COVID infections or vaccinations may increase Multiple Sclerosis (if low D) - several studies

---

The Potential Role of SARS-CoV-2 Infection and Vaccines in Multiple Sclerosis Onset and Reactivation: A Case Series and Literature Review - July 2023

Viruses . 2023 Jul 18;15(7):1569. doi: 10.3390/v15071569.
Eleonora Tavazzi 1, Anna Pichiecchio 1 2, Elena Colombo 1, Eleonora Rigoni 1, Carlo Asteggiano 1 2, Elisa Vegezzi 1, Francesco Masi 1 2, Giacomo Greco 1 2, Stefano Bastianello 2, Roberto Bergamaschi 1

The recent SARS-CoV-2 pandemic and related vaccines have raised several issues. Among them, the potential role of the viral infection (COVID-19) or anti-SARS-CoV-2 vaccines as causal factors of dysimmune CNS disorders, as well as the safety and efficacy of vaccines in patients affected by such diseases and on immune-active treatments have been analyzed. The aim is to better understand the relationship between SARS-CoV-2 infection/vaccines with dysimmune CNS diseases by describing 12 cases of multiple sclerosis/myelitis onset or reactivation after exposure to SARS-CoV-2 infection/vaccines and reviewing all published case reports or case series in which MS onset or reactivation was temporally associated with either COVID-19 (8 case reports, 3 case series) or anti-SARS-CoV-2 vaccines (13 case reports, 6 case series). All the cases share a temporal association between viral/vaccine exposure and symptoms onset. This finding, together with direct or immune-based mechanisms described both during COVID-19 and MS, claims in favor of a role for SARS-CoV-2 infection/vaccines in unmasking dysimmune CNS disorders. The most common clinical presentations involve the optic nerve, brainstem and spinal cord. The preferential tropism of the virus together with the presence of some host-related genetic/immune factors might predispose to the involvement of specific CNS districts.
 Download the PDF from VitaminDWiki

---

COVID-19 and Multiple Sclerosis: A Complex Relationship Possibly Aggravated by Low Vitamin D Levels - Feb 2023

Cells. 2023 Feb 21;12(5):684. doi: 10.3390/cells12050684.
William Danilo Fernandes de Souza 1, Denise Morais da Fonseca 2, Alexandrina Sartori 1

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an exceptionally transmissible and pathogenic coronavirus that appeared at the end of 2019 and triggered a pandemic of acute respiratory disease, known as coronavirus disease 2019 (COVID-19). COVID-19 can evolve into a severe disease associated with immediate and delayed sequelae in different organs, including the central nervous system (CNS). A topic that deserves attention in this context is the complex relationship between SARS-CoV-2 infection and multiple sclerosis (MS). Here, we initially described the clinical and immunopathogenic characteristics of these two illnesses, accentuating the fact that COVID-19 can, in defined patients, reach the CNS, the target tissue of the MS autoimmune process. The well-known contribution of viral agents such as the Epstein-Barr virus and the postulated participation of SARS-CoV-2 as a risk factor for the triggering or worsening of MS are then described. We emphasize the contribution of vitamin D in this scenario, considering its relevance in the susceptibility, severity and control of both pathologies. Finally, we discuss the experimental animal models that could be explored to better understand the complex interplay of these two diseases, including the possible use of vitamin D as an adjunct immunomodulator to treat them.
 Download the PDF from VitaminDWiki

From PDF: Connection between Multiple Sclerosis and Vitamin D

Numerous questions have been raised concerning the relationship between MS and vitD levels. Some of the most relevant ones, considering practical purposes, are: Is there a vitD deficiency in MS patients and is this a risk factor to develop) this disease and to present a more severe pathology? Is vitD supplementation indicated for MS patients?
How would vitD control MS pathogenesis?
The literature data concerning the relationship between vitD and MS support the concepts that there is a vitD deficiency in these patients, that this is a risk factor for disease development and that this deficit probably contributes to a more severe pathology. The hypothesis that adequate vi tD levels were relevant to preventing MS development emerged from the realization that this disease was more prevale nt an geographical regions with a lower solar incidence when the production of this vitamin by the skin, stimulated by UV light, is low. The high prevalence of vitD dsficiency in MS patients was formally described in 1994 [100]. This finding was subsequently validated by other authors who also showed a significant aerrel ation between this deficiency, MRI load and disease severity [101]. Several studies have been conducted to determine if vitD supplementation could be considered as an add-on therapy for MS. A study performed in relapsing-remitting patients investigated its supplementation in patients under IFN-p-1b [102]. Even though no difference has been observed in the annual relapse rate, the vitD supplemented group presented a reduced disease activity indicated by MRI. According to [103], the supplementation with vitD of MS patients under natalizumab treatment corrected hypovitaminosis and decreased annualized relapse rate. As vitD efficacy could rely on high doses and considering that this could trigger fatigue, muscle weakness, renal failure and cardiac arrhythmia, some clinical trials were designed to test possible deleterious outcomes. It was found, however, that even vitD supplements that elevated twice the top of physiological range did not elicithypercalcemia, hypercalciuria or any other detrimental effect [104]. Nonetheless, a clinical trial concerning the efficacy of a high vitD dose was inconclusive, neither supporting nor discrediting its potential benefit [105]. So far, there is no substantial evidence to approve this vitamin as an add-on therapy for MS [106]. Despite the literature discrepancies, these authors recommend implementing standardized study designs with well-defined variables concerning the kind of vitD supplement, its concentration, cohort composition, and the clinical and laboratory parameters to be evaluated. They also recommend the collection and storage of samples to assemble a bio-bank for further evaluations. Detailed reasoning and suggestions regarding their proposed study design are available in their publication.
Our research team has been testing vitD efficacy in EAE. Our findings indicate a clear window of opportunity for therapy with vitD in an animal model which could also be relevant for the human disease. We found that vitD is still effective when adminis­tered during the preclinical disease phase. However, it is important to clarify that earlier supplementation determines a more pronounced therapeutic effect [107,108].
It is well established that vitD signaling pathways are able to regulate both innate and adaptive immunity, keeping the associated inflammatory response within physiological limits. The immunomodulatory ability of vitD is clearly pleiotropic and reaches the majority of the immune cells in different phases of the immune response. This is explained by its interaction with the vitamin D receptor (VDR) expressed in immune cells including PMNs, macrophages, DCs, and B and T lymphocytes [109]. Understanding this essential VitD biological activity has sparked much interest in two aspects: vitD level in patients with inflammatory diseases and the possibility of its supplementation as a therapeutic measure. The interaction of the active form of vitD with VDR and the main effects over the immune system are illustrated in Figure 5. An overview of the main outcomes from vitD interaction with immune cells is presented in Table 1. Its potential as an adjunct or alternative therapy in inflammatory diseases is exemplified in Table 1.
The presumed protective effect of vitD on MS may occur in both the periphery and the CNS. As previously mentioned in this review, it has been suggested that the immune response against neural antigens is initiated in the peripheral lymphoid organs. VitD could already be effective at this initial stage by modulating the differentiation and function of APCs. It has been widely demonstrated that vitD affects the differentiation, maturation and function of DCs, directing them to a tolerogenic profile [107,142]. These APCs will then modulate naïve TCD4e lymphocytes toward a functional hypo-reactive state. VitD- induced tolerogenic DCs are also capable of driving the differentiation of Tregs. This effect was demonstrated in EAE by the adoptive transference of vitD-induced IDO+ DCs, which are immature and tolerogenic cells. This procedure increased the percentage of CD4+CD25+Foxp3+ Tregs in the lymph nodes of rats with EAE [143], The abiltty of VitD to decrease proliferation and differentiation of effector proinflammatory T cells in EAE was also demonstrated [144]. This effect was associated with the downmodulation of various metabolic and signaling routes which are essential for Th1/Th17 polarization. This inhibition was concurrent with reduced DNA methylation and the; upregulation of many non-coding RNA classes.
(One of the critical stages of MS immunopathogenesis is the BBB breakdown which can be detected in patients via gadolinium-enhanced MRI in the CNS [145]. An effect at this level is expected, considering that BBB endothelial cells express VDR. Our research team showed that calcitriol administration to a murine model of MS decreases neuroin­flammation and reduces BBB disruption [146]. Other experimental pieces of evidence have disclosed the molecular mechanisms underlying this protective effect. By using an in vitro system comprising a human brain microvascular endothelial cell line stimulated with TNF-a or sera from MS patients, the authors in [147] showed that vitD determined the upregulation of tight junction proteins and downregulation of cell adhesion molecules. VitD can also downmodulate neuroinflammation by targeting additional CNS cells. It decreases, for example, the production of TNF-a, IL-1p and the expression of IL-4 by astrocytes stimulated with LPS in vitro. This likely outcome was reproduced in neonatal rats injected with LPS [148]. The addition of vitD to stimulated microglial cells reduces the expression of Iba-1, MHC-II, CD86 and TLR-4 in vitro, and in EAE [146,149]. By using a model of demyelination in rats, the authors in [150] described that VitD also operates at the level of remyelination. VitD promotes the proliferation and differentiation of neural stem cells and their migration to the lesion site, where they subsequently differentiate into oligodendrocyte lineage cells and produce myelin basic protein. Lastly, the possibility that vitD is also acting through inflammasome inhibition must be considered. This system operates in the periphery during the initial induction/expansion of Th1/Th17 cells and also during the inflammatory process in the CNS. The demonstration in [151] that vitD negatively regulates the NLRP3 inflammasome via VDR signaling, effectively inhibiting IL-1 p secretion, gives some support to this additional level of vitD protection in MS.

From PDF: Connection between COVID-19 and Vitamin D

Analogous to the approach used to analyze the relationship between MS and vitD, we also limited the complex connection between COVID-19 and vitD to answer the same three questions: Is there vitD deficiency in COVID-19 patients and is this a risk factor for getting infected and to develop a more severe pathology? Is vitD supplementation indicated for COVID-19 patients?
How would vitD control COVID-19 pathogenesis?
An analysis between vitD levels and the number of COVID-19 cases in 20 European countries showed a significant negative correlation, suggesting that higher levels of this hormone could afford some protection against SARS-CoV-2 infection [152]. These findings were reinforced by the observation that many hospitalized COVID-19 patients presented vitD serum levels considered below the normal expected ones [153,154]. The majority of the findings also support an inverse correlation between vitD deficiency and a poor prognosis for COVID-19. According to [155], low vitD levels at hospital admission were associated with increased IL-6 production and predicted the severity of respiratory distress and mortality during the course of hospitalization. This association between vitD deficiency and severe COVID-19 has been confirmed by several other researchers [156-159]. From a theoretical point of view, based mainly on vitD's immunomodulatory properties, its adoption as an adjunct therapy for COVID-19 seems consistent. For instance, the authors in [160] have investigated the effect of oral vitD supplementation in mild to moderate COVID-19 patients with low levels of this vitamin. They observed that 5000 IU of vitD reduced the recovery time related to cough and loss of taste and smell. The adequate levels of vitD in the host have been associated with the reduced release of proinflammatory cytokines, thus lowering the risk of a cytokine storm; increased levels of anti-inflammatory cytokines; and enhanced secretion of natural antimicrobial peptides. It may also be involved in the enhancement of the Th2 immune response and activation of defensive cells such as macrophages, as illustrated in Figure 5. Contrary to these findings, several studies have concluded that there is no direct association between vitD concentrations and a poor prognosis of the disease [161]. By employing a meta-analysis and GRADE assessment of cohort studies and RCTs, the authors of [162] inferred that low vitD levels do not play a role in disease severity and that supplementation does not improve outcomes in hospitalized patients.
The explanation for these conflicting results could be partially related to intra- and inter-cohort variability. Other parameters, including supplementation protocols such as doses, period of supplementation, patient's age, presence of comorbidities and even the risk of bias, could contribute to this variability. This ambiguous scenario has prevented an official recommendation concerning the prophylactic or therapeutic use of vitD for COVID- 19 control [163]. The presumptive ability of vitD to control SARS-CoV-2 infectivity and COVID-19 severity would be mediated by different mechanisms. Some of them are related to the capacity of this hormone to increase the production of antimicrobial peptides, in particular cathelicidin antimicrobial peptide, also known as LL-37 [164]. LL-37 is produced by immune cells and epithelial cells from the skin and respiratory tract. Experimental data strongly suggests that this peptide can inhibit SARS-CoV-2 infection and other alterations that contribute to disease severity. Human cathelicidin can inhibit virus infection by directly interacting with the SARS-CoV-2 RDB and also by masking the ACE2 [165]. According to [166], a plethora of other biological activities have been ascribed to LL-37 and could contribute to its eventual preventive and therapeutic adoption against COVID-19. In this sense, this peptide is endowed with an immunomodulatory ability, could facilitate efficient NET clearance by macrophages and speed endothelial repair. These authors also addressed the fact that further investigations about the VitD/LL-37 axis in the context of COVID-19 are highly recommended considering that vitD could be a widely accessible strategy.
One of the hallmarks of severely affected COVID-19 patients is the presence of a cytokine storm, mainly triggered by the activation of cells from innate immunity. The well- established ability of vitD to directly control cytokine and chemokine production could provide another mechanism for vitD usefulness as an adjunct therapy for COVID-19. This effect derives mostly from the downmodulatory ability of vitD over Th1 and Th17 differentiation and cytokine production [167,168]. This mechanism is already suggested by clinical findings in COVID-19 patients. The authors in [169] described that vitD supplementation in geriatric intensive care patients suffering from COVID-19 reduced many inflammatory parameters, including IL-16, C-reactive protein, procalcitonin, D-Dimer, ferritin and lactate dehydrogenase. Its activity against endothelial dysfunction [170], and vascular thrombo­sis [170] could also contribute to the ability to control COVID-19 immunopathogenesis.

---

Multiple sclerosis is associated with worse COVID-19 outcomes compared to the general population: A population-based study - Nov 2023

Multiple Sclerois: VOL 79, 104947, NOV 2023 https://doi.org/10.1016/j.msard.2023.104947 PDF behind paywall

Highlights

• Before adjustment for age and sex, people living with MS patients had non-significant decreased odds of hospitalization and mortality compared to those without MS.
• After adjustment for age and sex, people living with MS had poor outcomes of COVID-19 compared to those without MS.
• There was an increased odds of hospitalization rate among PLWMS compared to MS-free individuals in the age group of 18–49.
• There was no significant difference between older people (50–79 years) with and without MS.

Background
We carried out the current study to compare COVID-19-related hospitalization and mortality rates between people living with multiple sclerosis (PLWMS) and MS-free controls from the Isfahan general population.
Method
In this retrospective population-based study, we used available data from four datasets of Isfahan University of Medical Sciences from January 1, 2020, to August 22, 2021. Data on all PLWMS, SARS-CoV-2 polymerase chain reaction (PCR) and rapid antigen test, hospitalization, and death were included. We compared the odds of COVID-19-related hospitalization and mortality between PLWMS and the control group before and after adjustment for age and sex. We categorized all people into young (18–49 years) and old age (50–79 years) groups and compared the hospitalization rate between people with and without MS.

Results
In total, 829 PLWMS and 2494 MS-free controls with confirmed COVID-19 were included. Hospitalization rates among PLWMS and MS-free controls were 16.2% and 16.5% (crude OR= 0.978, 95%CI: 0.79, 1.21). In the adjusted model, PLWMS with COVID-19 had 56% increased odds of hospitalization (OR=1.56, 95%CI: 1.23, 1.97). During follow-up, there were 11 (1.3%) and 49 (2%) COVID-19-related deaths among PLWMS and MS-free controls, respectively. No significant difference between people with and without MS in COVID-19-related mortality rate was observed (crude OR= 0.678, 95%CI: 0.351, 1.31; adjusted OR=2.013, 95%CI: 0.95, 4.26). We found increased odds of hospitalization in young PLWMS compared to those without MS at the same age (OR=1.699, 95%CI: 1.289, 2.240). But, no difference between older people with and without MS was detected (OR=1.005, 95%CI: 0.662, 1.524).

Conclusion
This study revealed higher odds of hospitalization and mortality due to COVID-19 among PLWMS in comparison to age- and sex-matched controls from the general population. Nevertheless, it remains unclear whether the elevated odds are directly associated with MS itself or if they are influenced by factors such as rituximab using, comorbidity, and disease severity.
 Download the PDF from VitaminDWiki

---

New Onset Multiple Sclerosis Post-COVID-19 Vaccination and Correlation With Possible Predictors in a Case-Control Study - March 2023

Cureus 15(3): e36323. doi:10.7759/cureus.36323
Majed Alluqmani

Introduction: Various inflammatory diseases have been associated with the administration of various vaccines. Several reports have associated vaccine administration with the demyelinating diseases of the central nervous system (CNS). However, no clear or strong scientific evidence exists to support the association of vaccine administration with the onset of demyelinating diseases. Some CNS demyelination diseases such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) were reported following the administration of COVID-19 vaccines. In this study, new onset multiple sclerosis (MS) following COVID-19 vaccine administration was reported.

Methods: In this longitudinal observational case-control study, a total of 65 participants were studied, who were divided into two groups. Group A included 32 MS patients who were diagnosed post-COVID-19 vaccine administration and group B included 33 participants who received COVID-19 vaccines and did not develop MS. Group B was used as a control. The Chi-square test and logistic regression analysis were carried out using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY) software.

Results: Univariate and multivariate logistic regression analysis was performed and a significant correlation between the risk factors and the development of MS post-COVID-19 vaccination was identified.

Conclusion: The risk factors, identified in this study, can be used as significant independent predictors for developing MS post-COVID-19 vaccinations.
 Download the PDF from VitaminDWiki

---

Vaccination and multiple sclerosis - Dr. Campbell, YouTube May 2023

17 minutes

---

VitaminDWiki - COVID infections and vaccinations decrease Vitamin D – many studies

---

VitaminDWiki - 12 studies in both categories VIRUS (COVID & Epstein) and MS

This list is automatically updated