Parkinson's Disease, SARS-CoV-2, and Frailty: Is There a Vicious Cycle Related to Hypovitaminosis D?

The literature has long established the association between aging and frailty, with emerging evidence pointing to a relationship between frailty and SARS-CoV-2 contagion. The possible neurological consequences of SARS-CoV-2 infection, associated with physical and cognitive frailty, could lead to a worsening of Parkinson's disease (PD) in infected patients or-more rarely-to an increase in the Parkinsonian symptomatology. A possible link between those clinical pictures could be identified in vitamin D deficiency, while the whole process would appear to be associated with alterations in the microbiota-intestine-brain axis that fall within the α-Synuclein Origin site and Connectome (SOC) model, and allow for the identification of a body-first PD and a brain-first PD. The model of care for this condition must consider intrinsic and extrinsic variables so that care by a multidisciplinary team can be successfully predicted. A multidimensional screening protocol specifically designed to identify people at risk or in the early stages of the disease should begin with the investigation of indices of frailty and microbiota-intestine-brain axis alterations, with a new focus on cases of hypovitaminosis D.

Low vitamin D levels are associated with Long COVID syndrome in COVID-19 survivors.

PURPOSE: Long-COVID is an emerging syndrome affecting 50-70% of COVID-19 survivors which still lacks predicting factors. Due to the extra-skeletal effects of vitamin D, we retrospectively assessed in COVID-19 survivors 6-months after hospitalization the association between 25(OH)vitamin D levels and Long-COVID. METHODS: Long-COVID was defined according to NICE-guidelines. Fifty Long-COVID and 50 non-Long-COVID subjects matched on a 1:1-basis were enrolled from an outpatient-post-COVID clinic-cohort seen from August to November 2020. Therapies/comorbidities affecting calcium/vitamin-D/bone metabolism, and/or admission in ICU during hospitalization were exclusion criteria. 25(OH)vitamin D was measured at hospital-admission and 6-months after discharge. RESULTS: We observed lower 25(OH)vitamin D levels, evaluated at follow-up, in subjects with Long-COVID than those without (20.1vs23.2 ng/mL-p = 0.03). Regarding the affected health-areas evaluated in the entire cohort, we observed lower 25(OH)vitamin D levels in those with neurocognitive symptoms at follow-up (n.7) as compared to those without (n.93) (14.6vs20.6 ng/mL-p = 0.042). In patients presenting vitamin D deficiency (<20 ng/mL) both at admission and at follow-up (n.42), those affected by Long-COVID (n.22) presented lower 25(OH)vitamin D levels, at follow-up, compared to those not affected (n.20) (12.7vs15.2 ng/mL-p = 0.041). In multiple-regression analyses, lower 25(OH)vitamin D levels, at follow-up, resulted as the only variable significantly associated with Long-COVID in our cohort (p = 0.008, OR 1.09-CI 1.01-1.16). CONCLUSIONS: COVID-19 survivors with Long-COVID have lower 25(OH)vitamin D levels as compared to matched-patients without Long-COVID. Our data suggest that vitamin D levels should be evaluated in COVID-19 patients after hospital-discharge. Role of vitamin D supplementation as preventive strategy of COVID-19 sequelae should be tested in randomized-controlled trials.

The Impact of Vitamin D Levels on Clinical Manifestations of Multisystem Inflammatory Syndrome in Children: A Cross-Sectional Study.

BACKGROUND: Hyperinflammatory response that resembles Kawasaki disease may develop in children after COVID-19 disease, and it is called multisystem inflammatory syndrome in children. The cause of MIS-C is dysregulated innate immune response and a subsequent cytokine storm that results in endothelial damage. It has been determined that low levels of serum 25(OH)D increase the risk of developing immune-related diseases and disorders. METHODS: To determine the incidence of hypovitaminosis D, and a possible correlation between 25(OH)D levels and the clinical severity of MIS-C, 21 patients hospitalized in the University Hospital of Split due to MIS-C were evaluated. RESULTS: Hypovitaminosis D was detected in 95% of MIS-C patients. We found a significant relationship between the severity of MIS-C and 25(OH)D levels, as patients with more severe MIS-C had lower 25(OH)D. MIS-C patients with lower vitamin D levels had worse systolic and diastolic function of the left ventricle according to echocardiograms. There was no relationship between 25(OH)D levels and the tested laboratory inflammatory and cardiac markers. CONCLUSION: Hypovitaminosis D is very common in children with MIS-C and influences the severity of the disease. VD could be a new potential biomarker in MIS-C, and VD replacement therapy should be considered early on in the treatment of MIS-C.

Low vitamin D levels predict outcomes of COVID-19 in patients with both severe and non-severe disease at hospitalization.

PURPOSE: Low vitamin D in COVID-19 have been related to worse outcomes. However, most of the studies conducted so far were not-controlled and retrospective, including biases potentially influencing this association. We evaluated 25(OH)vitamin D levels of patients with both severe and non-severe disease at hospital-admission, and in a cohort of control subjects. Moreover, we evaluated sACE-2 levels to investigate the mechanisms underlying the association between vitamin D and COVID-19. METHODS: COVID-19 patients were enrolled in a matched for age, sex and comorbidities 1:1-ratio based on the presence/or not of respiratory-distress/severe-disease at hospital-admission. Control matched subjects were enrolled from an outpatient-setting. RESULTS: Seventy-three COVID-19 patients (36 severe and 37 non-severe) and 30 control subjects were included. We observed a higher vitamin D deficiency (<20 ng/mL) prevalence in COVID-19 patients than control subjects (75% vs 43%). No differences were found regarding 25(OH)vitamin D and sACE-2 levels between patients with and without severe-disease at study entry. During the disease-course, in the severe group a life-threatening disease occurred in 17 patients (47.2%), and, in the non-severe group, a worsening disease occurred in 10 (27%). 25(OH)vitamin D levels, at admission, were negatively correlated with sACE-2 levels, and were lower in patients whose disease worsened as compared to those in whom it did not, independently from the disease severity at admission. In multivariate-analysis, lower 25(OH)vitamin D resulted as an independent risk factor for disease worsening. CONCLUSIONS: 25(OH)vitamin D levels at hospital-admission strongly predicted the occurrence of worsening outcomes in COVID-19 independently of the disease severity at presentation.

Rapidly Increasing Serum 25(OH)D Boosts the Immune System, against Infections-Sepsis and COVID-19.

Vitamin D deficiency is a global public health problem, a pandemic that commonly affects the elderly and those with comorbidities such as obesity, diabetes, hypertension, respiratory disorders, recurrent infections, immune deficiency, and malignancies, as well as ethnic minorities living in temperate countries. The same groups were worst affected by COVID-19. Since vitamin D deficiency weakens the immune system, it increases the risk of infections, complications, and deaths, such as from sepsis and COVID-19. Deficiency can be remedied cost-effectively through targeted food fortification, supplementation, and/or daily safe sun exposure. Its endocrine functions are limited to mineral metabolism, musculoskeletal systems, specific cell membrane interactions, and parathyroid gland functions. Except for the rapid, endocrine, and cell membrane-based non-genomic functions, all other biological and physiological activities of vitamin D depend on the adequate intracellular synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells via the genome. Calcitriol mediates autocrine (intracrine) and paracrine signalling in immune cells, which provides broader, protective immune functions crucial to overcoming infections. The synthesis of 1,25(OH)2D (calcitriol) in peripheral target cells is dependent on diffusion and endocytosis of D3 and 25(OH)D from the circulation into them, which requires maintenance of serum 25(OH)D concentration above 50 ng/mL. Therefore, in acute infections such as sepsis and respiratory infections like COVID-19, it is necessary to rapidly provide its precursors, D3 and 25(OH)D, through the circulation to generate adequate intracellular calcitriol. Immune defence is one of the crucial non-hormonal functions of vitamin D. A single oral (bolus) dose or divided upfront loading doses between 100,000 and 500,000 IU, using 50,000 IU vitamin D3 increase the serum 25(OH)D concentrations to a therapeutic level of above 50 ng/mL that lasts between two to three months. This takes three to five days to raise serum 25(OH)D. In contrast, a single oral dose of calcifediol (0.014 mg/kg body weight) can generate the needed 25(OH)D concentration within four hours. Considering both D3 and 25(OH)D enter immune cells for generating calcitriol, using the combination of D3 (medium-term) and calcifediol (immediate) is cost-effective and leads to the best clinical outcome. To maximise protection against infections, particularly to reduce COVID-19-associated complications and deaths, healthcare workers should advise patients on safe sun exposure, adequate vitamin D supplementation and balanced diets containing zinc, magnesium, and other micronutrients to support the immune system. Meanwhile, governments, the World Health Organisation, the Centers for Disease Control, and governments should consider similar recommendations to physicians and the public, change the outdated vitamin D and other micronutrient recommendations directed to their population, and organise targetted food fortification programs for the vulnerable groups. This article discusses a rational approach to maintaining a sustained serum 25(OH)D concentration above 50 ng/mL, necessary to attain a robust immune system for overcoming infections. Such would cost-effectively improve the population's health and reduce healthcare costs. It also describes three cost-effective, straightforward protocols for achieving and sustaining therapeutic serum 25(OH)D concentrations above 50 ng/mL (>125 nmol/L) to keep the population healthy, reduce absenteeism, improve productivity, and lower healthcare costs.

Obesity, Hypovitaminosis D, and COVID-19: the Bermuda Triangle in Public Health.

PURPOSE OF REVIEW: The COVID-19 pandemic has challenged public health to a significant extent by markedly increasing morbidity and mortality. Evidence suggests that obesity and hypovitaminosis D constitute important risk factors for SARS-CoV-2 infection, severity of disease, and poor outcomes. Due to their high prevalence globally, obesity and hypovitaminosis D are considered pandemics. This review presents current epidemiologic and genetic data linking obesity, hypovitaminosis D, and COVID-19, highlighting the importance of the convergence of three pandemics and their impact on public health. We also briefly summarize potential mechanisms that could explain these links. RECENT FINDINGS: Epidemiologic data have shown that obesity is an independent risk factor for COVID-19, severe disease and death, and genetic evidence has suggested a causal association between obesity-related traits and COVID-19 susceptibility and severity. Additionally, obesity is independently associated with hypovitaminosis D, which is highly prevalent in subjects with obesity. Hypovitaminosis D is independently associated with a higher risk for COVID-19, severity, hospitalization, infectious complications, acute respiratory distress syndrome, and poor outcomes. However, genome-wide association studies have not revealed any causal association between vitamin D levels and the risk for COVID-19, while there is no robust evidence for a beneficial role of vitamin D supplementation in the prevention and treatment of COVID-19. In the context of the ongoing COVID-19 pandemic, the epidemiologic impact of obesity and hypovitaminosis D is emphasized. Efforts to increase public awareness and reinforce preventive and therapeutic measures against obesity and hypovitaminosis D are strongly required.

Is There a Crucial Link Between Vitamin D Status and Inflammatory Response in Patients With COVID-19?

Background: Hypovitaminosis D has been suggested to play a possible role in coronavirus disease 2019 (COVID-19) infection. Methods: The aim of this study is to analyze the relationship between vitamin D status and a biochemical panel of inflammatory markers in a cohort of patients with COVID-19. A secondary endpoint was to evaluate the correlation between 25OHD levels and the severity of the disease. Ninety-three consecutive patients with COVID-19-related pneumonia were evaluated from March to May 2020 in two hospital units in Pisa, in whom biochemical inflammatory markers, 25OHD levels, P/F ratio at nadir during hospitalization, and complete clinical data were available. Results: Sixty-five percent of patients presented hypovitaminosis D (25OHD ≤ 20 ng/ml) and showed significantly higher IL-6 [20.8 (10.9-45.6) vs. 12.9 (8.7-21.1) pg/ml, p = 0.02], CRP [10.7 (4.2-19.2) vs. 5.9 (1.6-8.1) mg/dl, p = 0.003], TNF-α [8.9 (6.0-14.8) vs. 4.4 (1.5-10.6) pg/ml, p = 0.01], D-dimer [0.53 (0.25-0.72) vs. 0.22 (0.17-0.35) mg/l, p = 0.002], and IL-10 [3.7 (1.8-6.9) vs. 2.3 (0.5-5.8) pg/ml, p = 0.03]. A significant inverse correlation was found between 25OHD and all these markers, even adjusted for age and sex. Hypovitaminosis D was prevalent in patients with severe ARDS, compared with the other groups (75% vs. 68% vs. 55%, p < 0.001), and 25OHD levels were lower in non-survivor patients. Conclusions: The relationship between 25OHD levels and inflammatory markers suggests that vitamin D status needs to be taken into account in the management of these patients. If vitamin D is a marker of poor prognosis or a possible risk factor with beneficial effects from supplementation, this still needs to be elucidated.

Hypocalcemia in COVID-19 is associated with low vitamin D levels and impaired compensatory PTH response.

BACKGROUND: Hypocalcemia has been identified as a major distinctive feature of COVID-19, predicting poor clinical outcomes. Among the mechanisms underlying this biochemical finding, high prevalence of vitamin D (VD) deficiency in COVID-19 patients reported so far in several studies was advocated. However, robust data in favor of this hypothesis are still lacking. Therefore, aim of our study was to investigate the role of hypovitaminosis D and parathyroid hormone (PTH) levels in the development of hypocalcemia in COVID-19 patients. METHODS: Patients admitted to IRCCS Ospedale San Raffaele for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing calcium and VD metabolism. Serum levels of total calcium (tCa), ionized calcium (Ca2+), 25-OH-VD, and PTH were evaluated at admission. We defined VD deficiency as VD below 20 ng/mL, hypocalcemia as tCa below 2.2 mmol/L or as Ca2+ below 1.18 mmol/L, and hyperparathyroidism as PTH above 65 pg/mL. RESULTS: A total of 78 patients were included in the study. Median tCa and Ca2+ levels were 2.15 and 1.15 mmol/L, respectively. Total and ionized hypocalcemia were observed in 53 (67.9%) and 55 (70.5%) patients, respectively. VD deficiency was found in 67.9% of patients, but secondary hyperparathyroidism was detected in 20.5% of them, only. tCa levels were significantly lower in patients with VD deficiency and regression analyses showed a positive correlation between VD and tCa. CONCLUSIONS: In conclusion, we confirmed a high prevalence of hypocalcemia in COVID-19 patients and we showed for the first time that it occurred largely in the context of marked hypovitaminosis D not adequately compensated by secondary hyperparathyroidism.

Shedding light on vitamin D: the shared mechanistic and pathophysiological role between hypovitaminosis D and COVID-19 risk factors and complications.

Severe acute respiratory syndrome coronavirus (SARS-COV-2) is the culprit of the Coronavirus Disease (COVID-19), which has infected approximately 173 million people and killed more than 3.73 million. At risk groups including diabetic and obese patients are more vulnerable to COVID-19-related complications and poor outcomes. Substantial evidence points to hypovitaminosis D as a risk factor for severe disease, the need for ICU, and mortality. 1,25(OH)D, a key regulator of calcium homeostasis, is believed to have various immune-regulatory roles including; promoting anti-inflammatory cytokines, down regulating pro-inflammatory cytokines, dampening entry and replication of SARS-COV-2, and the production of antimicrobial peptides. In addition, there are strong connections which suggest that dysregulated 1,25(OH)D levels play a mechanistic and pathophysiologic role in several disease processes that are shared with COVID-19 including: diabetes, obesity, acute respiratory distress syndrome (ARDS), cytokine storm, and even hypercoagulable states. With evidence continuing to grow for the case that low vitamin D status is a risk factor for COVID-19 disease and poor outcomes, there is a need now to address the public health efforts set in place to minimize infection, such as lock down orders, which may have inadvertently increased hypovitaminosis D in the general population and those already at risk (elderly, obese, and disabled). Moreover, there is a need to address the implications of this evidence and how we may apply the use of cheaply available supplementation, which has yet to overcome the near global concern of hypovitaminosis D. In our review, we exhaustively scope these shared pathophysiologic connections between COVID-19 and hypovitaminosis D.

High Prevalence of Hypocalcemia in Non-severe COVID-19 Patients: A Retrospective Case-Control Study.

Purpose: To compare serum total calcium and phosphate levels in patients with non-severe COVID-19 with age, sex, and serum 25-hydroxyvitamin D level matched healthy adult cohort. Methods: In this retrospective case-control study, medical records of patients (≥18 years) diagnosed as non-severe COVID-19 admitted at and discharged from our tertiary care institution during the period from April 10, 2020 and June 20, 2020 were retrieved. Baseline investigations, notably, serum calcium, phosphate, albumin, magnesium, 25-hydroxyvitamin D, and C-reactive protein (CRP), were performed at admission before any form of calcium or vitamin D supplementation were considered. The biochemical parameters were compared with age, sex, and 25-hydroxyvitamin D matched healthy adult controls (1:1 ratio) derived from the Chandigarh Urban Bone Epidemiological Study (CUBES). Results: After exclusion, 72 patients with non-severe COVID-19 (63 mild and 9 moderate disease) and an equal number of healthy controls were included in the final analysis. Age, sex, serum 25-hydroxyvitamin D, and albumin levels were matched between the 2 groups. Hypovitaminosis D and hypocalcemia were seen in 97 and 67% of the patients, respectively. The patients had lower serum calcium (P value <0.001) and phosphate (P = 0.007) compared with the controls. There was no statistically significant correlation between serum calcium and CRP. Conclusions: Hypocalcemia is highly prevalent even in COVID-19 patients with non-severe disease probably implying that hypocalcemia is intrinsic to the disease. Prospective studies with larger number of patients are required to prove this hypothesis and unravel the underlying pathophysiological mechanisms.

Does solar ultraviolet radiation play a role in COVID-19 infection and deaths? An environmental ecological study in Italy.

A significantly stronger impact in mortality and morbidity by COVID-19 has been observed in the northern Italian regions compared to the southern ones. The reasons of this geographical pattern might involve several concurrent factors. The main objective of this work is to investigate whether any correlations exist between the spatial distribution of COVID-19 cases and deaths in the different Italian regions and the amount of solar ultraviolet (UV) radiation at the Earth's surface. To this purpose, in this environmental ecological study a mixed-effect exponential regression was built to explain the incidence of COVID-19 based on the environmental conditions, and demographic and pathophysiologic factors. Observations and estimates of the cumulative solar UV exposure have been included to quantify the amount of radiation available e.g., for pre-vitamin D3 synthesis or SARS-CoV-2 inactivation by sunlight. The analysis shows a significant correlation (p-value <5 × 10-2) between the response variables (death percentage, incidence of infections and positive tests) and biologically effective solar UV radiation, residents in nursing homes per inhabitant (NHR), air temperature, death percentage due to the most frequent comorbidities. Among all factors, the amount of solar UV radiation is the variable contributing the most to the observed correlation, explaining up to 83.2% of the variance of the COVID-19 affected cases per population. While the statistical outcomes of the study do not directly entail a specific cause-effect relationship, our results are consistent with the hypothesis that solar UV radiation impacted on the development of the infection and on its complications, e.g. through the effect of vitamin D on the immune system or virus inactivation by sunlight. The analytical framework used in this study, based on commonly available data, can be easily replicated in other countries and geographical domains to identify possible correlations between exposure to solar UV radiation and the spread of the pandemic.

Serum 25-hydroxyvitamin D levels and psychological distress symptoms in patients with affective disorders during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has given rise to stress worldwide, especially in vulnerable people like those suffering from mental illness. This study aims to investigate the psychological distress perceived by a cohort of patients with Major Depressive Disorder (MDD) or Bipolar Disorder (BD) after a seven-week period of lockdown measures, and to analyze serum 25-hydroxyvitamin D [25(OH)D] levels as a potential predictor of distress severity. METHODS: Fifty-nine remitted MDD and fifty-three euthymic BD patients were enrolled. An online dedicated survey was administered to obtain lockdown-related information and to evaluate COVID-19 related distress by using the Kessler 10 Psychological Distress Scale (K10). Patients' medical records were reviewed to collect sociodemographic and clinical data, including serum 25(OH)D levels dosed in the three months preceding the outbreak. A multivariate general linear model was adopted to test the effect of factors of interest on psychological distress. RESULTS: In our sample (n = 112), 29 subjects (25.9 %) reported no likelihood of psychological distress, whereas 35 (31.2 %) and 48 (42.9 %) displayed mild and moderate-to-severe likelihood of psychological distress, respectively. Low serum 25(OH)D levels (p = 0.005) and MDD diagnosis (p = 0.001) specifically predicted the severity of psychological distress. Living alone during the lockdown, a longer duration of illness, and smoking habits were more frequently detected in subjects with COVID-19 related distress. CONCLUSIONS: Low serum 25(OH)D levels and MDD diagnosis predicted an increased vulnerability to the stressful impact of the COVID-19 outbreak. Our results suggest that vitamin D may represent a biological factor mediating the psychological response to stress in individuals with affective disorders and provide further insight into tailoring intervention strategies.