ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of adrenal insufficiency

Abstract We provide guidance on prevention of adrenal crisis during the global COVID-19 crisis, a time with frequently restricted access to the usual level of healthcare. Patients with adrenal insufficiency are at an increased risk of infection, which may be complicated by developing an adrenal crisis; however, there is currently no evidence that adrenal insufficiency patients are more likely to develop a severe course of disease. We highlight the need for education (sick day rules, stringent social distancing rules), equipment (sufficient glucocorticoid supplies, steroid emergency self-injection kit) and empowerment (steroid emergency card, COVID-19 guidelines) to prevent adrenal crises. In patients with adrenal insufficiency developing an acute COVID-19 infection, which frequently presents with continuous high fever, we suggest oral stress dose cover with 20 mg hydrocortisone every 6 h. We also comment on suggested dosing for patients who usually take modified release hydrocortisone or prednisolone. In patients with adrenal insufficiency showing clinical deterioration during an acute COVID-19 infection, we advise immediate (self-)injection of 100 mg hydrocortisone intramuscularly, followed by continuous i.v. infusion of 200 mg hydrocortisone per 24 h, or until this can be established, and administration of 50 mg hydrocortisone every 6 h. We also advise on doses for infants and children.


Introductory remarks
This guidance has been drawn up to inform clinicians and healthcare staff in their quest to provide guidance on the optimal management of patients with adrenal insufficiency under the circumstances of an acute global healthcare capacity crisis due to COVID-19, the viral illness caused by the novel corona virus SARS-CoV-2.
For the purposes of this guidance, we define primary adrenal insufficiency (PAI) as all patients with loss of function of the adrenal itself, mostly either due to autoimmune adrenalitis, that is, Addison's disease described by the eponymous Thomas Addison, or other causes including congenital adrenal hyperplasia, bilateral adrenalectomy and adrenoleukodystrophy. The overwhelming majority of PAI patients suffer from both glucocorticoid and mineralocorticoid deficiency. Our guidance similarly applies to patients with secondary adrenal insufficiency (SAI) due to hypothalamic or pituitary disease; these patients typically suffer from glucocorticoid deficiency, in the majority in combination with deficiency of other hypothalamic-pituitary axes. Similarly, the same precautionary rules apply to patients with tertiary adrenal insufficiency due to chronic exogenous glucocorticoid therapy for treatment of other conditions. Patients at risk of tertiary adrenal insufficiency are those treated with prednisoloneequivalent doses of greater than 5 mg daily for longer than 4 weeks.

Are patients with adrenal insufficiency at an increased risk of COVID-19?
Yes, patients with adrenal insufficiency are at increased risk of COVID-19; they are at an increased risk of catching this infection and they have a higher risk of complications due to the potential for an adrenal crisis to be triggered by the infection. There is currently no evidence, however, suggestive of a higher likelihood of a severe course of disease in patients with AI falling ill with COVID-19.
• Risk of adrenal crisis during acute illness: Patients with adrenal insufficiency are at risk to develop a potentially life-threatening adrenal crisis if experiencing major stress, such as an acute illness. This requires administration of increased doses of glucocorticoid replacement to prevent and, if already in progress, treat the adrenal crisis (1,2,3). Adrenal crises are regularly observed in patients with PAI and SAI (4,5,6,7) and contribute to the observed increased mortality in these patients.

• Increased risk of infections in adrenal insufficiency:
Patients with PAI including Addison's disease and congenital adrenal hyperplasia have been shown to be at an increased risk of infections (8,9,10); this has also been shown for patients with SAI due to hypothalamic-pituitary disease (11). Furthermore, respiratory infections have been shown to contribute to the increased mortality observed in patients with PAI (12,13). In addition, patients with PAI have been shown to have significantly decreased natural killer cell cytotoxicity (14), an important function of the innate immune system in fighting viral infections. Therefore, patients with PAI can be assumed to be at an increased risk of infection with COVID-19. Patients receiving supraphysiologic, immunosuppressive doses of exogenous glucocorticoids for the treatment of another condition are at even higher risk of infection.

A. Prevention mode
All patients with established adrenal insufficiency should be provided with adequate self-management support to enable them to manage their conditions adequately and safely. Self-management support can be facilitated and communicated by mailshot, video, text, email phone call or videoconferencing, as appropriate. This should follow the 3E framework for self-management support (Educate, Equip and Empower).

Educate
• Ensure that all patients (and their families/partners/ carers) are educated in the use of 'the sick day rules', that is, the need to increase their usual glucocorticoid replacement dose during intercurrent illness and the need to self-inject hydrocortisone and call for emergency medical assistance when the oral medication cannot be reliably absorbed due to vomiting or diarrhoea and/or the presence of severe and major illness or trauma. General sick day rules for patients with adrenal insufficiency are described in detail in recently published clinical guidelines (15,16,17); see also https:// endo-ern.eu/wp-content/uploads/2019/03/20190312-Stressinstructie-addisoncrisis-hydrocortison-ENG-Endo-ERN-approved.pdf. However, for the purposes of this guidance, we have revised the generic sick day rules, having in mind patients with an acute COVID-19 infection, which frequently presents with high fever over sustained periods of time (see Table 1 and section B).
• Patients with adrenal insufficiency are at increased risk of COVID-19, albeit not as high as in patients undergoing cancer treatment or taking high doses of potent immunosuppressive drugs. All patients with adrenal insufficiency should 'observe stringent social distancing'. If they are working, they should either work from home or work under conditions that allow very stringent social distancing at all times. This means that adrenal insufficiency patients should not work in situations that do now allow them to keep their safe distance, as is the case, for example, for healthcare workers, carers and supermarket cashier staff. It will be important to provide patients with letters stating this fact to ensure their employers are informed and can adjust working conditions as appropriate.

Equip
• Ensure that the patient has 'sufficient supplies of oral glucocorticoid preparations' (usually hydrocortisone, but also cortisone acetate, prednisolone or prednisone). Ensure that patients who usually take modified release hydrocortisone preparations have a sufficient supply of immediate release, regular oral hydrocortisone for emergency use, for example, by prescribing an extra 4-week supply of hydrocortisone 10 mg three times daily. In patients with PAI including congenital adrenal hyperplasia also ensure sufficient mineralocorticoid supplies (fludrocortisone). Consider issuing prescriptions of 3-month hydrocortisone supplies every 2 months and arrange for them to be dispensed by mail; this will ensure that the patient has access to sufficient extra glucocorticoid doses in case of intercurrent illness. Patients should understand that they must continue taking their glucocorticoid replacement under all • Ensure that the patient is in possession of an 'up-todate hydrocortisone emergency self-injection kit' and that the patient and a relative/partner/friend is confident in self-administration of the injection. Consider refreshing knowledge by talking through the procedure over the phone and providing links to training videos (https://www.addisonsdisease.org.uk/ the-emergency-injection-for-the-treatment-of-adrenalcrisis and https://www.adrenals.eu/animations/how).

Empower
• Ensure that all patients are in possession of a 'steroid emergency card' or equivalent written instructions for healthcare staff on how to treat the patient in a major stress situation that prevents self-management. Figure  1 shows the recently issued UK version of the steroid card, developed further from a version originally proposed by a Swedish group (18)  They should monitor how much urine they pass; the excretion of only little amounts of dark, concentrated urine indicates insufficient hydration, which should prompt further increased oral fluid intake. Importantly, patients with adrenal insufficiency and an acute suspected or confirmed COVID-19 infection should also 'immediately take a double hydrocortisone morning dose and then increase their hydrocortisone replacement to 20 mg four times daily', that is, 20 mg hydrocortisone every 6 h, for example, at 0600 h, 1200 h, 1800 h and 2400 h ( Table 1). In children, their usual daily dose should be trebled and administered orally Steroid emergency card for patients with adrenal insufficiency issued by the UK National Health Service in March 2020 (downloadable at https://www.endocrinology.org/media/3563/new-nhs-emergency-steroid-card.pdf).  (15,16,17), the personal experience of the authors is that an acute COVID-19 infection is associated with significant and persistent acute inflammation and often continuous high fever, which in our view requires a more evenly spaced glucocorticoid cover throughout day and night. We have based our suggested doses on a three-compartment model of oral hydrocortisone delivery (19) (Fig. 2), drawing from experimental data from the Prevention of Adrenal Crisis in Stress (PACS) study (20) and a previous study on oral hydrocortisone pharmacokinetics (21). This modelling indicates that the mere doubling of the regular glucocorticoid dose could leave patients with prolonged periods of glucocorticoid deficiency during an acute and highly inflammatory infection such as COVID-19 (Fig. 2).

European Journal of Endocrinology
• Under no circumstances should patients hesitate to contact medical emergency services, 'if the clinical signs and symptoms of COVID-19 significantly worsen'. Patients (or their carers) should 'contact medical emergency services without delay and immediately administer their hydrocortisone emergency injection (100 mg i.m.)'. If for any reason they cannot administer the injection, they should immediately take 50-100 mg hydrocortisone orally, if possible, while waiting for medical emergency services to arrive. If need be, patients and their carers should consider making their own way to hospital and continue to take 50 mg hydrocortisone every 6 h. 'Signs and symptoms indicating clinical deterioration in patients affected by COVID-19', which typically occur 7-10 days after onset of the first COVID-associated symptoms, include: ⚬ feeling very dizzy on sitting or standing ⚬ feeling very thirsty despite drinking regularly ⚬ feeling very cold ⚬ shaking uncontrollably ⚬ becoming drowsy, confused or difficult to wake up  https://eje.bioscientifica.com ⚬ developing vomiting or severe diarrhoea ⚬ increasing shortness of breath with fast breathing (respiratory rate >24/min) or difficulty speaking in complete sentences.
• Following emergency injection of 100 mg hydrocortisone by self-injection or medical emergency personnel, the patients should be maintained on 'major stress dose hydrocortisone, that is, 200 mg over 24 h, preferably in the hospital setting administered via continuous i.v. infusion', which ensures that intermittent troughs in cortisol levels are avoided (Fig. 3)  • Co-incident type 1 diabetes is found in around 10% of patients with PAI (24,25,26). The clinical experience is that diabetic patients affected by COVID-19 quickly struggle to maintain glycaemic control, with significantly increased insulin requirements, and are more prone to diabetic ketoacidosis. A recent guidance on managing 'type 1 and type 2 diabetes   • Patients on stable replacement usually undergo annual checks of electrolytes and plasma renin to ensure adequacy of mineralocorticoid replacement, but during the COVID-19 crisis blood checks should be reserved for patients with clinical signs of hypotension, such as dizziness when standing up. Blood pressure self-measurement, for example, after sitting for at least 5 min and then again after standing up for a minute, should be encouraged; patients should also be taught how to take their heart rate and be advised which readings should prompt to contact their specialist care team for further advice (such as resting heart rate >100/min and systolic blood pressure <100 mmHg; otherwise healthy and well patients to remeasure after 1 h before contacting medical staff). Many healthcare centres have established bloodletting centres in convenient locations away from hospitals that can be used if a blood test is considered urgent.
• Routine glucocorticoid replacement therapy is monitored based on the patient's clinical performance and ability to cope with daily stress and does not require laboratory evaluation (29), thus history taking and discussions can easily take place via teleconferencing.

Disclaimer
Due to the emerging nature of the COVID-19 crisis, this document is not based on extensive systematic review or meta-analysis, but on rapid expert consensus. The document should be considered as guidance only; it is not intended to determine an absolute standard of medical care. Healthcare staff need to consider individual circumstances when devising the management plan for a specific patient.

Declaration of interest
Wiebke Arlt is the Editor-in-Chief of the European Journal of Endocrinology. W A was not involved in the review or editorial process for this paper, on which she is listed as an author. The other authors have nothing disclose.

Funding
This guidance did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.