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Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. To document the incidence of... more
Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. To document the incidence of hearing loss in cystic fibrosis (CF) children. Hearing function of 45 children from Great Ormond Street Hospital was assessed using pure-tone audiometry up to 20kHz and DPOAEs up to 8kHz. 39/45 of participants had received intravenous (IV) AGs, 23 of which received repeated IV AGs every 3 months. In this high exposure group, 8 (21%) had clear signs of ototoxicity; average 8-20kHz thresholds were elevated by ∼50dB and DPOAE amplitudes were >10dB lower at f2 3.2-6.3 kHz. The remaining 31/39 (79%) of AG exposed patients had normal, even exceptionally good hearing. The 21% incidence of ototoxicity we observed is substantial and higher than previously reported. However, our finding of normal hearing in children with equal AG exposure strongly suggests that other unknown factors, possibly genetic susceptibility, influence this outcome. We recommend comparable auditory testing in all CF patients with high AG exposures. Genetic analysis may help explain the dichotomy in response to AGs found.
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Objective Patients with cystic fibrosis (CF) are at risk of malnutrition and studies have reported associations between lower fat-free mass (FFM) and poor lung function (LF). The authors used the “gold standard” four-component model (4CM)... more
Objective Patients with cystic fibrosis (CF) are at risk of malnutrition and studies have reported associations between lower fat-free mass (FFM) and poor lung function (LF). The authors used the “gold standard” four-component model (4CM) to assess body composition (BC) and related the findings to LF. Methods BC was measured using the 4CM in 85 CF subjects aged 6–12 years, and results compared with (1) UK reference data; (2) data from healthy age and sex matched controls. LF (forced expiratory volume in 1 sec; FEV1 % predicted) was measured in patients and relationships with fat mass (FM) and FFM adjusted for height (FM and FFM indices (FMI and FFMI)) investigated. Results Compared to UK reference data, boys with CF (n=37) were shorter; (mean (SD) height SD scores (sds); −0.5 (1.0), p<0.05) but had higher BMI sds; (0.4 (1.0) p<0.01); girls with CF were shorter; (−0.6 (1.0) p<0.001) and had lower BMI sds; (−0.3 (1.0), p<0.05). Compared to matched controls, CF boys had greater FFMI sds; (0.6 (1.0), p<0.01) while CF girls had lower FMI sds; (−0.7 (0.9), p<0.001) and mineral mass index sds; (−0.8 (1.1), p<0.001); the mineral deficit was not apparent in prepubertal girls (n=24). Six children (5 boys) had BMI sds >1.64 (95th centile); this was due to increased FM in four boys only. CF girls had lower FEV1% predicted than boys (mean (SD) 77.6 (18.4) vs 91.3 (20.9); p<0.01). FM was significantly related to FEV1 in girls only (p<0.01) but there was no association between FFM and LF in either sex. Conclusion Using the gold standard 4CM, CF boys had normal BC, while CF girls had lower FM than controls even after adjusting for size. Six children had a BMI sds in the obese range but in two cases this was due to high FFM, not FM. In contrast to previous studies we found no association between FFM and LF. The significant positive association between FM and FEV1 in girls only may reflect the poorer nutritional status of the girls, even at this young age. Given that prognosis is worse in girls, this sex difference merits more attention.
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Research Interests: Gastroenterology, Cystic Fibrosis, Pediatric Gastroenterology, Medicine, Internal Medicine, and 10 moreBody Mass Index, Pseudomonas aeruginosa, Clinical Sciences, Public health systems and services research, Pseudomonas Aeruginosa, Chronic Inflammation, Abdominal Surgery, Abdominal Pain, Chronic Infection, and Paediatrics and reproductive medicine
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To evaluate whether dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) classify the same children as &#39;abnormal&#39; (SD (z) score (SDS) ≤-2). Speed of sound (SOS) was measured at the radius and tibia... more
To evaluate whether dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) classify the same children as &#39;abnormal&#39; (SD (z) score (SDS) ≤-2). Speed of sound (SOS) was measured at the radius and tibia using QUS and lumbar spine bone mineral density (BMD) using DXA in 621 subjects aged 5-20 years; healthy 412, cystic fibrosis 117 and obese 92. BMD SDS positively (p&lt;0.001) and tibia SOS SDS negatively correlated with size (p&lt;0.05). Disagreement between DXA and QUS for &#39;abnormal&#39; scans occurred in 6-31%. Those with abnormal BMD and normal SOS SDS had lower mean BMI SDS than those with normal BMD and abnormal SOS SDS. SOS measurements were unobtainable in some children, especially in the obese group. DXA and QUS identify different individuals as &#39;abnormal&#39;. Agreement between BMD and tibia SOS is lower in obese subjects. Without a gold-standard, it is difficult to determine which technique is more &#39;correct&#39;.
Research Interests: Radiology, Health Promotion, Obesity, Cystic Fibrosis, Health Education, and 15 moreNuclear medicine, Adolescent, Medicine, Humans, Child, Tibia, Bone Density, Clinical Sciences, Radius, Public health systems and services research, Densitometry, lumbar vertebrae, Child preschool, Bone Diseases, and Paediatrics and reproductive medicine
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Children with severe asthma have recurrent exacerbations and/or persistent symptoms despite maximal treatment with conventional medication. Severe asthma in childhood is particularly difficult to treat, with substantial morbidity. There... more
Children with severe asthma have recurrent exacerbations and/or persistent symptoms despite maximal treatment with conventional medication. Severe asthma in childhood is particularly difficult to treat, with substantial morbidity. There are few randomised controlled trials in these patients; evidence therefore has to be extrapolated from adult studies or paediatric studies of mild to moderate disease. The first step is often a detailed diagnostic evaluation. Patients with severe asthma can then be further categorised as one of: wrong diagnosis; significant comorbidity; difficult-to-treat; and true, therapyresistant asthma. There are very few licensed treatments for this challenging group of children including high-dose inhaled steroids, SMART regimen and anti-IgE therapy. Many of the other treatments used (e.g. methotrexate, ciclosporin) are unlicensed. It is important, therefore, to ensure that the basics are right. Adherence must be optimised, comorbidities treated, inhaler technique regularly checked and allergen load reduced to a minimum.
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Aim To establish if the home-use oral glucose tolerance test (OGTT) kit is acceptable as an alternative to the conventional in-hospital test and if this test increases the annual screening rate for cystic fibrosis-related diabetes (CFRD)... more
Aim To establish if the home-use oral glucose tolerance test (OGTT) kit is acceptable as an alternative to the conventional in-hospital test and if this test increases the annual screening rate for cystic fibrosis-related diabetes (CFRD) in children with cystic fibrosis (CF). Research design and methods This was a prospective, single centre, cohort study. Children with CF were provided with an OGTT kit to perform the test at home and return the detachable data recorder for analysis and interpretation. Children with CFRD were excluded from the study. Thirty-four children consented to participate and 29 children completed the study. Feedback questionnaires were provided with the OGTT kits and 16 of these were returned. Results Twenty-seven OGTT procedures were successfully completed at home on the first attempt. All parents (100%) and 14 children (88%) reported that the kit was easy to use. Thirteen parents (81%) and 11 (69%) children preferred the home-use OGTT to the in-hospital OGTT. All parents (100%) of the 11 children who had previously undertaken an in-hospital OGTT preferred home-use OGTT. The uptake of the home-use OGTT for Oct 2015–16 was 74% (n=29). The overall uptake including the conventional in-hospital OGTT (n=3) was 82%. The screening rate was higher compared to the previous two years (Oct 2013–14 and Oct 2014–15); 51% (p=0.002) and 52% (p=0.004) respectively (table 1).Abstract G559 Table 1 Screening rates following administration of home-use OGTT compared with screening rates using in-hospital OGTT in the previous 2 years Patients Time Period Oct 2013–14In-hospital OGTT Oct 2014–2015In-hospital OGTT Oct 2015–2016Home-use OGTT and in-hospital OGTT Eligible Patients, n 49 46 39 Screening uptake, n (%) 25 (51%) 24 (52%) 32 (82%) Conclusion The home-use OGTT kit is easy to use, acceptable to patients and preferred to the in-hospital alternative. The convenience and accessibility of home-use OGTT could have a significant impact on the screening rate for CFRD.
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Research Interests: Gastroenterology, Cystic Fibrosis, Medicine, Endoscopy, Biopsy, and 15 moreHumans, Child, Internal Medicine, Female, Male, Infant, Pediatric Pulmonology, Clinical Sciences, Gastrointestinal Endoscopy, Disease Management, Abdominal Pain, Cohort Studies, Gastrointestinal Diseases, Child preschool, and Paediatrics and reproductive medicine
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Children with severe asthma have recurrent exacerbations and/or persistent symptoms despite maximal treatment with conventional medication. Severe asthma in childhood is particularly difficult to treat, with substantial morbidity. There... more
Children with severe asthma have recurrent exacerbations and/or persistent symptoms despite maximal treatment with conventional medication. Severe asthma in childhood is particularly difficult to treat, with substantial morbidity. There are few randomised controlled trials in these patients; evidence therefore has to be extrapolated from adult studies or paediatric studies of mild to moderate disease. The first step is often a detailed diagnostic evaluation. Patients with severe asthma can then be further categorised as one of: wrong diagnosis; significant comorbidity; difficult-to-treat; and true, therapy resistant asthma. There are very few licensed treatments for this challenging group of children including high-dose inhaled steroids, SMART regimen and anti-IgE therapy. Many of the other treatments used (e.g. methotrexate, ciclosporin) are unlicensed. It is important, therefore, to ensure that the basics are right. Adherence must be optimised, comorbidities treated, inhaler technique regularly checked and allergen load reduced to a minimum.
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Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. To document the incidence of... more
Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. To document the incidence of hearing loss in cystic fibrosis (CF) children. Hearing function of 45 children from Great Ormond Street Hospital was assessed using pure-tone audiometry up to 20kHz and DPOAEs up to 8kHz. 39/45 of participants had received intravenous (IV) AGs, 23 of which received repeated IV AGs every 3 months. In this high exposure group, 8 (21%) had clear signs of ototoxicity; average 8-20kHz thresholds were elevated by ∼50dB and DPOAE amplitudes were &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;10dB lower at f2 3.2-6.3 kHz. The remaining 31/39 (79%) of AG exposed patients had normal, even exceptionally good hearing. The 21% incidence of ototoxicity we observed is substantial and higher than previously reported. However, our finding of normal hearing in children with equal AG exposure strongly suggests that other unknown factors, possibly genetic susceptibility, influence this outcome. We recommend comparable auditory testing in all CF patients with high AG exposures. Genetic analysis may help explain the dichotomy in response to AGs found.
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The mtDNA m.1555A&amp;amp;amp;amp;amp;amp;amp;amp;gt;G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases. Genetic and audiological... more
The mtDNA m.1555A&amp;amp;amp;amp;amp;amp;amp;amp;gt;G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases. Genetic and audiological assessments were conducted in a sample of 59 children with cystic fibrosis (CF) undergoing aminoglycoside treatment. Of the two m.1555G patients identified one had severe-profound deafness. Surprisingly, the second m.1555G patient exhibited well-preserved hearing despite repeated exposure. This may be a rare case of intact hearing in an m.1555G individual with aminoglycoside use. Alternatively, its penetrance may have been previously overestimated due to recruitment bias. Further studies are required to determine the true penetrance to inform m.1555A&amp;amp;amp;amp;amp;amp;amp;amp;gt;G genetic testing in similar clinical scenarios.
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Research Interests: Respiratory Medicine, Cystic Fibrosis, Quality of life, Evaluation, Evolution, and 11 moreTreatment Outcome, Prospective studies, Humans, Child, Clinical Sciences, Vital Capacity, Respiratory Tract Infections, Weight Gain, Cross-Over Studies, Exercise Test, and Cardiovascular medicine and haematology
There is increasing evidence to suggest the presence of chronic inflammation in the gastrointestinal (GI) tract of cystic fibrosis (CF) patients. Some CF patients continue to have very severe gastrointestinal symptoms despite conventional... more
There is increasing evidence to suggest the presence of chronic inflammation in the gastrointestinal (GI) tract of cystic fibrosis (CF) patients. Some CF patients continue to have very severe gastrointestinal symptoms despite conventional CF treatment. In our center, these patients are managed in a CF gastroenterology clinic, jointly with a pediatric gastroenterologist. A number have required GI endoscopy and biopsy. The aim of our study was to characterize these patients and determine whether endoscopy and biopsy changed their management. We reviewed all the patients seen in the CF gastroenterology clinic from 2004 to 2009, who had GI endoscopies performed. The GI symptoms these patients were experiencing included abdominal pain, nausea and vomiting, rectal bleeding, failure to thrive, loose stools, and constipation. Twelve patients had GI endoscopies with mucosal biopsies performed. The median [interquartile range (IQR)] age at referral to the CF gastroenterology clinic was 4 years [0.9-8]. Their body mass index (BMI) was 15.2 [13.7-15.5]. Twenty-five percent were homozygous delta F508. Two patients had previously had meconium ileus as neonates requiring surgical intervention. One other patient had needed abdominal surgery for intussusception. Ninty-two percent were pancreatic insufficient, 25% were chronically infected with Pseudomonas aeruginosa and 17% were on regularly 3 monthly intravenous antibiotics. Of the 10 patients who were able to perform spirometry, FEV1 was 101% [67-125] predicted. Nine of the 12 patients had evidence of mucosal inflammation in their biopsies, including duodenitis with eosinophilic infiltrate, chronic non-specific inactive gastritis, enteropathy with partial villous atrophy, and non-specific colitis. Immunosuppressive and anti-inflammatory therapies were commenced in these nine patients, including prednisolone, azathioprine, methotrexate, ketotifen, mesalazine, and sulfasalazine as well as the use of parenteral nutrition and elemental feeds. All the patients clinically responded to therapy. Five of the patients commenced on anti-inflammatory therapy had repeat biopsies 1-5 years following commencement of treatment and all showed histological improvement of the mucosal inflammation. GI endoscopy with mucosal biopsy has a significant role to play in the management of CF children with severe GI disease. In our study, it influenced the management in the majority of patients with severe GI symptoms. Furthermore, if GI mucosal inflammation is identified on biopsy, management with immunomodulatory agents may be clinically beneficial.
Research Interests: Cystic Fibrosis, Biopsy, Humans, Child, Weight Loss, and 13 moreFemale, Male, Infant, Pediatric Pulmonology, Gastrointestinal Endoscopy, Retrospective Studies, Disease Management, Abdominal Pain, Cohort Studies, Gastrointestinal Diseases, Severity of Illness Index, Child preschool, and Paediatrics and reproductive medicine
We assessed the safety and use of induced sputum (IS) in children with cystic fibrosis (CF). Forty-eight children (19 males) with CF, mean age 12.6 (range, 7.3-17.0) years and median forced expired volume in 1 sec (FEV(1)) 48% (range,... more
We assessed the safety and use of induced sputum (IS) in children with cystic fibrosis (CF). Forty-eight children (19 males) with CF, mean age 12.6 (range, 7.3-17.0) years and median forced expired volume in 1 sec (FEV(1)) 48% (range, 14-77%) predicted were recruited. Patients spontaneously expectorated sputum and then performed sputum induction by inhalation of nebulized 7% hypertonic saline. Samples were sent for bacteriological culture, and for measurement of the following inflammatory mediators: interleukin-8, myeloperoxidase, eosinophil cationic protein, and neutrophil elastase activity. FEV(1) was performed before and after inhalation of hypertonic saline. There was no increase in mediator levels in IS compared to expectorated sputum (ES) samples. Only 3 patients demonstrated significant bronchoconstriction following inhalation of hypertonic saline, by the method used. From the ES samples, Pseudomonas aeruginosa was isolated in 13 patients, Staphylococcus aureus in 7 patients, Stenotrophomonas maltophilia in 1 patient, and both Pseudomonas aeruginosa and Staphylococcus aureus in 5 patients. All these organisms were found in the IS samples. However, in 2 patients whose ES grew no organisms, one patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s IS grew Pseudomonas aeruginosa, and the other patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s IS grew Staphylococcus aureus. In our study, sputum induction was safe, with no proinflammatory effect.
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Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis (CF). Alternate-day rhDNase and hypertonic saline (HS) represent potential cheaper alternative therapies. However, not all... more
Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis (CF). Alternate-day rhDNase and hypertonic saline (HS) represent potential cheaper alternative therapies. However, not all patients improve on treatment. To assess response, many CF centers have developed formal n-of-1 trials of treatment to find out who benefits. Response to daily rhDNase at 3 months has been shown to be a good predictor of response at 1 year. There are no data correlating individual response at a shorter time period with 3-month response. We assessed whether individual responses to daily rhDNase, alternate-day rhDNase, and HS could be predicted from lung function response at 6 weeks, thus shortening the n-of-1 trial, or from baseline patient characteristics, therefore avoiding the need for an n-of-1 trial. In a randomized crossover trial, 48 CF children were allocated consecutively to 12 weeks of once-daily 2.5-mg rhDNase, alternate-day 2.5-mg rhDNase, and twice-daily 5 ml of 7% HS. Forced expiratory volume in 1 sec (FEV1) and forced vital capacity (FVC) were measured at baseline and then at 6 and 12 weeks into each treatment period. Lung function response to the drugs at 6 weeks was highly predictive of response at 3 months. There was some evidence that response to HS was worse in patients with lower baseline lung function. However, there was no association between response to alternate-day or daily rhDNase and baseline characteristics. In conclusion, response to rhDNase and HS at 6 weeks was highly predictive of response at 3 months. For daily and alternate-day rhDNase, at least, the drug needs to be administered for at most 6 weeks initially to assess long-term response to treatment. Response to treatment could not be reliably predicted from baseline characteristics.
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Cystic fibrosis-related diabetes (CFRD) is associated with a shortened life expectancy and greater deterioration in lung function than in CF patients with normal glucose metabolism. There are few published data on how CFRD affects growth... more
Cystic fibrosis-related diabetes (CFRD) is associated with a shortened life expectancy and greater deterioration in lung function than in CF patients with normal glucose metabolism. There are few published data on how CFRD affects growth in childhood. We carried out a retrospective case controlled study of growth and lung function in 34 children with CFRD attending three specialist centers in London. We found that for the 2 years leading to CFRD diagnosis (at a mean age of 13.1 years), the mean height velocity was significantly less compared to controls: 4.9 (standard deviation-SD 1.6) cm/year vs. 6.0 (SD 1.9) cm/year (P = 0.005). For the 2 years following diagnosis, height velocity remained significantly lower (3.4 (SD 2.2) cm/year vs. 4.4 (SD 2.2) cm/year, P = 0.02). Mean FEV(1) was reduced prior to diagnosis and at diagnosis, but was similar to controls 2 years after diagnosis. This study highlights the compromise in height velocity and lung function that occurs prior to diagnosis of CFRD in children with CF, and a reduction in height velocity should be considered an indicator of impaired glucose metabolism. It would be useful to know whether early treatment with insulin can help promote catch up growth.