ASTHMA TREATMENT AND THE HPA AXIS - Greenberger · Prestimulation and peak serum cortisol values following the administration of 1 µg of cosyntropin at baseline (top) and at 30 days

ASTHMA TREATMENT ASTHMA TREATMENT

AND THE HPA AXISAND THE HPA AXIS

Paul A. Greenberger, M.D.Paul A. Greenberger, M.D.

7/12/20107/12/2010

10:3010:30--10:5010:50

ObjectivesObjectives

�� To review HPA axis suppression and its To review HPA axis suppression and its

clinical significance in adults and childrenclinical significance in adults and children

�� To describe methods for diagnosing HPA To describe methods for diagnosing HPA

axis suppressionaxis suppression

�� To explain the implication on selection of To explain the implication on selection of

treatment for asthma and allergic diseasestreatment for asthma and allergic diseases








The HPA AxisThe HPA Axis

Exogenous Prednisone 7.5mg or Exogenous Prednisone 7.5mg or

Dexamethasone 0.75mg for 3+ WeeksDexamethasone 0.75mg for 3+ Weeks…………..

�� Decreased CRHDecreased CRH

�� Decreased ACTH Decreased ACTH

�� Decreased cortisol (0800 concentration)Decreased cortisol (0800 concentration)

�� Decreased response to stimulation with Decreased response to stimulation with

cosyntropin 1 mcg (low dose stimulation)cosyntropin 1 mcg (low dose stimulation)

Implications of HPA SuppressionImplications of HPA Suppression

�� No clinical adverse effects and asymptomaticNo clinical adverse effects and asymptomatic

�� Subnormal secretion of Cortisol (at baseline or Subnormal secretion of Cortisol (at baseline or

with stimulation) and asymptomaticwith stimulation) and asymptomatic…….or.or

�� Suppression of growthSuppression of growth

�� OsteopeniaOsteopenia

�� Severe Myalgia, Weakness, Fatigue Severe Myalgia, Weakness, Fatigue

�� Inability to respond to stress (surgery, shock, Inability to respond to stress (surgery, shock,

sepsis etc)sepsis etc)

�� Cushingoid obesity/syndromeCushingoid obesity/syndrome








Methods for DiagnosisMethods for Diagnosis

�� Testing the HypothalamusTesting the Hypothalamus

�� Testing the PituitaryTesting the Pituitary

�� Testing the AdrenalsTesting the Adrenals

�� Testing the whole axisTesting the whole axis

Testing Adrenal FunctionTesting Adrenal Function

�� Insulin Tolerance Test (whole axis)Insulin Tolerance Test (whole axis)-- unpleasant unpleasant (need glucose (need glucose <40mg/dL); <40mg/dL); risky if risky if cardiovascular disease, elderly, seizure disorderscardiovascular disease, elderly, seizure disorders

�� ACTHACTH-- CosyntropinCosyntropin……..(can miss secondary ..(can miss secondary adrenal insufficiency with 250 mcg)adrenal insufficiency with 250 mcg)

�� Metyrapone (not available in U.S.) testMetyrapone (not available in U.S.) test--risk of risk of temporary adrenal insufficiencytemporary adrenal insufficiency

�� CorticotropinCorticotropin--Releasing Hormone (CRH) has Releasing Hormone (CRH) has lower sensitivity (76%) but high specificity lower sensitivity (76%) but high specificity (96%)(96%)

Relevant to AsthmaRelevant to Asthma……

Adrenal InsufficiencyAdrenal Insufficiency

Primary Primary

((AddisonsAddisons DiseaseDisease----

Autoimmune, TB)Autoimmune, TB)

SecondarySecondary

((CorticosteroidsCorticosteroids))

Diagnosis of Secondary Adrenal Diagnosis of Secondary Adrenal

Insufficiency from CorticosteroidsInsufficiency from Corticosteroids

�� Background: Oral or high dose orally Background: Oral or high dose orally

inhaled corticosteroids block release of inhaled corticosteroids block release of

CRH and ACTHCRH and ACTH

�� Low cortisolLow cortisol

�� Impaired response to ACTH (Cosyntropin) Impaired response to ACTH (Cosyntropin)

low doselow dose--1 mcg vs higher dose1 mcg vs higher dose--250 mcg)250 mcg)

�� Impaired or no response to CRHImpaired or no response to CRH

Exogenous Prednisone 7.5mg or Exogenous Prednisone 7.5mg or

Dexamethasone 0.75mg for 3+ WeeksDexamethasone 0.75mg for 3+ Weeks…………..

�� Decreased CRHDecreased CRH

�� Decreased ACTH Decreased ACTH

�� Decreased 0800 cortisolDecreased 0800 cortisol

__________________________________________________________________________________

�� Is there low basal cortisol (Is there low basal cortisol (<5 mcg/dL or if 5<5 mcg/dL or if 5--13 13 mcg/dL, then needs stimulation test)?mcg/dL, then needs stimulation test)?

�� Is there a normal stimulated response of cortisol Is there a normal stimulated response of cortisol mcg/dL? (LST mcg/dL? (LST >> 22 mcg/dL, HST 22 mcg/dL, HST >> 30 mcg/dL)30 mcg/dL)

�� If subnormal response to stimulation, need If subnormal response to stimulation, need insulin tolerance test or metyrapone testinsulin tolerance test or metyrapone test

Primary Study OutcomesPrimary Study Outcomes——is there is there

blunted or reducedblunted or reduced

�� Basal Basal HPA AxisHPA Axis--Serum Cortisol AUC Serum Cortisol AUC 00--24 hr24 hr

�� DynamicDynamic HPA AxisHPA Axis--response to low dose response to low dose

cosyntropincosyntropin

�� Clinically meaningful suppressionClinically meaningful suppression is when is when

cosyntropin response is impairedcosyntropin response is impaired……in in

patients with asthma patients with asthma








Mean (± SE) percent change in serum cortisol AUC0–24 h following 29 days of treatment with PBO, CIC 640, CIC 1280, FP 880, and FP 1760.

Szefler S et al. Chest 2005;128:1104-1114

©2005 by American College of Chest Physicians

FPFP--CFCCFC

Mean (± SE) change from baseline in serum cortisol A UC0–24h over time for PBO, CIC 640, CIC 1280, FP 880, and FP 1760.



Prestimulation and peak serum cortisol values follo wing the administration of 1 µg of cosyntropin at baseline (top) and at 30 days end of study (middle).



Systemic Absorption of Inhaled Systemic Absorption of Inhaled

Corticosteroid Dry Power Inhalers Corticosteroid Dry Power Inhalers

in Patients Mattersin Patients Matters

�� Less in patients with asthma compared to Less in patients with asthma compared to

normal subjectsnormal subjects

�� Drug specificDrug specific

Mean (SE) plasma concentrations of (A) fluticasone propionate and (B) budesonide in healthy subjects and subjects with moderately severe asthma .

Harrison T W , Tattersfield A E Thorax 2003;58:258- 260

©2003 by BMJ Publishing Group Ltd and British Thoracic Society

AJRCCM 2005;165:1377AJRCCM 2005;165:1377--8383

Plasma Cortisol AUC 2000 to 0800Plasma Cortisol AUC 2000 to 0800

Plasma Cortisol AUC 2000 to 0800Plasma Cortisol AUC 2000 to 0800

Is There Additive HPA Suppression Is There Additive HPA Suppression

When There Is Nasal and Bronchial When There Is Nasal and Bronchial

Administration?Administration?

�� Yes or No?Yes or No?

�� Which route results in more systemic Which route results in more systemic

absorption?absorption?

ALLERGY ASTHMA PROC 2005; ALLERGY ASTHMA PROC 2005;

25:11525:115--2020

�� PATIENTS PATIENTS ≥≥ 12 YEARS12 YEARS

�� FLUTICASONE PROPIONATE (FP)FLUTICASONE PROPIONATE (FP)

�� ORALLY INHALED FP 88 OR 220 MCG BID ORALLY INHALED FP 88 OR 220 MCG BID

BY METERED DOSE INHALERBY METERED DOSE INHALER……26 WEEKS26 WEEKS

�� FP 250 MCG OR FP/SALMETEROL 250/50 FP 250 MCG OR FP/SALMETEROL 250/50

BY DISKUS (DRY POWDER)BY DISKUS (DRY POWDER)……12 WEEKS12 WEEKS

�� NASAL FPNASAL FP

�� AM CORTISOL AND POSTAM CORTISOL AND POST--STIMULATIONSTIMULATION

METHODS TO DETECT ABNORMAL METHODS TO DETECT ABNORMAL

RESPONSESRESPONSES

�� BASAL CORTISOL 0800.. ? WERE BASAL CORTISOL 0800.. ? WERE < 5 MCG/DL< 5 MCG/DL

�� POST STIMULATION PEAK CORTISOLPOST STIMULATION PEAK CORTISOL……< 18 MCG/DL< 18 MCG/DL

�� POST STIMULATION RISE OF < 7 MCG/DLPOST STIMULATION RISE OF < 7 MCG/DL

Is There Additive HPA Suppression Is There Additive HPA Suppression

When There Is Nasal and Bronchial When There Is Nasal and Bronchial

Administration?Administration?

�� Yes or No? NOYes or No? NO

�� TRIVIA QUESTION: Which route results in TRIVIA QUESTION: Which route results in

more SYSTEMIC absorption? NASALmore SYSTEMIC absorption? NASAL

SUMMARYSUMMARY

�� COMBINATIONS OF INTRANASAL AND ORALLY COMBINATIONS OF INTRANASAL AND ORALLY

INHALED CORTICOSTEROIDS IN INHALED CORTICOSTEROIDS IN

RECOMMENDED DOSES WOULD NOT CAUSE RECOMMENDED DOSES WOULD NOT CAUSE

HPA AXIS ABNORMALITIESHPA AXIS ABNORMALITIES

�� FIRST PASS EFFECT (LIVER METABOLISM) FIRST PASS EFFECT (LIVER METABOLISM)

MINIMIZES ORAL BIOAVAILABILITY MINIMIZES ORAL BIOAVAILABILITY

(FLUTICASONE, MOMETASONE, BUDESONIDE, (FLUTICASONE, MOMETASONE, BUDESONIDE,

CICLESONIDE < BECLOMETHASONE CICLESONIDE < BECLOMETHASONE

DIPROPIONATE)DIPROPIONATE)

Documents

ASTHMA TREATMENT AND THE HPA AXIS - Greenberger · Prestimulation and peak serum cortisol values following the administration of 1 µg of cosyntropin at baseline (top) and at 30 days