Do adipocytes serve as a reservoir for severe acute respiratory symptom coronavirus-2?

Obesity is associated with a higher risk of severe coronavirus disease 2019 (COVID-19) and increased mortality. In the current study, we have investigated the expression of ACE2, NRP1, and HMGB1, known to facilitate severe acute respiratory symptom coronavirus-2 (SARS-CoV-2) cell entry, in adipose tissue from non-COVID-19 control patients with normal weight, overweight, and obesity. All factors were expressed, but no significant differences between the groups were observed. Furthermore, diabetes status and medications did not affect the expression of ACE2. Only in obese men, the expression of ACE2 in adipose tissue was higher than in obese women. In the adipose tissue from patients who died from COVID-19, SARS-CoV-2 was detected in the adipocytes even though the patients died more than 3 weeks after the acute infection. This suggests that adipocytes may act as reservoirs for the virus. In COVID-19 patients, the expression of NRP1 was increased in COVID-19 patients with overweight and obesity. Furthermore, we observed an increased infiltration with macrophages in the COVID-19 adipose tissues compared to control adipose tissue. In addition, crown-like structures of dying adipocytes surrounded by macrophages were observed in the adipose tissue from COVID-19 patients. These data suggest that in obese individuals, in addition to an increased mass of adipose tissue that could potentially be infected, increased macrophage infiltration due to direct infection with SARS-CoV-2 and sustained viral shedding, rather than preinfection ACE2 receptor expression, may be responsible for the increased severity and mortality of COVID-19 in patients with obesity.

The interface of COVID-19, diabetes, and depression.

Comorbid diabetes with depression is a challenging and often under-recognized clinical problem. During the current COVID-19 pandemic, a communicable disease is thriving on the increasing incidences of these non-communicable diseases. These three different health problems are bidirectionally connected forming a vicious cycle. Firstly, depressed individuals show a higher risk of developing diabetes and patients with diabetes have a higher risk of developing symptoms of depression. Secondly, patients with diabetes have a higher risk of developing severe COVID-19 as well as of experiencing breakthrough infections. Thirdly, in both patients with type 2 diabetes and in COVID-19 survivors the prevalence of depression seems to be increased. Fourthly, lockdown and quarantine measurements during the COVID-19 pandemic has led to an increase in depression. Therefore, it is of importance to increase the awareness of this interface between depression, diabetes and COVID-19. Finally, as symptoms of post-COVID, diabetes and depression may be overlapping, there is a need for educating skilled personnel in the management of these comorbidities.

Clinical improvement of Long-COVID is associated with reduction in autoantibodies, lipids, and inflammation following therapeutic apheresis.

In the aftermath of the COVID-19 pandemic, we are witnessing an unprecedented wave of post-infectious complications. Most prominently, millions of patients with Long-Covid complain about chronic fatigue and severe post-exertional malaise. Therapeutic apheresis has been suggested as an efficient treatment option for alleviating and mitigating symptoms in this desperate group of patients. However, little is known about the mechanisms and biomarkers correlating with treatment outcomes. Here, we have analyzed in different cohorts of Long-Covid patients specific biomarkers before and after therapeutic apheresis. In patients that reported a significant improvement following two cycles of therapeutic apheresis, there was a significant reduction in neurotransmitter autoantibodies, lipids, and inflammatory markers. Furthermore, we observed a 70% reduction in fibrinogen, and following apheresis, erythrocyte rouleaux formation and fibrin fibers largely disappeared as demonstrated by dark field microscopy. This is the first study demonstrating a pattern of specific biomarkers with clinical symptoms in this patient group. It may therefore form the basis for a more objective monitoring and a clinical score for the treatment of Long-Covid and other postinfectious syndromes.

SARS-CoV-2 infection and its effects on the endocrine system

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the virus has been detected in various amounts in all endocrine tissues in post-mortem samples from COVID-19 patients. The infection with SARS-CoV-2 may directly lead to organ damage or dysfunction, such as hyperglycaemia or in rare cases, new-onset diabetes. Furthermore, an infection with SARS-CoV-2 may have indirect effects affecting the endocrine system. The exact mechanisms are not yet completely understood and have to be further investigated. Conversely, endocrine diseases may affect the severity of COVID-19 and emphasis has to be laid on reducing the prevalence, or enhance the treatment, of these often non-communicable diseases in the future.

SARS-CoV-2 infection and its effects on the endocrine system.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the virus has been detected in various amounts in all endocrine tissues in post-mortem samples from COVID-19 patients. The infection with SARS-CoV-2 may directly lead to organ damage or dysfunction, such as hyperglycaemia or in rare cases, new-onset diabetes. Furthermore, an infection with SARS-CoV-2 may have indirect effects affecting the endocrine system. The exact mechanisms are not yet completely understood and have to be further investigated. Conversely, endocrine diseases may affect the severity of COVID-19 and emphasis has to be laid on reducing the prevalence, or enhance the treatment, of these often non-communicable diseases in the future.

Post COVID and Apheresis - Where are we Standing?

A continual increase in cases of Long/Post COVID constitutes a medical and socioeconomic challenge to health systems around the globe. While the true extent of this problem cannot yet be fully evaluated, recent data suggest that up to 20% of people with confirmed SARS-CoV-2 suffer from clinically relevant symptoms of Long/Post COVID several weeks to months after the acute phase. The clinical presentation is highly variable with the main symptoms being chronic fatigue, dyspnea, and cognitive symptoms. Extracorporeal apheresis has been suggested to alleviate symptoms of Post/COVID. Thus, numerous patients are currently treated with apheresis. However, at present there is no data from randomized controlled trials available to confirm the efficacy. Therefore, physicians rely on the experience of practitioners and centers performing this treatment. Here, we summarize clinical experience on extracorporeal apheresis in patients with Post/COVID from centers across Germany.

Case report: Incidentally discovered case of pheochromocytoma as a cause of long COVID-19 syndrome

Pheochromocytomas (PCCs) are rare but potentially lethal tumors that arise from the adrenal medulla. The clinical suspicion and diagnosis of PCC can be challenging due to the non-specific nature of signs and symptoms. In many patients, infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could lead to long-term symptoms including fatigue, headaches, and cognitive dysfunction. Here, we present the case of a patient incidentally diagnosed with an adrenal mass that proved to be a PCC after imaging was performed due to persisting complaints after coronavirus disease 2019 (COVID-19) infection. A 37-year-old male patient was referred to our center because of a right-sided inhomogeneous adrenal mass, incidentally found during a computed tomographic scan of the thorax performed due to cough and dyspnea that persisted after COVID-19 infection. Other complaints that were present prior to COVID-19 infection included profuse sweating, dizziness, exhaustion with chronic fatigue, and concentration difficulties. The patient had no history of hypertension, his blood pressure was normal, and the 24-h ambulatory blood pressure monitoring confirmed normotension but with the absence of nocturnal dipping. Plasma normetanephrine was 5.7-fold above the upper limit (UL) of reference intervals (738 pg/ml, UL = 129 pg/ml), whereas plasma metanephrine and methoxytyramine were normal at 30 pg/ml (UL = 84 pg/ml) and <4 pg/ml (UL = 16 pg/ml), respectively. Preoperative preparation with phenoxybenzamine was initiated, and a 4-cm tumor was surgically resected. Profuse sweating as well as dizziness was resolved after adrenalectomy pointing toward PCC and not COVID-19-associated patient concerns. Altogether, this case illustrates the difficulties in recognizing the possibility of PCC due to the non-specific nature of signs and symptoms of the tumor, which in this case did not include hypertension and coincided with some of the symptoms of long COVID-19.

SARS-CoV-2-specicific humoral immunity in convalescent patients with mild COVID-19 is supported by CD4+ T-cell help and negatively correlated with Alphacoronavirus-specific antibody titer.

This study aimed at investigating the nature of SARS-CoV-2-specific immunity in patients with mild COVID-19 and sought to identify parameters most relevant for the generation of neutralizing antibody responses in convalescent COVID-19 patients. In the majority of the examined patients a cellular as well as humoral immune response directed to SARS-CoV-2 was detected. The finding of an anti-SARS-CoV-2-reactive cellular immune response in healthy individuals suggests a pre-existing immunity to various common cold HCoVs which share close homology with SARS-CoV-2. The humoral immunity to the S protein of SARS-CoV-2 detected in convalescent COVID-19 patients correlates with the presence of SARS-CoV-2-reactive CD4+ T cells expressing Th1 cytokines. Remarkably, an inverse correlation of SARS-CoV-2 S protein-specific IgGs with HCoV-NL63 and HCoV-229E S1 protein-specific IgGs suggests that pre-existing immunity to Alphacoronaviruses might have had an inhibitory imprint on the immune response to SARS-CoV-2-infection in the examined patients with mild COVID-19.

The Role of Endocrine and Metabolic System in COVID-19 Disease - The Transcampus Experience and Review of Evidence From International Collaborating Groups.

The COVID-19 Pandemic has led to a world health crisis with major socioeconomic consequences that have deeply affected our daily lives. Until the end of May 2022, more than 500 million people have been infected by COVID-19 and more than 6 million have died from the disease. Unprecedented efforts in research, illustrated by the more than 250 000 publications in PubMed, have led to the identification of important pathophysiological mechanisms affected by SARS-CoV-2 and have resulted in the development of effective vaccines and treatment protocols for patients with COVID-19.

Adrenal Gland Function and Dysfunction During COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic is currently one of the major health concerns worldwide accounting for many deaths and posing a great social and economic burden. Early activation of adrenal hormone secretion is pivotal to surviving systemic microbial infections. In addition, clinical studies demonstrated that glucocorticoids might also be beneficial in reducing disease progression and life deterioration in certain patients with COVID-19. Recent studies demonstrated that SARS-CoV-2 might target the adrenal glands, raising the possibility that at least some COVID-19 complications may be associated with adrenal dysfunction. Whether SARS-CoV-2 infection might cause adrenal dysfunction remains unknown. Histopathological examinations provided evidence that SARS-CoV-2 infection might indeed cause certain structural damage to the adrenal glands, especially concerning its vascular system. However, since no widespread cellular damage to cortical cells was observed, it is less likely that those changes could lead to an immediate adrenal crisis. This assumption is supported by the limited number of studies reporting rather adequate cortisol levels in patients with acute COVID-19. Those studies, however, could not exclude a potential late-onset or milder form of adrenal insufficiency. Although structural damage to adrenal glands is a rarely reported complication of COVID-19, some patients might develop a critical illness-related corticosteroid insufficiency (CIRCI), or iatrogenic adrenal insufficiency resulting from prolonged treatment with synthetic glucocorticoids. In this mini-review article, we aimed at describing and discussing factors involved in the adrenal gland function and possible dysfunction during COVID-19.

Diabetes and COVID-19: Short- and Long-Term Consequences.

When the corona pandemic commenced more than two years ago, it was quickly recognized that people with metabolic diseases show an augmented risk of severe COVID-19 and an increased mortality compared to people without these comorbidities. Furthermore, an infection with SARS-CoV-2 has been shown to lead to an aggravation of metabolic diseases and in single cases to new-onset metabolic disorders. In addition to the increased risk for people with diabetes in the acute phase of COVID-19, this patient group also seems to be more often affected by long-COVID and to experience more long-term consequences than people without diabetes. The mechanisms behind these discrepancies between people with and without diabetes in relation to COVID-19 are not completely understood yet and will require further research and follow-up studies during the following years. In the current review, we discuss why patients with diabetes have this higher risk of developing severe COVID-19 symptoms not only in the acute phase of the disease but also in relation to long-COVID, vaccine breakthrough infections and re-infections. Furthermore, we discuss the effects of lockdown on glycemic control.

Long-COVID, Metabolic and Endocrine Disease.

In the aftermath of the corona pandemic, long-COVID or post-acute COVID-19 syndrome still represents a great challenge, and this topic will continue to represent a significant health problem in the coming years. At present, the impact of long-COVID on our health system cannot be fully assessed but according to current studies, up to 40% of people who have been infected with SARS-CoV-2 suffer from clinically relevant symptoms of long-COVID syndrome several weeks to months after the acute phase. The main symptoms are chronic fatigue, dyspnea, and various cognitive symptoms. Initial studies have shown that people with overweight and diabetes mellitus have a higher risk of developing long-COVID associated symptoms. Furthermore, repeated treatment of acute COVID-19 and long-COVID with steroids can contribute to long-term metabolic and endocrine disorders. Therefore, a structured program with rehabilitation and physical activity as well as optimal dietary management is of utmost importance, especially for patients with metabolic diseases and/or long-COVID. Furthermore, the removal of autoantibodies and specific therapeutic apheresis procedures could lead to a significant improvement in the symptoms of long-COVID in individual patients.

COVID-19 Infections in Gonads: Consequences on Fertility?

COVID-19 may influence human fertility and sexuality in several ways. Different cell types in gonads show a constitutive expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), which provide potential entry pathways for SARS-CoV-2. In addition to the biological effects of a COVID-19 infection on the gonads, the impact of the ongoing COVID-19 pandemic on mental health issues and sexual behavior may affect reproduction. This review summarizes the current knowledge on the influence of COVID-19 on the gonads and discusses possible consequences on human fertility. In this context, the close interaction between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis in response to COVID-19-related stress is discussed. Some women noticed changes in their menstrual cycle during the COVID-19 pandemic, which could be due to psychological stress, for example. In addition, occasional cases of reduced oocyte quality and ovarian function are described after COVID-19 infection. In men, COVID-19 may cause a short-term decrease in fertility by damaging testicular tissue and/or impairing spermatogenesis. Moreover, decreased ratio testosterone/LH and FSH/LH in COVID-19 compared to aged-matched healthy men has been reported. Available data do not suggest any effect of the available SARS-CoV-2 vaccines on fertility. The effects of long COVID on human fertility have been reported and include cases with premature ovarian failure and oligomenorrhoea in women and erectile dysfunction in men. Despite the increasing knowledge about the effects of COVID-19 infections on human gonads and fertility, the long-term consequences of the COVID-19 pandemic cannot yet be assessed in this context.

Obesity and COVID-19: What are the Consequences?

Obesity is an increasing health problem all over the world. In combination with the current COVID-19 pandemic, this has turned into a massive challenge as individuals with overweight and obesity at all ages show a significant increase in their risk of getting severe COVID-19. Around 20% of all patients that were hospitalized for COVID-19 suffered from obesity alone, whereas obesity in combination with other metabolic comorbidities, such as type 2 diabetes and hypertension, account for up to 60% of all hospitalizations in relation to COVID-19. Therefore, it is of immense importance to put the spotlight on the high incidence of obesity present already in childhood both by changing the individual minds and by encouraging politicians and the whole society to commence preventive interventions for achieving a better nutrition for all social classes all over the world. In the current review, we aim to explain the different pathways and mechanisms that are responsible for the increased risk of severe COVID-19 in people with overweight and obesity. Furthermore, we discuss how the pandemic has led to weight gains in many people during lockdown. At the end, we discuss the importance of preventing such an interface between a non-communicable disease like obesity and a communicable disease like COVID-19 in the future.

Treating Insulin Resistance with Intermittent Personalized Nutrition to Sustain Metabolic Health and Functioning Immune System for Risk Reduction of Viral Diseases Especially COVID-19 and Long-COVID.

The Covid-19 pandemic has provided new and strong evidence for poor outcomes of viral infection in patients with poor metabolic health. Insulin resistance is at the root of many metabolic conditions and a key driver of their progression as it promotes ineffectual inflammation whilst impairing immune functions. In a vicious circle, insulin resistance facilitates SARS-CoV-2 infection, whilst infection drives insulin resistance. We discuss the underlying mechanisms and explore ways to improve metabolic health and prevent insulin resistance through early detection and targeted nutritional interventions. With proven efficacy in prediabetes, type 2 diabetes, and their cardiovascular and organ complications, as much as non-alcoholic liver disease, we argue to extend such approaches to ensure resilience to the current pandemic and viral challenges beyond.

[Practical recommendations for screening and management of functional disorders of the adrenal cortex in cases of SARS-CoV-2 infections]. / Praktische Empfehlungen zum Screening und Management von Funktionsstörungen der Nebennierenrinde bei einer akuten SARS-CoV-2-Infektion.

Diseases of the adrenal cortex require particular attention during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Firstly, SARS-CoV­2 infections can give rise to extrapulmonary manifestations and cause endocrine disorders, particularly in the adrenal cortex. Furthermore, patients with pre-existing insufficiency of the adrenal cortex or hypercortisonism are particularly at risk from a severe infection such as SARS-CoV­2, to suffer from additional complications or a more severe course of a SARS-CoV­2 infection with a higher mortality. Especially in hemodynamically unstable patients with a SARS-CoV­2 infection, diseases of the adrenal glands should also be considered in the differential diagnostics and if necessary clarified, if this is not already known. Prolonged treatment of patients with a SARS-CoV­2 infection with regimens containing high doses of glucocorticoids can also result in a secondary adrenal insufficiency. In order to address these special aspects, some practical recommendations for the diagnostic and therapeutic management of functional disorders of the adrenal glands in patients with a SARS-CoV­2 infection are therefore presented.

Liver, NAFLD and COVID-19.

Coronavirus disease 2019 (COVID-19) is characterized by a wide clinical spectrum that includes abnormalities in liver function indicative of liver damage. Conversely, people with liver diseases are at higher risk of severe COVID-19. In the current review, we summarize first the epidemiologic evidence describing the bidirectional relationship between COVID-19 and liver function/liver diseases. Additionally, we present the most frequent histologic findings as well as the most important direct and indirect mechanisms supporting a COVID-19 mediated liver injury. Furthermore, we focus on the most frequent liver disease in the general population, non-alcoholic or metabolic-associated fatty liver disease (NAFLD/MAFLD), and describe how COVID-19 may affect NAFLD/MAFLD development and progression and conversely how NAFLD/MAFLD may further aggravate a COVID-19 infection. Finally, we present the long-term consequences of the pandemic on the development and management of NAFLD.