Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus fumigatus that occurs in patients with asthma or cystic fibrosis. Here, we report a case of a young female with bronchial asthma who presented to our hospital with worsening breathlessness on exertion. She was diagnosed to have ABPA and was initiated on oral itraconazole while continuing inhaled long acting beta-2 adrenergic agonist and medium dose inhaled corticosteroid (ICS) for her asthma. Three months after initiation of therapy, the patient had significant improvement in breathlessness. However, she had weight gain, facial puffiness, increased facial hair and development of striae on her inner thighs, calf and lower abdomen. Her serum cortisol levels were found to be suppressed and hence a diagnosis of iatrogenic Cushing’s syndrome was made. Our case describes the potentially serious interaction between ICS and oral itraconazole, a treatment very commonly prescribed in patients with ABPA.
- Endocrine system
- Drug interactions
- Drugs: respiratory system
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Allergic bronchopulmonary aspergillosis (ABPA) is a complex hypersensitivity reaction in response to colonisation of airways with Aspergillus fumigatus. ABPA occurs almost exclusively in patients with underlying bronchial asthma or cystic fibrosis. Its prevalence in patients with asthma is estimated at 1%–2%.1 2 Rates of up to 32% have been reported from asthma referral centres.3
ABPA should be diagnosed and treated early to prevent the development of progressive, irreversible bronchiectasis or pulmonary fibrosis. The treatment of newly diagnosed ABPA typically consists of oral glucocorticoids (OCS) and/or antifungal agents such as itraconazole or voriconazole.4 Recent studies have demonstrated that oral itraconazole monotherapy can be used as an alternative to OCS, especially in patients with high risk of steroid-related complications.5 Patients with ABPA are also continued on inhaled bronchodilators and inhaled corticosteroids (ICS) for their coexisting asthma.
Inhaled budesonide is one of the most common ICS prescribed for patients with asthma. A portion of inhaled budesonide which gets absorbed into systemic circulation is metabolised in the liver by CYP3A4. At the doses prescribed for asthma, it has a very low potential of causing systemic side effects.6 Itraconazole is a known CYP3A4 inhibitor. When given together, this can increase the levels of budesonide and this can potentially cause hypothalamic–pituitary–adrenal (HPA) axis suppression and lead to Cushing’s syndrome. Although, there are several cases reported of iatrogenic Cushing’s syndrome with OCS, there are very few reports which describe the same with inhaled medium dose corticosteroids.
Here, we describe a case of iatrogenic Cushing’s syndrome in a patient with ABPA due to a combination of oral itraconazole and inhaled budesonide.
A young female student in her early 20s came to our outpatient department with a 2-year history of breathlessness on exertion. Breathlessness was insidious in onset and progressed from being only on exercise to having difficulty on climbing one flight of stairs over the last 3 months. There was no history of wheezing or chest tightness. She was a never-smoker and never consumed alcohol.
She was diagnosed to have bronchial asthma at the age of 7 and is on daily maintenance therapy with inhaled formoterol (24 μg/day) and inhaled budesonide (800 μg/day) in divided doses. She had no history of prior exacerbations.
At presentation, her vitals were as follows: pulse rate of 90 beats per minute; blood pressure of 110/80 mm Hg; respiratory rate of 20 per minute; temperature of 37 C and finger pulse oximetry saturation was 97% at room air. General examination was unremarkable and respiratory system examination revealed bilateral polyphonic wheeze.
Haematological investigations revealed normal total leucocyte counts of 10.8 x 10∧9 cells/L; an elevated absolute eosinophil count of 1726 cells/cumm (reference value: <300 cells/cumm) and an elevated serum IgE of 32 046 KIU/L (reference value: <150 KIU/L). Chest radiograph was unremarkable. Spirometry revealed reduced forced expiratory volume in first second/forced vital capacity (FEV1/FVC) ratio (55%), and reduced FEV1 of 0.73 L (27% predicted). Postbronchodilator challenge with inhaled levosalbutamol (200 μg), her FEV1 improved to 1.03 L (39% predicted). Fractional exhaled nitric oxide (FENO) values were elevated at 66 ppb (reference range: <25 ppb). The above findings were consistent with a diagnosis of severe asthma with T2 high overlap phenotype. Her Asthma Control Test (ACT) revealed a score of 15, indicating suboptimal asthma control. Patient’s inhaler usage and technique were evaluated and were found to be satisfactory.
She was evaluated subsequently for coexisting ABPA. Her serum A. fumigatus specific IgE and IgG were found to be elevated at 11.1 kUA/L and 34 mgA/L, respectively (reference value for A. fumigatus specific IgE: <0.35 kUA/L and for A. fumigatus specific IgG: <27 mgA/L). A high-resolution CT of the chest was performed which did not reveal any abnormality. Thus, a diagnosis of ABPA serologic was made, as per the modified international society for human and animal mycology (ISHAM) criteria.7 The patient was started on oral itraconazole 200 mg two times per day and her inhaled medications for asthma were continued.
At follow-up after 3 months, she had improvement in breathlessness and was able to exercise without any breathing difficulty. Pulmonary function tests showed improvement in FEV1 to 1.4 L (63% predicted) and a decrease in FENO to 15 ppb. Serum IgE reduced to 20 190 KIU/L and absolute eosinophil count was 412 cells/cumm (table 1). She, however, had weight gain of 6 kg over the last 3 months along with an increase in appetite and facial hair. She noticed facial puffiness along with increased redness of the face. She identified stretch marks over her calf, inner side of thighs and lower abdomen. Her menstrual cycles were regular. She was not taking any oral/topical/injectable corticosteroid or any complementary medicine. On physical examination, her blood pressure was 110/70 mm Hg. She had a moon face appearance with facial plethora. She had excess vellus hair over the chin, sidelocks and cheeks, however, there was no terminal hair seen. She had supraclavicular fullness, a buffalo hump and striae over the calf region, medial aspect of thighs and lower abdomen. The striae were 10–12 in number, around 1 cm wide and violaceous in appearance (figure 1A,B). There was no evidence of bruising, fungal skin infection, proximal myopathy or cataract.
Her laboratory evaluation revealed a suppressed morning (8:00 hour) cortisol of <1.5 nmol/L (reference range: 133–537 nmol/L); serum testosterone was <4.9 ng/dL (reference range: 5.71–77 ng/dL); serum prolactin 23 ng/mL (reference range : 3–18.6 ng/mL); serum thyroid stimulating hormone (TSH) 3.4 μIU/mL (reference range: 0.46–4.68 μIU/mL); serum potassium 3.8 mmol/L (reference range: 3.5–5.1 mmol/L); serum creatinine 0.58 mg/dL (reference range : 0.52–1.04 mg/dL) and glycated haemoglobin of 5.4% (reference value: <5.7%).
A diagnosis of iatrogenic Cushing’s syndrome with glucocorticoid induced secondary adrenal insufficiency due to a possible drug interaction between inhaled medium dose budesonide and oral itraconazole was made.
Described in the course of case report.
The patient presented with weight gain and increased facial hair growth. A differential diagnosis of polycystic ovarian syndrome (PCOS) was considered. On examination, the presence of cushingoid facies, supraclavicular fullness, violaceous thick striae, vellus hair, regular menstrual cycles and absence of hirsutism (absence of terminal hair) favoured exogenous Cushing’s syndrome. Vellus hair is specific to glucocorticoid excess states and terminal hair is related to androgen excess which can be due to PCOS or adrenocorticotropic hormone (ACTH) dependent Cushing’s syndrome. Thus, clinically this presentation favours iatrogenic cushings over PCOS. The presence of low testosterone levels also points against hyperandrogenism which can be seen in PCOS. The low testosterone levels in the index case can be explained by a suppressed ACTH (ie, expected in a patient with iatrogenic Cushing’s syndrome) that can lead to suppression of adrenal androgen production.
Oral itraconazole was given for a total of 4 months and then withheld. Inhaled formoterol (24 μg/day) and inhaled budesonide 800 μg/day were continued in two divided doses as before. For treatment of her secondary adrenal insufficiency, oral hydrocortisone was initiated at a dose of 20 mg per day in divided doses and was tapered over a month.
Outcome and follow-up
At follow-up after 1 month of stopping itraconazole, the patient was symptomatically better. She was back to her baseline weight and the cushingoid facies had disappeared. Striae had begun to fade and the excessive facial hair had reduced. Pulmonary function test revealed further improvement in FEV1 to 1.58 L. Haematological investigations revealed a decreased serum IgE of 9052 KIU/L; absolute eosinophil count of 219 cells/μL and a normal morning cortisol (8:00 hours) of 271 nmol/L.
This case illustrates the potential adverse interaction of inhaled budesonide and oral itraconazole in patients with ABPA. Itraconazole inhibits fungal cytochrome P450, preventing cell wall synthesis and leading to cell death. It is also a potent inhibitor of mammalian cytochrome P450 3A4. Unlike ketoconazole, it does not cause adrenal insufficiency when used as monotherapy.8
Budesonide is a potent corticosteroid. When administered with a metered-dose inhaler, up to 60% of the dose is deposited in the oropharynx which is then swallowed and subsequently absorbed from the gastrointestinal tract. Budesonide is then subjected to high first-pass metabolism in the liver and approximately only 10% of the ingested corticosteroid reaches the systemic circulation. Less than 20% of the dose delivered via inhalation reaches the lungs. Most of this dose will be bioavailable in the systemic circulation as unchanged active drug and is the larger determinant of the overall systemic bioavailability. Systemic budesonide metabolism occurs in the liver by the CYP3A4 isoenzyme to inactive metabolites.8
ICSs are known to produce adrenal suppression in a dose dependent manner. In a study by Gordon et al, they found that inhaled budesonide did not produce adrenal insufficiency at doses below 1.6 mg/day.9 However, in another study done by Molimard et al, the mean daily dose of inhaled budesonide causing adrenal insufficiency was 1.2 mg/day.10 There is no evidence that lower doses of inhaled budesonide in isolation can lead to adrenal suppression. Other inhaled steroids, such as fluticasone and beclomethasone, can also cause adrenal suppression in a dose-dependent manner.10
Itraconazole has been shown to inhibit the metabolism of orally administered corticosteroids. Itraconazole has also been found to inhibit the metabolism of systemically absorbed inhaled budesonide.11 In the study done by Raaska et al, itraconazole increased the mean total area under the plasma concentration-time curve of inhaled budesonide by 4.2-fold and the peak plasma concentration by 1.6-fold when compared with placebo. The mean terminal half-life of budesonide was prolonged from 1.6 to 6.2 hours by itraconazole.12
A study done by Skov et al found that in cystic fibrosis patients with ABPA, only those patients treated with a combination of inhaled budesonide plus itraconazole (11 out of 25 patients treated with the combination) developed adrenal suppression, whereas the patients who received either itraconazole alone or even high-dose inhaled budesonide alone had normal adrenal function.13
Hence, Cushing’s syndrome in patients treated with a combination of inhaled budesonide and itraconazole can be explained by an increased systemic concentration of budesonide which in turn suppresses the pituitary ACTH production leading to adrenal insufficiency. This interaction between itraconazole and inhaled budesonide, leading to high systemic budesonide levels, may explain the reported ability to reduce the OCS dose.14 Hence, the use of itraconazole may spare the administered dose of steroids but its effect or side effects, remain.
There are a few case reports published earlier describing the development of Cushing’s syndrome with a combination of itraconazole and inhaled budesonide8 15 16 A summary of such case reports is given in table 2. Despite being a combination commonly prescribed, it is unclear why only a few develop adrenal insufficiency and Cushing’s syndrome. Differences in percentage of absorbed drug, or individual differences in CYP3A4 enzyme activity, could explain the predilection of only a few to develop this clinically significant drug interaction.
The management of iatrogenic Cushing’s syndrome in these patients is not very well established. Patients in earlier case reports were managed by tapering the inhaled budesonide and stopping itraconazole. Oral hydrocortisone was supplemented in all till the HPA axis recovered. The recovery of the HPA axis can take weeks to months, and maintenance and stress dose of hydrocortisone should be continued till then. It is suggested to add a low-dose oral glucocorticosteroid or hydrocortisone to prevent development of glucocorticoid withdrawal syndrome (GWS). Patients should be counselled on GWS and are to be provided a plan of management if such symptoms develop. Slow taper of the oral steroid dose weekly or bimonthly is recommended.17
In one report, voriconazole was reintroduced after recovery from cushings, and it did not affect the oral hydrocortisone concentrations.8 Voriconazole is metabolised by CYP2C9, it inhibits CYP3A4, but its inhibitory effects are less than itraconazole.18 A recent case report of adrenal suppression with voriconazole and inhaled steroids has also been reported.19 However, it could be a reasonable alternative to itraconazole in ABPA patients and needs to be studied further
I am an asthma patient who used to take my inhalers regularly. Despite this, I was experiencing breathing difficulty on climbing stairs over the last few months. I have visited a doctor for an evaluation of my breathing difficulty. On examination, the doctor identified wheeze and ordered investigations. Chest x ray was normal but my blood work showed high levels of IgE and eosinophil count and I was diagnosed with ABPA. I was started on oral medication along with inhalers. My breathing difficulty improved but I started to notice weight gain, swelling of my face and upper back along with a lot of facial hair and skin stretch marks on my thigh, lower abdomen and calf. On further evaluation I was diagnosed as Cushing’s syndrome due to drug interaction. I was explained about the disease and was started on therapy. Post therapy currently all my symptoms have resolved. I am on daily inhalers for my asthma control and in regular follow up with the doctor.
There is a potential serious interaction between inhaled corticosteroids and oral itraconazole. CYP3A4 inhibition by oral itraconazole leads to higher levels of systemic absorbed corticosteroid, and this can lead to adrenal suppression and iatrogenic Cushing’s syndrome.
The hypothalamic–pituitary–adrenal axis should be assessed at regular intervals for patients on such combinations to diagnose and treat adrenal insufficiency early.
When oral antifungals need to be coprescribed with inhaled or oral corticosteroids, voriconazole could be considered an alternative to itraconazole as its inhibitory effects on CYP3A4 are lesser.
Patients being initiated on inhaled corticosteroids and itraconazole should be counselled about this potential drug interaction, and to report to the clinician if they observe any clinical signs of Cushing’s syndrome.
Patient consent for publication
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: VKG, VT, VPP and VNM. The following authors gave final approval of the manuscript: VKG, VT, VPP and VNM.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.