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.

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.

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.

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.

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.

COVID-19 and the pituitary.

BACKGROUND: Despite COVID-19 being identified as severe respiratory viral infection, progressively many relevant endocrine manifestations have been reported greatly contributing to the severity of the clinical presentation. Systemic involvement in COVID-19 is due to the ubiquitous expression of angiotensin-converting enzyme 2 (ACE2) receptor, responsible for the entry in the cells of SARS-CoV-2, Several reports in humans and animal models showed a significant ACE2 mRNA expression in hypothalamus and pituitary cells. Moreover, higher mortality and poorer outcomes have been widely described in COVID-19 patients with obesity, diabetes and vertebral fractures, which are all highly prevalent in subjects with pituitary dysfunctions. AIM: To review the main endocrine manifestations of COVID-19 with their possible implications for pituitary diseases, the possible direct and indirect involvement of the pituitary gland in COVID-19, the impact of COVID-19 on the management of established pituitary diseases which can be already at increased risk for worse outcomes and on neurosurgical activities as well as vaccination. CONCLUSIONS: Our review underlines that there could be a specific involvement of the pituitary gland which fits into a progressively shaping endocrine phenotype of COVID-19. Moreover, the care for pituitary diseases need to continue despite the restrictions due to the emergency. Several pituitary diseases, such as hypopituitarism and Cushing disease, or due to frequent comorbidities such as diabetes may be a risk factor for severe COVID-19 in affected patients. There is the urgent need to collect in international multicentric efforts data on all these aspects of the pituitary involvement in the pandemic in order to issue evidence driven recommendations for the management of pituitary patients in the persistent COVID-19 emergency.

Hypocalcemia in COVID-19: Prevalence, clinical significance and therapeutic implications.

COVID-19 extra-pulmonary features include several endocrine manifestations and these are becoming strongly clinically relevant in patients affected influencing disease severity and outcomes.At the beginning of COVID-19 pandemic no population data on calcium levels in patients affected were available and in April 2020 a first case of severe acute hypocalcemia in an Italian patient with SARS-CoV-2 infection was reported. Subsequently, several studies reported hypocalcemia as a highly prevalent biochemical abnormality in COVID-19 patients with a marked negative influence on disease severity, biochemical inflammation and thrombotic markers, and mortality. Also a high prevalence of vertebral fractures with worse respiratory impairment in patients affected and a widespread vitamin D deficiency have been frequently observed, suggesting an emerging "Osteo-Metabolic Phenotype" in COVID-19.To date, several potential pathophysiological factors have been hypothesized to play a role in determining hypocalcemia in COVID-19 including calcium dependent viral mechanisms of action, high prevalence of hypovitaminosis D in general population, chronic and acute malnutrition during critical illness and high levels of unbound and unsaturated fatty acids in inflammatory responses.Since hypocalcemia is a frequent biochemical finding in hospitalized COVID-19 patients possibly predicting worse outcomes and leading to acute cardiovascular and neurological complications if severe, it is reasonable to assess, monitor and, if indicated, replace calcium at first patient hospital evaluation and during hospitalization.

Results from ACROCOVID: an international survey on the care of acromegaly during the COVID-19 era.

With most global healthcare resources focused on COVID-19, altered resource allocation is disrupting the continuum of care for chronic endocrine conditions, including acromegaly. In order to assess the effects of COVID-19 on care of patients with acromegaly, we conducted an international online survey of endocrinologists. The questionnaire was drafted by a Steering Committee of acromegaly experts and covered both respondent demographics, contact and communication with patients, and patient care. Respondent awareness was generated through social media campaigns and the survey completed online using Google forms. The majority of endocrinologists who responded (N = 84) were based in Europe (67.9%) and were female (58.3%). Slightly more than half of respondents worked in a specialized pituitary center (52.4%) and a large minority cared for more than 50 acromegaly patients (47.6%). Most respondents (85.7%) indicated surgery was their first-line treatment, with only 14.3% indicating medical therapy as a first-choice treatment option. One-third (33.3%) of respondents reported having delayed a planned surgery due to a lack of COVID-19 testing provision and 54.8% due to a lack of surgical provision; 19.1% indicated that a lack of personal protective equipment had reduced their ability to treat patients with acromegaly. Just 21.4% of respondents reported no negative effects from the pandemic on diagnostic practice patterns, and just 19.1% reported no negative effect on patient follow-up practices. Many respondents (55.9%) indicated that remote methods had improved their ability to communicate with their patients and 69.0% indicated that they would continue to use methods of consultation necessitated by the COVID-19 pandemic. Our data suggest the COVID-19 pandemic is substantially affecting the care of acromegaly. However, these results also suggest that endocrinologists are embracing aspects of the 'new normal' to create a novel continuum of care better suited to the presumed post-COVID-19 environment. The goal of these changes must be both to improve care while shielding patients from more severe involvement in concomitant acute illnesses such COVID-19.