COVID-19 and Cushing’s syndrome: recommendations for a special population with endogenous glucocorticoid excess

Rosario Pivonello,a,b Rosario Ferrigno,a Andrea M Isidori,c Beverly M K Biller,d Ashley B Grossman,e,f and Annamaria Colaoa,b

Over the past few months, COVID-19, the pandemic disease caused by severe acute respiratory syndrome coronavirus 2, has been associated with a high rate of infection and lethality, especially in patients with comorbidities such as obesity, hypertension, diabetes, and immunodeficiency syndromes.

These cardiometabolic and immune impairments are common comorbidities of Cushing’s syndrome, a condition characterised by excessive exposure to endogenous glucocorticoids. In patients with Cushing’s syndrome, the increased cardiovascular risk factors, amplified by the increased thromboembolic risk, and the increased susceptibility to severe infections, are the two leading causes of death.

In healthy individuals in the early phase of infection, at the physiological level, glucocorticoids exert immunoenhancing effects, priming danger sensor and cytokine receptor expression, thereby sensitising the immune system to external agents. However, over time and with sustained high concentrations, the principal effects of glucocorticoids are to produce profound immunosuppression, with depression of innate and adaptive immune responses. Therefore, chronic excessive glucocorticoids might hamper the initial response to external agents and the consequent activation of adaptive responses. Subsequently, a decrease in the number of B-lymphocytes and T-lymphocytes, as well as a reduction in T-helper cell activation might favour opportunistic and intracellular infection. As a result, an increased risk of infection is seen, with an estimated prevalence of 21–51% in patients with Cushing’s syndrome. Therefore, despite the absence of data on the effects of COVID-19 in patients with Cushing’s syndrome, one can make observations related to the compromised immune state in patients with Cushing’s syndrome and provide expert advice for patients with a current or past history of Cushing’s syndrome.

Fever is one of the hallmarks of severe infections and is present in up to around 90% of patients with COVID-19, in addition to cough and dyspnoea. However, in active Cushing’s syndrome, the low-grade chronic inflammation and the poor immune response might limit febrile response in the early phase of infection. Conversely, different symptoms might be enhanced in patients with Cushing’s syndrome; for instance, dyspnoea might occur because of a combination of cardiac insufficiency or weakness of respiratory muscles. Therefore, during active Cushing’s syndrome, physicians should seek different signs and symptoms when suspecting COVID-19, such as cough, together with dysgeusia, anosmia, and diarrhoea, and should be suspicious of any change in health status of their patients with Cushing’s syndrome, rather than relying on fever and dyspnoea as typical features.

The clinical course of COVID-19 might also be difficult to predict in patients with active Cushing’s syndrome. Generally, patients with COVID-19 and a history of obesity, hypertension, or diabetes have a more severe course, leading to increased morbidity and mortality. Because these conditions are observed in most patients with active Cushing’s syndrome, these patients might be at an increased risk of severe course, with progression to acute respiratory distress syndrome (ARDS), when developing COVID-19. However, a key element in the development of ARDS during COVID-19 is the exaggerated cellular response induced by the cytokine increase, leading to massive alveolar–capillary wall damage and a decline in gas exchange. Because patients with Cushing’s syndrome might not mount a normal cytokine response, these patients might parodoxically be less prone to develop severe ARDS with COVID-19. Moreover, Cushing’s syndrome and severe COVID-19 are associated with hypercoagulability, such that patients with active Cushing’s syndrome might present an increased risk of thromboembolism with COVID-19. Consequently, because low molecular weight heparin seems to be associated with lower mortality and disease severity in patients with COVID-19, and because anticoagulation is also recommended in specific conditions in patients with active Cushing’s syndrome, this treatment is strongly advised in hospitalised patients with Cushing’s syndrome who have COVID-19. Furthermore, patients with active Cushing’s syndrome are at increased risk of prolonged duration of viral infections, as well as opportunistic infections, particularly atypical bacterial and invasive fungal infections, leading to sepsis and an increased mortality risk, and COVID-19 patients are also at increased risk of secondary bacterial or fungal infections during hospitalisation. Therefore, in cases of COVID-19 during active Cushing’s syndrome, prolonged antiviral treatment and empirical prophylaxis with broad-spectrum antibiotics should be considered, especially for hospitalised patients (panel ).

Panel

Risk factors and clinical suggestions for patients with Cushing’s syndrome who have COVID-19

Reduction of febrile response and enhancement of dyspnoea

Rely on different symptoms and signs suggestive of COVID-19, such as cough, dysgeusia, anosmia, and diarrhoea.

Prolonged duration of viral infections and susceptibility to superimposed bacterial and fungal infections

Consider prolonged antiviral and broad-spectrum antibiotic treatment.

Impairment of glucose metabolism (negative prognostic factor)

Optimise glycaemic control and select cortisol-lowering drugs that improve glucose metabolism. Hypertension (negative prognostic factor) Optimise blood pressure control and select cortisol-lowering drugs that improve blood pressure.

Thrombosis diathesis (negative prognostic factor)

Start antithrombotic prophylaxis, preferably with low-molecular-weight heparin treatment.

Surgery represents the first-line treatment for all causes of Cushing’s syndrome, but during the pandemic a delay might be appropriate to reduce the hospital-associated risk of COVID-19, any post-surgical immunodepression, and thromboembolic risks. Because immunosuppression and thromboembolic diathesis are common Cushing’s syndrome features, during the COVID-19 pandemic, cortisol-lowering medical therapy, including the oral drugs ketoconazole, metyrapone, and the novel osilodrostat, which are usually effective within hours or days, or the parenteral drug etomidate when immediate cortisol control is required, should be temporarily used. Nevertheless, an expeditious definitive diagnosis and proper surgical resolution of hypercortisolism should be ensured in patients with malignant forms of Cushing’s syndrome, not only to avoid disease progression risk but also for rapidly ameliorating hypercoagulability and immunospuppression; however, if diagnostic procedures cannot be easily secured or surgery cannot be done for limitations of hospital resources due to the pandemic, medical therapy should be preferred. Concomitantly, the optimisation of medical treatment for pre-existing comorbidities as well as the choice of cortisol-lowering drugs with potentially positive effects on obesity, hypertension, or diabates are crucial to improve the eventual clinical course of COVID-19.

Once patients with Cushing’s syndrome are in remission, the risk of infection is substantially decreased, but the comorbidities related to excess glucocorticoids might persist, including obesity, hypertension, and diabetes, together with thromboembolic diathesis. Because these are features associated with an increased death risk in patients with COVID-19, patients with Cushing’s syndrome in remission should be considered a high-risk population and consequently adopt adequate self-protection strategies to minimise contagion risk.

In conclusion, COVID-19 might have specific clinical presentation, clinical course, and clinical complications in patients who also have Cushing’s syndrome during the active hypercortisolaemic phase, and therefore careful monitoring and specific consideration should be given to this special, susceptible population. Moreover, the use of medical therapy as a bridge treatment while waiting for the pandemic to abate should be considered.

Acknowledgments

RP reports grants and personal fees from Novartis, Strongbridge, HRA Pharma, Ipsen, Shire, and Pfizer; grants from Corcept Therapeutics and IBSA Farmaceutici; and personal fees from Ferring and Italfarmaco. AMI reports non-financial support from Takeda and Ipsen; grants and non-financial support from Shire, Pfizer, and Corcept Therapeutics. BMKB reports grants from Novartis, Strongbridge, and Millendo; and personal fees from Novartis and Strongbridge. AC reports grants and personal fees from Novartis, Ipsen, Shire, and Pfizer; personal fees from Italfarmaco; and grants from Lilly, Merck, and Novo Nordisk. All other authors declare no competing interests.

References

1. Kakodkar P, Kaka N, Baig MN. A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19) Cureus. 2020;12 [PMC free article] [PubMed[]
2. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4:611–629. [PubMed[]
3. Cain DW, Cidlowski JA. Immune regulation by glucocorticoids. Nat Rev Immunol. 2017;17:233–247. [PubMed[]
4. Hasenmajer V, Sbardella E, Sciarra F, Minnetti M, Isidori AM, Venneri MA. The immune system in Cushing’s syndrome. Trends Endocrinol Metab. 2020 doi: 10.1016/j.tem.2020.04.004. published online May 6, 2020. [PubMed] [CrossRef[]
5. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the ‘Cytokine Storm’ in COVID-19. J Infect. 2020;80:607–613. [PMC free article] [PubMed[]
6. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost. 2020;18:1094–1099. [PubMed[]
7. Isidori AM, Minnetti M, Sbardella E, Graziadio C, Grossman AB. Mechanisms in endocrinology: the spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur J Endocrinol. 2015;173:R101–R113. [PubMed[]
8. Nieman LK, Biller BM, Findling JW. Treatment of Cushing’s syndrome: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2015;100:2807–2831. [PMC free article] [PubMed[]
9. Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing’s disease. Endocr Rev. 2015;36:385–486. [PMC free article] [PubMed[]
10. Newell-Price J, Nieman L, Reincke M, Tabarin A. Endocrinology in the time of COVID-19: management of Cushing’s syndrome. Eur J Endocrinol. 2020 doi: 10.1530/EJE-20-0352. published online April 1. [PubMed] [CrossRef[]

Adrenal incidentalomas—do they need follow up?

Are adrenal incidentalomas, which are found by chance on imaging, really harmless? In this paper, the authors looked at 32 studies, including 4121 patients with benign non-functioning adrenal tumours (NFATs) or adenomas that cause mild autonomous cortisol excess (MACE).

Only 2.5% of the tumours grew to a clinically significant extent over a mean follow-up period of 50 months, and no one developed adrenal cancer. Of those patients with NFAT or MACE, 99.9% didn’t develop clinically significant hormone (cortisol) excess. This was a group (especially those with MACE) with a high prevalence of hypertension, diabetes, and obesity. This could be because adrenal adenomas promote cardiometabolic problems, or vice versa, or maybe this group with multimorbidities is more likely be investigated.

Adrenal incidentalomas are already found in around 1 in 20 abdominal CT scans, and this rate is likely to increase as imaging improves. So it’s good news that this study supports existing recommendations, which say that follow-up imaging in the 90% of incidentalomas that are smaller than 4 cm diameter is unnecessary.

From https://blogs.bmj.com/bmj/2019/07/03/ann-robinsons-journal-review-3-july-2019/

Cushing’s Syndrome Patients at More Risk of Blood-clotting Problems After Adrenal Surgery

Cushing’s syndrome patients who undergo adrenal surgery are more likely to have venous thromboembolism — blood clots that originate in the veins — than patients who have the same procedure for other conditions, a study suggests.

Physicians should consider preventive treatment for this complication in Cushing’s syndrome patients who are having adrenal surgery and maintain it for four weeks after surgery due to late VTE onset.

The study, “Is VTE Prophylaxis Necessary on Discharge for Patients Undergoing Adrenalectomy for Cushing Syndrome?” was published in the Journal of Endocrine Society.

Cushing’s syndrome is a condition characterized by too much cortisol in circulation. In many cases, it is caused by a tumor in the pituitary gland, which produces greater amounts of the cortisol-controlling adrenocorticotropic hormone (ACTH). In other cases, patients have tumors in the adrenal glands that directly increase cortisol production.

When the source of the problem is the pituitary gland, the condition is known as Cushing’s disease.

The imbalance in cortisol levels generates metabolic complications that include obesity, high blood pressure, diabetes, and cardiovascular complications. Among the latter, the formation of blood clots in the deep veins of the leg, groin or arm — a condition called venous thromboembolism (VTE) — is higher in both Cushing’s disease and Cushing’s syndrome patients.

VTE is believed to be a result of excess coagulation factors that promote blood clot formation, and is thought to particularly affect Cushing’s disease patients who have pituitary gland surgery.

Whether Cushing’s syndrome patients who have an adrenalectomy — surgical removal of one or both adrenal glands — are at a higher risk for VTE is largely unknown. This is important for post-operative management, to decide whether they should have preventive treatment for blood clot formation.

Researchers at the National Cancer Institute in Maryland did a retrospective analysis of a large group of patients in the American College of Surgeons National Quality Improvement Program database.

A total of 8,082 patients underwent adrenal gland surgery between 2005 and 2016. Data on these patients included preoperative risk factors, as well as 30-day post-surgery mortality and morbidity outcomes. Patients with malignant disease and without specified adrenal pathology were excluded from the study.

The final analysis included 4,217 patients, 61.8% of whom were females. In total, 310 patients had Cushing’s syndrome or Cushing’s disease that required an adrenalectomy. The remaining 3,907 had an adrenal disease other than Cushing’s and were used as controls.

The incidence of VTE after surgery — defined as pulmonary embolism (a blockage of an artery in the lungs) or deep-vein thrombosis — was 1% in the overall population. However, more Cushing’s patients experienced this complication (2.6%) than controls (0.9%).

Those diagnosed with Cushing’s syndrome were generally younger, had a higher body mass index, and were more likely to have diabetes than controls. Their surgery also lasted longer — 191.2 minutes versus 142 minutes — as did their hospital stay – 2.4 versus two days.

Although without statistical significance, the researchers observed a tendency for longer surgery time for patients with Cushing’s syndrome than controls with VTE. They saw no difference in the time for blood coagulation between Cushing’s and non-Cushing’s patients, or postoperative events other than pulmonary embolism or deep-vein thrombosis.

In addition, no differences were detected for VTE incidence between Cushing’s and non-Cushing’s patients according to the type of surgical approach — laparoscopic versus open surgery.

These results suggest that individuals with Cushing syndrome are at a higher risk for developing VTE.

“Because the incidence of VTE events in the CS group was almost threefold higher than that in the non-CS group and VTE events occurred up to 23 days after surgery in patients with CS undergoing adrenalectomy, our data support postdischarge thromboprophylaxis for 28 days in these patients,” the researchers concluded.

From https://cushingsdiseasenews.com/2019/02/14/cushings-syndrome-patients-blood-clots-adrenal-surgery/

Vision Loss The First Sign Of Adrenal Tumour In 42-Year-Old Patient

A 42-year-old woman who presented to hospital with acute vision loss in her right eye was diagnosed with a benign tumour in her adrenal gland.

Writing in BMJ Case Reports, clinicians described how the patient presented with a visual acuity of 6/36 in her right eye and 6/6 in her left eye.

Investigations revealed an exudative retinal detachment in her right eye as well as a pigment epithelial detachment.

The patient had multifocal central serous retinopathy in both eyes.

The woman, who had hypertension and diabetes, was diagnosed with Cushing syndrome and a right adrenal adenoma was also discovered.

During a treatment period that spanned several years, the patient received an adrenalectomy followed by a maintenance dose of steroids.

The patient subsequently developed central serous retinopathy again which the clinicians believe might be related to steroid use.

The authors advised “careful deliberation” in prescribing a maintenance dose of steroids following removal of the adrenal glands because of the potential link to retinopathy.

From https://www.aop.org.uk/ot/science-and-vision/research/2018/12/17/vision-loss-the-first-sign-of-adrenal-tumour-in-42-year-old-patient

Cushing’s Patients at Risk of Life-threatening Pulmonary Fungal Infection

Cushing’s disease patients who exhibit nodules or masses in their lungs should be thoroughly investigated to exclude fungal infection with Cryptococcus neoformans, a study from China suggests.

While rare, the infection can be life-threatening, showing a particularly worse prognosis in patients with fluid infiltration in their lungs or with low white blood cell counts in their blood.

The study, “Cushing’s disease with pulmonary Cryptococcus neoformans infection in a single center in Beijing, China: A retrospective study and literature review,” was published in the Journal of the Formosan Medical Association.

Cortisol, a hormone that is produced in excess in Cushing’s disease patients, is a kind of glucocorticoid that suppresses inflammation and immunity. Consequently, subjects exposed to cortisol for long periods, much like immuno-compromised patients, are at high risk for infections.

In Cushing’s patients, the most common infections include Pneumocystis jiroveciAspergillus fumigatus, and Cryptococcosis — 95 percent of which are caused by C. neoformans.

But while “Cushing’s disease patients are susceptible to C. neoformans, the association between pulmonary C.neoformans and [Cushing’s disease] is poorly explored,” researchers said.

In an attempt to understand the clinical characteristics of Cushing’s patients who develop C.neoformans infections, researchers in Beijing, China, reviewed the clinical records of six patients at their clinical center.

Their analysis also included six other patients whose cases had been reported in previous publications.

Patients had a mean age of 44 and 10 were diagnosed initially with high blood pressure. Seven also had diabetes mellitus.

All patients had elevated cortisol levels in their urine and high levels of the adrenocorticotropic hormone (ACTH). Ultimately, all patients were found to have masses in their pituitary glands, causing the high cortisol and ACTH levels.

Patients complained of lung symptoms, including shortness of breath after physical activity, cough, and expectoration. But they had no fever or signs of blood in the lungs, which could suggest lung infection.

A CT scan of the chest then revealed lung nodules in four patients, and lung masses in five patients. Four patients, including one with a lung mass, also had lung air spaces filled with some material (pulmonary consolidation), which was consistent with pulmonary infection.

After analyzing lung nodule/mass biopsies, lung fluids, or blood samples, all patients were diagnosed with C. neoformans pulmonary cryptococcosis.

For their infection, patients received anti-fungal drugs, including amphotericin-B, fluconazole, flucytosine, and liposomal amphotericin. Cushing’s disease, however, was treated with surgery in 10 patients and ketoconazole in two patients.

Despite the treatments, five patients died during follow-up, including four who experienced co-infections or spreading of the cryptococcal infection and one patient with extensive bleeding after surgical removal of the gallbladder.

Among them, two patients had significantly low white blood cell levels and elevated cortisol levels, and four had infiltration in their lungs, suggesting these are markers of poor prognoses.

Researchers also noted that the patients who received ketoconazole died during in the reviewed studies. They attribute this to ketoconazole’s anti-fungal properties, which may interfere with its ability to manage Cushing’s symptoms.

Given the high susceptibility of Cushing’s disease patients to C. neoformans infections, “pulmonary nodules or masses should be aggressively investigated to exclude” this potentially fatal opportunistic infection, the researchers suggested.

“The infiltration lesions in chest CT scan and lymphopenia seem to be potential to reflect the poor prognosis,” they said.

From https://cushingsdiseasenews.com/2018/06/15/pulmonary-fungal-infection-threatens-cushings-disease-patients-study/

%d bloggers like this: