Send Orders for Reprints to [email protected] The Open Respiratory Medicine Journal, 2014, 8, (Suppl 1: M6) 93-100
93
Open Access
Inhaled Corticosteroids and Secondary Adrenal Insufficiency Vishnu Sannarangappa* and Ryan Jalleh Department of General Medicine, Modbury Hospital, 41-69 Smart Road, Modbury, SA 5092, Australia Abstract: Inhaled corticosteroids (ICS) have been used as first line treatment of asthma for many decades. ICS are a form of exogenous glucocorticosteroids that can suppress the endogenous production of glucocorticosteroids, a condition known as adrenal suppression (AS). As a result, cessation, decreasing the dose or changing the type of ICS may trigger features of adrenal insufficiency (AI). AI may cause a spectrum of presentations varying from vague symptoms of fatigue to potentially life threatening acute adrenal crises. This article reviews the current literature on ICS and AI particularly in adults (although majority of data available is from the paediatric population). It aims to increase awareness of the potential risk of AI associated with ICS use, delineate the pathogenesis of AI and to provide recommendations on screening and management. From our literature review, we have found numerous case reports that have shown an association between ICS and AI particularly in children and patients using high doses. However, there have also been reports of AI in adults as well as in patients using low to moderate doses of ICS. To conclude, we recommend screening for AI in select patient groups with an initial early morning serum cortisol. If results are abnormal, more definitive testing such as the low dose corticotropin stimulation test may be done to confirm the diagnosis.
Keywords: Adrenal insufficiency, adrenal suppression, inhaled corticosteroids. INTRODUCTION Asthma is one of the most common chronic conditions in Australia with over 2 million Australians currently diagnosed with asthma [1]. It is a complex disease affecting both adults and children with variable phenotypic expression [2]. Airway inflammation, bronchial hyper-responsiveness and airflow obstruction form the triad of asthma, clinically manifesting as cough, wheezing, breathlessness and chest tightness [3]. Asthma is one of the most common chronic diseases in the world and its incidence has been increasing in the past three decades. It is estimated to affect between 10 15% of children and adolescents in developed world countries [1, 4-6]. The incidence has been reported to be 12% higher in the elderly population [1]. An estimated 300 million people are suffering from asthma with >100 million additions likely by the year 2025 [7]. A systematic review has described the risk of AI with oral glucocorticoid withdrawal [8]. However, few studies have addressed the risk of AI with inhaled glucocorticoids. Glucocorticosteroids have been used in the treatment of asthma since 1956 due to their broad anti-inflammatory and immunosuppressive effects [9]. ICS have been shown to significantly reduce airway hyper-responsiveness, decrease the severity of symptoms, improve lung function and prevent acute exacerbations leading to a decrease in morbidity and mortality in asthma [10-13]. Many asthma management guidelines recommend ICS as the first line therapy at low *Address correspondence to this author at the Department of General Medicine, Modbury Hospital, 41-69 Smart Road Modbury SA 5092, Australia; Tel: +61 8 81612000; E-mail: [email protected]
1874-3064/14
doses in mild persistent asthma. They are also preferred therapy at a moderate doses along with long acting beta 2agonists for moderate asthma [11]. Higher doses are used only if symptoms persist despite the above combination therapy [3]. ICS are also used in over 70% COPD patients but the benefits are controversial as they reduce exacerbation by 20-25% in severe disease. Long-term treatment with ICS added to long-acting bronchodilators is recommended only for patients at high risk of exacerbations (FEV16,
CRH, Hypothalamus,, Pituitary,,
IL>6,, (TNFα),
ACTH,,
Chronic,inflamma6on,,
Adrenal,gland,,
exogenous,glucocor6coids,,
Cor6sol,,
Fig. (1). HPA axis response to acute and chronic stress leading from inflammation. CRH-corticotrophin releasing hormone, ACTHadrenocorticotrophic releasing hormone, IL-interleukin, TNF-tumor necrosis factor. Green arrows indicate activation, red arrows indicate suppression. HPA axis gets activated by specific cytokines released during inflammation (IL-1, IL6). IL-6 has been recognized as important in innate immune response [59]. Acute inflammation leads to activation of HPA axis and marked and prolonged elevation of plasma ACTH and cortisol, however chronic activation of HPA axis leads to a blunted ACTH and cortisol response as a protective adaptation mechanism [60]. Exogenous corticosteroids lead to suppression of the HPA axis in the same manner as cortisol that inhibits both CRH and ACTH synthesis [61].
A baseline serum ACTH concentration should be measured to rule out AI secondary to low ACTH concentration. If ACTH concentration is low, a thorough clinical examination including visual fields examination and measurement of other pituitary hormones is important to exclude a pituitary adenoma (most commonly a nonfunctioning adenoma). An 8 am serum cortisol concentration of 500 nmol/L at 8 am excludes secondary AI [41]. Higher cut off values for identifying AI has been used in some studies. Smith et al., [36] used a cut off value of 170 nmol/L for screening at risk children on ICS and found out that, out of the 43 children who had AI based on screening 20 were confirmed with AS with low dose (1 mcg) ACTH stimulation test (45.6%). Both standard dose and low dose ACTH stimulation tests are being used in identifying AI; although recently, the low dose ACTH stimulation test has been preferred method among some endocrinologists, there is no consensus as to which one is better and as such
we support either of the above tests (whichever is locally available) [67, 68]. In the ACTH stimulation test, a set quantity of corticotropin is administered intravenously or intramuscularly (250 mcg with standard dose test and 1 mcg with low dose test) and serum cortisol concentrations are measured at baseline, 30 minutes and 60 minutes after the stimulation. A peak concentration of >500 nmol/L (some laboratories use a lower cut of value and this should be considered and confirmed with local assay providers) would exclude AI, a concentration 12 years) using fluticasone propionate, maximal efficacy was achieved at a dose of 500 mcg/day. Of this, 90% of the benefit was achieved at doses of 100 to 250 mcg/day [21, 71]. Therefore, it is important to use the minimal required dose to achieve symptom control and if a higher dose is used it should be reduced as soon as possible [42]. In the case of COPD patients who are on ICS, a total daily dose of ICS ≥1000 mcg of fluticasone propionate appears to be associated with higher risk of AS. But the data in this regard is scant and treating physicians should keep an open mind to screen any COPD patients who are an more than 400 mcg/day of fluticasone propionate or its equivalent dosage, the risk of AS appears to be greater in COPD patients who are exposed to the highest dose of ICS than those with asthma [37]. Finally any patient who is on inhaled corticosteroids should be screened for AS if they have any signs or symptoms of AS regardless of the dosage.
AI, irrespective of the cause is one of the acute life threatening emergencies in both adult and paediatric patients. Clinicians need to be aware that this can happen in patients treated with ICS with unusual symptoms so as to manage them in a timely manner [23]. An endocrinologist should be involved in managing AS [57]. Management of AI involves, managing acute adrenal crisis, management of AI during physiological stress, patient education and information regarding medical alert bracelets. An acute adrenal crisis needs urgent rehydration with intravenous normal saline and replacement of glucocorticoids in the form of hydrocortisone 100 mg immediately followed by 50-100 mg IV/IM (intravenous/intramuscular) every 6 hours (depending on body surface area and age) [41]. AS associated with ICS may go unrecognized until a physiological stress results in adrenal crisis [57]. During minor illness or surgical procedures up to three times the physiological dose of corticosteroid replacement may be needed to compensate for lack of appropriate adrenal response to stress due to AS. This replacement dose requirement might be as high as 10 times the physiological dose during major illness/surgery [41]. Therefore patients should be cautioned about abrupt withdrawal of ICS after prolonged use especially if using a higher dose of ICS [22, 23]. Patients and their family should be educated about symptoms of AI (myalgia, lack of energy, weight loss, nausea, dizziness) and to seek immediate medical advice. Patients who are at risk of AS should carry medical alert bracelets [41, 57]. DISCUSSION HPA axis has a varied response to ICS in asthma patients. This appears to be due to varying HPA axis stressimmune response, which might be genetically predetermined. Generally in the vast majority of the patients use of ICS has a favorable response and regular use has been shown to improve lung function, quality of life, prevent hospitalization/exacerbations and reduce asthma related mortality. However in a minority of patients there is an Table 3.
There is no published data on management of this AS associated with ICS. All the recommendations have been based on best available literature and expert opinion. The key features of management would involve prevention, screening and managing AS. Ahmet et al., [57] and Schwartz et al., [21] in their review article have explained and given some insight to these key points. It is advisable to screen all the patients who are at risk (Tables 1-3) [21, 57]. As there are no specific symptoms that can predict ICS associated AS [36], any symptom of AI and any clinical scenario that could precipitate adrenal crisis in someone with AI should be an indication for screening for AS. Although there is no test that can identify AS with certainty, an 8 am morning serum cortisol concentration followed by 1 mcg or 250 mcg ACTH stimulation test if required is most practical way to identify AS in these patients [57]. Prompt management of AS with active involvement of an endocrinologist is essential in case of adrenal crisis; rehydration and intravenous hydrocortisone is mainstay of managing this condition in acute setting.
Patients who are at risk of AS and would benefit from screening for AS. 1
Patients who have symptoms of AS regardless of dose of ICS used
2
Patients who are on higher dose of ICS (≥400 mcg of Fluticasone propionate or equivalent)
3
Concomitant use of oral or inhaled steroids
4
Concomitant use of potent CYP3A4 inhibitor
5
Recurrent respiratory infections with slow recovery
6
Any planned surgical procedure
7
Poor growth, decreased body surface area, unexplained hypoglycemia
8
Gastroenteritis and/or chronic nausea and vomiting, diarrhea, dehydration
9
Any other serious medical/surgical illness
10
Heat stress, any other condition where AI might result in acute adrenal crisis.
Inhaled Steroids and Adrenal Insufficiency
CONCLUSION ICS therapy is essential in the treatment of asthma and in certain COPD patients with vast proven benefits both in morbidity and mortality, in adults and children alike. ICS is associated with AS in a minority of patients who are on ICS for their respiratory conditions with potential serious consequences, especially in a physiologically stressful condition. Treating clinicians, patients and their family need to be watchful of the serious, yet non-specific symptoms, so as to appropriately identify and manage this potential life threatening condition. Use of ICS at minimal recommended dosing with increasing dose only if required is helpful in preventing this complication. A robust clinician-patient involvement in educating, recognising, screening and regular follow up will certainly help in reducing this complication. More research needs to be undertaken especially in the older adults and elderly population who are using ICS for COPD management, and it appears that COPD patients who are using ICS are in fact at a greater risk of AS. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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Received: October 10, 2014
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Accepted: October 21, 2014
© Sannarangappa and Jalleh; Licensee Bentham Open. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.
93
Open Access
Inhaled Corticosteroids and Secondary Adrenal Insufficiency Vishnu Sannarangappa* and Ryan Jalleh Department of General Medicine, Modbury Hospital, 41-69 Smart Road, Modbury, SA 5092, Australia Abstract: Inhaled corticosteroids (ICS) have been used as first line treatment of asthma for many decades. ICS are a form of exogenous glucocorticosteroids that can suppress the endogenous production of glucocorticosteroids, a condition known as adrenal suppression (AS). As a result, cessation, decreasing the dose or changing the type of ICS may trigger features of adrenal insufficiency (AI). AI may cause a spectrum of presentations varying from vague symptoms of fatigue to potentially life threatening acute adrenal crises. This article reviews the current literature on ICS and AI particularly in adults (although majority of data available is from the paediatric population). It aims to increase awareness of the potential risk of AI associated with ICS use, delineate the pathogenesis of AI and to provide recommendations on screening and management. From our literature review, we have found numerous case reports that have shown an association between ICS and AI particularly in children and patients using high doses. However, there have also been reports of AI in adults as well as in patients using low to moderate doses of ICS. To conclude, we recommend screening for AI in select patient groups with an initial early morning serum cortisol. If results are abnormal, more definitive testing such as the low dose corticotropin stimulation test may be done to confirm the diagnosis.
Keywords: Adrenal insufficiency, adrenal suppression, inhaled corticosteroids. INTRODUCTION Asthma is one of the most common chronic conditions in Australia with over 2 million Australians currently diagnosed with asthma [1]. It is a complex disease affecting both adults and children with variable phenotypic expression [2]. Airway inflammation, bronchial hyper-responsiveness and airflow obstruction form the triad of asthma, clinically manifesting as cough, wheezing, breathlessness and chest tightness [3]. Asthma is one of the most common chronic diseases in the world and its incidence has been increasing in the past three decades. It is estimated to affect between 10 15% of children and adolescents in developed world countries [1, 4-6]. The incidence has been reported to be 12% higher in the elderly population [1]. An estimated 300 million people are suffering from asthma with >100 million additions likely by the year 2025 [7]. A systematic review has described the risk of AI with oral glucocorticoid withdrawal [8]. However, few studies have addressed the risk of AI with inhaled glucocorticoids. Glucocorticosteroids have been used in the treatment of asthma since 1956 due to their broad anti-inflammatory and immunosuppressive effects [9]. ICS have been shown to significantly reduce airway hyper-responsiveness, decrease the severity of symptoms, improve lung function and prevent acute exacerbations leading to a decrease in morbidity and mortality in asthma [10-13]. Many asthma management guidelines recommend ICS as the first line therapy at low *Address correspondence to this author at the Department of General Medicine, Modbury Hospital, 41-69 Smart Road Modbury SA 5092, Australia; Tel: +61 8 81612000; E-mail: [email protected]
1874-3064/14
doses in mild persistent asthma. They are also preferred therapy at a moderate doses along with long acting beta 2agonists for moderate asthma [11]. Higher doses are used only if symptoms persist despite the above combination therapy [3]. ICS are also used in over 70% COPD patients but the benefits are controversial as they reduce exacerbation by 20-25% in severe disease. Long-term treatment with ICS added to long-acting bronchodilators is recommended only for patients at high risk of exacerbations (FEV16,
CRH, Hypothalamus,, Pituitary,,
IL>6,, (TNFα),
ACTH,,
Chronic,inflamma6on,,
Adrenal,gland,,
exogenous,glucocor6coids,,
Cor6sol,,
Fig. (1). HPA axis response to acute and chronic stress leading from inflammation. CRH-corticotrophin releasing hormone, ACTHadrenocorticotrophic releasing hormone, IL-interleukin, TNF-tumor necrosis factor. Green arrows indicate activation, red arrows indicate suppression. HPA axis gets activated by specific cytokines released during inflammation (IL-1, IL6). IL-6 has been recognized as important in innate immune response [59]. Acute inflammation leads to activation of HPA axis and marked and prolonged elevation of plasma ACTH and cortisol, however chronic activation of HPA axis leads to a blunted ACTH and cortisol response as a protective adaptation mechanism [60]. Exogenous corticosteroids lead to suppression of the HPA axis in the same manner as cortisol that inhibits both CRH and ACTH synthesis [61].
A baseline serum ACTH concentration should be measured to rule out AI secondary to low ACTH concentration. If ACTH concentration is low, a thorough clinical examination including visual fields examination and measurement of other pituitary hormones is important to exclude a pituitary adenoma (most commonly a nonfunctioning adenoma). An 8 am serum cortisol concentration of 500 nmol/L at 8 am excludes secondary AI [41]. Higher cut off values for identifying AI has been used in some studies. Smith et al., [36] used a cut off value of 170 nmol/L for screening at risk children on ICS and found out that, out of the 43 children who had AI based on screening 20 were confirmed with AS with low dose (1 mcg) ACTH stimulation test (45.6%). Both standard dose and low dose ACTH stimulation tests are being used in identifying AI; although recently, the low dose ACTH stimulation test has been preferred method among some endocrinologists, there is no consensus as to which one is better and as such
we support either of the above tests (whichever is locally available) [67, 68]. In the ACTH stimulation test, a set quantity of corticotropin is administered intravenously or intramuscularly (250 mcg with standard dose test and 1 mcg with low dose test) and serum cortisol concentrations are measured at baseline, 30 minutes and 60 minutes after the stimulation. A peak concentration of >500 nmol/L (some laboratories use a lower cut of value and this should be considered and confirmed with local assay providers) would exclude AI, a concentration 12 years) using fluticasone propionate, maximal efficacy was achieved at a dose of 500 mcg/day. Of this, 90% of the benefit was achieved at doses of 100 to 250 mcg/day [21, 71]. Therefore, it is important to use the minimal required dose to achieve symptom control and if a higher dose is used it should be reduced as soon as possible [42]. In the case of COPD patients who are on ICS, a total daily dose of ICS ≥1000 mcg of fluticasone propionate appears to be associated with higher risk of AS. But the data in this regard is scant and treating physicians should keep an open mind to screen any COPD patients who are an more than 400 mcg/day of fluticasone propionate or its equivalent dosage, the risk of AS appears to be greater in COPD patients who are exposed to the highest dose of ICS than those with asthma [37]. Finally any patient who is on inhaled corticosteroids should be screened for AS if they have any signs or symptoms of AS regardless of the dosage.
AI, irrespective of the cause is one of the acute life threatening emergencies in both adult and paediatric patients. Clinicians need to be aware that this can happen in patients treated with ICS with unusual symptoms so as to manage them in a timely manner [23]. An endocrinologist should be involved in managing AS [57]. Management of AI involves, managing acute adrenal crisis, management of AI during physiological stress, patient education and information regarding medical alert bracelets. An acute adrenal crisis needs urgent rehydration with intravenous normal saline and replacement of glucocorticoids in the form of hydrocortisone 100 mg immediately followed by 50-100 mg IV/IM (intravenous/intramuscular) every 6 hours (depending on body surface area and age) [41]. AS associated with ICS may go unrecognized until a physiological stress results in adrenal crisis [57]. During minor illness or surgical procedures up to three times the physiological dose of corticosteroid replacement may be needed to compensate for lack of appropriate adrenal response to stress due to AS. This replacement dose requirement might be as high as 10 times the physiological dose during major illness/surgery [41]. Therefore patients should be cautioned about abrupt withdrawal of ICS after prolonged use especially if using a higher dose of ICS [22, 23]. Patients and their family should be educated about symptoms of AI (myalgia, lack of energy, weight loss, nausea, dizziness) and to seek immediate medical advice. Patients who are at risk of AS should carry medical alert bracelets [41, 57]. DISCUSSION HPA axis has a varied response to ICS in asthma patients. This appears to be due to varying HPA axis stressimmune response, which might be genetically predetermined. Generally in the vast majority of the patients use of ICS has a favorable response and regular use has been shown to improve lung function, quality of life, prevent hospitalization/exacerbations and reduce asthma related mortality. However in a minority of patients there is an Table 3.
There is no published data on management of this AS associated with ICS. All the recommendations have been based on best available literature and expert opinion. The key features of management would involve prevention, screening and managing AS. Ahmet et al., [57] and Schwartz et al., [21] in their review article have explained and given some insight to these key points. It is advisable to screen all the patients who are at risk (Tables 1-3) [21, 57]. As there are no specific symptoms that can predict ICS associated AS [36], any symptom of AI and any clinical scenario that could precipitate adrenal crisis in someone with AI should be an indication for screening for AS. Although there is no test that can identify AS with certainty, an 8 am morning serum cortisol concentration followed by 1 mcg or 250 mcg ACTH stimulation test if required is most practical way to identify AS in these patients [57]. Prompt management of AS with active involvement of an endocrinologist is essential in case of adrenal crisis; rehydration and intravenous hydrocortisone is mainstay of managing this condition in acute setting.
Patients who are at risk of AS and would benefit from screening for AS. 1
Patients who have symptoms of AS regardless of dose of ICS used
2
Patients who are on higher dose of ICS (≥400 mcg of Fluticasone propionate or equivalent)
3
Concomitant use of oral or inhaled steroids
4
Concomitant use of potent CYP3A4 inhibitor
5
Recurrent respiratory infections with slow recovery
6
Any planned surgical procedure
7
Poor growth, decreased body surface area, unexplained hypoglycemia
8
Gastroenteritis and/or chronic nausea and vomiting, diarrhea, dehydration
9
Any other serious medical/surgical illness
10
Heat stress, any other condition where AI might result in acute adrenal crisis.
Inhaled Steroids and Adrenal Insufficiency
CONCLUSION ICS therapy is essential in the treatment of asthma and in certain COPD patients with vast proven benefits both in morbidity and mortality, in adults and children alike. ICS is associated with AS in a minority of patients who are on ICS for their respiratory conditions with potential serious consequences, especially in a physiologically stressful condition. Treating clinicians, patients and their family need to be watchful of the serious, yet non-specific symptoms, so as to appropriately identify and manage this potential life threatening condition. Use of ICS at minimal recommended dosing with increasing dose only if required is helpful in preventing this complication. A robust clinician-patient involvement in educating, recognising, screening and regular follow up will certainly help in reducing this complication. More research needs to be undertaken especially in the older adults and elderly population who are using ICS for COPD management, and it appears that COPD patients who are using ICS are in fact at a greater risk of AS. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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Accepted: October 21, 2014
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