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.

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.

Long-Term Persisting SARS-CoV-2 RNA and Pathological Findings: Lessons Learnt From a Series of 35 COVID-19 Autopsies.

BACKGROUND: Long-term sequelae of coronavirus disease 2019 (COVID-19), including the interaction between persisting viral-RNA and specific tissue involvement, pose a challenging issue. In this study, we addressed the chronological correlation (after first clinical diagnosis and postmortem) between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and organ involvement. METHODS: The presence of postmortem SARS-CoV-2 RNA from 35 complete COVID-19 autopsies was correlated with the time interval between the first diagnosis of COVID-19 and death and with its relationship to morphologic findings. RESULTS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be evident up to 40 days after the first diagnosis and can persist to 94 hours after death. Postmortem SARS-CoV-2 RNA was mostly positive in lungs (70%) and trachea (69%), but all investigated organs were positive with variable frequency. Late-stage tissue damage was evident up to 65 days after initial diagnosis in several organs. Positivity for SARS-CoV-2 RNA in pulmonary swabs correlated with diffuse alveolar damage (p = 0.0009). No correlation between positive swabs and other morphologic findings was present. Cerebral (p = 0.0003) and systemic hemorrhages (p = 0.009), cardiac thrombi (p = 0.04), and ischemic events (p = 0.03) were more frequent in the first wave, whereas bacterial pneumonia (p = 0.03) was more prevalent in the second wave. No differences in biometric data, clinical comorbidities, and other autopsy findings were found. CONCLUSIONS: Our data provide evidence not only of long-term postmortem persisting SARS-CoV-2 RNA but also of tissue damage several weeks after the first diagnosis of SARS-CoV-2 infection. Additional conditions, such as concomitant bacterial pulmonary superinfection, lung aspergillosis, thromboembolic phenomena, and hemorrhages can further worsen tissue damage.

Sexual dimorphism in COVID-19: potential clinical and public health implications.

Current evidence suggests that severity and mortality of COVID-19 is higher in men than in women, whereas women might be at increased risk of COVID-19 reinfection and development of long COVID. Differences between sexes have been observed in other infectious diseases and in the response to vaccines. Sex-specific expression patterns of proteins mediating virus binding and entry, and divergent reactions of the immune and endocrine system, in particular the hypothalamic-pituitary-adrenal axis, in response to acute stress might explain the higher severity of COVID-19 in men. In this Personal View, we discuss how sex hormones, comorbidities, and the sex chromosome complement influence these mechanisms in the context of COVID-19. Due to its role in the severity and progression of SARS-CoV-2 infections, we argue that sexual dimorphism has potential implications for disease treatment, public health measures, and follow-up of patients predisposed to the development of long COVID. We suggest that sex differences could be considered in future pandemic surveillance and treatment of patients with COVID-19 to help to achieve better disease stratification and improved outcomes.

Autopsy-Based Pulmonary and Vascular Pathology: Pulmonary Endotheliitis and Multi-Organ Involvement in COVID-19 Associated Deaths.

BACKGROUND: Findings from autopsies have provided evidence on systemic microvascular damage as one of the underlying mechanisms of Coronavirus disease 2019 (CO-VID-19). The aim of this study was to correlate autopsy-based cause of death in SARS-CoV-2, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients with chest imaging and severity grade of pulmonary and systemic morphological vascular pathology. METHODS: Fifteen SARS-CoV-2 positive autopsies with clinically distinct presentations (age 22-89 years) were retrospectively analyzed with focus on vascular, thromboembolic, and ischemic changes in pulmonary and in extrapulmonary sites. Eight patients died due to COVID-19 associated respiratory failure with diffuse alveolar damage in various stages and/or multi-organ failure, whereas other reasons such as cardiac decompensation, complication of malignant tumors, or septic shock were the cause of death in 7 further patients. The severity of gross and histopathological changes was semi-quantitatively scored as 0 (absent), 1 (mild), and 3 (severe). Severity scores between the 2 groups were correlated with selected clinical parameters, initial chest imaging, autopsy-based cause of death, and compared using Pearson χ2 and Mann-Whitney U tests. RESULTS: Severe pulmonary endotheliitis (p = 0.031, p = 0.029) and multi-organ involvement (p = 0.026, p = 0.006) correlated significantly with COVID-19 associated death. Pulmonary microthrombi showed limited statistical correlation, while tissue necrosis, gross pulmonary embolism, and bacterial superinfection did not differentiate the 2 study groups. Chest imaging at hospital admission did not differ either. CONCLUSIONS: Extensive pulmonary endotheliitis and multi-organ involvement are characteristic autopsy features in fatal CO-VID-19 associated deaths. Thromboembolic and ischemic events and bacterial superinfections occur frequently in SARS-CoV-2 infection independently of outcome.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

BACKGROUND AND PURPOSE: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. METHODS: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. RESULTS: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. CONCLUSIONS: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

SARS-CoV-2 leads to a small vessel endotheliitis in the heart.

BACKGROUND: SARS-CoV-2 infection (COVID-19 disease) can induce systemic vascular involvement contributing to morbidity and mortality. SARS-CoV-2 targets epithelial and endothelial cells through the ACE2 receptor. The anatomical involvement of the coronary tree is not explored yet. METHODS: Cardiac autopsy tissue of the entire coronary tree (main coronary arteries, epicardial arterioles/venules, epicardial capillaries) and epicardial nerves were analyzed in COVID-19 patients (n = 6). All anatomical regions were immunohistochemically tested for ACE2, TMPRSS2, CD147, CD45, CD3, CD4, CD8, CD68 and IL-6. COVID-19 negative patients with cardiovascular disease (n = 3) and influenza A (n = 6) served as controls. FINDINGS: COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction. INTERPRETATION: ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19. FUNDING: No external funding was necessary for this study.

[Endotheliitis in COVID-19]. / Endotheliitis bei COVID-19.

COVID-19 disease is a systemic inflammatory viral reaction starting with the viral phase followed by the inflammatory phase. The first phase is rather mild and asymptomatic with only a small subset of infected patients turning into the inflammatory phase with high mortality. Patients with pre-existing cardiovascular diseases and cardiovascular risk factors pose a considerably higher risk to develop severe or lethal COVID-19 disease course. COVID-19 affects not only the epithelial cells of the lung parenchyma via ACE2, but also endothelial cells across the whole body thus leading to generalized endothelial damage and inflammation, so-called endotheliitis. The histological morphology of endotheliitis comprises the accumulation of lymphocytes, plasma cells and macrophages beneath the endothelial cells and within the perivascular spaces. Endothelial cells play an important role in the regulation of vascular tone and the maintenance of vascular homeostasis. Endotheliitis thus can shift the vascular equilibrium towards more pronounced vasoconstriction with subsequent organ ischemia, inflammation with associated tissue edema and a procoagulant state. Patients with pre-existing endothelial dysfunction (male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease) are particularly vulnerable and have adverse outcomes in COVID-19. This is a rationale for approaches to stabilize the endothelium. Most of these findings have been established from autopsies since the outbreak of the pandemic.

Higher prevalence of pulmonary macrothrombi in SARS-CoV-2 than in influenza A: autopsy results from 'Spanish flu' 1918/1919 in Switzerland to Coronavirus disease 2019.

Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID-19) has spread globally. The causes of death in COVID-19 are frequently compared to a seasonal influenza outbreak. Complete COVID-19 autopsy studies were almost non-existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID-19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID-19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the 'Spanish' influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID-19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID-19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID-19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS-related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events.

Case report of sequential bilateral spontaneous pneumothorax in a never-ventilated, lung-healthy COVID-19-patient.

INTRODUCTION: Patients with COVID-19 infection and severe lung parenchyma alterations may need mechanical ventilation with subsequent pneumothorax and eventually persistent air leak in case of pre-existing lung disease. PRESENTATION OF CASE: This report presents the case of a never-ventilated 58 years old male patient without pre-existing, underlying lung disease demonstrating severe lung parenchyma changes due to COVID-19-pneumonia. He suffered from recurrent bilateral spontaneous pneumothoraces, which were successfully treated with bilateral thoracoscopy and resections of the destroyed lung areas. Notably, he has already been under treatment with anticoagulation due to portal thrombosis 8 years ago. DISCUSSION: Although especially know from patients under mechanical ventilation, this patient suffered from spontaneous pneumothorax without ever been ventilated. Probably due to the severe vascular inflammatory changes and focal endothelitis like also seen in other organs of COVID-19 patients, the pneumothorax may lead to a prolonged air leak, which needs surgical therapy. The patients pre-existing anticoagulation therapy may prevented him from a mere severe course. CONCLUSION: Early surgical therapy may be considered in COVID-19 patients with persistent air leak, even if not mechanically ventilated. Simultaneously, the role of early anticoagulation needs further investigation.