Distinct clinical features of post COVID-19 vaccination early-onset Graves' disease (PoVEO GD).

CONTEXT: Several case reports of Graves' disease (GD) occurrence after COVID-19 vaccination were recently published and possibly related to the autoimmune syndrome induced by adjuvants (ASIA). The aim of our study was to evaluate possible distinctive features in the presentation and clinical course of patients with GD occurring early (within 4 weeks) after COVID-19 vaccination who attended our Endocrine Unit in 2021. DESIGN: Patients with first episode of GD attending a tertiary endocrine center between January 1st and December 31st 2021 were included. RESULTS: Sixty-four patients with first episode of GD were seen in 2021: 20 (31.2%) of them had onset within 4 weeks following vaccine administration. Compared to the other 44 patients, the 20 patients with post-vaccine early-onset (PoVEO) GD were older (median age: 51 years vs 35 years, p = 0.003) and more likely male (40.0% vs 13.6%, p = 0.018). At diagnosis, the biochemical and immune profiles were similar between the two groups. However, at 3 months after starting methimazole, PoVEO GD patients had significantly lower TRAb titer and were taking lower doses of methimazole than the other GD patients. None in the PoVEO group had sustained fT3 elevation. CONCLUSIONS: This relatively large series suggests that in 2021, PoVEO GD may be a new nosological entity representing one third of patients evaluated for new-onset GD in our center. Distinctive features included older age at onset, higher male prevalence and a better initial biochemical and immunological response to treatment. Further studies are warranted to clinically and biochemically differentiate these cases from sporadically occurred GD.

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.

Consensus and Controversial Aspects of Vitamin D and COVID-19.

OBJECTIVE: This work aims to review and discuss controversial topics in the field of vitamin D, SARS-CoV-2 infection, and COVID-19. METHODS: The International Conferences "Controversies in Vitamin D" are a series of workshops that started in 2017 featuring international experts and leaders in vitamin D research and clinical practice. The fifth annual conference was held in Stresa, Italy, September 15 to 18, 2021. EVIDENCE: Before the event, participants reviewed available studies on their assigned topic, drafted a related abstract, and presented their findings at the time of the conference. Relevant literature that became available since was also discussed within the panel and updated accordingly. CONSENSUS: Before the event, the drafted abstracts had been merged to prepare a preliminary document. After the conference presentations, in-depth discussions in open sessions led to consensus. The document was subsequently modified according to discussions and up-to-date literature inclusion. CONCLUSIONS: There is quite consistent evidence for an association between low 25 OH vitamin D (25(OH)D) levels and poor COVID-19 outcomes, despite heterogeneous publications of variable quality. However, the low vitamin D status in COVID-19 patients might also reflect reverse causality. Vitamin D supplementation might have a positive role in COVID-19 prevention. The evidence supporting a beneficial effect of vitamin D treatment in decreasing the risk of COVID-19 complications is conflicting. Conclusive statements regarding the beneficial effect of vitamin D in this context await high-quality, randomized controlled trials.

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.

Vitamin D in the older population: a consensus statement.

BACKGROUND: This paper reports results from the 5th International Conference "Controversies in Vitamin D" that was held in Stresa, Italy, 15-18 September 2021. The conference is part of this series that started in 2017 and has been conducted annually since. The objective of these conferences is to identify timely and controversial topics related to Vitamin D. Dissemination of the results of the conference through publications in peer-reviewed journals is an important means by which the most up to date information can be shared with physicians, investigators, and other health care professionals. Vitamin D and aging, the subject of this paper was featured at the conference. METHODS: Participants were selected to review available literature on assigned topics related to vitamin D and aging and to present their findings with illustrative material, the intent of which was to stimulate discussion and to arrive at a consensus. The presentations were directed towards the following areas: impact of aging on vitamin D production and levels; skeletal effects of vitamin D deficiency in the older population; falls and vitamin D in the aging; potential extra skeletal effects of vitamin D; and strategies to prevent vitamin D deficiency. A final topic was related to how vitamin D might influence the efficacy of vaccines for Covid-19. RESULTS: Hypovitaminosis D can lead to several skeletal and extra-skeletal outcomes. Older adults are at risk for vitamin D deficiency as both production and metabolism of vitamin D change with aging due to factors, such as reduced sun exposure and reduced production capacity of the skin. Skeletal consequences of these age-related changes can include reduced bone mineral density, osteomalacia and fractures. Potential extra-skeletal effects can include added risks for falls, reduced muscle strength, diabetes, cancer, and cardiovascular disease. Strategies to avoid these vitamin D deficiency-related negative outcomes include sun exposure, food fortification, and supplementation. While aging does not diminish sufficient reserve capacity for cutaneous vitamin D production, concerns about skin cancers and practical matters for the institutionalized elderly limit this option. Supplementation with vitamin D is the best option either pharmacologically or through food fortification. Regardless of treatment strategies, interventions to restore sufficient vitamin D status will show positive results only in those who are truly deficient. Thus, treatment goals should focus on avoiding 25(OH)D serum levels <30 nmol/l, with a goal to reach levels >50 nmol/l. CONCLUSIONS: The results of this conference has led to consensus on several issues. Vitamin D supplementation should be combined with calcium to reduce fractures in the older population. The goal for adequate Vitamin D status should be to reach a serum level of 25(OH)D >50 nmol/l. It appears that daily low-dose vitamin D regimens reduce the risk of falling, especially in the elderly, compared with infrequent, large bolus doses that may increase it. The role of Vitamin D supplementation on muscle strength remains to be clarified. On the other hand, supplementation decreases the risk of progression to T2D from prediabetes among those who are Vitamin Ddeficient. Of three possible strategies to establish vitamin D sufficiency - sunshine exposure, food fortification, and supplementation - the latter seems to be the most effective and practical in the aging population.

The osteo-metabolic phenotype of COVID-19: an update.

CONTEXT: In the multifaceted COVID-19 clinical scenario characterized by a multi-system disorder with negative implications not only on respiratory function but also on cardiac, hematological, neurological and endocrine-metabolic systems, a distinctive osteo-metabolic phenotype with an independent influence on disease severity and recovery of patients affected was early reported. AIM: To summarize and update the main evidences regarding the distinct components of this phenotype in acute and Long COVID-19, reinforcing its clinical relevance and discussing the main pathophysiological and clinical-therapeutic implications of the most recent reported findings. RESULTS: This emerging phenotype is characterized by a widespread acute hypocalcemia and hypovitaminosis D with an impaired compensatory parathyroid hormone response, and a high prevalence of skeletal complications such as vertebral fractures. The clinical relevance of this osteo-metabolic phenotype on acute COVID-19 is well characterized, and novel seminal evidences are progressively highlighting its importance also in predicting patient's long-term outcomes and Long COVID-19 occurrence. CONCLUSIONS: These findings reinforced the central role of a multidisciplinary team, including endocrinologists, in evaluating these patients for a proactive search of each aspect of the osteo-metabolic phenotype components since they may represent suitable therapeutic targets to prevent SARS-CoV-2 infection, poor COVID-19 outcomes, Long COVID-19 occurrence and even possibly better responses to COVID-19 vaccination.

Vertebral fractures at hospitalization predict impaired respiratory function during follow-up of COVID-19 survivors.

PURPOSE: Morphometric vertebral fractures (VFs) have been recently reported as an important component of the endocrine phenotype of COVID-19 and emerging data show negative respiratory sequelae at long-term follow-up in COVID-19 survivors. The aim of this study was to evaluate the impact of VFs on respiratory function in COVID-19 survivors. METHODS: We included patients referred to our Hospital Emergency Department and re-evaluated during follow-up. VFs were detected on lateral chest X-rays on admission using a qualitative and semiquantitative assessment and pulmonary function tests were obtained by Jaeger-MasterScreen-Analyzer Unit 6 months after discharge. RESULTS: Fifty patients were included. Median age was 66 years and 66% were males. No respiratory function data were available at COVID-19 diagnosis. VFs were detected in 16 (32%) patients. No differences between fractured and non-fractured patients regarding age and sex were observed. Although no difference was observed between VF and non-VF patient groups in the severity of pneumonia as assessed by Radiological-Assessment-of-Lung-Edema score at admission, (5 vs. 6, p = 0.69), patients with VFs were characterized as compared to those without VFs by lower Forced Vital Capacity (FVC, 2.9 vs. 3.6 L, p = 0.006; 85% vs. 110% of predicted, respectively, p = 0.001), Forced Expiratory Volume 1st s (FEV1, 2.2 vs. 2.8 L, p = 0.005; 92% vs. 110% of predicted, respectively, p = 0.001) and Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO 5.83 vs. 6.98 mmol/min/kPa, p = 0.036, 59% vs. 86.3% of predicted, respectively, p = 0.043) at 6-month follow up. CONCLUSIONS: VFs, expression of the endocrine phenotype of the disease, appear to influence medium-term impaired respiratory function of COVID-19 survivors which may significantly influence their recovery. Therefore, our findings suggest that a VFs assessment at baseline may help in identifying patients needing a more intensive respiratory follow-up and patients showing persistent respiratory impairment without evidence of pulmonary disease may benefit from VFs assessment to preventing the vicious circle of further fractures and respiratory deterioration.

Evaluation of Muscle Mass and Stiffness with Limb Ultrasound in COVID-19 Survivors.

BACKGROUND: acute illnesses, like COVID-19, can act as a catabolic stimulus on muscles. So far, no study has evaluated muscle mass and quality through limb ultrasound in post-COVID-19 patients. METHODS: cross sectional observational study, including patients seen one month after hospital discharge for SARS-CoV-2 pneumonia. The patients underwent a multidimensional evaluation. Moreover, we performed dominant medial gastrocnemius ultrasound (US) to characterize their muscle mass and quality. RESULTS: two hundred fifty-nine individuals (median age 67, 59.8% males) were included in the study. COVID-19 survivors with reduced muscle strength had a lower muscle US thickness (1.6 versus 1.73 cm, p =0.02) and a higher muscle stiffness (87 versus 76.3, p = 0.004) compared to patients with normal muscle strength. Also, patients with reduced Short Physical Performance Battery (SPPB) scores had a lower muscle US thickness (1.3 versus 1.71 cm, p = 0.01) and a higher muscle stiffness (104.9 versus 81.07, p = 0.04) compared to individuals with normal SPPB scores. The finding of increased muscle stiffness was also confirmed in patients with a pathological value (≥ 4) at the sarcopenia screening tool SARC-F (103.0 versus 79.55, p < 0.001). Muscle stiffness emerged as a significant predictor of probable sarcopenia (adjusted OR 1.02, 95% C.I. 1.002 - 1.04, p = 0.03). The optimal ultrasound cut-offs for probable sarcopenia were 1.51 cm for muscle thickness (p= 0.017) and 73.95 for muscle stiffness (p = 0.004). DISCUSSION: we described muscle ultrasound characteristics in post COVID-19 patients. Muscle ultrasound could be an innovative tool to assess muscle mass and quality in this population. Our preliminary findings need to be confirmed by future studies comparing muscle ultrasound with already validated techniques for measuring muscle mass and quality.

Vitamin D: Dosing, levels, form, and route of administration: Does one approach fit all?

The 4th International Conference on Controversies in Vitamin D was held as a virtual meeting in September, 2020, gathering together leading international scientific and medical experts in vitamin D. Since vitamin D has a crucial role in skeletal and extra-skeletal systems, the aim of the Conference was to discuss improved management of vitamin D dosing, therapeutic levels and form or route of administration in the general population and in different clinical conditions. A tailored approach, based on the specific mechanisms underlying vitamin D deficiency in different diseases that were discussed, was recommended. Specifically, in comparison to healthy populations, higher levels of vitamin D and greater amounts of vitamin D were deemed necessary in osteoporosis, diabetes mellitus, obesity (particularly after bariatric surgery), and in those treated with glucocorticoids. Emerging and still open issues were related to target vitamin D levels and the role of vitamin D supplementation in COVID-19 since low vitamin D may predispose to SARS-CoV-2 infection and to worse COVID-19 outcomes. Finally, whereas oral daily cholecalciferol appears to be the preferred choice for vitamin D supplementation in the general population, and in most clinical conditions, active vitamin D analogs may be indicated in patients with hypoparathyroidism and severe kidney and liver insufficiency. Parenteral vitamin D administration could be helpful in malabsorption syndromes or in states of vitamin D resistance.Specific guidelines for desired levels of vitamin D should be tailored to the different conditions affecting vitamin D metabolism with the goal to define disease-specific normative values.

Vitamin D Levels Are Associated With Blood Glucose and BMI in COVID-19 Patients, Predicting Disease Severity.

CONTEXT: A high prevalence of vitamin D (VD) deficiency in COVID-19 patients has been reported and hypothesized to increase COVID-19 severity likely because of its negative impact on immune and inflammatory responses. Furthermore, clear associations between hypovitaminosis D and fat body mass excess and diabetes, factors associated with COVID-19 severity, have been widely recognized. OBJECTIVE: The aim of this study was to evaluate in COVID-19 patients the relationship between VD levels and inflammatory response, body mass index (BMI), blood glucose (GLU), and disease severity. METHODS: Patients admitted to San Raffaele-Hospital for COVID-19 were enrolled in this study, excluding those with comorbidities and therapies influencing VD metabolism. 25-Hydroxyvitamin D levels, plasma GLU levels, BMI, and inflammatory parameters were evaluated at admission. RESULTS: A total of 88 patients were included. Median VD level was 16.3 ng/mL and VD deficiency was found in 68.2% of patients. VD deficiency was found more frequently in male patients and in those affected by severe COVID-19. Regression analyses showed a positive correlation between VD and PaO2/FiO2 ratio, and negative correlations between VD and plasma GLU, BMI, neutrophil/lymphocyte ratio, C-reactive protein, and interleukin 6. Patients with both hypovitaminosis D and diabetes mellitus, as well those with hypovitaminosis D and overweight, were more frequently affected by a severe disease with worse inflammatory response and respiratory parameters, compared to those without or just one of these conditions. CONCLUSION: We showed, for the first-time, a strict association of VD levels with blood GLU and BMI in COVID-19 patients. VD deficiency might be a novel common pathophysiological mechanism involved in the detrimental effect of hyperglycemia and adiposity on disease severity.

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.

COVID-19 and hypopituitarism.

Besides the pulmonary manifestations caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), an emerging endocrine phenotype, which can heavily impact on the severity of the syndrome, has been recently associated with coronavirus disease 2019 (COVID-19). Patients with pituitary diseases or the pituitary gland itself may also be involved in COVID-19 clinical presentation and/or severity, causing pituitary apoplexy.Moreover, hypopituitarism is frequently burdened by several metabolic complications, including arterial hypertension, hyperglycemia, obesity and vertebral fractures, which have all been associated with poor outcomes and increased mortality in patients infected by SARS-CoV-2.This review will discuss hypopituitarism as a condition that might have a bidirectional relationship with COVID-19 due to the frequent presence of metabolic comorbidities, to the direct or indirect pituitary damage or being per se a potential risk factor for COVID-19. Finally, we will address the current recommendations for the clinical management of vaccines in patients with hypopituitarism and adrenal insufficiency.

Adiponectin to leptin ratio reflects inflammatory burden and survival in COVID-19.

AIM: Obesity is a risk factor for COVID-19, but the underlying mechanisms are unclear. We investigated the role of adiponectin (an anti-inflammatory adipokine), leptin (a pro-inflammatory adipokine) and their ratio (Adpn/Lep) in this context. DESIGN: Single-centre, prospective observational study. METHODS: Adiponectin and leptin were measured in 60 COVID-19 patients with mild (not hospitalised, n=11), moderate (hospitalised but not requiring intensive care, n=25) and severe (admission to the intensive care unit [ICU] or death, n=24) disease. RESULTS: Adiponectin and leptin levels were similar across severity groups, but patients with moderate severity had the highest Adpn/Lep ratio (1.2 [0.5; 2.0], 5.0 [1.6; 11.2], 2.1 [1.0; 3.6] in mild, moderate and severe disease; P = 0.019). Adpn/Lep, but not adiponectin or leptin alone, correlated with systemic inflammation (C reactive protein, CRP: Spearman's rho 0.293, P = 0.023). When dividing patients into Adpn/Lep tertiles, adiponectin was highest, whereas leptin was lowest in the third (highest) tertile. Patients in the highest Adpn/Lep tertile had numerically lower rates of obesity, diabetes and hypertension, and lower rates of death or admission to ICU versus other tertiles. At linear regression in the whole cohort, CRP significantly predicted Adpn/Lep (ß 0.291, P = 0.022), while female gender (ß -0.289, P = 0.016), diabetes (ß -0.257, P = 0.028), and hypertension (ß -239, P = 0.043) were negative predictors. CONCLUSIONS: We speculate that the rise in Adpn/Lep, due to increased adiponectin and reduced leptin, is a compensatory response to systemic inflammation. In patients with worse cardiometabolic health (e.g. diabetes, hypertension) this mechanism might be blunted, possibly contributing to higher mortality.

Weight trajectories and abdominal adiposity in COVID-19 survivors with overweight/obesity.

BACKGROUND: COVID-19 is associated with unintentional weight loss. Little is known on whether and how patients regain the lost weight. We assessed changes in weight and abdominal adiposity over a three-month follow-up after discharge in COVID-19 survivors. METHODS: In this sub-study of a large prospective observational investigation, we collected data from individuals who had been hospitalized for COVID-19 and re-evaluated at one (V1) and three (V2) months after discharge. Patient characteristics upon admission and anthropometrics, waist circumference and hunger levels assessed during follow-up were analyzed across BMI categories. RESULTS: One-hundred-eighty-five COVID-19 survivors (71% male, median age 62.1 [54.3; 72.1] years, 80% with overweight/obesity) were included. Median BMI did not change from admission to V1 in normal weight subjects (-0.5 [-1.2; 0.6] kg/m2, p = 0.08), but significantly decreased in subjects with overweight (-0.8 [-1.8; 0.3] kg/m2, p < 0.001) or obesity (-1.38 [-3.4; -0.3] kg/m2, p < 0.001; p < 0.05 vs. normal weight or obesity). Median BMI did not change from V1 to V2 in normal weight individuals (+0.26 [-0.34; 1.15] kg/m2, p = 0.12), but significantly increased in subjects with overweight (+0.4 [0.0; 1.0] kg/m2, p < 0.001) or obesity (+0.89 [0.0; 1.6] kg/m2, p < 0.001; p = 0.01 vs. normal weight). Waist circumference significantly increased from V1 to V2 in the whole group (p < 0.001), driven by the groups with overweight or obesity. At multivariable regression analyses, male sex, hunger at V1 and initial weight loss predicted weight gain at V2. CONCLUSIONS: Patients with overweight or obesity hospitalized for COVID-19 exhibit rapid, wide weight fluctuations that may worsen body composition (abdominal adiposity). CLINICALTRIALS. GOV REGISTRATION: NCT04318366.

Vitamin D in the Covid-19 era: a review with recommendations from a G.I.O.S.E.G. expert panel.

Vitamin D (VITD) is a key hormone for bone health and has relevant extra-skeletal effects that might play a role in the prevention and treatment of COronaVIrus Disease 19 (COVID-19). Literature regarding this scenario is voluminous but controversial. Glucocorticoid Induced Osteoporosis Skeletal Endocrinology Group (G.I.O.S.E.G) has been present in the scientific debate about the use of VITD and has regularly interfaced national regulatory agencies to ensure appropriateness of its employment. Given the current pandemic and the questions on COVID-19 and VITD, G.I.O.S.E.G. appointed an expert panel to advise how to consider this issue best. The results of these deliberations are reported in the current recommendation paper.

Low Levels of Vitamin D Are Associated With Markers of Immuno-Inflammatory Response and Clinical Outcome in Covid-19

High prevalence of vitamin D (VD) deficiency in COVID-19 patients was reported by several studies. Since VD is a key regulating factor of both innate and adaptive immunity, it was hypothesized that VD deficiency may predispose to SARS-CoV-2 infection and lower levels of VD could be related to increased COVID-19 severity and worse outcome risks. However, to date, only few studies partially investigated the relationship between VD and inflammatory and immune response and clinical features of COVID-19 patients. The aim of this study is to evaluate the influence of vitamin D levels on COVID-19 inflammatory activity, clinical pattern and disease severity. Patients admitted to San Raffaele University Hospital for COVID-19 from February 2020 were enrolled in this study. We excluded patients with comorbidities and therapies influencing VD metabolism. 25OH-Vitamin D levels were evaluated at admission in hospital and VD insufficiency and deficiency were defined as VD level below 30 ng/mL and 20 ng/mL, respectively. A total of 88 patients were included in the study. Median (IQR) VD levels were 16.3 (11.2–23.9) ng/mL. VD insufficiency and deficiency were found in 88.6% and in 68.2% of patients, respectively. Linear regression analyses showed a positive correlation between VD levels and PaO2/FiO2 ratio (p=0.019;r=0.254), and negative correlations between VD levels and Neutrophil/Lymphocyte (N/L) ratio (p=0.04;r=-0.19), C-reactive protein (CRP) levels (p=0.047;r=-0.18) and Interleukin 6 (IL-6) levels (p=0.04;r=-0.22). Lower VD levels were found in patients affected by severe disease (needs for high-flow oxygen therapy and/or noninvasive mechanical ventilation, admitted to ICU and/or dead) than non-severe patients (13.4 ng/mL [10.37–19.15] vs 18.45 ng/mL [15.15–24.95];p=0.007). Moreover, patients with VD deficiency had higher levels of CRP, LDH, IL-6, IFN-gamma (p=0.04, p=0.01, p=0.002, p=0.04;respectively), lower PaO2/FiO2 and higher N/L ratios (p=0.008, p=0.004;respectively), and higher rate of severe disease (65% vs 39%, p=0.02), as compared to VD non-deficient ones. In conclusion, low VD levels are widely found in hospitalized COVID-19 and may lead to increased disease severity through an excessive immune-inflammatory response. Our data suggest that reaching adequate vitamin D levels in risky population may contribute to prevention of COVID-19 occurrence and severity.