Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool

Minnetti, Marianna; Hasenmajer, Valeria; Sbardella, Emilia; Angelini, Francesco; Simeoli, Chiara; Di Paola, Nicola; Cozzolino, Alessia; Pivonello, Claudia; De Alcubierre, Dario; Chiloiro, Sabrina; Baldelli, Roberto; De Marinis, Laura; Pivonello, Rosario; Pofi, Riccardo; Isidori, Andrea M

doi:10.1530/EJE-22-0454

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Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool

research-article

Author(s): Marianna Minnetti ¹ , Valeria Hasenmajer ¹ , Emilia Sbardella ¹ , Francesco Angelini ¹ , Chiara Simeoli ² , Nicola Di Paola ² , Alessia Cozzolino ¹ , Claudia Pivonello ² , Dario De Alcubierre ¹ , Sabrina Chiloiro ³ ^, ⁴ , Roberto Baldelli ⁵ , Laura De Marinis ³ ^, ⁴ , Rosario Pivonello ² , Riccardo Pofi ¹ ^, ⁶ ^, , Andrea M Isidori ¹ ^,

Publication date (Electronic): 14 September 2022

Journal: European Journal of Endocrinology

Publisher: Bioscientifica Ltd

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Abstract

Objective

Registry data show that Cushing’s syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool.

Methods

We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test–retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections.

Results

In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3–9.9)), mycoses (4.4 (2.1–8.8)), and flu (2.9 (1.4–5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7–8.0)) and flu (3.2 (1.5–6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6–3.9)), mycoses (2.3 (1.4–3.8)), and gastrointestinal infections (2.2 (1.5–3.3)), independently of any glucocorticoid replacement dose.

Conclusions

The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

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Most cited references 63

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This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency.

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: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.

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Lynnette K Nieman, Beverly M K Biller, James Findling … (2008)

The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome. The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments. After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma. We recommend initial use of one test with high diagnostic accuracy (urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-h dexamethasone suppression test). We recommend that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test. Patients with concordant abnormal results should undergo testing for the cause of Cushing's syndrome. Patients with concordant normal results should not undergo further evaluation. We recommend additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.

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Author and article information

Journal

Journal ID (nlm-ta): Eur J Endocrinol

Journal ID (iso-abbrev): Eur J Endocrinol

Journal ID (hwp): EJE

Title: European Journal of Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0804-4643

ISSN (Electronic): 1479-683X

Publication date (Electronic): 14 September 2022

Publication date Collection: 01 November 2022

Volume: 187

Issue: 5

Pages: 719-731

Affiliations

[1 ]Department of Experimental Medicine , Sapienza University of Rome – Policlinico Umberto I Hospital, Rome, Italy

[2 ]Dipartimento di Medicina Clinica e Chirurgia , Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy

[3 ]Pituitary Unit , Department of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Rome, Italy

[4 ]Dipartimento di Medicina e Chirurgia Traslazionale , Università Cattolica del Sacro Cuore, Rome, Italy

[5 ]Endocrinology Unit , Department of Oncology and Medical Specialties, A.O. San Camillo-Forlanini, Rome, Italy

[6 ]Oxford Centre for Diabetes , Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK