Metabolic and Endocrine Complications of Long-COVID-19: A Review.

Over the past two years, the outbreak of coronavirus disease of 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has centralized the interest of the health care systems and the scientific world. The majority of COVID-19-infected individuals recover fully. However, about 12-50% of patients experience various mid- and long-term effects after recovering from the initial illness. These mid- and long-term effects are collectively known as post-COVID-19 condition or 'long-COVID'. In the coming months, the long-term consequences of COVID-19 on the metabolic and endocrine systems may expect to rise and pose a global healthcare challenge. This review article discusses the possible metabolic and endocrine complications of long-COVID and the relevant research findings.

Obesity: A critical risk factor in the COVID-19 pandemic.

Obesity is an emerging independent risk factor for susceptibility to and severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Previous viral pandemics have shown that obesity, particularly severe obesity (BMI > 40 kg/m2 ), is associated with increased risk of hospitalization, critical care admission and fatalities. In this narrative review, we examine emerging evidence of the influence of obesity on COVID-19, the challenges to clinical management from pulmonary, endocrine and immune dysfunctions in individuals with obesity and identify potential areas for further research. We recommend that people with severe obesity be deemed a vulnerable group for COVID-19; clinical trials of pharmacotherapeutics, immunotherapies and vaccination should prioritize inclusion of people with obesity.

A Comprehensive Review of COVID-19-Associated Endocrine Manifestations.

Coronavirus disease 2019 (COVID-19) has played a significant part in systematic damage, affecting lives and leading to significant mortality. The endocrine system is one of the systems affected by this pandemic outbreak. The relationship between them has been identified in previous and ongoing research. The mechanism through which severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can achieve this is similar to that for organs that express angiotensin-converting enzyme 2 receptors, which is the primary binding site of the virus. Endocrine cells widely express angiotensin-converting enzyme 2 receptors and transmembrane serine protease 2, the primary mediators initiating the acute phase of the disease. This review aimed to identify and discuss the endocrine complications of COVID-19. This primary focus is on presenting thyroid disorders or newly diagnosed diabetes mellitus (DM). Thyroid dysfunction with subacute thyroiditis, Graves' disease, and hypothyroidism caused by primary autoimmune thyroiditis has been reported. Pancreatic damage leads to type 1 DM because of the autoimmune nature of the disease and type 2 DM because of postinflammatory insulin resistance. Because follow-up data on COVID-19 on the endocrine glands are limited, long-term investigations are needed to assess specific effects.

Endocrine system after 2 years of COVID-19 vaccines: A narrative review of the literature.

Purpose: The purpose of this study was to describe the current knowledge on the potential endocrine adverse effects post-COVID-19 vaccines. Methods: A PubMed/MEDLINE, Web of Science, and Scopus research was performed. Case reports, case series, original studies, and reviews written in English and published online up to 31 July 2022 were selected and reviewed. The final reference list was defined based on the relevance of each paper to the scope of this review. Results: The available data showed that endocrine side effects are generally rare and with favorable outcome, being thyroid disorders the most common. Conversely, data on type 1 diabetes mellitus are rare; adrenal and pituitary events are even anecdotal. Finally, the available clinical studies suggest no impact on female reproductive system and on male and couple fertility. Conclusion: Overall, these data show that, after 2 years of COVID-19 vaccines, the endocrine system is not heavily threatened.

Vitamin D Endocrine System and COVID-19: Treatment with Calcifediol.

The COVID-19 pandemic is the greatest challenge facing modern medicine and public health systems. The viral evolution of SARS-CoV-2, with the emergence of new variants with in-creased infectious potential, is a cause for concern. In addition, vaccination coverage remains in-sufficient worldwide. Therefore, there is a need to develop new therapeutic options, and/or to optimize the repositioning of drugs approved for other indications for COVID-19. This may include the use of calcifediol, the prohormone of the vitamin D endocrine system (VDES) as it may have potential useful effects for the treatment of COVID-19. We review the aspects associating COVID-19 with VDES and the potential use of calcifediol in COVID-19. VDES/VDR stimulation may enhance innate antiviral effector mechanisms, facilitating the induction of antimicrobial peptides/autophagy, with a critical modulatory role in the subsequent host reactive hyperinflammatory phase during COVID-19: By decreasing the cytokine/chemokine storm, regulating the renin-angiotensin-bradykinin system (RAAS), modulating neutrophil activity and maintaining the integrity of the pulmonary epithelial barrier, stimulating epithelial repair, and directly and indirectly decreasing the increased coagulability and prothrombotic tendency associated with severe COVID-19 and its complications. Available evidence suggests that VDES/VDR stimulation, while maintaining optimal serum 25OHD status, in patients with SARS-CoV-2 infection may significantly reduce the risk of acute respiratory distress syndrome (ARDS) and severe COVID-19, with possible beneficial effects on the need for mechanical ventilation and/or intensive care unit (ICU) admission, as well as deaths in the course of the disease. The pharmacokinetic and functional characteristics of calcifediol give it superiority in rapidly optimizing 25OHD levels in COVID-19. A pilot study and several observational intervention studies using high doses of calcifediol (0.532 mg on day 1 and 0.266 mg on days 3, 7, 14, 21, and 28) dramatically decreased the need for ICU admission and the mortality rate. We, therefore, propose to use calcifediol at the doses described for the rapid correction of 25OHD deficiency in all patients in the early stages of COVID-19, in association, if necessary, with the new oral antiviral agents.

Influence of COVID-19 vaccines on endocrine system.

The COVID-19 pandemic has posed a significant health threat globally. Timely and appropriate vaccination is a key step to reduce the morbidity and mortality from COVID-19. The clinical course of COVID-19 infection and the effects of COVID-19 vaccination are influenced by patients' health situations and involve a systemic physiological reaction. Just like an "endocrine phenotype" of COVID-19 infection, endocrine dysfunction after COVID-19 vaccination also acquired clinical concerns. In the present review, we briefly introduce the commonly available vaccines against SARS-CoV-2, summarize the influence of COVID-19 vaccines on the endocrine system, and explore the underlying pathogenic mechanisms.

The endocrine system function disturbances during and after SARS-CoV-2 infection.

Several receptors for the angiotensin-converting enzyme 2 (ACE2), essential for the penetration of SARS-CoV-2 into cells, are located in the tissues of the endocrine glands. Therefore, it has been suggested that SARS-CoV-2 infection results in the development of hormonal disturbances. To date, several cases of endocrine disturbances related to the dysfunction of all endocrine glands during and after SARS-CoV-2 infection have been described. In this review, we discuss the endocrine system disturbances in patients with COVID-19 and post-COVID-19 syndrome. Based on the case reports described in the literature, patients with COVID-19 may develop endocrine disturbances that are immediately life-threatening. In addition, patients with post-COVID-19 syndrome may develop chronic endocrine disturbances. In summary, the diagnostics of endocrine system disturbances based on clinical symptoms should be taken into account in both patients with COVID-19 and post-COVID-19 syndrome.

Beta coronaviruses and human endocrine system: new data (review of literature).

A new dangerous respiratory disease COVID-19 was first reported in China in December 2019, the pathogen SARS-Coronavirus 2 (SARS-CoV-2), belonging to the beta coronavirus genus, which, in addition to SARS-CoV-2, includes SARS-CoV-1 and MERS-CoV. The genome of SARS-CoV-2 is almost 80% similar to SARS-CoV-1 and 50% to MERS-CoV. The mechanisms of infection of SARS-CoV-1 and SARS-CoV-2 are also similar and occur through the binding of the virus to the type 2 angiotensin-converting enzyme protein (ACE2), which is widely represented in the human body with predominant expression in endocrine tissues. In this connection, SARS-CoV-1 and SARS-CoV-2 affect the organs of the endocrine system, causing damage and hormonal changes that affect the prognosis of the course of COVID-19. This literature review is devoted to the analysis of changes in the organs of the endocrine system that occur during infection with SARS-CoV-1 and SARS-CoV-2, as well as the potential effect of hormones on susceptibility to SARS-CoV-2.

Endocrine Follow-up During Post-Acute COVID-19: Practical Recommendations Based on Available Clinical Evidence.

OBJECTIVE: COVID-19 affects multiple endocrine organ systems during the disease course. However, follow-up data post-COVID-19 is scarce; hitherto available limited data suggest that most of the biochemical endocrine dysfunctions observed during acute phase of COVID-19 tend to improve after recovery. Hence, we aim to provide a rational approach toward endocrine follow-up of patients during post-acute COVID-19. METHODS: We performed a literature review across PubMed/MEDLINE database looking into the effects of COVID-19 on endocrine system and subsequent long-term endocrine sequelae. Accordingly, we have presented a practical set of recommendations regarding endocrine follow-up post-acute COVID-19. RESULTS: COVID-19 can lead to new-onset hyperglycemia/diabetes mellitus or worsening of dysglycemia in patients with preexisting diabetes mellitus. Hence, those with preexisting diabetes mellitus should ensure optimum glycemic control in the post-COVID-19 period. New-onset diabetes mellitus has been described post-acute COVID-19; hence, a selected group of patients (aged <70 years and those requiring intensive care unit admission) may be screened for the same at 3 months. Thyroid dysfunction (euthyroid sick syndrome and atypical thyroiditis) and adrenal insufficiency have been described in COVID-19; however, thyroid/adrenal functions usually normalize on follow-up; hence, widespread screening post-acute COVID-19 should not be recommended. Pituitary apoplexy and male hypogonadism have rarely been documented in COVID-19; therefore, appropriate follow-up may be undertaken as per clinical context. Hypocalcemia during COVID-19 is not uncommon; however, routine estimation of serum calcium post-COVID-19 is not warranted. CONCLUSION: The recommendations herein provide a rational approach that would be expected to guide physicians to better delineate and manage the endocrine sequelae during post-acute COVID-19.

The Prognostic Role of Metabolic and Endocrine Parameters for the Clinical Severity of COVID-19.

OBJECTIVE: An outbreak of coronavirus disease-19 (COVID-19) began in December 2019 and spread globally, overwhelming the entire world. COVID-19 is a public health emergency of international concern. Due to its high morbidity and mortality rate, recognition of its risk and prognostic factors is important. We aimed to understand the relationship between metabolic and endocrine parameters and the prognosis of COVID-19. METHODS AND MATERIALS: This was a cross-sectional clinical study. A total of 70 patients with severe COVID-19 were enrolled. Laboratory results at the first admission time (including complete blood count, C-reactive protein, lactate dehydrogenase, blood glucose, calcium, phosphate, albumin, creatinine, magnesium, lipid profiles, liver enzymes, thyroid hormones, cortisol, and vitamin D) and outcome data were recorded. We divided patients into (1) intensive care unit- (ICU-) admitted and non-ICU-admitted and (2) survivors and nonsurvivors for estimation of severity and prognosis. We determined the risk factors associated with critical illness and poor prognosis. RESULTS: Patients with higher white blood cell (WBC) count and phosphate levels had significantly higher ICU admission rates. According to univariate analysis, serum levels of T3, phosphate, and WBC as well as the duration of hospitalization were associated with mortality. Multivariate analysis revealed that only WBC and duration of hospitalization were independent predictors for mortality rate in COVID-19 patients. CONCLUSION: Our findings suggest that longer duration of hospitalization and higher WBC count are associated with poor outcomes in patients with COVID-19.

Molecular Endocrinology and Metabolism in 2021: What's New.

The last two years, despite the very serious COronaVIrus Disease-2019 (COVID-19) pandemic, have been quite productive in the field of molecular endocrinology and metabolism and our journal section has contributed extensively on that [...].

Clinical aspects of SARS-CoV-2 infection and vitamin D : COVID-19 and the endocrine system: special issue for reviews in endocrine and metabolic disorders (Felipe Casaneuva, Editor in Chief) A. Giustina and JP Bilezikian, Guest Editors.

In December 2019, the first cases of severe acute respiratory syndrome due to a new coronavirus (SARS-Cov-2), later designated as Covid-19, were described in China. With rapid advance of the infection to several continents, in March 2020, WHO declared this to be a pandemic. In April 2020, the first papers suggesting a possible role of Vitamin D deficiency in the severity of this infection began to appear and dozens of articles evaluating a potential relationship of vitamin D with COVID have emerged subsequntly. This possibility was raised based on pre-existing evidence of the effects of Vitamin D on the immune system, and more specifically on acute respiratory viral infections. In addition, most Covid-19 victims belong to groups at risk for vitamin D deficiency such as the elderly, obese, chronically ill, and specific ethnic groups. Although with some contradictory reports exist, most observational and cohort studies find a relationship of low vitamin D status with greater Covid severity, others, including the few interventional studies available show inconsistent results. This paper aims to present the rapidly expanding literature to date regarding the clinical relevance of vitamin D in Covid-19 and, consequently, the reasonableness of avoiding its deficiency to keep the immune system able to respond in the best way to this acute viral infection. In the meantime, we wait for publication of several prospective randomized controlled studies that are underway, evaluating the effects of treatment with vitamin D or metabolites on the severity of Covid-19 outcomes.

Impact of COVID-19 on the Endocrine System: A Mini-review.

The coronavirus disease 2019 (COVID-19) pandemic continues to exert a significant impact on global health care systems, causing devastating mortality and morbidity. As time passes and our understanding of this novel respiratory virus deepens, it is increasingly clear that its effects extend beyond that of the respiratory system. The coronavirus responsible for COVID-19, severe acute respiratory syndrome coronavirus 2, obtains cellular access through the angiotensin-converting enzyme 2 (ACE2) receptor in a process requiring the transmembrane serine protease 2 (TMPRSS2) protein. Both ACE2 and TMPRSS2 are widely expressed in many endocrine glands. This, along with several case reports of thyroid and pituitary disruption in patients with COVID-19, has resulted in significant interest in its impact on the endocrine system. Indeed, as mortality is abated by the increasing availability of effective vaccines, there is increasing focus on the long-term effects on health in COVID-19 survivors. This review summarizes data investigating the effects of COVID-19 on each of the endocrine axes to guide appropriate investigations and optimal management.

Coronaviruses and Endocrine System: A Systematic Review on Evidence and Shadows.

Coronaviruses are a big family of viruses that can infect mammalians and birds. In humans they mainly cause respiratory tract infections, with a large spectrum of severity, from mild, self-limited infections to highly lethal forms as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and Coronavirus Disease 2019 (COVID-19). Scanty data are reported for the involvement of endocrine glands in human coronaviruses, in particular SARS-CoV-2. In this review, we summarize endocrinological involvement in human coronaviruses, including data on animal coronaviruses. Avians, ferrets and bovine are affected by specific coronavirus syndromes, with variable involvement of endocrine glands. SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as a target receptor, so ACE2 plays a central role in viral transmission and initial organ involvement. Autoptic studies on SARS patients revealed that thyroid, parathyroid, pituitary gland, endocrine pancreas and especially adrenals and testis could be impaired by different mechanisms (direct damage by SARS-CoV, inflammation, vascular derangement and autoimmune reactions) and few clinical studies have evidenced functional endocrine impairment. Only few data are available for COVID-19 and gonads and endocrine pancreas seem to be involved. International endocrinological societies have brought some recommendations for the COVID-19 pandemic, but further studies need to be performed, especially to detect long-term hormonal sequelae.

Basic mechanisms of SARS-CoV-2 infection. What endocrine systems could be implicated?

Although SARS-CoV-2 viral attacks starts by the interaction of spike protein (S Protein) to ACE2 receptor located at the cell surface of respiratory tract and digestive system cells, different endocrine targets, endocrine organs and metabolic conditions are of fundamental relevance for understanding disease progression and special outcomes, in particular those of fatal consequences for the patient. During pandemic, moreover, a specific phenotype of COVID-19 metabolic patient has been described, characterized by being at particular risk of worse outcomes. In the present paper we describe the mechanism of viral interaction with endocrine organs, emphasizing the specific endocrine molecules of particular relevance explaining COVID-19 disease evolution and outcomes.

Blood glucose regulation in context of infection.

The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.

Repurposing existing drugs for COVID-19: an endocrinology perspective.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is a multi-systemic infection caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), that has become a pandemic. Although its prevailing symptoms include anosmia, ageusia, dry couch, fever, shortness of brief, arthralgia, myalgia, and fatigue, regional and methodological assessments vary, leading to heterogeneous clinical descriptions of COVID-19. Aging, uncontrolled diabetes, hypertension, obesity, and exposure to androgens have been correlated with worse prognosis in COVID-19. Abnormalities in the renin-angiotensin-aldosterone system (RAAS), angiotensin-converting enzyme-2 (ACE2) and the androgen-driven transmembrane serine protease 2 (TMPRSS2) have been elicited as key modulators of SARS-CoV-2. MAIN TEXT: While safe and effective therapies for COVID-19 lack, the current moment of pandemic urges for therapeutic options. Existing drugs should be preferred over novel ones for clinical testing due to four inherent characteristics: 1. Well-established long-term safety profile, known risks and contraindications; 2. More accurate predictions of clinical effects; 3. Familiarity of clinical management; and 4. Affordable costs for public health systems. In the context of the key modulators of SARS-CoV-2 infectivity, endocrine targets have become central as candidates for COVID-19. The only endocrine or endocrine-related drug class with already existing emerging evidence for COVID-19 is the glucocorticoids, particularly for the use of dexamethasone for severely affected patients. Other drugs that are more likely to present clinical effects despite the lack of specific evidence for COVID-19 include anti-androgens (spironolactone, eplerenone, finasteride and dutasteride), statins, N-acetyl cysteine (NAC), ACE inhibitors (ACEi), angiotensin receptor blockers (ARB), and direct TMPRSS-2 inhibitors (nafamostat and camostat). Several other candidates show less consistent plausibility. In common, except for dexamethasone, all candidates have no evidence for COVID-19, and clinical trials are needed. CONCLUSION: While dexamethasone may reduce mortality in severely ill patients with COVID-19, in the absence of evidence of any specific drug for mild-to-moderate COVID-19, researchers should consider testing existing drugs due to their favorable safety, familiarity, and cost profile. However, except for dexamethasone in severe COVID-19, drug treatments for COVID-19 patients must be restricted to clinical research studies until efficacy has been extensively proven, with favorable outcomes in terms of reduction in hospitalization, mechanical ventilation, and death.