11C-methionine PET aids localization of microprolactinomas in patients with intolerance or resistance to dopamine agonist therapy.

PURPOSE: To assess the potential for 11C-methionine PET (Met-PET) coregistered with volumetric magnetic resonance imaging (Met-PET/MRCR) to inform clinical decision making in patients with poorly visualized or occult microprolactinomas and dopamine agonist intolerance or resistance. PATIENTS AND METHODS: Thirteen patients with pituitary microprolactinomas, and who were intolerant (n = 11) or resistant (n = 2) to dopamine agonist therapy, were referred to our specialist pituitary centre for Met-PET/MRCR between 2016 and 2020. All patients had persistent hyperprolactinemia and were being considered for surgical intervention, but standard clinical MRI had shown either no visible adenoma or equivocal appearances. RESULTS: In all 13 patients Met-PET/MRCR demonstrated a single focus of avid tracer uptake. This was localized either to the right or left side of the sella in 12 subjects. In one patient, who had previously undergone surgery for a left-sided adenoma, recurrent tumor was unexpectedly identified in the left cavernous sinus. Five patients underwent endoscopic transsphenoidal selective adenomectomy, with subsequent complete remission of hyperprolactinaemia and normalization of other pituitary function; three patients are awaiting surgery. In the patient with inoperable cavernous sinus disease PET-guided stereotactic radiosurgery (SRS) was performed with subsequent near-normalization of serum prolactin. Two patients elected for a further trial of medical therapy, while two declined surgery or radiotherapy and chose to remain off medical treatment. CONCLUSIONS: In patients with dopamine agonist intolerance or resistance, and indeterminate pituitary MRI, molecular (functional) imaging with Met-PET/MRCR can allow precise localization of a microprolactinoma to facilitate selective surgical adenomectomy or SRS.

The appearance of the adrenal glands on computed tomography in multiple endocrine neoplasia type 1.

AIMS: To review the morphology of the adrenal glands in multiple endocrine neoplasia type 1 (MEN1) on computed tomography (CT) to compare the results with established normal values for adrenal size and nodularity and to correlate adrenal size with serum cortisol secretory dynamics. MATERIALS AND METHODS: Two observers independently reviewed the adrenal CT in 28 patients with MEN1, measuring the maximum width of the body of the gland and the medial and lateral limbs. Incidence and location of nodules >5 mm within the gland were recorded. Following exclusion of known cases of Cushing's syndrome, adrenal gland size was compared with previously documented normative data. Adrenal gland size was compared between patients with normal and abnormal cortisol dynamics. RESULTS: Comparison of mean adrenal size in MEN1 patients with normative data showed that the adrenal limbs were significantly larger in MEN1 than normal (P<0.0001 in all four limbs). Adrenal body was also significantly larger (P<0.05). Nodules were demonstrated in 17 (60%) of patients (versus 0.4-2% in the normal population). No statistically significant correlation was demonstrated between adrenal limb hyperplasia and abnormal cortisol dynamics. CONCLUSIONS: In patients with MEN1, adrenal limb hyperplasia and adrenal nodules are significantly more common than in the normal population, a phenomenon not previously documented in a quantitative manner. There was no significant correlation between adrenal limb hyperplasia and abnormal cortisol dynamics.

Distinguishing phenotypes of childhood wheeze and cough using latent class analysis.

Airway disease in childhood comprises a heterogeneous group of disorders. Attempts to distinguish different phenotypes have generally considered few disease dimensions. The present study examines phenotypes of childhood wheeze and chronic cough, by fitting a statistical model to data representing multiple disease dimensions. From a population-based, longitudinal cohort study of 1,650 preschool children, 319 with parent-reported wheeze or chronic cough were included. Phenotypes were identified by latent class analysis using data on symptoms, skin-prick tests, lung function and airway responsiveness from two preschool surveys. These phenotypes were then compared with respect to outcome at school age. The model distinguished three phenotypes of wheeze and two phenotypes of chronic cough. Subsequent wheeze, chronic cough and inhaler use at school age differed clearly between the five phenotypes. The wheeze phenotypes shared features with previously described entities and partly reconciled discrepancies between existing sets of phenotype labels. This novel, multidimensional approach has the potential to identify clinically relevant phenotypes, not only in paediatric disorders but also in adult obstructive airway diseases, where phenotype definition is an equally important issue.

Wheeze and asthma prevalence and related health-service use in white and south Asian pre-schoolchildren in the United Kingdom.

BACKGROUND: Epidemiological data for south Asian children in the United Kingdom are contradictory, showing a lower prevalence of wheeze, but a higher rate of medical consultations and admissions for asthma compared with white children. These studies have not distinguished different asthma phenotypes or controlled for varying environmental exposures. OBJECTIVE: To compare the prevalence of wheeze and related health-service use in south Asian and white pre-schoolchildren in the United Kingdom, taking into account wheeze phenotype (viral and multiple wheeze) and environmental exposures. METHODS: A postal questionnaire was completed by parents of a population-based sample of 4366 white and 1714 south Asian children aged 1-4 years in Leicestershire, UK. Children were classified as having viral wheeze or multiple trigger wheeze. RESULTS: The prevalence of current wheeze was 35.6% in white and 25.5% in south Asian 1-year-olds (P<0.001), and 21.9% and 20.9%, respectively, in children aged 2-4 years. Odds ratios (ORs) (95% confidence interval) for multiple wheeze and for viral wheeze, comparing south Asian with white children, were 2.21 (1.19-4.09) and 1.43 (0.77-2.65) in 2-4-year-olds after controlling for socio-economic conditions, environmental exposures and family history. In 1-year-olds, the respective ORs for multiple and viral wheeze were 0.66 (0.47-0.92) and 0.81 (0.64-1.03). Reported GP consultation rates for wheeze and hospital admissions were greater in south Asian children aged 2-4 years, even after adjustment for severity, but the use of inhaled corticosteroids was lower. CONCLUSIONS: South Asian 2-4-year-olds are more likely than white children to have multiple wheeze (a condition with many features of chronic atopic asthma), after taking into account ethnic differences in exposure to some environmental agents. Undertreatment with inhaled corticosteroids might partly explain their greater use of health services.

Serum IGF-I levels in the diagnosis and monitoring of acromegaly.

Insulin-Like Growth Factor-I (IGF-I) is a reliable marker of disease activity and growth hormone (GH) status in acromegaly, but its clinical utility has been hampered over the years by various issues including a lack of robust reference range data and variability in assay sensitivity and specificity. In acromegaly IGF-I correlates well with GH activity and nadir GH on oral glucose tolerance test (OGTT) and is the most sensitive and specific test in diagnosis, where serum IGF-I is persistently seen to be elevated to a range that is distinct from that in healthy individuals. However it should not be relied on exclusively for diagnosis or used as the sole indication of disease severity and GH burden. Successful medical or surgical treatment of acromegaly is usually associated with normalisation of serum IGF-I but there is discordance between GH and IGF-I in some patients. Patients with a normal IGF-I but an abnormal GH suppression to OGTT are at risk of relapse and therefore it should not be used alone to establish disease remission. In contrast to the diagnosis of acromegaly, there is also considerable overlap in serum IGF-I with normality after primary treatment of disease, even in the presence of persisting GH excess. Gender, age and prior radiotherapy alters the relationship between GH and IGF-I and reliance on one marker of disease activity such as IGF-I is particularly precarious in certain disease states. However an elevated serum IGF-I has been shown to be associated with excess mortality and normalising IGF-I normalises mortality making it a useful marker. The tightening up of the assays means that establishing absolute concentrations as well as standard deviation scores are essential to allow cross-study comparisons. This becomes especially important in the use of Pegvisomant, where IGF-I becomes the sole biochemical marker of disease activity.

Growth hormone deficiency and replacement in patients with treated Cushing's Disease, prolactinomas and non-functioning pituitary adenomas: effects on body composition, glucose metabolism, lipid status and bone mineral density.

BACKGROUND/AIMS: This study was designed to determine whether previous Cushing's disease (CD) or prolactinoma (PRL) could exert adverse effects additional to those of growth hormone (GH) deficiency as a consequence of variable degrees of prior hypogonadism or hypercatabolism. We report the effects of 5 years GH treatment in 124 GH deficiency adults; 42 patients with non-functioning pituitary adenomas (NFPA), 43 with treated PRL and 39 with treated CD. METHODS: Fasting plasma glucose, HbA(1c), lipoprotein profile, anthropometry and bone mineral density (BMD) were measured at baseline, 6 months and annually up to 5 years. RESULTS: Mean body mass index remained unchanged in the PRL group and tended to increase in the NFPA group. In contrast, body mass index decreased in the CD group. Decreases in waist and waist/hip ratio were seen in all groups at 6 months. Decreases in total cholesterol and low-density lipoprotein cholesterol were seen in all groups and remained sustained at 5 years. Plasma glucose and HbA(1c) increased at 6 months. Subsequently, plasma glucose returned to baseline values at 5 years; in contrast, HbA(1c )remained unchanged at the end of the study. Baseline lumbar spine and hip BMD were lower in the PRL and CD groups than in the NFPA group, decreased over 1 year in all groups and subsequently increased by 2 years in NFPA with a subsequent increase in lumbar spine BMD in PRL and CD groups delayed to 3-5 years. CONCLUSIONS: Baseline characteristics and response to GH replacement are qualitatively similar in NFPA, PRL and CD patients. Because improvements in BMD occur later in PRL and CD patients, an extended trial of GH therapy may be indicated in those patients who were commenced on GH therapy as an additional treatment for reduced BMD.

Parental understanding of wheeze and its impact on asthma prevalence estimates.

The epidemiology of wheeze in children, when assessed by questionnaires, is dependent on parents' understanding of the term "wheeze". In a questionnaire survey of a random population sample of 4,236 children aged 6-10 yrs, parents' definition of wheeze was assessed. Predictors of a correct definition were determined and the potential impact of incorrect answers on prevalence estimates from the survey was assessed. Current wheeze was reported by 13.2% of children. Overall, 83.5% of parents correctly identified "whistling or squeaking" as the definition of wheeze; the proportion was higher for parents reporting wheezy children (90.4%). Frequent attacks of reported wheeze (adjusted odds ratio (OR) 3.0), maternal history of asthma (OR 1.5) and maternal education (OR 1.5) were significantly associated with a correct answer, while the converse was found for South Asian ethnicity (OR 0.6), first language not English (OR 0.6) and living in a deprived neighbourhood (OR 0.6). In summary, the present study showed that misunderstanding could lead to an important bias in assessing the prevalence of wheeze, resulting in an underestimation in children from South Asian and deprived family backgrounds. Prevalence estimates for the most severe categories of wheeze might be less affected by this bias and questionnaire surveys on wheeze should incorporate measures of parents' understanding of the term wheeze.

The therapy of pre-school wheeze: appropriate and fair?

The current study aimed to assess prevalence and distribution of use of asthma medication for wheeze in pre-school children in the community. We sent a postal questionnaire to the parents of a random population-based sample of 4,277 UK children aged 1-5 years; 3,410 participated (children of south Asian decent were deliberately over-represented). During the previous 12 months, 18% of the children were reported to have received bronchodilators, 8% inhaled corticosteroids (ICS) and 3% oral corticosteroids. Among current wheezers these proportions were 55%, 25%, and 12%, respectively. Use of ICS increased with reported severity of wheeze, but did not reach 60% even in the most severe category. In contrast, 42% of children receiving ICS reported no or very infrequent recent wheeze. Among children with the episodic viral wheeze phenotype, 17% received ICS compared with 40% among multiple-trigger wheezers. Use of ICS by current wheezers was less common in children of South Asian ethnicity and in girls. Although a high proportion of pre-school children in the community used asthma inhalers, treatment seemed to be insufficiently adjusted to severity or phenotype of wheeze, with relative under-treatment of severe wheeze with ICS, especially in girls and South Asian children, but apparent over-treatment of mild and episodic viral wheeze and chronic cough.

A novel point mutation in P450c17 (CYP17) causing combined 17alpha-hydroxylase/17,20-lyase deficiency.

CONTEXT: Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare cause of congenital adrenal hyperplasia and hypogonadism. Novel single amino acid changes in P450c17 provide potentially important insights into key structural domains for enzyme function. OBJECTIVE, DESIGN, AND SETTING: We report a novel missense mutation in P450c17 in a 17-yr-old female presenting with a malignant mixed germ cell tumor with yolk sac elements who demonstrated clinical and biochemical features of combined 17alpha-hydroxylase/17,20-lyase deficiency. METHODS: Quantitative urinary steroid analysis was performed by high resolution gas chromatography. All eight coding exons of CYP17 were PCR amplified and sequenced. The position of arginine at codon 96 was modeled using the CYP17 structure 2c17 (www.rcsb.org). The CYP17 genes were subcloned into pcDNA3, expressed in HEK-293 cells, and chromatographed. PATIENT AND RESULTS: 17alpha-Hydroxylase deficiency was confirmed by marked reductions in urinary and serum cortisol, androgens, and estradiol. Mutational analysis revealed a novel homozygous R96Q missense mutation in P450c17, affecting an amino acid in a key substrate-binding region of the enzyme, leading to complete inactivity. CONCLUSION: The description of a second missense mutation at codon 96 (R96W and R96Q) in the substrate-binding region of P450c17 provides strong evidence for the key role of this amino acid in 17alpha-hydroxylase/17,20-lyase function. An association between a malignant germ cell tumor and 17alpha-hydroxylase deficiency has not been reported previously, although the presence of gonadoblastoma in the ovary of a patient with this condition has recently been described.

Parents' accounts of wheeze and asthma related symptoms: a qualitative study.

AIMS: To examine parents' accounts of how they recognise and judge respiratory symptoms in children, and to investigate their interpretations of respiratory survey questions about wheeze, shortness of breath, and cough. METHODS: Qualitative study using semistructured interviews. Data were analysed using the constant comparative method. Nineteen parents of children aged under 6 years were recruited from a cohort of parents who had responded to an earlier respiratory symptom survey and from one general practice. RESULTS: Parents judged respiratory symptoms using a range of cues, including changes in the sound of breathing and changes in appearance and behaviour. Experiential resources and contextual factors played an important role in parents' judgements. Interpretations of questions about respiratory symptoms were varied, particularly in relation to the terms "attacks of wheeze" and "shortness of breath". Parents' descriptions of wheeze differed from descriptions of the sound of wheeze used in some survey questionnaires. Parents drew fine distinctions between different "types" of cough and identified a distinct "asthma" cough. CONCLUSIONS: Attention needs to be given to the complexity of reporting respiratory symptoms in children and to the importance of contextual factors in parents' judgements. We suggest that questions which require parents to report on children's internal feelings or states be avoided. Consideration should be given to providing parents with explicit direction on what cues to attend to or ignore in reporting symptoms, and to clarifying some questions that are currently used in clinical practice and in surveys.

Are all wheezing disorders in very young (preschool) children increasing in prevalence?

BACKGROUND: Distinct wheezing disorders co-exist in young (preschool) children, some of which (early transient wheeze and viral wheeze) are thought to be unrelated to atopy. Investigation of changes in prevalence of wheezing disorders in preschool children could provide important clues about underlying mechanisms responsible for increasing prevalence of asthma in schoolchildren. METHODS: Repeated population surveys of the prevalence of respiratory symptoms were done by parent-completed postal questionnaires in random samples of 1650 (1990) and 2600 (1998) caucasian children aged 1-5 years living in the county of Leicestershire, UK. FINDINGS: The response rates were 86% (1422 of 1650) in 1990 and 84% (2127 of 2522) in 1998. Between 1990 and 1998, there was a significant increase in the prevalance of reported wheeze ever (16% to 29%, p<0.0001), current wheeze (12% to 26%, p<0.0001), diagnosis of asthma (11% to 19%, p<0.0001), treatment for wheeze (15% to 26%, p<0.0001), and admission for wheeze or other chest trouble (6% to 10%, p<0.0001). The increase occurred both in children with viral wheeze (9% to 19%) and in those with the classic asthma pattern of wheezing with multiple triggers (6% to 10%). There was also an increase in transient early wheezers (3% to 5%), persistent wheezers (5% to 13%), and late-onset wheezers (6% to 8%), and in all severity groups. The increase could not be accounted for by putative household risk factors because these declined between the 2 years. INTERPRETATION: The fact that all preschool wheezing disorders increased (including viral wheeze) makes it probable that factors unrelated to atopy are implicated in the changing epidemiology of wheeze in childhood.

Prevalence of wheeze during childhood: retrospective and prospective assessment.

The question "Has your child ever had wheezing or whistling in the chest at any time in the past?" is a simple and widely used proxy measure for the lifetime prevalence of asthma. Our aim was to test its validity in a longitudinal survey, comparing retrospective recall with prospective assessment of lifetime prevalence. A population-based cohort of 1,422 children, surveyed twice previously, was studied again at age 8-13 yrs by postal questionnaire using standardized questions from the International Study of Asthma and Allergies in Childhood (ISAAC). Of those traced (1,190) questionnaires were returned by 89%. The prevalence of current wheeze was higher than in the previous surveys (20.5% versus 12.4% and 12.5%). Reported "wheeze ever" increased significantly from survey 1 (15.6%) to survey 2 (22.4%) and survey 3 (39.2%) and was very similar to the cumulative lifetime prevalence assessed prospectively over three surveys (42.8%). The retrospective question had a good negative predictive value (97%) and a reasonable positive predictive value (65%) compared to prospective assessment. Children reporting "wheeze ever" (but not current wheeze) in surveys 1 and 2 had at survey 3 an asthma prevalence higher than never-wheezers but lower than current-wheezers. It is concluded that retrospective recall of wheeze at age 8-13 yrs is a valid proxy measure for the lifetime prevalence of wheeze.

Recurrent cough: natural history and significance in infancy and early childhood.

We investigated the outcome for a sample of children in whom recurrent cough was reported in the preschool years to determine 1) whether they shared the characteristics attributed to cough variant asthma, and 2) the proportion who developed classical wheezy asthma at follow-up during the early school years. A cohort of children identified as having recurrent cough in the preschool period was reassessed during the early school years. Previously identified asymptomatic preschool children who remained symptom-free provided a comparison group with respect to current respiratory symptoms, lung function, bronchial reactivity to inhaled methacholine, atopic status, peak flow variability, and recorded night cough. The response rate was modest, with 41% attending the follow-up study; information on current symptoms was available from a further 16%. Ascertainment of current symptoms showed that 70 of 125 (56.0% [95% CI 47.3-64.5%]) were symptom-free at follow-up, 46 (36.8% [28.7-45.5%]) continued to have recurrent cough in the absence of colds, and 9 (7.2% [3.6-12.8%]) reported recent attacks of wheeze. When comparing the 46 children whose recurrent cough persisted from the preschool period through to follow-up with subjects from the asymptomatic comparison group, the former had significantly more night cough (50.0% vs. 16.8%; P< 0.01), were more likely to be treated (10.9% vs. 1.7%; P=0.01), or were diagnosed (26.1% vs. 5.7%; P < 0.001) as asthmatic. They also showed greater bronchial reactivity than their asymptomatic counterparts (1.23 mg/ml vs. 3.35 mg/ml; P=0.002). Atopic status and other indices of lung function were similar between groups. We conclude that there are a group of children with long-term recurrent cough who display features consistent with a diagnosis of cough variant asthma, but at 2-4 years of follow-up, few progress to develop asthma characterized by wheeze.

Night cough in a population-based sample of children: characteristics, relation to symptoms and associations with measures of asthma severity.

Nocturnal cough in asthma is a common but poorly understood phenomenon. The aims of this study were to determine the relationship between recorded night cough, reported night cough and current wheeze in a population-based sample of children previously identified as wheezy, and to examine the relationship of nocturnal cough to current symptoms, markers of asthma severity and environmental exposure. Children were reassessed in the early school years by measuring current symptoms, ventilatory function, bronchial reactivity, peak flow variability, respiratory symptom diaries and home monitoring of overnight cough, transcutaneous arterial oxygen saturation, room temperature and humidity. Night studies were performed on 59 asymptomatic children and 41 children with current wheeze. Cough occurred more frequently in current wheezers compared to asymptomatic children (16 out of 41 (39%) vs 11 out of 59 (19%)), and more cough episodes were recorded (median 3.5 vs 2.0). Night cough was not associated with bronchial reactivity, peak flow variability, degree of morning dip, mean overnight arterial oxygen saturation, ventilatory function, maternal smoking or treatment of asthma. However, it was associated with lower overnight air temperature. Although night cough is more common in current wheezers, there is poor agreement between recorded and reported night cough. Objective tests of asthma severity are of little use in predicting its presence in this age group. The sleeping environment deserves further study.

The natural history of respiratory symptoms in preschool children.

We studied the natural history of preschool respiratory symptoms in a population-based sample of children followed during the early school years. Current symptoms, ventilatory function, bronchial responsiveness to methacholine (BR), atopic status, and peak expiratory flow variability (PEFV) were assessed. Among those initially asymptomatic (210 subjects), 83.3% remained symptom-free, 6.7% started to wheeze, and 10% developed recurrent cough. Nearly half (46.9%) of the initial wheezing group (145 subjects) became symptom-free, 37.9% continued to wheeze, and 15.2% reported recurrent cough. Over half (56.0%) of the cough group (127 subjects) became symptom-free, 7.2% developed wheeze, and 36.8% reported continuing cough. Preschool wheezers showed the greatest BR (geometric mean 1.91 mg/ml) and the highest atopic prevalence (AP) (43.6%) when compared with the preschool asymptomatic group (BR: 3.39 mg/ml; AP: 23.8%) and the cough group (BR: 2.62 mg/ml; AP: 26.7%) (p = 0.0001 and p = 0.006 respectively). Children whose wheeze had persisted from the preschool period exhibited the poorest ventilatory function, the highest BR, a high AP, and high PEFV. The study shows that fewer than half of preschool wheezy children continued to wheeze in the early school years but those with persistent wheeze display many of the clinical characteristics consistent with a diagnosis of asthma.

Wheeze in preschool children and its relation with doctor diagnosed asthma.

OBJECTIVE: To describe the characteristics of wheeze and its relation with doctor diagnosed asthma in children aged 5 years and under. DESIGN: Questionnaire survey of population based random sample of children registered on Leicestershire Health Authority's child health index for immunisation; questionnaire completed by parents. SUBJECTS: 1650 white children born in 1985 to 1989 who were surveyed in 1990. MAIN OUTCOME MEASURES: Age distribution, severity, precipitants, seasonal characteristics, and diurnal variation of wheeze, family history of asthma/atopy, and their association(s) with doctor diagnosed asthma. RESULTS: There were 1422 replies (86.2%). Two hundred and twenty two (15.6%) were reported to have wheezed and of these 121 (8.6%) had formally been diagnosed as having asthma. More than 80% of the former had recurrences of wheeze and 40% (72) had three or more episodes in the preceding 12 months. Age, number of episodes per year, the severity of shortness of breath with attacks, and precipitants other than colds were the major factors determining the probability that a wheezy child will be diagnosed as having asthma. The data also suggest that despite the strong association of symptom based criteria with the label asthma, asthma was not diagnosed by these same severity criteria in one quarter of cases. CONCLUSIONS: Clinical and physiological follow up studies of children identified as asthmatic by the above criteria during the preschool years should validate or refute the predictive value of these measures of wheeze severity.

Relationship between respiratory symptoms and cough receptor sensitivity.

The relationship was studied between preschool and current respiratory symptoms and cough receptor sensitivity in children. Forty six white children aged 7 years were investigated. They were divided into three groups: (i) healthy children; (ii) children with a history of idiopathic cough; and (iii) children with a history of wheezing. Cough receptor sensitivity was assessed by the inhalation of serially increasing concentrations of nebulised citric acid. The concentration which first induced a cough was the cough threshold and was taken as a measure of cough receptor sensitivity. The cough threshold was unrelated to respiratory symptoms, bronchial responsiveness, parental smoking, and atopic status. A wide variation in cough threshold was seen. Although these results suggest that idiopathic cough is unrelated to cough receptor sensitivity as assessed by the citric acid cough threshold, it is unclear whether threshold measurements are an accurate reflection of receptor sensitivity.