Alternative Management of Cushing's Syndrome During Covid-19 Pandemic

Cushing's syndrome results from prolonged exposure to glucocorticoids. Surgery is often the first-line treatment for this condition, regardless of etiology. However, the COVID-19 pandemic caused a decrease in surgical procedures due to the risk of infection transmission. There are still emergency cases of Cushing's syndrome that are admitted to the hospital and require urgent management. The current treatment should be focused on medical management and endovascular embolization in selective cases. Embolization can be performed in facilities where there aretrained personnel with experience in adrenal embolization. Surgery, which traditionally is a first-line therapy, can increase the risk of infection, therefore, it should be avoided. The current review provides a brief description of the possible options for the management of adrenal Cushing's syndrome during the COVID-19 pandemic.Copyright © 2022 Bentham Science Publishers.

Successful Immunomodulatory Treatment of COVID-19 in a Patient With Severe ACTH-Dependent Cushing's Syndrome: A Case Report and Review of Literature.

Introduction: Patients with Cushing's syndrome (CS) represent a highly sensitive group during corona virus disease 2019 (COVID-19) pandemic. The effect of multiple comorbidities and immune system supression make the clinical picture complicated and treatment challenging. Case report: A 70-year-old female was admitted to a covid hospital with a severe form of COVID-19 pneumonia that required oxygen supplementation. Prior to her admission to the hospital she was diagnosed with adrenocorticotropic hormone (ACTH)-dependent CS, and the treatment of hypercortisolism had not been started yet. Since the patient's condition was quickly deteriorating, and with presumend immmune system supression due to CS, we decided on treatement with intraveonus immunoglobulins (IVIg) that enabled quick onset of immunomodulatory effect. All comorbidities were treated with standard of care. The patient's condition quickly stabilized with no direct side effects of a given treatment. Conclusion: Treatment of COVID-19 in patients with CS faces many challenges due to the complexity of comorbidity effects, immunosupression and potential interactions of available medications both for treatment of COVID-19 and CS. So far, there are no guidelines for treatment of COVID-19 in patients with active CS. It is our opinion that immunomodulating therapies like IVIg might be an effective and safe treatment modality in this particularly fragile group of patients.

Ectopic ACTH by Carcinoid Tumor Mimicking Nelson Syndrome in a Patient with Bilateral Adrenalectomy

Introduction: Nelson syndrome has been reported in up to 25% of adults after bilateral adrenalectomy (BLA) for Cushing’s disease (CD). It usually manifests as an expanding pituitary mass, rising adrenocorticotropic (ACTH) hormone levels and, in many patients, the development of hyperpigmentation. We review the clinical course of a patient with rising ACTH levels after BLA for presumed CD. Although the diagnosis of Nelson syndrome was considered, he was found 9 years after BLA to have an ectopic ACTH secreting bronchial carcinoid tumor as a cause for the elevated ACTH levels. Case Description: A 35 year old male was evaluated at another institution in 2010 after he presented with weight gain, new onset hypertension, muscle weakness with multiple falls, depression, irritability and emotional lability. He was diagnosed with CD and was referred to a university center where he underwent trans-sphenoidal pituitary surgery in May 2011. An adenoma was seen on frozen section but not on the final pathology. He developed transient symptoms of adrenal insufficiency on the second post-operative day. Because of persistent hypercortisolism he underwent BLA in November 2011. We started following him in 2012 and signs of hypercortisolism gradually resolved. He appeared euadrenal on hydrocortisone 10 mg am, 5 mg 12 noon and 5 mg 6 pm and fludrocortisone 0.05 mg daily. ACTH levels increased from 54 pg/ml (6-50) in 2012 to 1024 pg/ml in 2019. He had no hyperpigmentation and MRI of the pituitary from 2014-20 did not show a pituitary mass. During an evaluation for COVID-19 infection in May 2020, a chest x ray revealed a right lower lobe lung mass measuring 3.3 x 2.0 cm. He underwent right lower lobe lung lobectomy in July 2020 and pathology revealed a carcinoid tumor-spindle cell pattern which stained strongly positive for ACTH and weakly positive for chromogranin. ACTH levels after the surgery decreased to 16.3 pg/ml. Discussion: Some authors have suggested that Nelson syndrome be considered in patients with BLA who have one of the following: an expanding pituitary mass or ACTH levels >500 p/ml at 3 different time points after surgery. This case highlights the need to consider ectopic ACTH syndrome as another cause for rising ACTH levels after BLA for CD especially in those patients who are not found to have a discreet adenoma after pituitary surgery.

[Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization].

AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

Management and Medical Therapy of Mild Hypercortisolism.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

A New Clinical Model to Estimate the Pre-Test Probability of Cushing's Syndrome: The Cushing Score.

Background: Hypercortisolism accounts for relevant morbidity and mortality and is often a diagnostic challenge for clinicians. A prompt diagnosis is necessary to treat Cushing's syndrome as early as possible. Objective: The aim of this study was to develop and validate a clinical model for the estimation of pre-test probability of hypercortisolism in an at-risk population. Design: We conducted a retrospective multicenter case-control study, involving five Italian referral centers for Endocrinology (Turin, Messina, Naples, Padua and Rome). One hundred and fifty patients affected by Cushing's syndrome and 300 patients in which hypercortisolism was excluded were enrolled. All patients were evaluated, according to current guidelines, for the suspicion of hypercortisolism. Results: The Cushing score was built by multivariable logistic regression, considering all main features associated with a clinical suspicion of hypercortisolism as possible predictors. A stepwise backward selection algorithm was used (final model AUC=0.873), then an internal validation was performed through ten-fold cross-validation. Final estimation of the model performance showed an average AUC=0.841, thus reassuring about a small overfitting effect. The retrieved score was structured on a 17.5-point scale: low-risk class (score value: ≤5.5, probability of disease=0.8%); intermediate-low-risk class (score value: 6-8.5, probability of disease=2.7%); intermediate-high-risk class (score value: 9-11.5, probability of disease=18.5%) and finally, high-risk class (score value: ≥12, probability of disease=72.5%). Conclusions: We developed and internally validated a simple tool to determine pre-test probability of hypercortisolism, the Cushing score, that showed a remarkable predictive power for the discrimination between subjects with and without a final diagnosis of Cushing's syndrome.

Osilodrostat: A Review of Recent Clinical Studies and Practical Recommendations for its Use in the Treatment of Cushing Disease.

OBJECTIVE: Cushing disease (CD) is characterized by chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. Surgery remains the first-line treatment option; however, medical therapy is essential if surgery is contraindicated or fails to achieve remission or when recurrence occurs after surgical remission. Osilodrostat (Isturisa), a novel steroidogenic inhibitor, is now approved for the treatment of CD in the United States and Cushing syndrome in Europe. Herein, we review pharmacology and data on the efficacy, safety, and clinical use of osilodrostat and provide guidance on its use in treating patients with CD. METHODS: We reviewed the literature and published clinical trial data of osilodrostat use in patients with Cushing syndrome. Detailed information related to the clinical assessment of osilodrostat use, potential drug-to-drug interactions, drug initiation, dose titration, and the monitoring of drug tolerability were discussed. RESULTS: Clinical trial data demonstrated that osilodrostat, by virtue of inhibiting 11-ß hydroxylase, potently and rapidly decreased the 24-hour urinary free cortisol levels and sustained these reductions, with improved glycemia, blood pressure, body weight, and quality of life as well as lessened depression. Osilodrostat may interact with certain drugs, resulting in QT prolongation, which requires careful assessment of concomitant medications and periodic monitoring using electrocardiogram, respectively. The common adverse effects include adrenal insufficiency, hypokalemia, edema, and hyperandrogenic symptoms, which can be minimized using a slower up-titration dosing regimen. CONCLUSION: Osilodrostat is an effective, new treatment option for CD, with positive effects on cardiovascular and quality of life parameters as well as tolerable adverse effects. This article provides a review of the pharmacology of osilodrostat and offers practical recommendations on the use of osilodrostat to treat CD.

Endocrine risk factors for COVID-19: Endogenous and exogenous glucocorticoid excess.

Patients with endogenous or exogenous glucocorticoid (GC) excess exhibit a range of side effects, including an increased risk of infections. Via both mechanism, immune impairments and cardiometabolic concomitant diseases, patients with GC excess could be at increased risk for COVID-19. The impact on incidence and outcome of a SARS-CoV-2 infection in this population are not yet completely clear. This review aims to compile the data available to date and to discuss the existing literature on this topic. Further we highlight potential effects of SARS-CoV-2 on the hypothalamic-pituitary-adrenal axis as well as the influence of endogenous or exogenous GC excess on SARS-CoV-2 mRNA vaccination. There is growing evidence suggesting an increased risk of infection and severe outcome in patients with high-dose GC therapy after contracting SARS-CoV-2. The few data and case reports on patients with endogenous GC excess and SARS-CoV-2 infection point in a similar direction: chronic GC excess seems to be associated with an unfavorable course of COVID-19. Whether this is mainly a primary immune-mediated effect, or also triggered by the many GC-associated comorbidities in this population, is not yet fully understood. Patients with endogenous or exogenous GC excess should be considered as a vulnerable group during the SARS-CoV-2 pandemic. Regardless of the cause, vaccination and consistent surveillance and control of associated comorbidities are recommended.

Image of the month: Diagnostic and therapeutic challenges in the management of ectopic ACTH syndrome: a perfect storm of hypercortisolism, hyperglycaemia and COVID-19.

Cushing's syndrome is a rare endocrine disorder requiring a high degree of clinical suspicion and meticulous investigations to diagnose and manage optimally. Delayed diagnosis and suboptimal treatment are associated with increased morbidity and mortality. Uncontrolled hypercortisolism leads to multiple cardiovascular and metabolic complications. Key risk factors identified for COVID-19-related adverse clinical outcomes (such as diabetes, hypertension and obesity) are, in fact, core clinical manifestations of Cushing's syndrome. Occurrence of SARS-CoV-2 infection in someone with uncontrolled hypercortisolism could, therefore, lead to disastrous medical consequences. We report a case highlighting challenges in the diagnosis and management of aggressive Cushing's syndrome secondary to ectopic adrenocorticotropic hormone (ACTH) secretion from an, as yet unidentified, neuroendocrine tumour. Our patient also contracted SARS-CoV-2 infection during investigations, which posed additional difficulties with aggravation of cardiometabolic complications. We also identify lack of clinical evidence to address management of this unique combination of two potentially life-threatening illnesses.

Practical Considerations for the Management of Cushing's Disease and COVID-19: A Case Report.

Introduction: Italy, since the end of February 2020, is experiencing the corona virus disease 2019 (COVID-19) pandemic that may present as an acute respiratory infection. We report on COVID-19 pneumonia in the context of a complex case of Cushing's disease (CD). Case Report: A 67-year-old man with CD, who was admitted to our hospital, presented with signs and symptoms of adrenal insufficiency with persistent hypotension and glycemia toward the lower limits. We progressively withdrew almost all treatments for diabetes and CD (pasireotide and metyrapone), and i.v. hydrocortisone was necessary. A tendency to hyperkalemia was probably associated to enoxaparin. We summarized the many possible interactions between medications of Cushing's syndrome (CS) and COVID-19. Conclusion: Adrenal insufficiency might be a clinical challenge that needs a prompt treatment also in CS patients during COVID-19 infection. We should consider the possibility to titrate or temporary halt medical therapies of CS in the context of COVID-19 infection. Unexpected hyperkalemia in CS patients under treatment with heparin might be the signal of aldosterone suppression.