5 181 Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 461–472syndrome High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: results from the ERCUSYN registry Elena Valassi1, Antoine Tabarin2, Thierry Brue3, Richard A Feelders4, Martin Reincke5, Romana Netea-Maier6, Miklós Tóth7, Sabina Zacharieva8, Susan M Webb1, Stylianos Tsagarakis9, Philippe Chanson10,11,12, Marija Pfeiffer13, Michael Droste14, Irina Komerdus15, Darko Kastelan16, Dominique Maiter17, Olivier Chabre18, Holger Franz19, Alicia Santos1, Christian J Strasburger20, Peter J Trainer21, John Newell-Price22 and Oskar Ragnarsson23 on behalf of the ERCUSYN Study Group† 1IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, UAB, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain, 2Department of Endocrinology, Diabetes and Nutrition, University of Bordeaux, Bordeaux, France, 3Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale INSERM U1251, Marseille Medical Genetics, Marseille, France and Assistance Publique Hôpitaux de Marseille (APHM), Hôpital de la Conception, Marseille, France, 4Erasmus University Medical Centre, Rotterdam, The Netherlands, 5Medizinische Klinik und Poliklinik IV, Campus Innestadt, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany, 6Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 72nd Department of Medicine, Semmelweis University, Budapest, Hungary, 8Medical University of Sofia, Sofia, Bulgary, 9Athens Polyclinic General Hospital & Evangelismos Hospital, Athens, Greece, 10Univ Paris-Sud, Université Paris-Saclay UMR-S1185, Le Kremlin Bicêtre, Paris, France, 11Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Service de Endocrinologie et des Maladies de la Reproduction, Le Kremlin Bicêtre, Paris, France, 12Institut National de la Santé et de la Recherche Médicale U1185, Le Kremlin Bicêtre, Paris, France, 13Klinicni Center, Ljubljana, Slovenia, 14Praxis für Endokrinologie Droste, Oldenburg, Germany, 15Moscow Regional Research Clinical Institute n.a. Vladimirsky, Moscow, Russia, 16Department of Endocrinology, University Hospital Zagreb, Zagreb, Croatia, 17UCL Cliniques Universitaires St Luc, Brussels, Belgium, 18Hospitalier Universitaire, Grenoble, France, 19Lohmann & Birkner Health Care Consulting GmbH, Berlin, Germany, 20Division of Clinical Endocrinology, Department of Medicine CCM, Charité-Universitätsmedizin, Berlin, Germany, 21Department of Endocrinology, Christie Hospital, Manchester, UK, Correspondence 22Academic Unit of Diabetes, Endocrinology and Reproduction, Department of Oncology and Metabolism, The Medical should be addressed School, University of Sheffield, Sheffield, UK, and 23Institute of Medicine at Sahlgrenska Academy, University of to E Valassi Gothenburg and the Department of Endocrinology, Sahlgrenska University Hospital, Gothenburg, Sweden Email †(Details of the ERCUSYN Study Group is provided in the Acknowledgements section) EValassi@santpau.cat Abstract Objective: Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate the causes and time of death in a large cohort of patients with CS and to establish factors associated with increased mortality. Methods: In this cohort study, we analyzed 1564 patients included in the European Registry on CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) overall follow-up time in ERCUSYN was 2.7 (1.2–5.5) years. Results: Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary-dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and 2 due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n = 8) and progression of the underlying tumor (n = 10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of deaths in these 27 patients were infections (n = 10; 37%). In a regression analysis, age, ectopic CS and active disease were independently associated with overall death before and within 90 days from the start of treatment. Conclusion: Mortality rate was highest in patients with ectopic CS. Infectious diseases were European Journal of the commonest cause of death soon after diagnosis, emphasizing the need for careful clinical Endocrinology vigilance at that time, especially in patients presenting with concomitant diabetes mellitus. (2019) 181, 461–472 https://eje.bioscientifica.com © 2019 European Society of Endocrinology Published by Bioscientifica Ltd. https://doi.org/10.1530/EJE-19-0464 Printed in Great Britain Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access -19-0464 European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 462 syndrome Introduction other causes (CS due to other causes), most of whom with undetermined source of cortisol excess (44%). Diagnosis Patients with Cushing’s syndrome (CS) have increased of adrenal carcinoma was an exclusion criterion. The mortality (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). This median (IQR) overall follow-up time in ERCUSYN was 2.7 applies both to patients with CS of pituitary (pituitary- (1.2–5.5) years. dependent CS) and adrenal origin (adrenal-dependent CS) A detailed description of the database layout has (1, 2), as well as patients with ectopic CS (ectopic CS) who been provided previously (17). This study interrogated have the worst prognosis (1, 2, 15). data entered in the ‘Death’, ‘Diagnosis’, ‘Therapy’ and Although standardized mortality rate (SMR) is lower ‘Follow-up visit’ sections of the register, in order to obtain in patients who have been treated for CS as compared information on mortality and its potential determinants with untreated patients, an increased risk is still observed, at baseline, before and within 90 days of treatment and at especially in patients who are not in biochemical long-term follow-up. remission after treatment (1, 2, 5, 6, 7, 8, 10, 14). The remission status was based on information Vascular disease is the main cause of death in CS included in the ‘Follow-up visit’ section of the database. patients (2, 4, 8, 12, 14). Indeed, the risk of cardiovascular This section contains several biochemical testing, and cerebrovascular events is greater in patients with including morning serum cortisol, 24-h urinary free active CS as compared with the general population and cortisol and overnight 1-mg dexamethasone suppression persists during long-term follow-up, even after remission test (DST). Centers are asked to provide information on has been achieved (7, 14). both the value of hormone measurement and its diagnostic Determinants of mortality have been sparsely studied interpretation, that is, ‘low’, ‘normal’, ‘high’, according to in patients with CS. Older age at diagnosis (2, 3, 8, 12, 13), whether the value is below, within or above the normal preoperative ACTH concentrations (11), duration of active range of the assay used in each center. Participants are also hypercortisolism (11), number of treatments received (9), asked to indicate if a given patient is in ‘remission’ or still coexistence of diabetes mellitus (8, 9) and hypertension (8) has active hypercortisolism. have been associated with increased long-term mortality. Also, male gender, depression at diagnosis, bilateral adrenalectomy and glucocorticoid replacement predicted long-term mortality in pituitary-dependent CS patients Statistical methods in remission (11). Notwithstanding, rate and predictors Statistical analyses were performed with IBM® SPSS® of perioperative mortality have not been extensively Statistics, version 25. Categorical variables are presented studied thus far. as number (n) and percentage (%). Normally distributed The aim of this study was to evaluate the cause of continuous variables are presented as mean ± s.d. and death in the large cohort of CS patients included in the non-normally distributed as median (25–75 percentiles European Registry on Cushing’s Syndrome (ERCUSYN) or range). For comparison between two groups we used and to establish the factors associated with mortality, unpaired t-test or Mann–Whitney U test as appropriate. both perioperatively and during long-term follow-up. For proportions, Pearson chi-square or Fishers exact test was used. The influence of gender, age at diagnosis, remission Subjects and methods status and duration of active hypercortisolism on mortality (total mortality as well as mortality before and At the time of the analysis, the ERCUSYN database included within 90 days from treatment) in patients with pituitary 1564 CS patients entered between January 1, 2000 and and adrenal-dependent CS was analyzed by Cox regression January 31, 2017, from 57 centers in 26 European countries with backward elimination (model 1). Since duration of (16). For this study, we analyzed data from 1045 (67%) symptoms before diagnosis was not normally distributed, patients with pituitary-dependent CS, 385 (25%) with this variable was log transformed before it was used in the adrenal-dependent CS, and 89 (5%) with ectopic CS. Of regression analyses. In model 2, the influence of diabetes thirty-seven (42%) ectopic CS patients who had histology mellitus and muscle weakness at diagnosis on mortality report available, 27% had bronchial carcinoid, 14% small- was analyzed after adjustment for age at diagnosis and cell lung carcinoma, and 5% pancreatic neuroendocrine remission status. The results from the regression analysis tumor. We also analyzed data from 45 (3%) patients with are presented as hazard ratios (HR) with 95% confidence https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 463 syndrome intervals (CIs). Kaplan–Meier plot was used to illustrate baumannii, and one by Pseudomonas aeruginosa. Two survival in patients with pituitary-dependent CS, adrenal- patients died of urinary tract infections, one of which dependent CS and ectopic CS. The mean cumulative caused by Escherichia coli, Enterococcus faecalis and Proteus survival rate at 1 and 5 years was based on Kaplan–Meier mirabilis. Two patients died of sepsis, one of which caused estimates with 95% CI. by Escherichia coli and an unspecified gram negative Patients were classified as being ‘in remission’ when bacterium and the other caused by unspecified gram their cortisol values were either ‘low/undetectable’ or negative bacterium. One patient died due to meningitis ‘within the normal range’, according to the criteria used by an unspecified agent, and another died due to type A in each center. Because information on early postoperative influenza. remission status was not available for all patients, the Twenty of 23 (87%) patients with pituitary-dependent remission status at last follow-up visit was used in the CS had a benign ACTH producing pituitary adenoma and regression analysis, although this may determine a three (13%) had an aggressive ACTH-producing pituitary potential immortality bias. tumor, defined as radiologically invasive, rapidly growing A P value of <0.05 was considered statistically and therapy resistant tumour (18). The median time from significant. diagnosis to death in patients with pituitary-dependent CS was 78 weeks (IQR 11–216; range 1–620). Fourteen of 22 (64%; information missing in one) patients with Results pituitary-dependent CS were in remission at the time of death. The commonest cause of death were infections Forty-nine ERCUSYN patients (3%) had died at the time (n = 6 (43%)), cerebrovascular diseases (n = 3 (21%)) and of the analysis; 23 (47%) with pituitary-dependent CS, 6 progression of an aggressive ACTH-producing pituitary (12%) with adrenal-dependent CS, 18 (37%) with ectopic tumor (n = 3 (21%)) (Table 2). CS and two (4%) with CS due to other causes, both Four of six (66%) patients with adrenal-dependent with unknown source of the hypercortisolism (Table 1). CS who died had a benign cortisol-producing adrenal Patients who died were more often males, were older, had adenoma, one (17%) had macronodular hyperplasia and more often ectopic CS, and had shorter duration of active one (17%) had primary pigmented nodular adrenocortical CS as compared to the remaining cohort (Tables 2 and 3). disease. The median time from diagnosis to death in Overall, death occurred in 2.2% of pituitary- patients with adrenal-dependent CS was 11 weeks (range dependent CS, 1.5% of adrenal-dependent CS, 20% of 3–18). Three (50%) patients with adrenal-dependent CS ectopic CS, and 4.5% of patients with other/unknown died due to infections, two (33%) from cardiovascular causes of hypercortisolism. The estimated 1-year disease, and one (17%) due to pulmonary embolism. cumulative survival rate was 0.42 (95% CI 0.27–0.56) The median time from diagnosis to death in patients for patients with ectopic CS, 0.96 (95% CI 0.93–0.99) for with ectopic CS was 4 (IQR 3–18; range 2–170) weeks and patients with pituitary-dependent CS, and 0.92 (95% CI most of the patients (n = 12; 67%) died due to progression 0.87–0.99) for patients with adrenal-dependent CS. The of the underlying tumor. estimated 5-year cumulative survival rate was 2.9 (95% CI 2.4–3.5) for patients with ectopic CS, 4.8 (95% CI 4.7–4.9) Comorbidities at diagnosis for patients with pituitary-dependent CS, and 4.8 (95% CI 4.7–4.9) for patients with adrenal-dependent CS (Fig. 1). Patients who died had a higher prevalence of diabetes Of 42 patients whose cause of death was described, 15 mellitus (61 vs 35%; P < 0.001) and were more likely (36%) died due to progression of the underlying disease, to complain of muscle weakness (88 vs 68%; P = 0.07), 13 (31%) due to infections, 7 (17%) due to cardiovascular at diagnosis, as compared with those who survived or cerebrovascular disease and two due to pulmonary (Tables 2 and 3). The prevalence of hypertension, skin embolism (Table 2). Of 12 patients with known disease manifestations and depression at diagnosis did not differ status, and who died from infection, 8 (67%) were in between those who died as compared with those who remission and were receiving glucocorticoid replacement, survived. In a regression analysis (model 1), including and 4 (33%) had active disease. patients with pituitary and adrenal-dependent CS, age Etiology of infections was reported in 11 patients at diagnosis and active disease were independently (85%). Five patients died due to pneumonia, two of which associated with increased mortality (Table 4). Gender and caused by Staphylococcus aureus, one by Acinetobacter duration of active CS were not associated with mortality. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 464 syndrome Table 1 Baseline characteristics of the ERCUSYN cohort (n = 1564). Deceased patients (n = 49) Remaining cohort (n = 1515) P Gender 0.001  Female, n (%) 29 (59) 1209 (80)  Male, n (%) 20 (41) 300 (20) Age at diagnosis, mean ± s.d. (years) 57 ± 14 44 ± 14 <0.001 Years with active CS, median (IQR) 1 (0.5–2) 2 (1–4) 0.001 BMI, mean ± s.d. (kg/m2) 28.3 ± 5.9 30.1 ± 6.6 0.02 Etiology <0.001  Pituitary-dependent CS 23 (47) 1022 (67)  Adrenal-dependent CS 6 (12) 380 (25)  Ectopic CS 18 (37) 71 (5)  CS due to other causes 2 (4) 42 (3) Symptoms and signs at diagnosis*  Hypertension, yes/no (%) 36/11 (77) 1060/338 (76) 0.9  Diabetes mellitus, yes/no (%) 27/17 (61) 466/885 (35) <0.001  Muscle weakness, yes/no (%) 37/5 (88) 847/388 (68) 0.007  Skin manifestation, yes/no (%) 36/10 (78) 1004/362 (74) 0.3  Depression, yes/no (%) 16/18 (47) 411/748 (36) 0.2 Remission at the last clinical visit** <0.001  Yes 26 (57) 888 (76)  No 20 (43) 133 (11)  Partial – 149 (13) Glucocorticoid replacement at the last clinical visit*** 0.3  Yes 25 778  No 1 104 *Information on hypertension, diabetes mellitus, muscle weakness, skin manifestation and depression at diagnosis was missing in 120 (7.7%), 170 (10.9%), 288 (18.4%), 153 (9.8%) and 372 (23.8%) of the patients, respectively. **Information on remission status at the last clinical visit was available for 46 patients who had died and 1170 patients alive. ***Patients in remission. Statistically significant (P < 0.05) values are expressed in bold. CS, Cushing’s syndrome. After adjustment for age at diagnosis and remission duration of active CS, active disease, diabetes mellitus, status, neither diabetes mellitus nor muscle weakness muscle weakness, and gender were not (Table 4). was significantly associated with increased mortality (model 2; Table 4). Discussion 90-day mortality We have demonstrated that mortality rate is around 2% Of 49 deceased patients, 22 (45%) died within 90 days from after a median follow-up of 3 years in 1430 patients with the start of treatment and 5 (10%) before any treatment either pituitary-dependent CS or adrenal-dependent CS was given. Of these, 7 (33%) had pituitary-dependent who have been included in the ERCUSYN, during the CS, 6 (24%) had adrenal-dependent CS, 12 (57%) had period 2000–2017. Not surprisingly, a greater mortality ectopic CS, and 2 (10%) had CS due to other causes. The rate was found in ectopic CS, mainly due to progression commonest causes of deaths were infections (n = 10; 37%) of the underlying tumor. and progression of the underlying tumor (7; 26%). In 43% of patients with pituitary-dependent CS or Sixty-two per cent of patients who died before or within adrenal-dependent CS, death occurred prior to treatment 90 days from the start of treatment had diabetes mellitus or within 3 months since the start of any treatment, at diagnosis, as compared to 38% in the whole ERCUSYN mainly due to infections. In fact, infections were cohort (P = 0.01). The prevalence of hypertension, also the commonest cause of death during follow-up muscle weakness, skin manifestations and depression after treatment. In previous cohorts, most of which did not differ between the groups (data not shown). In a encompassing patients from a single center, mortality rate regression analysis, including patients with pituitary and ranged from 3.7 to 27.5% in pituitary-dependent CS and adrenal-dependent CS, age was independently associated from 3 to 10.8% in adrenal-dependent CS (1, 2, 3, 4, 5, with death within 90 days from the start of treatment but 6, 7, 8, 9, 10, 11, 12, 13, 14) during a longer follow-up https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 465 syndrome https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Table 2 Individual data on 49 patients in ERCUSYN who had died at the time of the analysis; 23 (45%) with pituitary-dependent CS, 6 (14%) with adrenal-dependent CS, 18 (35%) with ectopic CS and two (6%) with CS due to other causes. Time Time from from first Duration diagnosis treatment of Age at to death to death symptoms Skin Diabetes Muscle Glucocorticoid Gender diagnosis Etiology Treatment Cause of death (days) (days) (yrs) BMI Hypertension manifestations Depression mellitus weakness Remisssion replacement F 21 PD-CS MT Cardiovascular 23 20 0 1 0 No No F 61 PD-CS MT Infection (pneumonia 34 34 3 26.0 1 0 1 1 1 Yes Yes due to Acinetobacter baumannii) F 65 PD-CS MT Unknown 65 38 0 1 0 0 0 0 No No F 45 PD-CS TSS Cerebrovascular 551 43 2 27.4 1 1 0 1 1 Yes Yes F 65 PD-CS MT Embolism 54 43 2 41.7 1 1 1 1 1 Yes Yes F 71 PD-CS TSS Infection (pneumonia due 130 89 1 26.5 1 1 0 1 1 Yes Yes to unspecified agent) F 71 PD-CS MT Infection (unknown agent) 220 219 2 24.6 No No F 48 PD-CS TSS Cerebrovascular 283 239 1 24.4 1 1 1 1 Unknown No M 57 PD-CS TSS Infection (meningitis due 396 247 2 22.5 1 1 1 0 1 Yes Yes to unspecified agent) F 79 PD-CS RT+MT Unknown 370 322 3 0 1 1 1 Yes Yes F 66 PD-CS RT+MT Unknown 827 515 1 37,5 1 1 0 1 1 No No F 72 PD-CS MT Infection (pneumonia 588 574 1 26.7 1 1 1 Yes Yes due to Staphylococcus aureus followed by sepsis due to Staphylococcus epidermidis) M 66 PD-CS TSS+RT Prostate cancer 808 679 1 26.1 1 1 1 0 1 No No F 56 PD-CS RT+MT Cerebrovascular 1179 1161 2 41.3 1 1 0 1 1 Yes Yes F 70 PD-CS TSS Sudden death 1377 1228 2 0 0 1 Yes Yes F 38 PD-CS TSS Neurodegenerative disease 1562 1462 3 21.9 0 0 1 0 Yes Yes F 72 PD-CS TSS Unknown 1832 1782 27.6 1 1 1 Yes Yes M 71 PD-CS TSS+RT Unknown 2175 2174 0 29.1 1 1 0 Yes Yes F 59 PD-CS TSS Colon cancer 4336 4129 0,5 1 1 1 1 Yes Yes F 57 PD-CS No Tx Infection (type A 7 1 1 1 1 1 No Tx No influenza) M 57 PD-CS, TSS Tumor progression 728 672 6 23.5 0 0 1 1 1 No No Aggressive M 43 PD-CS, TSS+RT Tumor progression 1780 1668 3 28.9 1 1 0 0 1 No No Aggressive M 64 PD-CS, TSS+RT Tumor progression 2613 2608 2 27.8 Yes Yes Aggressive F 29 AD-CS UnilADX Embolism 67 12 0,5 29.4 1 1 0 0 Yes Yes F 64 AD-CS UnilADX Cardiovascular 124 26 1 1 0 1 1 Yes Yes F 55 AD-CS UnilADX Infection (UTI due to 78 56 0,5 27.9 1 1 1 0 1 Yes Yes Escherichia coli, Enterococcus faecalis and Proteus mirabilis) M 65 AD-CS MT Cardiovascular 77 77 0,5 30.7 0 0 0 0 1 Unknown Unknown F 70 AD-CS (Macro) BilADX Infection (sepsis due to 123 38 10 31.2 1 1 1 0 0 Yes Yes unspecified gram negative bacterium) F 71 AD-CS No Tx Infection (UTI due to 20 5 1 1 No Tx No (PPNAD) unspecified agent) (Continued ) Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 466 syndrome https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Table 2 Continued. Time Time from from first Duration diagnosis treatment of Age at to death to death symptoms Skin Diabetes Muscle Glucocorticoid Gender diagnosis Etiology Treatment Cause of death (days) (days) (yrs) BMI Hypertension manifestations Depression mellitus weakness Remisssion replacement F 61 E-CS No Tx Infection (pneumonia due 13 0,1 25.2 0 1 0 1 1 No No to Pseudomonas aeruginosa) M 60 E-CS MT Tumor progression 28 7 0,3 25.5 1 1 1 1 1 No No M 55 E-CS MT Tumor progression 44 12 21.4 0 1 0 0 1 No Yes M 47 E-CS MT Tumor progression 17 17 12 0 0 1 No No M 92 E-CS MT Tumor progression 27 20 0,2 23.0 1 1 1 1 1 No No F 33 E-CS Primary Infection (Sepsis due to 34 21 0,5 21.4 1 1 0 1 1 Yes Yes tumor Escherichia coli and unspecified gram negative bacterium) M 62 E-CS BilADX Unknown 310 22 2 23.6 1 1 1 1 1 Yes Yes M 51 E-CS MT Tumor progression 70 25 4 35.9 1 0 1 1 1 No No M 46 E-CS MT Tumor progression 29 29 0,3 44.8 1 1 0 1 0 No No F 47 E-CS BilADX Infection (aspiration 433 34 27.4 1 1 1 1 1 Yes Yes pneumonia due to Staphylococcus aureus followed by sepsis due to Enterobacter cloacae) M 57 E-CS BilADX Tumor progression 59 51 1 24.6 1 1 0 0 1 Yes Yes M 46 E-CS MT Tumor progression 120 119 0 25.7 1 1 0 1 1 Yes Yes M 50 E-CS MT Tumor progression 144 129 26.6 1 0 0 1 1 No No F 67 E-CS BilADX Tumor progression 205 191 1 24.8 1 1 1 1 Yes Yes F 51 E-CS BilADX Tumor progression 773 731 0 23.6 0 1 0 0 1 Yes Yes M 41 E-CS BilADX Tumor progression 1191 1070 1 24.3 0 1 0 0 1 Yes Yes M 48 E-CS Primary Renal failure 1104 1083 1,5 33.8 1 1 1 1 1 Yes No tumor M 53 E-CS No Tx Cardiovascular 20 0,5 32.1 1 1 1 1 1 No Tx No F 63 Unknown UnilADX Infection 16 5 0 37.9 1 0 1 1 Unknown No F 21 Unknown No Tx Unknown 132 1 1 0 0 0 0 No Tx Yes Known causes of infection are shown in bold. AD-CS, adrenal-dependent CS; BilADX, bilateral adrenalectomy; BMI, body mass index (kg/m2); CS, Cushing’s syndrome; E-CS, ectopic CS; MT, medical therapy; PD-CS, pituitary-dependent CS; RT, radiotherapy; TSS, trans-sphenoidal surgery; Tx, therapy; UnilADX, unilateral adrenalectomy; UTI, urinary tract infections. Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 467 syndrome Table 3 Baseline characteristics of patients who died, classified by etiology (patients with OTH-CS are excluded from the table). PIT-CS (n = 23) ADR-CD (n = 6) ECT-CS (n = 18) P* Gender 0.001  Female, n (%) 17 (74) 5 (83) 5 (28)  Male, n (%) 6 (26) 1 (17) 13 (72) Age at diagnosis, mean ± s.d. (years) 60 ± 13 59 ± 16 54 ± 13 0.15 Years with active CS, median (IQR) 2 (1–2.8) 0.5 (0.4–6.3) 0.5 (0.2–1.5) 0.08 BMI, mean ± s.d. (kg/m2) 28.4 ± 6.0 29.8 ± 1.5 27.3 ± 6.1 0.45 Symptoms and signs at diagnosis  Hypertension, yes/no (%) 16/5 (76) 5/1 (83) 13/5 (72) 0.67  Diabetes mellitus, yes/no (%) 12/8 (60) 1/4 (20) 13/4 (77) 0.11  Muscle weakness, yes/no (%) 16/1 (94) 3/2 (60) 17/1 (94) 0.40  Skin manifestation, yes/no (%) 16/4 (80) 5/1 (83) 15/3 (83) 0.83  Depression, yes/no (%) 7/6 (54) 2/2 (50) 7/9 (44) 0.60 Remission at the last clinical visit 0.26  Yes 14 (64) 4 (80) 9 (50)  No 8 (36) 1 (20) 9 (50) P*, PIT-CS and ADR-CS vs ectopic CS. Statisticaly significant (P < 0.05) values are expressed in bold. ADR-CS, adrenal-dependent CS; ECT-CS, CS from an ectopic source; OTH-CS, CS from other etiologies; PIT-CS, pituitary-dependent CS. period (ranging from 7 to 15 years) as compared with that to patients with confirmed CS, and start prophylactic described in the present study. treatment for atypical infections in patients with severe Perioperative mortality has previously been reported CS (22). According to the World Health Organization in few studies (2, 5). Hammer et  al. found that 4 of 29 (WHO), the burden of health care-associated infections is deaths occurred within 2.5 months of transsphenoidal relevant even in high-income countries, where up to 12% surgery (TSS) due to myocardial infarction and/or cardiac of patients acquire at least one infectious disease during failure (5). Bolland et  al. reported one death in the their hospital stay (23). This number may be even higher immediate postoperative period due to ischemic heart in patients with CS who are hospitalized and/or undergo disease, and two before starting any treatment, due to invasive diagnostic procedures. While future studies infection and pulmonary embolism, respectively (2). should assess the prevalence of infections during both the While bacterial infections were the most prevalent pre- and postoperative setting in CS patients, and identify cause of death in CS in historical reports (19), deaths due the most effective treatment to prevent and control to vascular diseases are more common in recent studies (2, 8, 9, 12). Although mortality rate for cardiovascular disease is expected to increase in our cohort as follow-up duration is extended, our data show that infections are still a life- threatening comorbidity in these vulnerable patients and suggest that effective preventive measures should be initiated at the time of diagnosis. It is well known that hypercortisolism is related to immunosuppression and cellular immunodeficiency (20), which increases the hosts’ susceptibility to common viruses, bacteria, fungal infections and opportunistic pathogens (21). Data obtained from the Danish National Registry of Patients indicated that risk for infections in CS patients is higher during the year preceding surgery as compared with the general population, and persists elevated for at least 3 months postoperatively (7). As a matter of fact, the Endocrine Figure 1 Society Clinical Practice Guideline on Treatment in CS Kaplan–Meier plot showing 5-year cumulative survival in recommended, as an ‘ungraded best practice statement’, patients with pituitary-dependent CS, adrenal-dependent CS which clinicians offer age-appropriate immunization and ectopic CS. + denotes censored patients. https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 468 syndrome Table 4 Cox regression models analyzing the influence of age at diagnosis, gender, remission status and duration of active hypercortisolism on mortality (total and mortality within 90 days from diagnosis) in patients with pituitary-dependent CS and adrenal-dependent CS (model 1) and the influence of diabetes mellitus and muscle weakness at diagnosis on mortality, after adjustment for age at diagnosis and remission status (model 2). Duration of symptoms before diagnosis was log transformed before it was used in the regression analyses. Hazard ratio 95% CI P Total mortality (model 1)  Age at diagnosis (years) 1.12 1.08–1.17 <0.001  Male gender 1.2 0.5–3.5 0.6  Active disease (not in remission) 2.8 1.1–7.1 0.03  Duration of active CS (log) 0.7 0.6–1.4 0.7 Total mortality (model 2)  Age at diagnosis (years) 1.10 1.06–1.15 <0.001  Active disease (not in remission) 3.4 1.3–8.7 0.01  Diabetes mellitus 2.0 0.8–5.3 0.14  Muscle weakness 1.7 0.5–5.9 0.4 Mortality within 90 days (model 1)  Age at diagnosis (years) 1.12 1.05–1.19 0.001  Male gender – – 1.0  Active disease (not in remission) 0.9 0.1–8.2 1.0  Duration of active CS (log) 1.0 0.5–2.1 1.0 Mortality within 90 days (model 2)  Age at diagnosis (years) 1.10 1.04–1.17 0.002  Active disease (Not in remission) 1.7 0.3–8.6 0.5  Diabetes mellitus 1.6 0.4–6.4 0.5  Muscle weakness 0.7 0.2–2.9 0.6 Statisticaly significant (P < 0.05) values are expressed in bold. infectious disease in them, clinicians should be aware of or persistent hypercortisolism. However, glucocorticoid this frequent and potentially lethal complication, and replacement was not more frequent in the patients who start, at the time of diagnosis, a standardized protocol of died as compared with those who survived. prevention, including Pneumocystis carinii prophylaxis, Older age at diagnosis, active disease and ectopic CS and age-appropriate immunization, especially against independently predicted both perioperative and long- influenza, Herpes zoster, and pneumococcus (22, 24). term mortality, in line with previous studies (2, 8, 9, Because active disease is an important determinant 11, 12, 13). Although the presence of diabetes mellitus of mortality, rapid control of cortisol excess should or muscle weakness at diagnosis was not a significant also be achieved as soon as possible after diagnosis (8). determinant of mortality after adjusting for age, ectopic Moreover, Sarlis et al. demonstrated that risk of bacterial origin and active disease, these comorbidities were more or opportunistic infections progressively increased with frequently reported in the patients who died. Previous more severe hypercortisolism (24). However, we could studies demonstrated that coexistence of diabetes mellitus not evaluate the severity of the hypercortisolism in was associated with mortality in CS patients (2, 3, 8, 9). the ERCUSYN patients since information on the upper It is well known that a close link exists between diabetes limit of normal range of the assays used at each center and both cardiovascular disease and infections (24, 25). is lacking. Nevertheless, our data showed that 58% of patients who It has been suggested that inadequate glucocorticoid died from infections had diabetes, especially during the substitution may be associated with increased risk of death perioperative period, consistent with the deleterious effect for infections (14), especially in remitted CS patients. We of hyperglycemia on both cell- and antibody-mediated cannot exclude that Addisonian crisis, due to insufficient response (25). In a recent retrospective cohort study using administration of stress-dose steroids, may also explain a large primary care database in England, the infection some of the deaths reported, especially in those patients rate was almost twice as high among patients with type 2 who died from unknown reasons. diabetes compared to matched, non-diabetic population Interestingly, all patients in our cohort who died (25). Indeed, diabetes may be associated with 12% of due to infection had either glucocorticoid replacement lethal nosocomial infections, and a linear association https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 469 syndrome between the degree of postoperative hyperglycaemia and had been diagnosed almost 20 years previously. While risk of surgical site infections, mainly after discharge, this limitation is due to missing data on subsequent visits, has also been described (25, 26). Thus, a strict control of inclusion and follow-up of patients with CS from countries hyperglycemia is highly recommendable in CS patients in all around Europe in the ERCUSYN is ongoing and further order to reduce potentially lethal infections after surgery. analysis on mortality and its relative determinants over a The impact of myopathy on the morbimortality in longer period of observation is pending. Underreporting patients with CS is still to be elucidated. Skeletal muscle of some deaths is also a limitation of this study, as it mass loss due to atrophy of type IIa, fast fibers, slowing is not based on an exhaustive mortality registry and muscle fiber conduction and deterioration of muscle therefore, some ERCUSYN participants may not be quality have been proposed as potential mechanisms aware of whether fatal outcome occurred in some of leading to myopathy in patients exposed to either their patients. Another limitation is the lack of both exogenous or endogenous glucocorticoid excess (27, quantitative data and standardized methods to evaluate 28). Data from the ERCUSYN have previously showed both preoperative magnitude of hypercortisolism and that about 70% of patients with active CS complained of postsurgical biochemical status. This is due to both intra- muscle weakness (17). Sipple et al. reported that resolution and inter-center differences in the assays used and lack of weakness may occur later than many other symptoms of information on the normal range for each of them. associated with hypercortisolism, given that it may persist Finally, information on early postoperative remission up to 18 months after uni- or bilateral adrenalectomy for status was not available for all patients. Therefore, the CS (29). Berr et al. described greater impairment of hand- remission status at the last follow-up visit was used in grip strength in active CS as compared with controls, the regression analysis, making it possible that immortal which persisted or even worsened after remission time bias may influence the results without affecting their (30). Coexistence of pituitary deficiencies, occurrence clinical relevance. of glucocorticoid withdrawal syndrome, need for In conclusion, mortality was highest in patients with postoperative glucocorticoid replacement, severity and ectopic CS. Infectious diseases were the commonest cause duration of hypercortisolism all may contribute to the of death soon after diagnosis and initiation of treatment, development and maintenance of muscle weakness (31). emphasizing the need for careful clinical vigilance at that Low hand muscle strength has been described to time especially in patients with diabetes mellitus who predict all-cause death and cardiovascular death in a seem to be especially vulnerable. large, longitudinal population study enrolling subjects aged 35–70 years (32). Moreover, sarcopenia, defined as low muscle mass and strength, and impaired physical Declaration of interest A T received financial support, research grants, and consultant fees performance, affects mortality in several human models, from Novartis and HRA pharma. T B has received institutional research including elderly people, severely ill patients, and patients support from Pfizer and consultancy/lectureship fees from Novartis, Ipsen, who underwent general surgery or liver transplantation Strongbridge and Pfizer. M R received financial support, research grants, consultant or speaker fees from Ipsen, Novartis, Pfizer. M T has received (33, 34, 35, 36). Future studies using objective measures consultant and speaker fees from Novartis, Ipsen and Pfizer. S M W received of muscle function should clarify if muscle weakness at financial support, research grants, consultant or speaker fees from Ipsen, diagnosis is a clinical marker of elevated mortality risk Novartis, Pfizer, HRA and Strongbridge. D M received consultant and speaker fees from HRA Pharma, Ipsen, Novartis, Novo-Nordisk and Pfizer. in CS patients. Furthermore, whether muscle weakness C J S has received lecture fees, consultancy remuneration or research determines mortality in CS patients or simply reflects the support from HRA Pharma, Novartis and Strongbridge. The other authors presence of other factors which have been associated with declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study. increased mortality such as the severity of hypercortisolism, glucocorticoid replacement and hypopituitarism, needs also to be elucidated in futures studies (31). Funding The main strength of this study is reporting data ERCUSYN was set up with funding from the EU (PHP 800200) and been on perioperative mortality, a subject previously sparsely supported by unrestricted grants from Novartis, Ipsen, HRA and the European Society of Endocrinology. studied, and the real-life setting by using the ERCUSYN database. The study has, however, also limitations such as paucity of information on pituitary hormone function Acknowledgement and replacement, and the relatively short median ERCUSYN Study Group: A Ambrogio, Istituto Auxologico Italiano IRCCS, follow-up time despite some centers entered patients who University of Milan, Italy; G Aranda, Department of Endocrinology, https://eje.bioscientifica.com Downloaded from Bioscientifica.com at 12/13/2022 11:42:14AM via free access European Journal of Endocrinology Clinical Study E Valassi and others Causes of death in Cushing’s 181:5 470 syndrome Hospital Clinic Barcelona, IDIBAPS, UB, Barcelona, Spain; M Arosio, Unit AD Reghina, Elias Hospital, Bucharest, Romania; P Riesgo, Neurosurgery of Endocrine Diseases & Diabetology, Department of Clinical Sciences Department, Hospital Universitario de la Ribera, Alzira, Spain; M Roberts, and Community Health, University of Milan, Milan, Italy; M Balomenaki, Christie Hospital, NHS Trust, Manchester, UK; S Roerink, Radboud Athens Polyclinic General Hospital, Evangelismos Hospital, Athens, University Medical Center, Nijmegen The Netherlands; O Roig, IIB-Sant Pau Greece; P Beck-Peccoz, Endocrinology and Diabetology Unit, Fondazione and Department of Endocrinology/Medicine, Hospital Sant Pau, UAB, and IRCCS Ca' Granda – Ospedale Maggiore Policlinico, University of Milan, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER- Milan, Italy; C Berr-Kirmair, Medizinische Klinik und Poliklinik IV, Campus ER, Unidad 747), ISCIII; C Rowan, Christie Hospital, NHS Trust, Manchester, Innestadt, Klinikum der Universität München, München, Germany; UK; P Rudenko, Estonian Endocrine Society, Tallinn, Estonia; MA Sahnoun, M. Bolanowski, Wroclaw Medical University, Wroclaw, Poland; J Bollerslev, Aix-Marseille Université, CNRS, CRN2M UMR 7286, 13344 cedex 15, Section of Specialized Endocrinology, Oslo University Hospital, and Faculty Marseille, and APHM, Hôpital Conception, Marseille, France; J Salvador, of Medicine, University in Oslo, Oslo, Norway; Brue Thierry, Association University of Navarra, Pamplona, Spain; HA Sigurjonsdottir, Landspitali pour le Devéloppement des Recherches Biologiques et Médicales; University Hospital, Reykjavik, Iceland and Faculty of Medicine, University of D Carvalho, Hospital de San Joao, Porto, Portugal; F Cavagnini, Istituto Iceland, Reykjavik, Iceland; T Skoric Polovina, Department of Endocrinology, Auxologico Italiano IRCCS, Milan, Italy; E Christ, University Hospital of Bern, University Hospital Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia; R Inelspital, Division of Endocrinology, Diabetology and Clinical Nutrition, Smith, Oxford Radcliffe Hospitals NHS Trust, Oxford, UK; B Stachowska, Bern, Switzerland; F Demtröder Zentrum fur Endokrinologie, Diabetologie, Department of Endocrinology, Diabetology and Isotope Therapy Wroclaw Rheumatologie Dr Demtröder & Kollegen im MVZ Dr. Eberhard & Partner Medical University, Wroclaw, Poland; G Stalla, Max-Planck-Gessellschaft und Klinikum Dortmund, Germany; J Denes, Division of Endocrinology, zur Forderung der Wissenschaften e.V., Munich, Germany; J Tőke, 2nd 2nd Department of Medicine, State Health Center, Budapest, Hungary; Departement of Medicine, Semmelweis University, Budapest, Hungary; C Dimopoulou, Max-Planck-Gessellschaft zur Forderung der Wissenschaften E Hubina, Division of Endocrinology, 2nd Department of Medicine, State e.V., Munich, Germany; A Dreval, Moscow Regional Research Clinical Health Center, Budapest, Hungary; S Vinay, Christie Hospital, NHS Trust, Institute n.a. 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