Increased risk of hospitalization, intensive care and death due to COVID-19 in patients with adrenal insufficiency: A Swedish nationwide study.

BACKGROUND: Patients with adrenal insufficiency (AI) have excess morbidity and mortality related to infectious disorders. Whether patients with AI have increased morbidity and mortality from COVID-19 is unknown. METHODS: In this linked Swedish national register-based cohort study, patients with primary and secondary AI diagnosis were identified and followed from 1 January 2020 to 28 February 2021. They were compared with a control cohort from the general population matched 10:1 for age and sex. The following COVID-19 outcomes were studied: incidence of COVID-19 infection, rates of hospitalization, intensive care admission and death. Hazard ratios (HR) with 95% confidence intervals (95% CI) adjusted for socioeconomic factors and comorbidities were estimated using Cox regression analysis. RESULTS: We identified 5430 patients with AI and 54,300 matched controls: There were 47.6% women, mean age was 57.1 (standard deviation 18.1) years, and the frequency of COVID-19 infection was similar, but the frequency of hospitalization (2.1% vs. 0.8%), intensive care (0.3% vs. 0.1%) and death (0.8% vs. 0.2%) for COVID-19 was higher in AI patients than matched controls. After adjustment for socioeconomic factors and comorbidities, the HR (95% CI) was increased for hospitalization (1.96, 1.59-2.43), intensive care admission (2.76, 1.49-5.09) and death (2.29, 1.60-3.28). CONCLUSION: Patients with AI have a similar incidence of COVID-19 infection to a matched control population, but a more than twofold increased risk of developing a severe infection or a fatal outcome. They should therefore be prioritized for vaccination, antiviral therapy and other appropriate treatment to mitigate hospitalization and death.

Assessment of adrenal response in patients with stable cirrhosis and ascites using different short Synacthen tests and definitions.

BACKGROUND AND AIMS: The definition of relative adrenal insufficiency (RAI) in patients with cirrhosis remains controversial. We investigated the serum and salivary cortisol (SalC) response after low-dose and standard-dose Synacthen test in patients with stable cirrhosis and ascites. METHODS: Ninety-five cirrhotic patients with ascites were prospectively evaluated from January 2014 to January 2018. Low-dose [adrenocorticotrophic hormone (ACTH): 1 µg] and standard-dose (ACTH: 250 µg) Synacthen test were successively performed. Paired serum total and saliva cortisol were taken at baseline, 30 min (low-dose test) and 60 min (standard-dose test). Salivary and Δserum total cortisol criteria included post-ACTH SalC < 12.7 ng/ml and/or SalC increase <3 ng/ml and serum total cortisol increase <9 µg/dl, respectively. RESULTS: The prevalence of RAI varied according to the definition used. SalC-defined RAI was significantly more common after low-dose than standard-dose test (54.7% vs. 20%; P < 0.001). Δserum total cortisol-defined RAI was also significantly more frequent after low-dose than standard-dose test (66.3% vs. 24.2%; P < 0.001). Considering low-dose test/SalC criteria as reference diagnostic criteria, standard-dose/salivary and Δserum total cortisol criteria showed low specificity for RAI diagnosis (43.9% and 52.7%, respectively). Survival probability was significantly lower in patients with low-dose test/SalC-defined RAI compared to those without (53.8% vs. 79.1%; P = 0.01). SalC-defined RAI after low-dose test was significantly more common than that defined after standard-dose test (72.7% vs. 30.3%; P < 0.001) among patients who died. CONCLUSION: Low-dose test/SalC definition can identify RAI in about half of patients with stable cirrhosis and ascites and is associated with increased mortality.

Tiered healthcare in South Africa exposes deficiencies in management and more patients with infectious etiology of primary adrenal insufficiency.

OBJECTIVE: We wished to determine the prevalence, etiology, presentation, and available management strategies for primary adrenal insufficiency (PAI) in South Africa (SA), hypothesizing a prevalence greater than the described 3.1 per million. There is great inequity in healthcare allocation, as two parallel healthcare systems exist, potentially modifying PAI patients' clinical profiles, private being better resourced than public healthcare. METHODS: An online survey of physicians' experience relating to PAI. RESULTS: The physicians were managing 811 patients, equal to a prevalence of 14.2 per million. Likely causes of PAI in public/ academic vs private settings included: AIDS-related [304 (44.8%) vs 5 (3.8%); p<0.001], tuberculosis [288 (42.5%) vs 8 (6.0%); p<0.001], autoimmune disease [50 (7.4%) vs 88 (66.2%); p<0.001], malignancy [27 (4.0%) vs 7 (5.3%); p = 0.500], genetic including adrenoleukodystrophy (ALD) [5 (0.7%) vs 16 (12.0%); p<0.001], respectively. Overall, more patients presented with nausea [101 (74.3%) and vomiting 89 (65.9%), than diarrhoea 76 (58.9%); p = 0.008 and 126 (15.5%) in adrenal crisis. Features suggestive of a crisis were hypoglycaemia [40 (78.4%) vs 42 (48.8%); p = 0.001], shock [36 (67.9%) vs 31(36.9%); p<0.001], and loss of consciousness [25 (52.1%) vs 27 (32.9%); p = 0.031]. Greater unavailability of antibody testing in the public vs. the private sector [32 (66.7%) vs 30 (32.1%); p = 0.001], [serum-ACTH 25 (52.1%) vs 16 (19.5%); p<0.001] and glucocorticoids were [26 (54.2%) vs 33 (40.2%); p = 0.015]. Many patients, 389(66.7%) were not using identification, indicating that they need steroids in an emergency. CONCLUSION: A survey of South African physicians suggests a higher prevalence than previously reported. Patients presented with typical symptoms, and 15.5% presented in adrenal crisis. Significant disparities in the availability of physicians' expertise, diagnostic resources, and management options were noted in the public versus private settings. Greater awareness among health practitioners to timeously diagnose PAI is required to prevent a life-threatening outcome.

Management of Adrenal Insufficiency Risk After Long-term Systemic Glucocorticoid Therapy in Duchenne Muscular Dystrophy: Clinical Practice Recommendations.

Long-term glucocorticoid therapy has improved outcomes in patients with Duchenne muscular dystrophy. However, the recommended glucocorticoid dosage suppresses the hypothalamic-pituitary-adrenal axis, leading to adrenal insufficiency that may develop during severe illness, trauma or surgery, and after discontinuation of glucocorticoid therapy. The purpose of this review is to highlight the risk of adrenal insufficiency in this patient population, and provide practical recommendations for management of adrenal insufficiency, glucocorticoid withdrawal, and adrenal function testing. Strategies to increase awareness among patients, families, and health care providers are also discussed.

Assessment of hair cortisol as a potential biomarker for possible adrenal suppression due to inhaled corticosteroid use in children with asthma: A retrospective observational study.

BACKGROUND: Inhaled corticosteroids (ICS) are the recommended long-term control therapy for asthma in children. However, concern exists regarding potential adrenal suppression with chronic ICS use. Our pilot study reported that hair cortisol in children was 50% lower during ICS therapy than prior to therapy, suggestive of adrenal suppression. OBJECTIVE: To evaluate hair cortisol concentration (HCC) as a potential biomarker for possible adrenal suppression from ICS use in children with asthma. METHODS: A retrospective observational study was performed at asthma clinics in Vancouver, Winnipeg, and Toronto, Canada. Children (n = 586) were recruited from July 2012 to December 2014 inclusive of those without asthma, with asthma not using ICS, and with asthma using ICS. The most recent three-month HCC was measured by enzyme immunoassay and compared among the groups. Quantile regression analysis was performed to identify factors potentially affecting HCC. RESULTS: The median HCC was not significantly different among the children: No ICS (n = 47, 6.7 ng/g, interquartile range (IQR) 3.7-9.8 ng/g), ICS Treated (n = 360, 6.5 ng/g, IQR 3.8-14.3 ng/g), and Controls (n = 53, 5.8 ng/g, IQR 4.6-16.7 ng/g). 5.6% of the children using ICS had hair cortisol <2.0 ng/g compared to none in the control groups (P < .05, comparing ICS Treated (20/360) to all Controls combined (0/100)) and only half had been exposed to systemic corticosteroids. Age, sex, BMI, and intranasal corticosteroid use were significantly associated with HCC. CONCLUSIONS: Results suggest HCC may be a potential biomarker for adrenal suppression as a population of children using ICS with HCC < 2.0 ng/g was identified compared to none in the control groups. Further research is needed to determine if those children have or are at risk of adrenal suppression or insufficiency.

GLUCOCORTICOID-INDUCED ADRENAL INSUFFICIENCY: A STUDY OF THE INCIDENCE IN HOSPITAL PATIENTS AND A REVIEW OF PERI-OPERATIVE MANAGEMENT.

OBJECTIVE: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure. METHODS: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover. RESULTS: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period. CONCLUSION: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients. ABBREVIATIONS: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio.

MANAGEMENT OF ENDOCRINE DISEASE: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review.

In this article, we review published studies covering epidemiology, natural course and mortality in primary adrenal insufficiency (PAI) or Addison's disease. Autoimmune PAI is a rare disease with a prevalence of 100-220 per million inhabitants. It occurs as part of an autoimmune polyendocrine syndrome in more than half of the cases. The patients experience impaired quality of life, reduced parity and increased risk of preterm delivery. Following a conventional glucocorticoid replacement regimen leads to a reduction in bone mineral density and an increase in the prevalence of fractures. Registry studies indicate increased mortality, especially evident in patients diagnosed with PAI at a young age and in patients with the rare disease autoimmune polyendocrine syndrome type-1. Most notably, unnecessary deaths still occur because of adrenal crises. All these data imply the need to improve the therapy and care of patients with PAI.

Assessment of the effect of continuous sedation with mechanical ventilation on adrenal insufficiency in patients with traumatic brain injury.

The aim of this study was to assess the effect of continuous propofol sedation plus prolonged mechanical ventilation on adrenal insufficiency (AI) in patients with traumatic brain injury (TBI). Eighty-five adult patients diagnosed with moderate TBI (Glasgow Coma Scale (GCS) score 9-13) from October 2011 to October 2012 were included in this prospective study. The patients comprised three groups: no mechanical ventilation and sedation (n=27), mechanical ventilation alone (n=24) and mechanical ventilation plus sedation (n=34). The low-dose short Synacthen test was performed at 8:00 on the first, third, and fifth days after TBI. Logistic regression analysis was performed to identify factors affecting the use of mechanical ventilation and sedation, and the incidence of AI. On the fifth day after injury, the mean baseline cortisol and simulated cortisol levels were significantly lower in the mechanical ventilation plus sedation group compared with the other two groups. Multivariate regression analysis showed that the Acute Physiology and Chronic Health Evaluation (APACHE) score was independently associated with treatment with mechanical ventilation and sedation compared to mechanical ventilation alone. Furthermore, hypoxemia on admission and shock were associated with the development of AI. The findings showed that sedation is associated with an increased incidence of AI. Patients with TBI who are treated with continuous sedation should be monitored for AI carefully.

Addison's disease with polyglandular autoimmunity carries a more than 2·5-fold risk for adrenal crises: German Health insurance data 2010-2013.

OBJECTIVE: Adrenal crises are potentially life-threatening complications in patients with adrenal insufficiency (AI). Our objective was to investigate the frequency of adrenal crises in different forms of AI. DESIGN/PATIENTS: The Statutory Health Insurance (SHI) database of the Techniker Krankenkasse - covering more than 12% of the German population - was analysed for diagnostic codes from 1 January 2010 to 31 December 2013. MEASUREMENTS: By analysis of routine data from a large healthcare provider. Diagnoses of AI were recorded and classified in primary AI, secondary AI and autoimmune polyglandular syndrome (APS). The ICD-code E27·2 (AC) was retrieved in all cohorts. RESULTS: We found a prevalence of 222/million for secondary and 126/million for primary AI. AC was documented with a frequency of 4·8/100 patient years. Crises were significantly more frequent in patients with primary (7·6/100 patient years) compared to those with secondary AI (3·2/100 patient years; P < 0·0001). Prevalence of crises was higher in individuals with APS (10·9/100 patient years) and highest in patients with primary AI and type 1 diabetes (12·5/100 patient years). CONCLUSIONS: Applying a SHI database comprising more than 9 million individuals, we identified robust data about the risk of AC in different groups of patients with AI. Our data confirm and extend the clinical observation that patients with APS are at highest risk for AC. Approximately 1 of 8 patients with primary AI and type 1 diabetes suffers from an AC each year. Specific targeting of efforts aiming at the prevention of AC is necessary.

Assessment of adrenal function in patients with acute hepatitis using serum free and total cortisol.

BACKGROUND: Adrenal dysfunction is frequently reported in severe acute hepatitis using serum total cortisol. AIMS: Because 90% of serum cortisol is bound to proteins that are altered during stress, we investigated the effect of decreased cortisol-binding proteins on serum total and free cortisol in severe acute hepatitis. METHODS: 43 severe and 31 non-severe acute hepatitis and 29 healthy controls were enrolled consecutively and studied prospectively. Baseline (T0) and cosyntropin-stimulated (T60) serum total and free cortisol concentrations were measured. RESULTS: T0 and T60 serum total cortisol did not differ significantly between severe, non-severe hepatitis and healthy controls. Conversely, serum free cortisol (T0p=0.012; T60p<0.001) concentrations increased from healthy controls to severe hepatitis, accompanied by a decrease in corticosteroid-binding globulin and albumin (all p<0.001). In acute hepatitis (n=74), patients with "low" corticosteroid-binding globulin (<28mg/L) had higher T0 serum free cortisol than others (103.1 [61.2-157] vs. 56.6 [43.6-81.9]nmol/L, p=0.0024). Analysis of covariance showed that at equal concentration of total cortisol, the free cortisol concentration was significantly higher in severe than in non-severe hepatitis (p<0.001) or healthy controls (p<0.001). CONCLUSIONS: In severe hepatitis, the decrease in cortisol-binding proteins impairs correct diagnosis of adrenal dysfunction. This could be corrected by measuring or estimating free cortisol.

Health-related quality of life in primary and secondary adrenal insufficiency.

Adrenal insufficiency (AI) is characterized by a deficient production of glucocorticoids with or without associated mineral corticoid and/or adrenal androgen deficiencies. Despite the low prevalence of AI, its impact on the affected patient is very high, and can be life-threatening disease if not adequately treated. Several glucocorticoid treatment regimens are available, but none is capable of perfectly imitating the cortisol circadian rhythm. Cortisol rhythmicity and treatment of other possible concomitant conditions often associated (e.g., autoimmune disorders and panhypopituitarism) are essential to improve outcome of AI. Morbidity often present in treated AI include an unhealthy metabolic profile, bad quality of sleep, infertility, sexual dysfunction and worse health-related quality of life. This review focuses on psychological morbidity and impaired quality of life in patients with primary or secondary AI of any origin, including a special section devoted to congenital adrenal hyperplasia.

Assessment of adrenal function in cirrhotic patients: salivary cortisol should be preferred.

BACKGROUND & AIMS: Adrenal insufficiency is a common disorder among cirrhotic patients. Adrenal function is usually assessed with serum total cortisol assays. Free cortisol (active fraction) represents only 10% of serum total cortisol, the remaining 90% being linked to cortisol-binding globulin (CBG) and albumin. In cirrhotic patients, the synthesis of these proteins is reduced, which could lead to an overestimation of the prevalence of adrenal insufficiency. Salivary cortisol assessment adequately reflects free cortisol plasma concentration. However, this method has never been validated in cirrhotic patients. The objectives of this report were to assess the following parameters by a prospective observational study: (1) correlation between salivary, serum total and free cortisol, (2) adrenal insufficiency prevalence using salivary and serum assays, (3) parameters associated with a discrepancy between both tests, and (4) adrenal insufficiency risk factors among cirrhotic patients. METHODS: Salivary and serum total cortisol were assessed before and 1h following an injection of corticotropin (250 microg) in patients hospitalized for cirrhosis complications without shock. CBG was measured and free cortisol was assessed by the Coolens formula. RESULTS: Eighty-eight patients were included in the study (Child-Pugh C: 68.2%). Free cortisol was more strongly correlated with salivary than with serum total cortisol (Spearman coefficient=0.91 vs. 0.76, respectively, p<0.001). Among included patients, 9.1% had adrenal insufficiency according to salivary cortisol and 33.0% had adrenal insufficiency according to serum total cortisol (p=0.001). Hypoalbuminemia was the only factor associated with a discrepancy between the results of both tests. Adrenal insufficiency risk factors were ascites and low HDL-cholesterol plasma concentration. CONCLUSION: Using serum total cortisol assays overstate adrenal insufficiency prevalence among cirrhotic patients, mainly because of inaccurate concentrations related to hypoalbuminemia. Salivary cortisol assays should be preferably used in these patients.