Hypothalamic-pituitary-adrenal axis suppression in asthma: A glucocorticoid receptor polymorphism may protect.

BACKGROUND: Asthmatic children on corticosteroids can develop hypothalamic-pituitary-adrenal axis suppression (HPAS). Single nucleotide polymorphisms (SNPs) rs242941 and rs1876828 of the corticotrophin-releasing hormone receptor 1 (CRHR1) gene were associated with lower stimulated cortisol (F) levels, whereas rs41423247 of the glucocorticoid receptor (NR3C1) gene was associated with higher basal F levels. The objective of the current study was to confirm whether these three SNPs are associated with HPAS in asthmatic children. METHODS: DNA was extracted from saliva obtained from 95 asthmatic children, who had previously undergone basal F and metyrapone testing. Thirty-six children were classified as suppressed. Non-suppressed children were subclassified according to their post-metyrapone adrenocorticotropin (PMTP ACTH) level into a middle (106-319 pg/mL) and a high (>319 pg/mL) ACTH response group. TaqMan® polymerase chain reaction assays were utilized. RESULTS: Only rs41423247 was inversely associated with HPAS (OR = 0.27 [95% CI 0.06-0.90]). Its GC genotype was inversely associated with HPAS (log odds = -1.28, P = .021). √PMTP ACTH was associated with CC (effect size = 10.85, P = .005) and GC genotypes (effect size = 4.06, P = .023). The C allele is inherited as a dominant trait (effect size = -1.31 (95% CI -2.39--0.33; P = .012). In the high ACTH response group, both genotypes affected the PMTP ACTH (effect sizes 1.41 and 15.46; P-values .023 and <2 × 10-26 for GC and CC, respectively). CONCLUSIONS: The C allele of rs41423247 was found to be protective against HPAS. CC genotype is associated with the highest PMTP ACTH response.

Performance of glucagon stimulation test in diagnosing central adrenal insufficiency in children when utilising the Roche Elecsys® cortisol II assay: a pilot study.

OBJECTIVES: The glucagon stimulation test (GST) is used for the simultaneous assessment of central adrenal insufficiency (CAI) and growth hormone deficiency. The new Roche cortisol II (C II) assay was recently introduced, confounding interpretation of the GST. The performance of the GST in diagnosing central adrenal insufficiency (CAI), utilising the C II assay, was therefore compared with that of the overnight metyrapone test (ONMTPT). METHODS: A diagnostic accuracy study was performed by retrospectively analysing folders and laboratory records of 25 children and adolescents investigated for hypopituitarism with the GST and the ONMTPT between September 2016 and December 2019. The peak serum cortisol (C) of the GST, the post-metyrapone serum 11-deoxycortisol and adrenocorticotropin levels of the ONMTPT were recorded. Diagnostic performance of the GST at a previously suggested cut-off of 374 nmol/L was evaluated. RESULTS: Seventeen boys and 8 girls, aged 1.7-16.3 years (median 7.3 years) were identified. The sensitivity of the post-GST C-level at 374 nmol/L was 0.40 (95% confidence interval [CI] 0.17-0.69), specificity 0.64 (95% CI 0.39-0.84), positive predictive value 0.44 (95% CI 0.19-0.73), negative predictive value 0.60 (95% CI 0.36-0.80), accuracy 0.54 (95% CI 0.35-0.72), positive likelihood ratio (+LR) 0.93 (95% CI 0.49-1.77) and negative LR 1.12 (95% CI 0.40-3.15). The area under the receiver of operating characteristics (ROC) curve was 0.379 (95% CI 0.142-0.615). CONCLUSIONS: This study suggests that the GST at any C II cut-off cannot replace the ONMTPT as a diagnostic test for CAI in children. Findings should be confirmed in a larger study.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids--more common than expected?

BACKGROUND: Hypothalamic pituitary adrenal axis suppression (HPAS) when treating asthmatic children with inhaled corticosteroids (ICS) is thought to be rare. OBJECTIVE: To determine the prevalence of HPAS in asthmatic children treated with ICS and nasal steroids (NS). METHODS: Twenty-six asthmatic children were recruited. Clinical features of HPAS, height, weight, height and weight velocity, steroid dose, adherence, symptom control and lung functions were documented. Metyrapone test was performed if the serum cortisol was > 83 nmol/L (> 3 microg/dL). RESULTS: No child had a serum cortisol < 83 nmol/L (< 3 microg/dL). Prevalence of HPAS was 35 (CI = 17%-56%). Daily NS dose/ m2 and cumulative NS dose/m2 were significantly (p = 0.03) inversely correlated with the post-metyrapone ACTH (r = -0.42 for both). Current ICS dose was not associated with the post-metyrapone ACTH (r = 0). There was a weak correlation with the daily ICS dose/m2 (r = -0.12) and cumulative ICS dose/m2 (r = -0.26). CONCLUSIONS: A third of asthmatic children on ICS and NS develop HPAS. Contributing factors are the use of NS, body size and cumulative dose of ICS.

Screening for hypothalamic-pituitary-adrenal axis suppression in asthmatic children remains problematic: a cross-sectional study.

OBJECTIVE: To determine which parameter is the most useful screening test for hypothalamic-pituitary-adrenal suppression in asthmatic children. DESIGN: Cross-sectional study. SETTING: Paediatric allergy clinics in Cape Town, South Africa. PARTICIPANTS: 143 asthmatic children of mostly mixed ancestry, aged 5-12 years. OUTCOME MEASURES: Primary outcome measures included Spearman correlation coefficients (r) calculated between the postmetyrapone (PMTP) serum adrenocorticotropic hormone (ACTH), 11-deoxycortisol (11DOC), 11DOC+ cortisol (C) and height, weight, height velocity, weight velocity, change in systolic blood pressure from supine to standing, early morning urinary free cortisol (UFC), morning C, ACTH and dehydroepiandrosterone sulfate (DHEAS). Secondary outcome measures were the receiver operating characteristics (ROC) curve and the diagnostic statistics for the most promising test. RESULTS: All screening variables were weakly correlated with the three PMTP outcomes. Only DHEAS and UFC (nmol/m(2)) were statistically significant-DHEAS for PMTP ACTH and 11DOC (r=0.20, p=0.025 and r=0.21, p=0.017); UFC (nmol/m(2)) for PMTP 11DOC and 11DOC+C (r=0.19, p=0.033 and r=0.20, p=0.022). The area under ROC curve for DHEAS in the 5-year to 9-year age group was 0.69 (95% CI 0.47 to 0.92). At DHEAS cut-off of 0.2 µmol/L: sensitivity=0.88 (CI 0.47 to 1.00), specificity=0.61 (CI 0.42 to 0.78), positive predictive value=0.37 (CI 0.16 to 0.62), negative predictive value=0.95 (CI 0.75 to 1.00), accuracy=0.67 (CI 0.50 to 0.81), positive likelihood ratio=2.26 (CI 1.35 to 3.78), negative likelihood ratio=0.20 (CI 0.03 to 1.30). CONCLUSIONS: No parameter is useful as a universal screening test. DHEAS may be suitable to exclude HPAS before adrenarche. Further research is needed to confirm these findings and identify factors, for example, genetic that may predict or protect against HPAS.

Biceps skin-fold thickness may detect and predict early lipoatrophy in HIV-infected children.

BACKGROUND: The prevalence of potentially stigmatizing lipoatrophy in children receiving antiretroviral therapy in Southern Africa is high, affecting around a third of children. Early diagnosis of lipoatrophy is essential for effective intervention to arrest progression. METHODS: Prepubertal children receiving antiretroviral therapy were recruited from a hospital-based family HIV clinic in Cape Town and followed up prospectively. Lipoatrophy was identified and graded by consensus between 2 HIV pediatricians. A dietician performed anthropometric measurements of trunk and limb fat. Anthropometric measurements in children with and without lipoatrophy were compared using multivariable linear regression adjusting for age and gender. The most discerning anthropometric indicators of lipoatrophy underwent receiver operating characteristic curve analysis. The precision of anthropometric measurements performed by an inexperienced healthcare worker was compared with that of a research dietician. RESULTS: Of 100 recruits, 36 had lipoatrophy at baseline and a further 9 developed lipoatrophy by 15-month follow-up. Annual incidence of lipoatrophy was 12% (confidence interval [CI]: 5-20%) per person-year of follow-up. A biceps skin-fold thickness <5 mm at baseline had a sensitivity of 89% (CI: 67-100%) and a specificity of 60% (CI: 46-75%) for predicting development of lipoatrophy by 15-month follow-up. Negative and positive predictive values were 97% (CI: 91-100%) and 32% (CI: 14-50%). CONCLUSION: Biceps skin-fold thickness <5 mm in prepubertal children exposed to thymidine analogue-based antiretroviral therapy may be a useful screening tool to identify children who are likely to develop lipoatrophy. The variation in precision of measurements performed by an inexperienced healthcare worker only marginally impacted performance.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic school children.

BACKGROUND AND OBJECTIVE: Hypothalamic-pituitary-adrenal axis suppression (HPAS) when treating children with corticosteroids is thought to be rare. Our objective was to determine the prevalence of and predictive factors for various degrees of HPAS. METHODS: Clinical features of HPAS, doses, adherence, asthma score, and lung functions were recorded in 143 asthmatic children. The overnight metyrapone test was performed if morning cortisol was >83 nmol/L. Spearman correlations coefficients (r) were calculated between 3 postmetyrapone outcomes and each continuous variable. A multiple linear regression model of √postmetyrapone adrenocorticotropic hormone (ACTH) and a logistic regression model for HPAS were developed. RESULTS: Hypocortisolemia was seen in 6.1% (1.8-10.5), hypothalamic-pituitary suppression (HPS) in 22.2% (14.5-29.9), adrenal suppression in 32.3% (23.7-40.9), HPAS in 16.3% (9.3-23.3), and any hypothalamic-pituitary-adrenal axis dysfunction in 65.1% (56.5-72.9). Log daily nasal steroid (NS) dose/m(2) was associated with HPAS in the logistic regression model (odds ratio = 3.7 [95% confidence interval: 1.1-13.6]). Daily inhaled corticosteroids (ICSs) + NS dose/m(2) predicted HPAS in the univariate logistic regression model (P = .038). Forced expiratory volume in 1 second/forced vital capacity <80% was associated with HPAS (odds ratio = 4.1 [95% confidence interval: 1.0-14.8]). Daily ICS + NS/m(2) dose was correlated with the postmetyrapone ACTH (r = -0.29, P < .001). BMI (P = .048) and percent adherence to ICS (P < .001) and NS (P = .002) were predictive of √postmetyrapone ACTH (R(2) = .176). CONCLUSIONS: Two-thirds of children on corticosteroids may have hypothalamic-pituitary-adrenal axis dysfunction. In one-third, central function had recovered but adrenal suppression persisted. Predictive factors for HPAS are NS use, BMI, and adherence to ICS and NS.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids (Part 2)--the risk as determined by gold standard adrenal function tests: a systematic review.

The evidence for hypothalamic-pituitary-adrenal axis (HPA) suppression by inhaled corticosteroids (ICS) was found to be conflicting. Reviewers have not distinguished between gold standard and basal adrenal function tests. The utility of the latter is limited by physiological and pathological variability as well as by methodological concerns. The risk of HPA suppression in asthmatic children and adolescents treated with ICS, as determined by gold standard adrenal function tests, needs to be established. A systematic review of the literature from January 1973 to July 2005 was performed. The Medline and Cochrane databases were searched, the reference lists of retrieved articles were inspected and pharmaceutical companies were approached. Randomized-controlled trials, cohort and case-control studies designed to detect HPA suppression caused by ICS, diagnosed by the insulin tolerance test (ITT) or the metyrapone test, performed on asthmatics of all ages not on oral steroids, were included and assessed for methodological quality. Of the 22 identified studies only four met the criteria for inclusion. All of these were published before 1988 and only one was methodologically sound. The cohort study showed that the baseline risk for HPA suppression is 0% while the absolute risk is 100% in asthmatic children treated with a beclomethasone dipropionate metered dose inhaler at a dose of 250-600 mug/m(2)/day for 6-42 months. As suggested by other observations these results could be generalized to other ICS. They may be of clinical significance especially if children are subjected to stress. Further research is needed to establish the cumulative dose for all ICS at which HPA suppression will be precipitated. Guidelines for future trials are suggested.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled corticosteroids: part 1. Which test should be used?

The effect of inhaled corticosteroids (ICS) on the hypothalamic-pituitary-adrenal axis (HPA) has been regarded as a 'benign physiological response'. A recent survey suggests that adrenal crisis might be more common in asthmatic children on ICS than previously thought. The clinical features of adrenal insufficiency are non-specific and can easily be missed. Accurate biochemical assessment of the axis is therefore mandatory. A review of the literature determined that all basal adrenal function tests, including plasma cortisol profiles, cannot identify which children can respond to stress. There is no evidence to suggests that the degree of the physiological adjustment of the HPA to ICS predicts clinically significant HPA suppression. Only gold standard adrenal function tests can assess the integrity of the whole axis. Of the two available tests, the correctly performed overnight metyrapone test (with ACTH levels) is safe and better by far. The use of cortisol profiles should only be used to demonstrate differences in systemic activity of various ICS and delivery devices. Regulatory bodies should insist on trials that evaluate the HPA with a gold standard adrenal function test before it is declared safe and allowed to be marketed. A re-analysis of studies that have utilized gold standard adrenal function tests only might identify the lowest safe dose and duration of ICS.