. Follow-Up
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Specific Nutrients in the NSS | Dose | Function |
---|---|---|
Cyanocobalamin | 10 mg | B complex has demonstrated effects on immune response, proinflammatory cytokine levels, respiratory function, endothelial integrity, and hypercoagulability. B complex binding to the active site of the nsp 12 and 3C-like protein of SARS-CoV-2, blocking viral RNA transcription [15]. Thiamine inhibits carbonic anhydrase isoenzymes in vitro and could limit hypoxia and decrease hospitalization in early stages of COVID-19 [16]. Pyridoxine upregulates IL-10. Cobalamin modulates gut microbiota and low levels elevate methylmalonic acid and homocysteine, increasing inflammation, reactive oxygen species, and oxidative stress. Methylcobalamin forms adenosylcobalamin for mitochondrial energy production [17]. |
Thiamin | 100 mg | |
Pyridoxine | 100 mg | |
Spirulina Maxima | 5 g | Spirulina Maxima (SM) is a natural biological source of ACE inhibitory peptides, which are used to enhance ACE2 activity for the treatment of tissue injury of several organs in severe cases of coronavirus infection. ACE inhibitory peptides modulate oxidative stress, cytokine release syndrome, and tissue injury in SARS-CoV2 and other coronavirus infections through regulation of ACE2 activity [18]. C-phycocyanin, an extract of SM blocks in vitro hemagglutination of viruses such as influenza [15]. |
Folic acid | 5 mg | Folic acid (FA) inhibits the furin protease that SARS-CoV-2 needs to enter the host cell; FA components (histidine and lepidine) block SARS-CoV-2 transcription and replication by forming hydrogen bonds with the SARS-CoV-2 enzyme 3CL hydrolase, counteracting 3CLpro (Mpro) which counteracts the host innate immune response [19]. FA inhibits RNA expression of various viruses at the post-transcriptional level [20]. |
Glutamine | 10 g | Glutamine (Gln) stimulates the immune system by inhibiting inflammatory responses [21]. In COVID-19 the depletion of Gln reserves represses the increase in CD8+ T lymphocytes, IL-2 and IFN-γ [22]. Gln stimulates collagen production in fibroblasts and stimulates lung myofibroblast differentiation in patients infected with EBV, HVC, HV8, and SARS-CoV-2 [23]. Gln increases ventilatory response and is employed to maximize alveolar exchange in lung cancer and asthma [24]. Administering 30 g/day of Gln improves oxygen saturation and reduces progression to MVA, hospital stay, and intensive care unit (ICU) admission [25,26]. |
Vegetable protein (Brewer’s yeast-Saccharomyces cerevisiae SC and Amaranth) | 20 g | The balance of proteins of high biological value (PHBV) increases antibody production, modulates inflammatory response, stimulates GALT, MALT, and BALT [27]. Brewer’s yeast provides Saccharomyces cerevisiae (SC) and has an immunomodulatory effect by stimulating GPCR/YSD, prevents ACE2 receptor binding to SARS-CoV-2 protein S, and modulates the activation of MAPKs, inhibiting the production of IL-1β, IL-6, and TNF-α [26]. SC in vitro promotes muscle amino acid reserve recovery during SARS-CoV-2 infection, and also regulates the Cop9 signalosome pathway (CSN), a protein complex that regulates Cullin-RING ubiquitin ligase (CRL) activity, thus preventing protein degradation [28]. |
Ascorbic acid | 2 g | During SARS-CoV-2 infection, ascorbic acid (AA) modulates ROS production, reduces glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity, resulting in the prevention of cell death [29], pneumocytes preservation, and attenuates the activation of immune response [30,31]. AA inhibits immune cell lactate and preserves innate immunity of alveolar epithelial type II cells in SARS-CoV-2 infection [32]. |
Zinc | 40 mg | Zinc (Zn) inhibits SARS-CoV-2 replication in vitro through inhibition of RNA-dependent RNA polymerase (RdRp) and 3C like viral proteinase (3CLpro). Zn upregulates TNF-α and IL-1β levels, modulates cytokine storm in COVID-19 [32]. In SARS-CoV-2 infection Zn enhances the synthesis of metalloenzymes, ACE and ACE 2, that when disabled have beneficial therapeutic effects on the disease progression [33]. |
Selenium | 200 mcg | Selenium (Se) integrates glutathione peroxidases, selenoprotein F, K, S, and thioredoxin reductases (TXNRD), which promote differentiation and proliferation of innate and adaptive immunity [34]. Se participates in alveolar distention together with the surfactant factor. TXNRD1 upregulates Nrf2 in lung epithelial cells and decreases the expression of NF-κB, IL-1β, IL-6, and TNF-α, thereby regulating the immune and inflammatory response in COVID-19 [35]. Se increases the proliferation of T and NK lymphocytes; 200 µg/day decrease viral transcription and replication, inhibiting the major protease (Mpro) of SARS-CoV-2 [36]. |
Cholecalciferol | 4000 IU | Cholecalciferol (D3) activates chemotaxis, decreasing the expression of IL-1, 2, 6, 12, IFN-γ, and TNF-α activation, inhibits antigen-presenting cells, therefore has anti-proliferative effect of T cells [37]. In COVID-19, D3 increases the proliferation and differentiation of keratinocytes, endothelial cells, osteoblasts, and lymphocytes; increases the production of IL-10, IL-4, IL-5, and transforms growth factor-β; D3 activates the TH1 response [38]. Its antioxidant effect increases Nrf2 factor activity, activates the Nrf2-Keap1 (Kelch-like ECH-associated protein 1) pathway and maintains redox balance in COVID-19. The effect on the regulation of RAAS (renin-angiotensin-aldosterone system), promotes the inhibition of renin gene transcription, blocking the CREB-CBP/p300 complex, which intervenes in the homeostasis of superoxide dismutase (SOD), Glucose 6-phosphate dehydrogenase, glutathione reductase (GR), and glutathione peroxidase (GP), inhibit genes that attenuate SAH, systemic inflammation, and renal and cardiovascular lesions [39]. |
Resveratrol | 400 mg | Resveratrol inhibits NF-κB and activation of SIRT1 and p53 signaling pathways. Activation of SIRT1 increases NAD levels and enhances mitochondrial function, regulating the inflammatory response and dysfunctional physiological processes. The activation of SIRT1 and Superoxide Dismutase (SOD) by Resveratrol increased ACE2 function and decreased inflammation [40]. |
Omega-3 fatty acids | 2 g | Omega-3 PUFA constitute membrane phospholipids and regulate membrane fluidity and protein complex assembly in lipid bilayers; modulate the expression, stability, and enzymatic activities of ACE2 and TMPRSS2. Omega-3 LC-PUFA, DHA regulates lipid raft formation [41]. ACE2 and TMPRSS2 are described to be present mainly in lipid pools. Lipid rafts have been shown to be involved in SARS-CoV entry into Vero E6 cells; 80% of the surfactant factor is constituted by phospholipids, mainly omega-3 PUFAs that contribute to adequate alveolar distension by regulating the production of type II pneumocytes and surfactant factor [32]. |
Arginine | 1.5 g | Arginine (Arg) decreases cell apoptosis caused by SARS-CoV-2, it also matures CD3+ lymphocytes and regulates the production of CD8 T lymphocytes; When Arg reserves are decreased in COVID-19, it reduces the immune response through TLR4/MAPK signaling; in addition, the viral spike protein in SARS-CoV-2 contains arginine residues that modulate receptor binding to the virus membrane [42]. Arginine increases the ventilatory response and is used to increase alveolar exchange in lung cancer and asthma [23,24]. |
Magnesium. | 800 mg | In SARS-CoV-2, magnesium (Mg) activates protein kinases, stimulates T-cell receptors and production by generating ATP, controls cell membrane inflammation, and has vasodilatory and antithrombotic effects. Is a modulator of the release of acetylcholine and histamine in the inflammatory cascade in viral infections [43] |
Saccharomyces boulardii (SB) | 500 mg | Saccharomyces boulardii (SB) has immunological effect, activates Th1 and Th2 response, improves endocrine regulation and increases chemotaxis. At intestinal level it significantly increases the concentration of IgA (important in SARS-CoV-2 diarrhea); also inhibits the synthesis of IL-8; reduces the activation of MAPK Erk1/2, JNK/SAPK and the nuclear translocation of NF-kB [44]. Increases short-chain fatty acids (SCFA) synthesis that regulate the immune response, inflammation and activates the gut-lung axis [41]. |
Inuline | 20 g | Consumption of inulin-type fructans has been associated with regulation of the immune system, modulation of GI peptides, production of SCFA and modulation of triglyceride metabolism. SCFA are a source of energy for colonocytes, stimulating the synthesis of IL-10 by macrophages, neutrophils and T cells, as well as inhibiting the synthesis of TNF- α and IL-6 [27]. |
(A) | |||
---|---|---|---|
Characteristics | CG | IG | p-Value |
n = 40 | n = 40 | ||
Mean ± SD age—years | 53.9 ± 10.3 | 51.5 ± 11.4 | 0.351 |
Female gender—no. (%) | 13 (32.5) | 15 (37.5) | 0.407 |
Male gender—no. (%) | 27 (67.5) | 25 (62.5) | 0.407 |
Risk factors and coexisting conditions—no. (%) | |||
Overweight | 38 (95) | 36 (90) | 0.338 |
Obesity | 14 (32) | 13 (32.5) | 1 |
DM 2 | 13 ± 0.325 | 11 ± 0.275 | 0.404 |
Cardiovascular disease | 17 (42.5) | 10 (25) | 0.078 |
Hyperlipidemia | 11 (27.5) | 7 (17.5) | 0.422 |
Gastrointestinal Disease | 14 (35) | 13 (32.5) | 1 |
Total Risk Factors | 2.92 ± 1.42 | 2.57 ± 1.35 | 0.261 |
COVID-19 Symptoms—no. (%) | |||
Dyspnea | 24 (60) | 26 (65) | 0.409 |
Nausea and vomit | 6 (15) | 7 (17.5) | 0.5 |
Hyposmia | 12 (30) | 15 (37.5) | 0.637 |
Dysgeusia | 18 (45) | 20 (50) | 0.412 |
Headache | 26 (65) | 29 (72.5) | 0.315 |
Myalgia | 32 (80) | 30 (75) | 0.395 |
Diarrhea | 18 (45) | 12 (30) | 0.124 |
Anorexia | 20 (50) | 21 (52.5) | 0.500 |
Total of symptoms | 7.05 ± 2.11 | 6.8 ± 2.23 | 0.608 |
Gastrointestinal Clinic | |||
Bristol—no. (%) | 9 (50%) | 5 (27.8%) | 0.153 |
No. of defecations—Mean ± SD | 0.54 ± 0.6 | 0.52 ± 0.73 | 0.717 |
Abdominal distension—no. (%) | 28 (70%) | 28 (70%) | 0.596 |
Vital Signs Mean ± SD | |||
Breathing Frequency—bpm | 21.18 ± 3.01 | 21.48 ± 3.01 | 0.378 |
Oxygen Saturation—% | 92.73 ± 4.17 | 94 ± 3.18 | 0.144 |
Heart Rate—bpm | 70.7 ± 15.4 | 75.5 ± 9.88 | 0.105 |
Temperature—°C | 36.27 ± 0.73 | 36.3 ± 0.62 | 0.935 |
Oxygen flow—L/min | 5.9 ± 3.82 | 6 ± 3.29 | 0.571 |
Qsofa—pts | 0.425 ± 0.59 | 0.65 ± 0.62 | 0.100 |
(B) | |||
Characteristics | CG | IG | p-Value |
n = 40 | n = 40 | ||
Nutritional Status—Mean ± SD | |||
MNA®—pts | 11.13 ± 2.26 | 11.38 ± 1.65 | 0.828 |
BMI—kg/m2 | 29.35 ± 3.89 | 29.98 ± 4.07 | 0.403 |
Hydric balance—mL/day | −203.4 ± 966 | −301.5 ± 1167 | 0.806 |
Medication—no. (%) | |||
Antihypertensive | 13 (32.5) | 9 (22.5) | 0.227 |
Antidiabetics | 9 (22.5) | 11 (27.5) | 0.398 |
Antilipids | 3 (7.5) | 3 (7.50) | 0.662 |
Antibiotics | 1 (2.50) | 4 (10) | 0.359 |
Antiacids | 6 (15) | 6 (15) | 0.662 |
NSAIDs | 8 (20) | 12 (30) | 0.220 |
Laboratory studies—Mean ± SD | |||
Hb—g/dL | 15.53 ± 2.222 | 15.54 ± 2.088 | 0.987 |
MCHC—G/Dl | 33.39 ± 1.4 | 33.46 ± 1.17 | 0.753 |
Platelets—103/µL | 222.2 ± 53.93 | 248.4 ± 139.9 | 0.790 |
Leukocytes—103/µL | 8.97 ± 4.15 | 8.46 ± 4.36 | 0.400 |
Neutrophils—% | 83.5 ± 8.87 | 80.78 ± 9.29 | 0.172 |
Glycemia—mg/dL | 135.4 ± 59.39 | 134.8 ± 58.83 | 0.872 |
Total cholesterol—mg/dL | 142.8 ± 42.82 | 135 ± 23.53 | 0.335 |
Triglycerides—mg/dL | 147.5 ± 58.92 | 132.8 ± 37.39 | 0.533 |
AST—U/L | 48.06 ± 28.81 | 46.4 ± 49.65 | 0.214 |
ALT- U/L | 47.69 ± 31.9 | 50.44 ± 50.88 | 0.914 |
Albumin—g/dL | 3.53 ± 0.44 | 3.57 ± 0.41 | 0.768 |
Ferritin—ng/mL | 1070 ± 899.3 | 1270 ± 1142 | 0.572 |
Fibrinogen—mg/dL | 592.2 ± 170.4 | 607.4 ± 162.9 | 0.721 |
CRP—mg/dL | 157.3 ± 106.7 | 135.3 ± 94.92 | 0.313 |
D dimer—ng/dL | 291.2 ± 179.9 | 444.9 ± 954.9 | 0.927 |
Creatinine—mg/dL | 0.88 ± 0.31 | 0.86 ± 0.22 | 0.734 |
Urea—mg/dL | 33.95 ± 15.84 | 32.95 ± 10.78 | 0.710 |
BUN—mg/dL | 15.87 ± 7.39 | 15.43 ± 5.02 | 0.690 |
GFR—mL/min/1.73 m2 | 90.15 ± 20.2 | 93.59 ± 17.4 | 0.673 |
Procalcitonin—ng/mL | 0.364 ± 0.6 | 0.18 ± 0.188 | 0.356 |
(A) | |||||||||
CG | IG | Intergroup p-Value | |||||||
Clinical Evolution | n | Baseline | Day 3 | p-Value | n | Baseline | Day 3 | p-Value | |
Oxygen flow—L (intragroup) | 40 | 5.9 ± 3.8 | 6 ± 4.4 | 0.919 | 40 | 6 ± 3.2 | 4.5 ± 3.5 | 0.014 * | |
qSOFA—pts | 40 | 0.42 ± 0.59 | 0.51 ± 0.57 | 0.608 | 40 | 0.65 ± 0.62 | 0.43 ± 0.49 | 0.040 * | |
Number of defecations on day 3 | 37 | 0.81 ± 0.90 | 36 | 1.41 ± 1.13 | 0.014 * | ||||
Distension on day 3 | 31 | 51.60% | 31 | 19.40% | 0.008 * | ||||
PHQ-9 test—pts (intragroup) | 6 | 3.66 ± 2.5 | 1.50 ± 2.8 | 0.187 | 10 | 5.3 ± 3.4 | 1.9 ± 1.4 | 0.003 * | |
Oxygen Saturation > 90% on day 3 | 40 | 85% | 40 | 92.50% | 0.241 | ||||
Hydric Balance on day 3—mL | 17 | 123.4 ± 453.8 | 18 | 456.6 ± 485.5 | 0.043 * | ||||
Bristol scale on day 3 | 24 | 33.30% | 31 | 41.90% | 0.356 | ||||
40-day follow-up | n | Day 40 | n | Day 40 | |||||
Saturation without Supplementary Oxygen—% | 28 | 90.39 ± 3.4 | 38 | 92.08 ± 2.5 | 0.030 * | ||||
Need for home Oxygen flow—% | 27 | 85.2% | 39 | 66.70% | 0.078 | ||||
Time of home Oxygen use—days | 17 | 57.6 ± 24.6 | 23 | 43.8 ± 16.2% | 0.098 | ||||
Post-COVID syndrome—% | 24 | 37.50% | 34 | 23.50% | 0.195 | ||||
Weight decrease—% of patients | 11 | 72.70% | 18 | 44.40% | 0.135 | ||||
Gastrointestinal symptoms—% | 24 | 16.70% | 37 | 8.10% | 0.266 | ||||
(B) | |||||||||
Discharge (n = 72) | Death (n = 8) | p-Value | |||||||
Baseline Values | n | % | n | % | |||||
Fibrinogen > 700 mg/dL | 13 | 18.50 | 6 | 75.00 | 0.002 * | ||||
Procalcitonin > 0.5 ng/mL | 4 | 5.5 | 4 | 50 | 0.003 * | ||||
Blood Urea Nitrogen > 22 mg/dL | 5 | 6.90 | 4 | 50 | 0.004 * | ||||
RCP > 150 mg/L | 28 | 38.8 | 7 | 87.5 | 0.011 * | ||||
Neutrophils > 80% | 45 | 62.50 | 8 | 100 | 0.031 * | ||||
Leukocytes > 10 × 103/μL | 18 | 25.00 | 5 | 62.50 | 0.040 * | ||||
Urea > 40 mg/dL | 12 | 16.6 | 4 | 50 | 0.047 * |
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Leal-Martínez, F.; Abarca-Bernal, L.; García-Pérez, A.; González-Tolosa, D.; Cruz-Cázares, G.; Montell-García, M.; Ibarra, A. Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial. Int. J. Environ. Res. Public Health 2022, 19, 1172. https://doi.org/10.3390/ijerph19031172
Leal-Martínez F, Abarca-Bernal L, García-Pérez A, González-Tolosa D, Cruz-Cázares G, Montell-García M, Ibarra A. Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial. International Journal of Environmental Research and Public Health. 2022; 19(3):1172. https://doi.org/10.3390/ijerph19031172
Chicago/Turabian StyleLeal-Martínez, Fernando, Lorena Abarca-Bernal, Alejandra García-Pérez, Dinnaru González-Tolosa, Georgina Cruz-Cázares, Marco Montell-García, and Antonio Ibarra. 2022. "Effect of a Nutritional Support System to Increase Survival and Reduce Mortality in Patients with COVID-19 in Stage III and Comorbidities: A Blinded Randomized Controlled Clinical Trial" International Journal of Environmental Research and Public Health 19, no. 3: 1172. https://doi.org/10.3390/ijerph19031172