This study was to provide innovative information on bio-fortification and to implement strategies for improving vitamin D3 in wheat products. The commercially available wheat grains were passed through different milling processes via Hammer mill (HM) and Roller mill (RM) to yield wheat flour of different particle sizes (HM-CWF, HM-FWF, RM-WF and RM-MF). The obtained flours were fortified with commercially available vitamin D3 oil premix. Fortification efficiency was higher in finer flour (HM-FWF and RM-MF). Fortification had no significant effect on the color of the flour. Physico-chemical analysis revealed higher damaged starch in HM flour than in RM which was confirmed through scanning electron microscope. Water absorption capacity enhanced with larger particle size with simultaneous reduction in dough development time. Chapatis were prepared with fortified HM-CWF, HM-FWF, and RM-WF, whereas bread was made with RM-MF. Fortification has no significant effect on the texture and color of prepared chapati and bread. Sensory analysis revealed a slightly higher positive effect in the fortified sample with overall acceptability. HM-FWF Chapatis had the best retention of vitamin D3 (85%), and the fortified bread prepared from RM-MF had 70% retention. This research suggests that fortifying fine flour with vitamin D3 is more effective than using coarse flour.

The online version contains supplementary material available at 10.1007/s13197-024-06066-1.

Even though in mid-2023 the World Health Organization declared the end of the public health emergency of international concern status for COVID-19, many areas of uncertainty about SARS-CoV-2 infection pathophysiology remain. Although in the last 4 years pharmaceutical industries widely invested in the development of effective antiviral treatments and vaccines, large disparities in their availability worldwide still exist, thus fostering the investigation of nutritional supplements as adjuvant therapeutic approaches for disease management, especially in resource-limited settings. During the COVID-19 pandemic, vitamin D has been widely used as an over-the-counter solution to improve disease evolution, thanks to its known immunomodulatory and anti-inflammatory actions. Ecological and observational studies support a relationship between hypovitaminosis D and COVID-19 negative outcomes and, according to this evidence, several research groups investigated the role of vitamin D supplementation in protecting from SARS-CoV-2 infection and/or improving disease evolution. This narrative review is intended to offer insights into the existing data on vitamin D's biological effects in respiratory infections, especially in COVID-19. Furthermore, it will also offer a brief overview of the complex interplay between vitamin D and vaccine-elicited immune response, with special attention to anti-COVID-19 vaccines.

The prevalence of vitamin D deficiency among intensive care unit (ICU) patients is potentially associated with an increased risk of mechanical ventilation, sepsis, prolonged hospital stays, and mortality. Although ICU patient care has significantly improved in recent years, the role of vitamin D supplementation remains under investigation. A literature review was conducted using PubMed, Web of Science, Embase, and Cochrane databases, focusing on randomized controlled trials published in the past five years on vitamin D supplementation in adult ICU patients. Patients' baseline vitamin D levels, administration routes, doses, biomarker changes, mechanical ventilation duration, length of hospital stay, and mortality were analyzed. Although vitamin D supplementation appears safe and may reduce ICU stay duration and mechanical ventilation time and improve SOFA scores, its impact on overall mortality remains uncertain. Routine supplementation for all ICU patients is not currently recommended; clinical decisions should consider individual baseline vitamin D levels, patient characteristics, severity of illness, doses, and administration methods.

Advantages and disadvantages of intermittent versus daily vitamin D supplementation especially in adults with or at risk of osteoporosis are discussed by the Osteoporosis Research and Information Group (GRIO). The analysis of the literature suggests that intermittent long-term high doses vitamin D supplementation (such as 60,000IU/month or more), may increase the risk of falls, fracture and premature death in certain populations, while daily doses of 800-1000IU with calcium decrease falls and non-vertebral fractures in the elderly with vitamin D deficiency. In patients with or at risk of osteoporosis we hence recommend measuring the 25(OH)D concentration prior to supplementation and to provide vitamin D supplementation (with optimization of calcium intake if needed) to obtain a concentration between 30 and 60ng/mL. We recommend the use of an initial loading dose, especially in those who need a quick repletion of vitamin D store (symptoms of osteomalacia and/or 25(OH)D concentration <12ng/mL, patients eligible for treatment with potent antiresorptive therapy), followed by a maintenance dose. A daily supplementation should be the rule when possible. When daily forms are however not available or not reimbursed, we recommend, like other experts, to continue using intermittent dosing with the smallest available dose (≤50,000IU) and the shortest interval between doses as a stopgap until reimbursement or adequate daily pharmaceutical forms (pills or soft capsules of 1000, 2000IU) are available.

Background/Objectives: Given the crucial health benefits of vitamin D, addressing severe deficiencies is a pressing medical concern. This study aimed to evaluate the effectiveness and safety of two new weekly doses of calcifediol (100 µg and 125 µg) for long-term management in patients with severe vitamin D deficiency, defined as plasma 25(OH)D levels ≤10 ng/mL. Methods: This study was a randomized, two-cohort, controlled, double-blind, multicentre phase II-III trial. Subjects were randomized 2:2:1 to weekly calcifediol 100 µg, 125 µg or a placebo. The primary endpoint was the proportion of patients achieving plasma 25(OH)D levels of ≥20 ng/mL and/or ≥30 ng/mL by week 16. Results: A total of 276 patients (mean age: 55.2 years, SD 15.42) were randomized. By week 16, 92.3% and 91.8% of patients in the calcifediol 100 µg and 125 µg groups, respectively, reached ≥20 ng/mL, compared to 7.3% in the placebo group. Levels of ≥30 ng/mL were achieved by 49% (100 µg) and 76.4% (125 µg) of participants, with none in the placebo group. Calcifediol demonstrated superior efficacy at all response levels and time points (p < 0.0001). Plasma 25(OH)D concentrations increased by week 24 and remained stable. The incidence of adverse events was comparable across groups. Conclusions: A weekly calcifediol dose of 100 µg demonstrates the best profile of efficacy and tolerability, providing a reliable solution for achieving and maintaining adequate vitamin D levels in patients with severe deficiency.

This systematic review (SR) highlights principles for nutrient clinical trials and explore the diverse physiological functions of vitamin D beyond its traditional role in the musculoskeletal system related to clinical study designs.

Thousands of published research articles have investigated the benefits of vitamin D (a nutrient example taken in this SR) beyond the musculoskeletal system, including the immune, pulmonary, and cardiovascular systems; pregnancy; autoimmune disorders; and cancer. They illustrated vitamin D's molecular mechanisms, interactions, and genomic and nongenomic actions.

This SR was designed to identify shortcomings in clinical study designs, statistical methods, and data interpretation that led to inconsistent findings in vitamin D-related publications. SR also highlights examples and insights into avoiding study design errors in future clinical studies, including randomized controlled clinical trials (RCTs). The SR adheres to the latest PRISMA statement, guidelines, and the PICOS process.

Inappropriate or flawed study designs were frequent in clinical trials. Major failures discussed here include too short clinical study duration, inadequate or infrequent doses, insufficient statistical power, failure to measure baseline and achieved levels, and recruiting vitamin D-sufficient participants. These design errors have led to misleading interpretations. Thus, conclusions from such studies should not be generalized or used in guidelines, recommendations, or policymaking.

Adequately powered epidemiological studies and RCTs with sufficient vitamin D and duration in individuals with vitamin D deficiency reported favorable clinical outcomes, enriching the literature, enabling to understand its physiology and mechanisms. Proper study designs with rigorous methodologies and cautious interpretation of outcomes are crucial in advancing the nutrient field. The principles discussed apply not only to vitamin D, but also other micro-nutrients and nutraceutical research. Adhering to them enhances the credibility and reliability of clinical trials, SRs, and meta-analysis outcomes. The study emphasizes the importance of focused, hypothesis-driven, well-designed, statistically powered RCTs to explore the diverse benefits of nutrients, conducted in index nutrient deficient participants, and avoidance of study design errors. Findings from such studies should be incorporated into clinical practice, policymaking, and public health guidelines, improving the health of the nation and reducing healthcare costs.

Clinical trials consistently demonstrate an inverse correlation between serum 25-hydroxyvitamin D [25(OH)D; calcifediol] levels and the risk of symptomatic SARS-CoV-2 disease, complications, and mortality. This systematic review (SR), guided by Bradford Hill's causality criteria, analyzed 294 peer-reviewed manuscripts published between December 2019 and November 2024, focusing on plausibility, consistency, and biological gradient. Evidence confirms that cholecalciferol (D3) and calcifediol significantly reduce symptomatic disease, complications, hospitalizations, and mortality, with optimal effects above 50 ng/mL. While vitamin D requires 3-4 days to act, calcifediol shows effects within 24 h. Among 329 trials, only 11 (3%) showed no benefit due to flawed designs. At USD 2/patient, D3 supplementation is far cheaper than hospitalization costs and more effective than standard interventions. This SR establishes a strong inverse relationship between 25(OH)D levels and SARS-CoV-2 vulnerability, meeting Hill's criteria. Vitamin D3 and calcifediol reduce infections, complications, hospitalizations, and deaths by ~50%, outperforming all patented, FDA-approved COVID-19 therapies. With over 300 trials confirming these findings, waiting for further studies is unnecessary before incorporating them into clinical protocols. Health agencies and scientific societies must recognize the significance of these results and incorporate D3 and calcifediol for prophylaxis and early treatment protocols of SARS-CoV-2 and similar viral infections. Promoting safe sun exposure and adequate vitamin D3 supplementation within communities to maintain 25(OH)D levels above 40 ng/mL (therapeutic range: 40-80 ng/mL) strengthens immune systems, reduces hospitalizations and deaths, and significantly lowers healthcare costs. When serum 25(OH)D levels exceed 70 ng/mL, taking vitamin K2 (100 µg/day or 800 µg/week) alongside vitamin D helps direct any excess calcium to bones. The recommended vitamin D dosage (approximately 70 IU/kg of body weight for a non-obese adult) to maintain 25(OH)D levels between 50-100 ng/mL is safe and cost-effective for disease prevention, ensuring optimal health outcomes.

COVID-19 remains globally pandemic, and although several meta-analyses have explored the association between vitamin D and COVID-19 relative to clinical outcomes, a unified view has not yet emerged.

To summarize the evidence for associations between vitamin D levels and COVID-19-related clinical outcomes and to assess the strength and validity of these associations.

PubMed, Embase, Web of Science, Scopus, and the Cochrane Database of Systematic Reviews databases were searched from January 1, 2020, to June 15, 2024.

Two reviewers independently extracted data and assessed study quality.

Low vitamin D levels increased the risk of infection by 1.26- to 2.18-fold, the risk of severe illness by 1.50- to 5.57-fold, the risk of intensive care unit (ICU) admission by more than 2-fold, and the risk of death by 1.22- to 4.15-fold. In addition, patients with vitamin D deficiency had an average increase in length of hospital stay of 0.54 days compared with patients with high vitamin D levels. Overall, vitamin D supplementation may reduce severity (eg, ICU admissions, need for mechanical ventilation) and shorter length of hospital stay but has a nonsignificant effect on infection and mortality rates. In addition, there were significant differences in vitamin D levels between individuals testing positive for COVID-19 and those testing negative (mean difference [MD] = -3.22 ng mL-1; 95% CI, -5.18 to -1.25), those with severe cases and those with mild cases (MD = -4.60 ng mL-1; 95% CI, -5.49 to -3.71), and nonsurvivors and survivors of COVID-19 infection (MD = -6.59 ng mL-1; 95% CI: -8.94 to -4.24).

Low vitamin D levels are associated with higher infection rates, more severe disease, and higher mortality rates among individuals with COVID-19, whereas vitamin D supplementation may reduce patients' disease severity. The beneficial effects on infection rates and mortality remain to be further explored, however, in higher-quality, randomized controlled studies. Nonetheless, caution is warranted because the methodological quality of most meta-analyses and the level of evidence for most outcomes are very low.

PROSPERO registration No. CRD42022385036.

This review will provide an overview of the immune system and then describe the effects of frailty, obesity, specific micronutrients and the gut microbiota on immunity and susceptibility to infection including data from the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic where relevant. A key role for the immune system is providing host defence against pathogens. Impaired immunity predisposes to infections and to more severe infections and weakens the response to vaccination. A range of nutrients, including many micronutrients, play important roles in supporting the immune system to function. The immune system can decline in later life and this is exaggerated by frailty. The immune system is also weakened with obesity, generalised undernutrition and micronutrient deficiencies, which all result in increased susceptibility to infection. Findings obtained during the SARS-CoV-2 pandemic support what was already known about the effects of ageing, frailty and obesity on immunity and susceptibility to infection. Observational studies conducted during the pandemic also support previous findings that multiple micronutrients including vitamins C, D and E, zinc and selenium and long-chain n-3 fatty acids are important for immune health, but whether these nutrients can be used to treat those already with coronavirus disease discovered in 2019 (COVID-19), particularly if already hospitalised, is uncertain from current inconsistent or scant evidence. There is gut dysbiosis in patients with COVID-19 and studies with probiotics report clinical improvements in such patients. There is an inverse association between adherence to a healthy diet and risk of SARS-CoV-2 infection and hospitalisation with COVID-19 which is consistent with the effects of individual nutrients and other dietary components. Addressing frailty, obesity and micronutrient insufficiency will be important to reduce the burden of future pandemics and nutritional considerations need to be a central part of the approach to preventing infections, optimising vaccine responses and promoting recovery from infection.

Herpes simplex keratitis (HSK) is a disease characterized by the recurrent infection of the cornea, mainly due to infection caused by herpes simplex virus type 1. The suppression of recurrence can suppress progressive corneal scarring, ulcers, and perforation. Cornea contains vitamin D receptors (VDRs). VDR agonists show antimicrobial activity.

In this case report, I describe two female patients aged 76 and 85 years old in whom the administration of a VDR agonist led to the suppression of the recurrence of HSK. The former patient had repeated HSK recurrence for over 10 years after the initial infection. The latter patient developed HSK immediately after vitrectomy, and her cornea remained susceptible to infection, resulting in recurrence. Both patients were trying to suppress recurrence by applying acyclovir ophthalmic ointment, but their medication adherence was declining. So, they switched to oral treatment with 0.5 μg of the VDR agonist per day, and since then, there has been no recurrence of HSK. Oral treatment with the VDR agonist is still ongoing.

This report highlights the cases where ways were examined to improve medication adherence in elderly patients who had a risk of HSK recurrence. Both patients responded to VDR agonist treatment and were able to suppress recurrence.

Despite a large number of published studies, the effect of vitamin D3 supplementation on mortality in hospitalized patients, as well as the recommended dose and duration of therapy, is unclear. In our retrospective study, we aimed to investigate the impact of vitamin D deficiency and moderately high-dose vitamin D3 supplementation on mortality and disease outcomes in patients with COVID-19 infection.

We analyzed data from 148 COVID-19-infected hospitalized patients in two different departments, Internal Medicine and Oncology, at Semmelweis University. The severity of COVID-19 and the treatment used were the same except at one of the departments, where patients received circa 90,000 IU of vitamin D3. We compared in-hospital mortality rates between the groups. In a subgroup analysis, we evaluated the efficacy and safety of vitamin D3 supplementation by assessing 25(OH)D and 1,25(OH)2D concentrations on days 0, 4, and 8.

As a result of the supplementation, the deficiency was resolved in 4 days in deficient patients, and none of the 25(OH)D or 1,25(OH)2D concentrations exceeded the normal range. Mortality was significantly lower and decreased 67% in the group receiving vitamin D3 supplementation, regardless of baseline 25(OH)D concentrations.

The supplemental dosage, 3 × 30,000 IU of vitamin D3, is effective and safe and may reduce mortality in COVID-19 infection.

Long COVID or Post-acute sequelae of COVID-19 is an emerging syndrome, recognized in COVID-19 patients who suffer from mild to severe illness and do not recover completely. Most studies define Long COVID, through symptoms like fatigue, brain fog, joint pain, and headache prevailing four or more weeks post-initial infection. Global variations in Long COVID presentation and symptoms make it challenging to standardize features of Long COVID. Long COVID appears to be accompanied by an auto-immune multi-faceted syndrome where the virus or viral antigen persistence causes continuous stimulation of the immune response, resulting in multi-organ immune dysregulation.

This review is focused on understanding the risk factors of Long COVID with a special emphasis on the dysregulation of the gut-brain axis. Two proposed mechanisms are discussed here. The first mechanism is related to the dysfunction of angiotensin-converting enzyme 2 receptor due to Severe Acute Respiratory Syndrome Corona Virus 2 infection, leading to impaired mTOR pathway activation, reduced AMP secretion, and causing dysbiotic changes in the gut. Secondly, gut-brain axis dysregulation accompanied by decreased production of short-chain fatty acids, impaired enteroendocrine cell function, and increased leakiness of the gut, which favors translocation of pathogens or lipopolysaccharide in circulation causing the release of pro-inflammatory cytokines. The altered Hypothalamic-Pituitary-Adrenal axis is accompanied by the reduced level of neurotransmitter, and decreased stimulation of the vagus nerve, which may cause neuroinflammation and dysregulation of serum cortisol levels. The dysbiotic microbiome in Long COVID patients is characterized by a decrease in beneficial short chain fatty acid-producing bacteria (Faecalibacterium, Ruminococcus, Dorea, and Bifidobacterium) and an increase in opportunistic bacteria (Corynebacterium, Streptococcus, Enterococcus). This dysbiosis is transient and may be impacted by interventions including probiotics, and dietary supplements.

Further studies are required to understand the geographic variation, racial and ethnic differences in phenotypes of Long COVID, the influence of viral strains on existing and emerging phenotypes, to explore long-term effects of gut dysbiosis, and gut-brain axis dysregulation, as well as the potential role of diet and probiotics in alleviating those symptoms.

The COVID-19 pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has profoundly impacted global health, with pneumonia emerging as a major complication in severe cases. The pathogenesis of COVID-19 is marked by the overproduction of reactive oxygen species (ROS) and an excessive inflammatory response, resulting in oxidative stress and significant tissue damage, particularly in the respiratory system. Antioxidants have garnered considerable attention for their potential role in managing COVID-19 pneumonia by mitigating oxidative stress and modulating immune responses. This review provides a comprehensive overview of the literature on the use of antioxidants in hospitalized patients with mild-to-moderate COVID-19. Studies exploring antioxidants, including vitamins, trace elements, nitric oxide (NO), ozone (O3), glutathione (GSH), L-carnitine, melatonin, bromelain, N-acetylcysteine (NAC), and numerous polyphenols, have yielded promising outcomes. Through their ROS-scavenging properties, these molecules support endothelial function, reduce the thrombosis risk, and may help mitigate the effects of the cytokine storm, a key contributor to COVID-19 morbidity and mortality. Clinical evidence suggests that antioxidant supplementation may improve patient outcomes by decreasing inflammation, supporting immune cell function, and potentially shortening recovery times. Furthermore, these molecules may mitigate the symptoms of COVID-19 by exerting direct antiviral effects that inhibit the infection process and genomic replication of SARS-CoV-2 in host cells. Moreover, antioxidants may work synergistically with standard antiviral treatments to reduce viral-induced oxidative damage. By integrating findings from the literature with real-world data from our clinical experience, we gain a more profound understanding of the role of antioxidants in managing COVID-19 pneumonia. Further research combining comprehensive literature reviews with real-world data analysis is crucial to validate the efficacy of antioxidants and establish evidence-based guidelines for their use in clinical practice.

Randomised trials conducted from 2006 to 2021 indicated that vitamin D supplementation (VDS) was able to prevent severe COVID-19 and acute respiratory infections (ARI). However, larger randomised trials published in 2022 did not confirm the health benefits of VDS in COVID-19 patients.

To examine through a systematic review with meta-analysis the characteristics of randomised trials on VDS to COVID-19 patients and admission to intensive care unit (ICU), and of randomised trials on VDS for the prevention of ARI.

A systematic search retrieved randomised trials on VDS to COVID-19 patients and admission to ICU. Data on VDS and ARI were extracted from the meta-analysis of Jolliffe et al. 2021. Groups were formed including trials with total numbers of patients below or above the median size of all trials. The associations between VDS vs no VDS, and admission to ICU were evaluated using random-effects models from which summary odds ratios (SOR) and 95% confidence intervals (CI) were obtained. Meta-analyses were done for all trials and for each group of trials, which allowed testing a possible effect modification of trial size. Publication bias was assessed using the Louis-Furuya-Kanaruori (LFK) index (no bias if index between -1 and +1) and the trim and fill method.

Nine trials on VDS for preventing admission to ICU were identified, including 50 to 548 patients. The summary odds ratio (SOR) was 0.61 (95% CI: 0.39-0.95) for all trials, 0.34 (0.13-0.93) for trials including 50 to <106 patients and 0.88 (0.62-1.24) for trials including 106 to 548 patients (interaction p = 0.04). The LFK index was -3.79, and after trim and fill, the SOR was 0.80 (0.40-1.61). The SOR for the 37 trials on VDS for ARI prevention included 25 to 16,000 patients. The SOR was 0.92 (0.86-0.99) for all trials, 0.69 (0.57-0.83) for trials including 25 to <248 patients and 0.98 (0.94-1.03) for trials including 248 to 16,000 patients (interaction p = 0.0001). The LFK index was -3.11, and after trim and fill, the SOR was 0.96 (0.88-1.05).

Strong publication bias affected small randomised trials on VDS for the prevention of severe COVID-19 and of ARI. Systematic reviews should beware of small-size randomised trials that generally exaggerate health benefits.

During the COVID-19 pandemic, several observational studies proved a certain efficacy of nutraceuticals, herbal products, and other dietary supplements as adjuvant therapies used alongside antiviral drugs. Although their use has not been widespread in Italy, according to preliminary evidence, many supplements with demonstrated immunomodulatory effects, such as vitamins C and D, herbal medicines and essential oils, might relieve the respiratory symptoms of COVID-19, since SARS-CoV-2 can activate inflammasome-mediated inflammatory signaling pathways. Other observational studies have shown that herbal treatments, such as Echinacea purpurea and ginseng, help alleviate respiratory symptoms and reduce serum levels of inflammatory cytokines, which are typically overexpressed in both adult and pediatric SARS-CoV-2 patients. Further, vitamins C and D can attenuate the immune response thanks to their cytokine suppression ability and to their known antimicrobial activity and potential to modulate T helper cell response. The strong immune response triggered by SARS-CoV-2 infection is responsible for the severity of the disease. Preliminary data have also shown that L-arginine, an endothelial-derived relaxing factor, is able to modulate endothelial damage, which appears to be one of the main targets of this systemic disease. Finally, some essential oils and their isolated compounds, such as eucalyptol, may be helpful in reducing many of the respiratory symptoms of COVID-19, although others, such as menthol, are not recommended, since it can lead to an undervaluation of the clinical status of a patient. In this narrative review, despite the lack of strong evidence in this field, we aimed to give an overview of the current available literature (mainly observational and cross-sectional studies) regarding herbal products and dietary supplements and their use in the treatment of mild disease from SARS-CoV-2 infection. Obviously, dietary supplements and herbal products do not constitute a standardized treatment for COVID-19 disease, but they could represent an adjunctive and useful treatment when used together with antivirals.

Current evidence is inconsistent on whether vitamin D supplementation can prevent COVID-19 infection or improve its clinical outcomes. To better understand and look into the issue, we went through the background knowledge of COVID-19 and vitamin D, searched in Pubmed [by using key words in the title containing "randomized clinical trial", "COVID-19", and "vitamin D (25-hydroxyvitamin D, or cholecalciferol, or calcidiol, or calcifediol) supplementation"] for publications of studies on vitamin D/supplementation in COVID-19 patients, especially those about the randomized clinical trials (RCTs). After reviewing these papers, we did a short background review of vitamin D and the pathophysiology of COVID-19, summarized the key features of the 25 RCTs in text and tabulated in a table of some of the features, commented, compared and discussed the differences between RCTs (for example, change the serum 25-hydroxyvitamin D concentration from nmol/L to ng/mL, making the comparison easier). The take-home question of the review is that serum 25-hydroxyvitamin D concentration is an important indicator of the supplementation effect of vitamin D correction but may not be reliable in predicting the supplementation effect on the clinical outcomes of COVID-19.

The COVID-19 pandemic caused by the SARS-CoV-2 virus was arguably one of the worst public health disasters of the last 100 years. As many infectious disease experts were focused on influenza, MERS, ZIKA, or Ebola as potential pandemic-causing agents, SARS-CoV-2 appeared to come from nowhere and spread rapidly. As with any zoonotic agent, the initial pathogen was able to transmit to a new host (humans), but it was poorly adapted to the immune environment of the new host and resulted in a maladapted immune response. As the host-pathogen interaction evolved, subsequent variants of SARS-CoV-2 became less pathogenic and acquired immunity in the host provided protection, at least partial protection, to new variants. As the host-pathogen interaction has changed since the beginning of the pandemic, it is possible the clinical results discussed here may not be applicable today as they were at the start of the pandemic. With this caveat in mind, we present an overview of the immune response of severe COVID-19 from a clinical research perspective and examine clinical trials utilizing immunomodulating agents to further elucidate the importance of hyperinflammation as a factor contributing to severe COVID-19 disease.

Calcifediol and glucocorticoids have been repositioned for the treatment of COVID-19 and may reduce severity, the need for intensive care unit admission and death.

to identify class or profiles of patients hospitalized and treated with COVID-19 pneumonia using latent class clustering methods to assess the clinical and prognostic relevance of the resulting patients' profiles. Poor prognosis was defined as death or need for ICU admission, good prognosis, the opposite. With special interest in differential responses to calcifediol.

Reina Sofia University Hospital, Córdoba Spain.

Retrospective observational cohort study of patients admitted for COVID-19.

gov public database (NCT05819918).

(i) Age ≥ 18 and ≤ 90 years, (ii) Pneumonia characterized by the presence of infiltrates on chest X-ray or CT scan, (iii) SARS-CoV-2 infection, confirmed, and (iv) CURB Scale 65 >1.

Latent class analysis, for obtaining homogeneous clusters, without specifying a priori the belonging group, and selecting the optimal number of clusters by minimizing information criteria. Evaluating the differences between groups for each variable by means of chi-square, Fisher's exact test and Kruskal-Wallis test.

707 patients hospitalized from 10 March 2020 until 4 March 2022 were included. For the treatment variable, differences were found between class 3 (60 % treated with calcifediol only) and classes 1 (less than 1 % calcifediol only vs. 82 % treated with both), 2 (less than 1 % calcifediol only vs. 82 % treated with both) and 4 (1 % calcifediol only vs. 84 % treated with both). Class 3, (60 % with calcifediol), had a significantly better prognosis compared to patients treated with glucocorticoids alone (OR: 15.2, 95 % CI: [3.73-142], p<0.001) or no treatment (OR: 7.38, 95 % CI: [2.63-30.2], p<0.001).

our real-life study shows that calcifediol treatment significantly reduces the need for ICU admission and improved prognosis in patients hospitalized for COVID-19 pneumonia, especially in the profile of patients receiving it without glucocorticoids.

As of the 7th of July 2024, 775,754,322 confirmed cases of COVID-19, including 7,053,902 deaths worldwide, had been reported to the WHO (World Health Organization). Nevertheless, untill the 15th of July 2024, a total of 13,578,710,228 vaccine doses had been administered, with almost no country spared from COVID-19 attacks. The pathophysiology of this virus is complicated, and several symptoms require a deep understanding of the actual mechanisms. It is unclear why some patients develop severe symptoms while others do not, although literature suggests a role for vitamin D. Vitamin D plays a crucial role in the infection or in ameliorating the severity of symptoms. The mechanism of action of vitamin D and vitamin D deficiency (VDD) is well understood. VDD is associated with increased hospitalization of severely ill patients and increased levels of COVID-19-caused mortality. Recent studies suggest that vitamin D levels and genetic variations in the vitamin D receptor (VDR) gene significantly impact the severity and outcomes of COVID-19, especially in the infections caused by Delta and Omicron variants. Furthermore, VDD causes immune system dysregulation upon infection with SARS-CoV-2, indicating that vitamin D sufficiency is crucial in fighting against COVID-19 infection. The therapeutic effect of vitamin D raises interest in its potential role as a prophylactic and treatment adjunct. We evaluate the immunomodulatory effects of vitamin D and its ability to enhance the efficacy of new antiviral drugs like molnupiravir and paxlovid against SARS-CoV-2. This review discusses the role of vitamin D sufficiency and VDD in COVID-19 initiation and progression, emphasizing the molecular mechanisms by which vitamin D exerts its actions as a proactive step for the next pandemic. However, there is still no clear evidence of vitamin D's impact on prevention and treatment, leading to contradictory findings. Therefore, large-scale randomized trials are required to reach a definitive conclusion. A bibliometric analysis of publications related to vitamin D, immunity, and COVID-19 revealed a significant increase in research activity in this area, particularly in 2020-2024, underscoring the growing recognition of vitamin D's potential role in the context of the pandemic.

Vitamin D deficiency is associated with severe COVID 19 and poor outcomes. However, the role of Vitamin D supplementation on mortality is controversial. The current meta analysis aimed to investigate the same among patients with COVID 19.

We searched six databases from inception up to July 2023. The keywords used were COVID 19, SARS COV 2, mortality, Vitamin D, calcitriol, cholecalciferol, Calcifediol, survival, death, small dose, and high dose. Eight hundred and sixteen studies were retrieved, 103 full texts were screened, and 14 randomized controlled trials were included in the meta analysis. A structured checklist was used to gather the author's name, country, year of publication, Vitamin D dose, age, sex, number of patients, mortality, and comorbidities. The Cochrane system for meta analysis (RevMan, version 5.4) was used for the data analysis.

No association was found between Vitamin D supplementation and mortality among patients with COVID 19, odd ratio, 1.16, 95% confidence interval (CI), 0.84-1.59, and P = 0.36. No difference between high and low dose Vitamin D supplementation, odd ratio, 0.65, 95% CI, 0.37-1.57, and P = 0.13. In a sub analysis, no significant statistical difference was found between low dose Vitamin D supplementation versus placebo, and when considering patients who were Vitamin D deficient, odd ratio, 1.10, 95% CI, 0.74-1.63. The P = 0.64 and, odd ratio, 0.99, 95% CI, 0.71-1.40, and P = 0.97 respectively.

No association was evident between Vitamin D supplementation and mortality among patients with COVID 19 irrespective of doses and Vitamin D status. Further studies are needed to address the timing and frequency of Vitamin D supplementations.

Vitamin D's role in COVID-19 management remains controversial. This meta-analysis aimed to evaluate the efficacy of vitamin D supplementation in patients with SARS-CoV-2 infection, focusing on mortality, intensive care unit (ICU) admissions, intubation rates, and hospital length of stay (LOS).

A systematic review of PubMed/MEDLINE, Scopus, Cochrane, and Google Scholar databases was conducted. Randomized controlled trials (RCTs) and analytical studies investigating vitamin D supplementation in COVID-19 patients were included. The meta-analysis was performed using STATA MP 18.5, employing random-effect or fixed-effect models based on heterogeneity.

Twenty-nine studies (twenty-one RCTs, eight analytical) were analyzed. Vitamin D supplementation significantly reduced ICU admissions (OR = 0.55, 95% CI: 0.37 to 0.79) in RCTs and analytical studies (OR = 0.35, 95% CI: 0.18 to 0.66). Intubation rates were significantly reduced in RCTs (OR = 0.50, 95% CI: 0.27 to 0.92). Mortality reduction was significant in analytical studies (OR = 0.45, 95% CI: 0.24 to 0.86) but not in RCTs (OR = 0.80, 95% CI: 0.61 to 1.04). Subgroup analyses revealed more pronounced effects in older patients and severe COVID-19 cases. LOS showed a non-significant reduction (mean difference = -0.62 days, 95% CI: -1.41 to 0.18).

This meta-analysis suggests potential benefits of vitamin D supplementation in COVID-19 patients, particularly in reducing ICU admissions. However, the evidence varies across outcomes and patient subgroups. Discrepancies between RCTs and analytical studies highlight the need for further large-scale, well-designed trials accounting for baseline vitamin D status, standardized supplementation protocols, and patient characteristics to inform clinical guidelines for vitamin D use in COVID-19 management.

Vitamin D is a steroid hormone that protects against viral infections by influencing innate and adaptive immune responses. The effectiveness of vitamin D3 supplementation in COVID-19 is unknown. The study's goal was to elucidate the relationship between blood vitamin D levels and COVID-19 clinical outcomes by examining the effect of a single high dose of vitamin D3 on the length of hospital stay in COVID-19 patients.

The descriptive, retrospective study was performed from March to May 2021 at a referral center for patients with COVID-19, in Bam, Iran. A checklist consisting of demographic variables was used to gather data, and laboratory assessments of serum 25(OH) D were evaluated and documented. The connection between serum vitamin D and patient clinical outcomes was investigated after patients were given a single oral dose of 200,000 IU of vitamin D3.

71 COVID-19 patients were treated. Radiological results did not change substantially amongst individuals with various levels of 25(OH)D. After a single dosage of vitamin D3, mean blood levels of 25-hydroxyvitamin D increased considerably and the need for intubation and SpO2 decreased, and as did the respiratory rate in patients requiring hospitalization due to COVID-19.

A single administration of 200,000 IU of vitamin D3 significantly reduced the severity of COVID-19.

Vitamin D3 and its metabolites calcifediol have been recommended as effective drugs for novel coronavirus disease 2019 (COVID-19) therapy in many studies, since the outbreak of this global dramatic pandemic. In this study, we made a striking discovery that Calcifediol demonstrates robust inhibitive effect on the of the papain-like cysteine protease (PLpro), a critical proteolytic enzyme for the severe acute respiratory syndrome coronavirus-2(SARS-COV-2), through a small-scale FRET-based screening experiment. The practical bindings of Calcifediol to PLpro were also demonstrated by several in vitro interaction studies. All the evidence had revealed the inhibition might be caused by the targeted binding event. Consequently, our discovery represents a significant finding that the beneficial therapeutic impact of Calcifediol on COVID-19 may be attributed not only to its immunoregulatory properties but also to its inhibition of PLpro. This finding strongly bolsters the case for the clinical use of Vitamin D3 and its derivative Calcifediol in the treatment of COVID-19.

Experimental and observational studies suggest that circulating micronutrients, including vitamin D (VD), may increase COVID-19 risk and its associated outcomes. Mendelian randomization (MR) studies provide valuable insight into the causal relationship between an exposure and disease outcomes.

The aim was to conduct a systematic review and meta-analysis of causal inference studies that apply MR approaches to assess the role of these micronutrients, particularly VD, in COVID-19 risk, infection severity, and related inflammatory markers.

Searches (up to July 2023) were conducted in 4 databases.

The quality of the studies was evaluated based on the MR-STROBE guidelines. Random-effects meta-analyses were conducted where possible.

There were 28 studies (2 overlapped) including 12 on micronutrients (8 on VD) and COVID-19, 4 on micronutrients (all on VD) and inflammation, and 12 on inflammatory markers and COVID-19. Some of these studies reported significant causal associations between VD or other micronutrients (vitamin C, vitamin B6, iron, zinc, copper, selenium, and magnesium) and COVID-19 outcomes. Associations in terms of causality were also nonsignificant with regard to inflammation-related markers, except for VD levels below 25 nmol/L and C-reactive protein (CRP). Some studies reported causal associations between cytokines, angiotensin-converting enzyme 2 (ACE2), and other inflammatory markers and COVID-19. Pooled MR estimates showed that VD was not significantly associated with COVID-19 outcomes, whereas ACE2 increased COVID-19 risk (MR odds ratio = 1.10; 95% CI: 1.01-1.19) but did not affect hospitalization or severity of the disease. The methodological quality of the studies was high in 13 studies, despite the majority (n = 24) utilizing 2-sample MR and evaluated pleiotropy.

MR studies exhibited diversity in their approaches but do not support a causal link between VD/micronutrients and COVID-19 outcomes. Whether inflammation mediates the VD-COVID-19 relationship remains uncertain, and highlights the need to address this aspect in future MR studies exploring micronutrient associations with COVID-19 outcomes.

PROSPERO registration no. CRD42022328224.

The interaction of the SARS-CoV-2 spike protein with membrane-bound angiotensin-converting enzyme-2 (ACE-2) receptors in epithelial cells facilitates viral entry into human cells. Despite this, ACE-2 exerts significant protective effects against coronaviruses by neutralizing viruses in circulation and mitigating inflammation. While SARS-CoV-2 reduces ACE-2 expression, vitamin D increases it, counteracting the virus's harmful effects. Vitamin D's beneficial actions are mediated through complex molecular mechanisms involving innate and adaptive immune systems. Meanwhile, vitamin D status [25(OH)D concentration] is inversely correlated with severity, complications, and mortality rates from COVID-19. This study explores mechanisms through which vitamin D inhibits SARS-CoV-2 replication, including the suppression of transcription enzymes, reduced inflammation and oxidative stress, and increased expression of neutralizing antibodies and antimicrobial peptides. Both hypovitaminosis D and SARS-CoV-2 elevate renin levels, the rate-limiting step in the renin-angiotensin-aldosterone system (RAS); it increases ACE-1 but reduces ACE-2 expression. This imbalance leads to elevated levels of the pro-inflammatory, pro-coagulatory, and vasoconstricting peptide angiotensin-II (Ang-II), leading to widespread inflammation. It also causes increased membrane permeability, allowing fluid and viruses to infiltrate soft tissues, lungs, and the vascular system. In contrast, sufficient vitamin D levels suppress renin expression, reducing RAS activity, lowering ACE-1, and increasing ACE-2 levels. ACE-2 cleaves Ang-II to generate Ang(1-7), a vasodilatory, anti-inflammatory, and anti-thrombotic peptide that mitigates oxidative stress and counteracts the harmful effects of SARS-CoV-2. Excess ACE-2 molecules spill into the bloodstream as soluble receptors, neutralizing and facilitating the destruction of the virus. These combined mechanisms reduce viral replication, load, and spread. Hence, vitamin D facilitates rapid recovery and minimizes transmission to others. Overall, vitamin D enhances the immune response and counteracts the pathological effects of SARS-CoV-2. Additionally, data suggests that widely used anti-hypertensive agents-angiotensin receptor blockers and ACE inhibitors-may lessen the adverse impacts of SARS-CoV-2, although they are less potent than vitamin D.

As the novel coronavirus disease 2019 (COVID-19) pandemic subsides, the clinical sequelae are becoming more problematic. Interestingly, the statistical data indicate that Africa has experienced the lowest number of cases and deaths, with an unexpected phenomenon where the number of deaths from COVID-19 has not increased significantly. Several studies have investigated the relationship between diet and coronavirus. However, no systematic review/meta-analysis has conclusively linked diet (phytochemicals and vitamin D) and the gut microbiota in the context of COVID-19.

This study examined the responses to COVID-19 in Japan and Africa, formulating the following hypotheses: (1) a healthy diet is effective against COVID-19, (2) blood vitamin D levels are associated with COVID-19 mortality, and (3) COVID-19 is associated with the gut microbiota. To investigate these hypotheses, a keyword search and meta-analysis were conducted using PubMed, and each hypothesis was tested.

This study found that a healthy diet, particularly rich in phytochemicals such as polyphenols and flavonoids, is effective against COVID-19. An association was detected between blood vitamin D levels and COVID-19 mortality. The gut microbiota was linked to COVID-19 and its amelioration. These findings may have significant implications for not only understanding COVID-19 but also future prevention of pneumonia.

The COVID-19 pandemic has emerged as a major global health crisis. Vitamin D, a crucial fat-soluble vitamin, has been recommended for COVID-19 patients, though evidence of its effectiveness is inconsistent. This systematic literature review and meta-analysis aimed to evaluate the impact of vitamin D supplementation on COVID-19-related outcomes. A comprehensive search was conducted across PubMed, Scopus, Web of Science, Embase, and Cochrane databases. Primary outcomes included mortality and hospital length of stay, while secondary outcomes encompassed C-reactive protein (CRP), ferritin, D-dimer, hemoglobin (Hb) concentrations, and lymphocyte, neutrophil, and platelet counts. Data analysis was performed using Stata™ Version 14. A total of 16 trials were analyzed. The meta-analysis revealed that vitamin D supplementation significantly reduced hospital length of stay (mean difference = -1.16; 95% confidence interval [CI]: -2.23, -0.09; p = .033) with significant heterogeneity (I2 = 69.2%, p = .002). Subgroup analysis showed a more pronounced reduction in studies with vitamin D dosages ≤10 000 international units (IU) (mean difference = -1.27; 95% CI: -1.96, -0.57; p < .001) and in patients over 60 years old (mean difference = -1.84; 95% CI: -2.53, -1.14; p < .001). Additionally, vitamin D significantly reduced CRP concentrations in older adults (>60 years) (mean difference = -1.13; 95% CI: -2.07, -0.18; p = .019). No significant changes were found in ferritin, D-dimer, Hb concentrations, or in lymphocyte, neutrophil, and platelet counts (p > .05). In conclusion, while vitamin D supplementation did not significantly affect most COVID-19-related biomarkers, however, it reduces the length of hospital stay.

COVID-19 has substantial effects on respiratory health and overall well-being. Recent studies suggest vitamin D as a potential treatment, but the results are inconclusive.

The authors conducted a systematic review of randomized controlled trials (RCTs) to examine the link between vitamin D and patients with COVID-19.

The authors searched electronic databases PubMed, Cochrane, CINAHL, EMBASE and Google Scholar from their inception till August 2023.

Inclusion criteria used in our systematic review include: (1) patients who tested positive for COVID-19, (2) intervention was vitamin D supplementation, (3) the comparator was either a placebo, standard care of treatment, or, no treatment, (4) at least one of the clinical outcomes of interest were investigated, (5) study design being RCTs.

Two independent reviewers manually extracted information from selected articles, including study characteristics, patient characteristics, and the primary outcomes: all-cause mortality, ICU and hospital stay length and secondary outcomes: mechanical ventilation, supplemental oxygen, ICU admission, and adverse events. Risk ratios or mean differences and 95% CIs were calculated using a random-effects model.

The authors' analysis included 14 RCTs with 2165 patients. Vitamin D significantly reduced ICU admissions and lowered the need for mechanical ventilation compared to placebo. However, it did not significantly affect hospital stay length, ICU stay length, mechanical ventilation duration, mortality, or the need for supplemental oxygen.

Vitamin D does not significantly improve certain clinical outcomes, such as hospital and ICU stay length, for patients with COVID-19. However, it still may be significantly beneficial in decreasing the burden on intensive care services.

Vitamin D, known for its role in bone health, is now being explored for its immunomodulatory effects. This study aimed to evaluate the impact of vitamin D supplementation on mortality in coronavirus disease 2019 (COVID-19) patients through a systematic review and meta-analysis of randomized controlled trials.

A comprehensive search was conducted across PubMed, Scopus, Web of Science, and preprint servers for eligible trials up to July 8, 2024. Two investigators independently screened the records and assessed the risk of bias using the Cochrane Risk of Bias Tool. Trials were eligible if they compared vitamin D with control interventions in adults with COVID-19. Data extraction and analysis were carried out independently, employing a random-effects model to estimate pooled odds ratios for mortality.

Nineteen randomized controlled trials with 2495 participants were included. The meta-analysis showed a significant reduction in all-cause mortality with vitamin D supplementation (pooled OR 0.72, 95% CI 0.53-0.98; I2 = 20%). Subgroup analysis for severe COVID-19 cases also indicated significant mortality reduction (pooled OR 0.57, 95% CI 0.35-0.92; I2 = 18%).

Vitamin D supplementation appears to reduce mortality in COVID-19 patients, especially in severe cases. These findings highlight the potential benefits of vitamin D as an adjunct treatment in COVID-19, though further large-scale trials are needed to confirm these effects and determine optimal dosing.

To analyze the impact of different methods of Vitamin D administration on the prognosis of COVID-19 patients.

A comprehensive literature search was conducted across four databases: PubMed, Embase, Web of Science, and Cochrane, up to January 5, 2024. Eligible studies included randomized controlled trials and cohort studies that compared Vitamin D supplementation with control groups in COVID-19 patients. Outcomes of interest were mortality rate, ICU (Intensive Care Unit) admission rate, length of hospital stay, and endotracheal intubation rate. Subgroup analyses were performed based on the dosing regimen (single-dose vs. continuous-dose), total Vitamin D intake within 14 days (≥100,000 IU vs. <100,000 IU), and baseline serum Vitamin D levels (deficient group: 25OHD < 30 ng/mL vs. non-restricted group). A random-effects model was employed for meta-analysis to account for heterogeneity among studies.

A total of 21 studies involving 4,553 participants were included. In terms of mortality, Vitamin D supplementation significantly reduced the mortality rate (RR = 0.72, 95% CI: 0.54-0.94, I 2 = 54%, p = 0.02), with continuous dosing being more effective (RR = 0.53, 95% CI: 0.34-0.83, I 2 = 55%, p = 0.006) compared to single-dose (RR = 0.88, 95% CI: 0.69-1.12, I 2 = 21%, p = 0.3), and lower total doses (<100,000 IU) showing greater benefit (RR = 0.30, 95% CI: 0.21-0.44, I 2 = 0%, p < 0.0001). Mortality was significantly reduced in the Vitamin D-deficient group (25OHD < 30 ng/mL) (RR = 0.73, 95% CI: 0.59-0.89, I 2 = 0%, p = 0.002) but not in the non-restricted group. Regarding ICU admission, supplementation reduced ICU admission rates (RR = 0.58, 95% CI: 0.38-0.88, I 2 = 74%, p = 0.01), with continuous dosing (RR = 0.44, 95% CI: 0.22-0.90, I 2 = 74%, p = 0.02) being more effective than single-dose (RR = 0.79, 95% CI: 0.61-1.03, I 2 = 22%, p = 0.08), and lower doses (<100,000 IU) providing more significant reduction (RR = 0.31, 95% CI: 0.21-0.47, I 2 = 0%, p = 0.001). ICU admission rates were significantly reduced in the Vitamin D-deficient group (RR = 0.63, 95% CI: 0.42-0.93, I 2 = 0%, p = 0.02) but not in the non-restricted group (RR = 0.59, 95% CI: 0.32-1.11, I 2 = 86%, p = 0.1). For length of hospital stay, no significant differences were observed between Vitamin D and control groups (MD = -1, 95% CI: -2.16 to 0.16, p = 0.13), and subgroup analyses by dosing regimen, total dose, and baseline Vitamin D levels also showed no significant differences. Similarly, for endotracheal intubation, there was no significant difference in intubation rates between groups (RR = 0.78, 95% CI: 0.56-1.08, p = 0.13), and subgroup analyses confirmed no significant effect of different dosing strategies or baseline Vitamin D status on intubation rates.

Vitamin D supplementation improves clinical outcomes in COVID-19 patients by reducing mortality and ICU admission rates, particularly when administered continuously with a total dose of less than 100,000 IU over 14 days, and among those with baseline Vitamin D deficiency (25OHD < 30 ng/mL). However, there were no significant effects on the length of hospital stay or endotracheal intubation rates, regardless of the dosing regimen or baseline Vitamin D levels. These findings emphasize the importance of considering both the total dose over 14 days and baseline Vitamin D status to optimize therapeutic benefits.

Vitamin D is a steroid hormone that is naturally produced in the body or obtained through dietary sources, primarily under the influence of UVB radiation. This essential nutrient has a vital role in numerous physiological processes, encompassing immune function, cell growth, differentiation, insulin regulation, and cardiovascular well-being, along with its pivotal role in sustaining the delicate equilibrium of calcium and phosphate concentrations in the body. Moreover, vitamin D reinforces mucosal defense and bolsters the immune system through immunomodulation, making it a critical component of overall health. Numerous studies have unveiled the profound connection between vitamin D and the predisposition to respiratory tract infections, including well-known viruses such as influenza and the novel severe acute respiratory syndrome coronavirus 2. Vitamin D deficiency has been consistently linked to increased severity of coronavirus disease 2019 (COVID-19) and a heightened risk of mortality among afflicted individuals. Retrospective observational studies have further substantiated these findings, indicating that levels of vitamin D are linked with both the occurrence and severity of COVID-19 cases. Vitamin D has its influence on viral infections through a multitude of mechanisms, such as promoting the release of antimicrobial peptides and fine-tuning the responses of the immune system. Additionally, vitamin D is intertwined with the intricate network of the renin-angiotensin system, suggesting a potential impact on the development of complications related to COVID-19. While further clinical trials and extensive research are warranted, the existing body of evidence strongly hints at the possible use of vitamin D as a valuable tool in the prophylaxis and management of COVID-19 and other viral infectious diseases.

The underlying medical conditions and gut dysbiosis is known to influence COVID-19 severity in high-risk patients. The current review proposed the optimal usage of nutraceuticals & pharmacological interventions can help regulate the protective immune response and balance the regulatory functionality of gut microbiota. Many studies have revealed that the probiotic interventions viz., Lactobacillus rhamnosus, L. plantarum & other bacterial spp. reduce IFNγ & TNF-α and increase IL-4 & IL-10 secretions to control the immunostimulatory effects in upper respiratory tract infection. Dietary fibres utilized by beneficial microbiota and microbial metabolites can control the NF-kB regulation. Vitamin C halts the propagation of pathogens and vitamin D and A modulate the GM. Selenium and Flavonoids also control the redox regulations. Interferon therapy can antagonize the viral replications, while corticosteroids may reduce the death rates. BCG vaccine reprograms the monocytes to build trained immunity. Bifidobacterium and related microbes were found to increase the vaccine efficacy. Vaccines against COVID-19 and season flu also boost the immunity profile for robust protection. Over all, the collective effects of these therapeutics could help increase the opportunities for faster recovery from infectious diseases.

The nutraceutical supplements and pharmacological medicines mediate the modulatory functionalities among beneficial microbes of gut, which in turn eliminate pathogens, harmonize the activity of immune cells to secrete essential regulatory molecular receptors and adaptor proteins establishing the homeostasis in the body organs through essential microbiome. Therefore, the implementation of this methodology could control the severity events during clinical sickness and reduce the mortalities.

We aimed to investigate the preventive effect of vitamin D2 on COVID-19 and the improvement of symptoms after COVID-19 infection. The study recruited 228 health care workers who tested negative PCR or antigen for COVID-19. Subjects were randomly allocated to vitamin D2 or non-intervention at a ratio 1:1. Subjects recorded PCR or antigen tests and the symptoms of COVID-19 twice a week during the follow-up visit. The concentration of serum 25-hydroxyvitamin D (25(OH)D), C-reaction protein (CRP), complement component C1q and inflammatory cytokines were measured. The rates of COVID-19 infection were 50.5% in the vitamin D2 group and 52.4% in the non-intervention group (P = 0.785). There was no difference in the COVID-19 symptoms between the two groups. The mean 25(OH)D level significantly increased from 14.1 to 31.1 ng/mL after administration (P < 0.001). The difference between the two groups was not significant for the concentrations of CRP, C1q and inflammatory cytokines on the thirtieth day of the trial. According to the second level of vitamin D, there was a 14.3% difference in positive infection rates between the vitamin D adequate (> 30 ng/mL) and deficient groups (< 20 ng/mL). Adequate vitamin D had a tendency to prevent COVID-19.Trial registration: ClinicalTrials.gov NCT05673980, dated: 12/2022.

Several studies have reported outbreaks of Kawasaki disease among children amid the coronavirus disease 2019 (COVID-19) pandemic. Vitamin D possesses high utility in modulating the immune system to repair and prevent severe inflammation in COVID-19. This study aims to explore the association between Kawasaki disease and vitamin D levels in pediatric patients and describe the potential role of vitamin D in promoting recovery and preventing complications associated with Kawasaki disease in pediatric patients with COVID-19. The association between Kawasaki disease and vitamin D was explored adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines, utilizing databases such as PubMed, Google Scholar, and ScienceDirect. The association between COVID-19 and Kawasaki disease was also assessed by reviewing relevant literature.Most studies indicated that patients with Kawasaki disease had lower vitamin D levels. Vitamin D supplementation was also found to be deficient in the pediatric population with Kawasaki disease. Inflammation of the endothelium, cytokine storms, and endothelial dysfunction in patients suffering from COVID-19 may contribute to the development of Kawasaki disease. Vitamin D is believed to have protective potential for Kawasaki disease outcomes by modulating the inflammatory response. Administering vitamin D to pediatric patients with viral infections like COVID-19 is expected to accelerate clinical improvement and prevent complications from Kawasaki disease.

The original COVID-19 vaccines, developed against SARS-CoV-2, initially mitigated hospitalizations. Bivalent vaccine boosters were used widely during 2022-23, but the outbreaks persisted. Despite this, hospitalizations, mortality, and outbreaks involving dominant mutants like Alpha and Delta increased during winters when the population's vitamin D levels were at their lowest. Notably, 75 % of human immune cell/system functions, including post-vaccination adaptive immunity, rely on adequate circulatory vitamin D levels. Consequently, hypovitaminosis compromises innate and adaptive immune responses, heightening susceptibility to infections and complications. COVID-19 vaccines primarily target SARS-CoV-2 Spike proteins, thus offering only a limited protection through antibodies. mRNA vaccines, such as those for COVID-19, fail to generate secretory/mucosal immunity-like IgG responses, rendering them ineffective in halting viral spread. Additionally, mutations in the SARS-CoV-2 binding domain reduce immune recognition by vaccine-derived antibodies, leading to immune evasion by mutant viruses like Omicron variants. Meanwhile, the repeated administration of bivalent boosters intended to enhance efficacy resulted in the immunoparesis of recipients. As a result, relying solely on vaccines for outbreak prevention, it became less effective. Dominant variants exhibit increased affinity to angiotensin-converting enzyme receptor-2, enhancing infectivity but reducing virulence. Meanwhile, spike protein-related viral mutations do not impact the potency of widely available, repurposed early therapies, like vitamin D and ivermectin. With the re-emergence of COVID-19 and impending coronaviral pandemics, regulators and health organizations should proactively consider approval and strategic use of cost-effective adjunct therapies mentioned above to counter the loss of vaccine efficacy against emerging variants and novel coronaviruses and eliminate vaccine- and anti-viral agents-related serious adverse effects. Timely implementation of these strategies could reduce morbidity, mortality, and healthcare costs and provide a rational approach to address future epidemics and pandemics. This perspective critically reviews relevant literature, providing insights, justifications, and viewpoints into how the scientific community and health authorities can leverage this knowledge cost-effectively.

With the emergence of the COVID-19 pandemic, the absence of established evidence-based treatment protocols led healthcare professionals and the public to explore experimental treatments, including high doses of vitamin D supplements. This study aimed to assess changes in serum 25-hydroxyvitamin D levels during the pandemic, employing a retrospective cohort analysis of data from Charleston Area Medical Center (CAMC). The study analyzed serum 25-hydroxyvitamin D levels in a cohort of 35,556 patients treated at CAMC in 2019, a representative pre-pandemic period, to 2021, a representative pandemic period. Our findings revealed a significant increase in mean serum 25-hydroxyvitamin D levels as compared with 2019 (37 ± 21 vs. 31 ± 15 ng/mL, p ≤ 0.001). Additionally, in 2021, there were significantly more patients exhibiting serum levels in the highest quintiles, specifically >100 ng/mL (1.6% vs. 0.2%), 75-100 ng/mL (4.6% vs. 1.2%), and 50-75 ng/mL (16.0% vs. 8.4%), p ≤ 0.001. This upsurge suggests increased intake of vitamin D supplements, potentially fueled by widespread discussions that were taking place largely on the internet regarding the efficacy of vitamin D against COVID-19. Our findings underscore the critical need for evidence-based public health messaging, especially during health crises, to prevent unnecessary health risks and ensure patient safety.

Medical treatment of coronavirus 19 disease (COVID-19) is a therapeutic challenge. The available data strongly suggest that calcifediol treatment may reduce the severity of COVID-19, and corticosteroids are the treatment of choice worldwide for severe COVID-19. Both have a very similar action profile, and their combined use in patients may modify the contribution of each administered compound.

To evaluate how treatment with calcifediol and/or corticosteroids in medical practice modified the need for ICU admission, death, or poor prognosis of patients hospitalized with COVID-19 during the first outbreaks.

A retrospective observational cohort study of patients admitted for COVID-19 to the Pneumology Unit of the Hospital Universitario Reina Sofía (Córdoba, Spain).

Patients were treated with calcifediol or/and corticosteroids with the best available therapy and standard care, according to clinical practice guidelines.

Admission to the intensive care unit (ICU) or death during hospitalization and poor prognosis.

Seven hundred and twenty-eight patients were included. According to the treatment received, they were included in four groups: calcifediol (n = 68), glucocorticoids (n = 112), both (n = 510), or neither (n = 38). Of the 578 patients treated with calcifediol, 88 were admitted to the ICU (15%), while of the 150 not treated with calcifediol, 39 required ICU admission (26%) (p < 0.01). Among the patients taking calcifediol without glucocorticoids, only 4 of 68 (5.8%) required ICU admission, compared to 84 of 510 (16.5%) treated with both (p = 0.022). Of the 595 patients who had a good prognosis, 568 (82.01%) had received treatment with calcifediol versus the 133 patients with a poor prognosis, of whom 90 (67.66%) had received calcifediol (p < 0.001). This difference was not found for corticosteroids.

The treatment of choice for hospitalized patients with moderate or mild COVID-19 could be calcifediol, not administering corticosteroids, until the natural history of the disease reaches a stage of hyperinflammation.

efficacy of therapeutic cholecalciferol supplementation for severe COVID-19 is sparingly studied.

effect of single high-dose cholecalciferol supplementation on sequential organ failure assessment (SOFA) score in moderate-to-severe COVID-19.

participants with moderate to severe COVID-19 with PaO2/FiO2 ratio < 200 were randomized to 0.6 million IU cholecalciferol oral (intervention) or placebo.

primary outcome was change in Day 7 SOFA score and pre-specified secondary outcomes were SOFA and 28-day all-cause mortality.

in all, 90 patients (45 each group) were included for intention-to-treat analysis. 25(OH)D3 levels were 12 (10-16) and 13 (12-18) ng/ml (P = 0.06) at baseline; and 60 (55-65) ng/ml and 4 (1-7) ng/ml by Day 7 in vitamin D and placebo groups, respectively. The SOFA score on Day 7 was better in the vitamin D group [3 (95% CI, 2-5) versus 5 (95% CI, 3-7), P = 0.01, intergroup difference - 2 (95% CI, -4 to -0.01); r = 0.4]. A lower all-cause 28-day mortality [24% compared to 44% (P = 0.046)] was observed with vitamin D.

single high-dose oral cholecalciferol supplementation on ICU admission can improve SOFA score at Day 7 and reduce in-hospital mortality in vitamin D-deficient COVID-19. ClinicalTrials.gov  id: NCT04952857 registered dated 7 July 2021. What is already known on this topic-vitamin D has immunomodulatory role. Observational and isolated intervention studies show some benefit in COVID-19. Targeted therapeutic vitamin D supplementation improve outcomes in severe COVID-19 is not studied in RCTs. What this study adds-high-dose vitamin D supplementation (0.6 Million IU) to increase 25(OH)D > 50 ng/ml is safe and reduces sequential organ failure assessment score, in-hospital mortality in moderate to severe COVID-19. How this study might affect research, practice or policy-vitamin D supplementation in vitamin D-deficient patients with severe COVID-19 is useful may be practiced.

The therapeutic effects of vitamin D supplementation on Coronavirus disease 2019 (COVID-19) aggravation remain controversial and inconclusive. To probe into this contentious issue, we performed the present meta-analysis of randomized controlled trials (RCTs).

Literature published up to June 2023 was retrieved from Cochrane Library, PubMed, Web of Science and Embase. RCTs assessing mortality, intensive care unit (ICU) admission, mechanical ventilation (MV), length of hospitalization (LOH), and inflammatory markers containing C-reactive protein (CRP), D-dimer, interleukin-6 (IL-6), lactate dehydrogenase (LDH) were included. 19 RCTs were involved in the analysis and were conducted subgroup analyses on the baseline COVID-19 severity and vitamin D administration.

In the severity subgroup, statistically significant effects in moderate to severe group were observed in ICU admission (OR 0.43, 95% CI 0.23, 0.80; p = 0.008), MV (OR 0.44, 95% CI 0.27, 0.72; p = 0.001) and LOH (SMD -0.49, 95% CI -0.92, -0.06; p = 0.027). In the administration subgroup, effects of ICU admission (OR 0.39, 95% CI 0.16, 0.97; p = 0.044), MV (OR 0.18, 95% CI 0.07, 0.46; p = 0.000) and LOH (SMD -0.50, 95% CI -0.96, -0.04; p = 0.034) were more pronounced in patients supplied with multiple-dose vitamin D than single-dose. Although the result of mortality showed no statistically significant effect, it indicated a reduced trend (OR 0.87, 95% CI 0.63, 1.12; p > 0.05). The results of inflammatory markers reached no statistical differences.

This meta-analysis revealed that moderate to severe COVID-19 patients supplied with multiple doses of vitamin D were less apt to need ICU admission, mechanical ventilation and have shorter hospital stays.

The role of vitamin D3 (VitD3) in modulating innate and adaptive immunity has been reported in different disease contexts. Since the start of the coronavirus disease-2019 (COVID-19) pandemic, the role of VitD3 has been highlighted in many correlational and observational studies. However, the exact mechanisms of action are not well identified. One of the mechanisms via which VitD3 modulates innate immunity is by regulating the NLRP3-inflammasome pathway, being a main underlying cause of SARS-CoV-2-induced hyperinflammation.

Blood specimens of severe COVID-19 patients with or without VitD3 treatment were collected during their stay in the intensive care unit and patients were followed up for 29 days. qPCR, western blot, and ELISA were done to investigate the mechanism of action of VitD3 on the NLRP3 inflammasome activation.

We here report the ability of VitD3 to downregulate the NLRP3-inflammsome pathway in severe COVID-19 patients. Lower inflammasome pathway activation was observed with significantly lower gene and protein expression of NLRP3, cleaved caspase-1, ASC and IL-1β among severe COVID-19 patients treated with VitD3. The reduction of the inflammasome pathway was associated with a reduction in disease severity markers and enhancement of type I IFN pathway.

Our data reveals an important anti-inflammatory effect of VitD3 during SARS-CoV-2 infection. Further investigations are warranted to better characterize the ability of VitD3 to control disease pathogenesis and prevent progression to severe states. This will allow for a more efficient use of a low cost and accessible treatment like VitD3.

This study aims to investigate the clinical course and factors associated with hospital admission and mortality among SARS-CoV-2 patients within the Nairobi Metropolitan Area. The study utilizes a multicenter retrospective cohort design, collecting clinical characteristics and laboratory parameters of hospitalized patients from March 2020 to May 2022. Data analysis includes percentages, frequencies, chi-square tests, Kaplan-Meier analysis, pairwise comparisons, and multivariate regression models. Ethical considerations are observed throughout the research process. The study findings highlight significant associations between comorbidities, such as hypertension, and increased mortality risk due to COVID-19. Symptoms including fever, cough, dyspnea, chest pain, sore throat, and loss of smell/taste are also identified as predictors of mortality. Abnormal laboratory parameters, such as oxygen saturation, procalcitonin, glucose levels, serum creatinine, and gamma-glutamyl transpeptidase, are associated with mortality. However, demographic factors and certain vital signs do not exhibit significant associations. Recommendations based on this study suggest increased monitoring and management of comorbidities, early identification and management of symptoms, regular monitoring of laboratory parameters, continued research and collaboration, and implementation of preventive measures. Overall, a multidisciplinary approach involving healthcare professionals, researchers, policymakers, and the public is crucial to improve COVID-19 outcomes and reduce mortality rates. Adaptation of strategies based on emerging evidence and resource allocation is essential for effective management of the pandemic.