Screening for hypothalamic-pituitary

Screening for hypothalamic-pituitary-adrenal
suppression in asthmatic children on
corticosteroids is not possible when employing
clinical & static biochemical parameters
E. Zöllner1), C. Lombard2), U. Galal2) ,
S.F Hough1), E.M. Irusen1), E. Weinberg3)
1)
Endocrine & Allergy Units, Tygerberg Hospital,
2) Biostatistics Unit, Medical Research Council, Cape Town, South Africa
3) UCT Lung Institute & Red Cross Children’s Hospital
Background
• Up to 2/3 of all asthmatic children on corticosteroid (CS)
therapy were found to have a degree of hypothalamic pituitary
adrenal axis suppression (HPAS).
• HPAS may not be recognised until the child presents with an
adrenal crisis or non-specific symptoms.
• Only dynamic testing will identify which children are at risk
of adrenal crisis, but this is impractical.
• A screening test should thus be identified.
Objective
To determine which clinical/biochemical parameter is
the most useful screening test for HPAS in asthmatic
children.
Methods
• 143 asthmatic children, 5-18 years old, on inhaled
corticosteroids (ICS), with/without additional CS therapy,
were recruited from the allergy units of Tygerberg & Red
Cross Children’s Hospitals and the UCT Lung Institute.
• Height, weight, height velocity (HV), weight velocity (WV),
change in systolic BP from recumbent to standing (ΔSBP)
were recorded.
• Early morning urine (06:00-07:00h) for urinary free cortisol
(UFC) was collected.
• Morning serum (08:00-09:00h) cortisol (C), ACTH &
dehydroepiandrosterone sulphate (DHEAS) was obtained.
• Overnight metyrapone (MTP) test was performed if C > 83nmol/l.
Table 1: Spearman correlations between PMTP
ACTH, 11 DOC, 11DOC+C and screening variables
Screening Variable
ACTH
11DOC
r
r
P
P
11DOC+C
r
P
Height SDS
0.12
0.186 -0.13
0.120 -0.05 0.542
Weight SDS
0.10
0.262 -0.01
0.195 -0.10 0.279
HV SDS
0
0.999 0.07
0.420 0.07
0.452
WV SDS
-0.04 0.638 0.07
0.421 0.09
0.302
ΔSBP
0
0.992 0.05
0.538 -0.04 0.616
C
0.05
0.538 0.08
0.374 0.12
0.176
ACTH
0.10
0.248 0.04
0.640 0.10
0.263
DHEAS
0.20
0.025 0.21
0.017 0
0.995
UFC (nmol/m2)
0.08
0.379 0.19
0.033 0.20
0.022
UFC (nmol/mmolCr) 0.08
0.397 0.14
0.111 0.16
0.064
Table 2: HPAS* by age group and gender
Age (years)
Category
Males
Females
Total
5-9
10-14
15-18
Total
No HPAS
18
32
9
59
HPAS
2
6
2
10
Total
20
38
11
69
No HPAS
14
25
9
48
HPAS
6
3
1
10
Total
20
28
10
58
No HPAS
32
57
18
107
HPAS
8
9
3
20
Total
40
66
21
127§
* PMTP ACTH<106pg/ml AND 11DOC<208nmol/l AND 11DOC+C<400nmol/l
§ Number of patients who had DHEAS levels measured
0
.25
.5
.75
1
Fig. 1: Predicted ROC curves of DHEAS versus HPAS* by age
from a ROC regression model.
0
.25
DHEAS
.5
1-Specificity
.75
5-9 years
10-14 years
15-18 years
1
0.00
0.25
0.50
0.75
1.00
Fig. 2: ROC curve of DHEAS versus HPAS for 5-9 yr age group
0.00
0.25
Area under ROC curve = 0.6935
(0.4716-0.9155)
0.50
1 - Specificity
0.75
1.00
Table 3: Diagnostic performance of DHEAS
at 0.2 µmol/l for 5-9 year old age group
Index of test validity
Value 95% Confidence interval
Sensitivity
Specificity
Positive predictive value
Negative predictive value
Accuracy
Positive likelihood ratio
Negative likelihood ratio
0.87
0.61
0.37
0.95
0.58
2.26
0.20
0.47-1.00
0.42-0.78
0.16-0.62
0.75-1.00
0.55-0.81
1.35-3.78
0.03-1.30
Conclusions & Recommendations
• No clinical or static biochemical parameter is useful as a
universal screening test for HPAS in asthmatic children.
• DHEAS may be useful to rule out HPAS in children prior to
adrenarche.
• Basal adrenal function tests are not suitable for research studies.
• The utility of DHEAS as a screening tool needs to be confirmed
in a larger study.
Acknowledgements
Financial support: Medical Research Council
University of Stellenbosch
SA Thoracic Society
Harry Crossley Foundation
Red Cross Children’s Hospital
Recruitment: Sisters Hill, Poggenpoel, Pontac, Steyn,
All paediatricians & MOs
Lab support: GSH & TBH NHLS, BARC, Roche, B. Fenemore
Disclosure Statement
The authors have nothing to declare.
Assays
• Serum total C & UFC were measured with the ADVIA Centaur
automated chemiluminescent assay.
• 11-desoxycortisol (11DOC) levels were established by a
competitive RIA (Biosource).
• ACTH was measured by an automated sequential immunometric
assay (Immulite 2000).
• DHEAS levels were determined by an electrochemiluminescence
immunoassay (Modular Analytics E170).
Statistical Analysis
• Spearman correlations (r) between the post-metyrapone
(PMTP) ACTH, 11DOC, 11DOC+C and each screening
variable were determined.
• A ROC regression model for DHEAS was used to look at
association of age & sex.
• A receiver operating characteristics (ROC) curve was drawn
for the most promising test.
• Diagnostic statistics and their 95% confidence intervals were
calculated.
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