Ranjan Suri

Comparison of hypertonic saline and alternate-day or daily recombinant human deoxyribonuclease in children with cystic fibrosis: a randomised trial

BACKGROUND Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis. Alternate-day treatment, if equally effective, would reduce the drug cost. Hypertonic saline improved lung function to the same degree as rhDNase in short-term studies. We compared the effectiveness of daily rhDNase, hypertonic saline, and alternate-day rhDNase in children with cystic fibrosis. METHODS In an open cross-over trial, 48 children were allocated in random order to 12 weeks of once-daily rhDNase (2.5 mg), alternate-day rhDNase (2.5 mg), and twice-daily 5 mL 7% hypertonic saline. The primary outcome was forced expiratory volume in 1 s (FEV(1)). Secondary outcomes were forced vital capacity, number of pulmonary exacerbations, weight gain, quality of life, exercise tolerance, and the total costs of hospital and community care. FINDINGS Mean FEV(1) increased by 16% (SD 25%), 14% (22%), and 3% (21%) with daily rhDNase, alternate-day rhDNase, and hypertonic saline, respectively. There was no difference between daily and alternate-day rhDNase (2% [95% CI -4 to 9], p=0.55). However, daily rhDNase showed a significantly greater increase in FEV(1) than hypertonic saline (8% [2 to 14], p=0.01). The average difference in 12-week cost between daily and alternate-day rhDNase was pound513 (95% CI -546 to 1510) and that between daily rhDNase and hypertonic saline was pound1409 (440 to 2318). None of the secondary clinical outcomes showed significant differences between treatments. INTERPRETATION Hypertonic saline, delivered by jet nebuliser, is not as effective as daily rhDNase, although there is variation in individual response. There is no evidence of a difference between daily and alternate-day rhDNase.

The Use of Human Deoxyribonuclease (rhDNase) in the Management of Cystic Fibrosis

In patients with cystic fibrosis (CF), the poor clearance of airway secretions promotes recurrent cycles of pulmonary infection and inflammation. In recent years, novel drugs have been developed to alter the properties of the secretions in an attempt to aid chest physiotherapy in improving airway clearance. Once-daily nebulised recombinant human deoxyribonuclease (rhDNase; dornase alfa; Pulmozyme®) is the most widely used mucoactive therapy in patients with CF. It has been shown to reduce the viscoelasticity of sputum from patients with CF and enhance the clearance of secretions. Clinical trials have shown rhDNase to be a well tolerated treatment that improves pulmonary function and reduces respiratory exacerbations. However, the response to treatment is heterogeneous and only a proportion of patients with CF actually benefit from the treatment. At present, we are unable to predict which patients will benefit from rhDNase. Many CF centers have developed formal n-of-1 trials of treatment to find out who benefits and to justify prescribing the agent. rhDNase is an expensive therapy and is mainly used in patients over the age of 5 years with moderate to severe lung disease. However, studies have shown that rhDNase may be useful in patients with milder lung disease. Comparisons with another mucoactive drug, hypertonic saline, have shown rhDNase to be more effective. Recently, it has been shown that giving rhDNase on an alternate-day basis, rather than daily, is equally effective, potentially reducing costs and treatment time.

Effects of hypertonic saline, alternate day and daily rhDNase on healthcare use, costs and outcomes in children with cystic fibrosis

Background: Daily recombinant human deoxyribonuclease (rhDNase) is an established but expensive treatment in cystic fibrosis (CF). An alternative lower cost therapy is hypertonic saline (HS), which has been shown to improve lung function in short term studies. This study compares the costs and consequences of daily rhDNase with alternate day rhDNase and HS in children with CF. Methods: In an open, randomised, crossover trial, 48 children with CF were allocated consecutively to 12 weeks of once daily 2.5 mg rhDNase, alternate day 2.5 mg rhDNase, and twice daily 5 ml 7% HS. Outcomes assessed included forced expiratory volume in 1 second (FEV1) and quality of life. All healthcare resource use was prospectively recorded for each patient. Unit costs were collected and combined with resource use data to give the total health service costs per patient for each treatment strategy. Results: Daily rhDNase resulted in a significantly greater increase in mean FEV1 than HS (8%, 95% CI 2 to 14) but there was no significant difference in FEV1 between daily and alternate day rhDNase (2%, 95% CI –4 to 9). Over a 12 week period the mean incremental costs of daily rhDNase compared with HS was £1409 (95% CI £440 to £2318), and the incremental cost of using daily rather than alternate day rhDNase was £513 (95% CI –£546 to £1510). Conclusions: Daily rhDNase is more effective than 5 ml 7% HS twice daily delivered by jet nebuliser, but significantly increases healthcare costs. Administering rhDNase on an alternate day rather than a daily basis is as effective, with a potential for cost savings.

High-frequency audiometry reveals high prevalence of aminoglycoside ototoxicity in children with cystic fibrosis

BACKGROUND Intravenous aminoglycoside (IV AG) antibiotics, widely used in patients with cystic fibrosis (CF), are known to have ototoxic complications. Despite this, audiological monitoring is not commonly performed and if performed, uses only standard pure-tone audiometry (PTA). The aim of this study was to investigate ototoxicity in CF children, to determine the most appropriate audiological tests and to identify possible risk factors. METHODS Auditory assessment was performed in CF children using standard pure tone audiometry (PTA), extended high-frequency (EHF) audiometry and distortion-product otoacoustic emissions (DPOAE). RESULTS 70 CF children, mean (SD) age 10.7 (3.5) years, were recruited. Of the 63 children who received IV AG, 15 (24%) children had ototoxicity detected by EHF audiometry and DPOAE. Standard PTA only detected ototoxicity in 13 children. Eleven of these children had received at least 10 courses of IV AG courses. A 25 to 85 dBHL hearing loss (mean±SD: 57.5±25.7 dBHL) across all EHF frequencies and a significant drop in DPOAE amplitudes at frequencies 4 to 8 kHz were detected. However, standard PTA detected a significant hearing loss (>20 dBHL) only at 8 kHz in 5 of these 15 children and none in 2 subjects who had significantly elevated EHF thresholds. The number of courses of IV AG received, age and lower lung function were shown to be risk factors for ototoxicity. CONCLUSIONS CF children who had received at least 10 courses of IV AG had a higher risk of ototoxicity. EHF audiometry identified 2 more children with ototoxicity than standard PTA and depending on facilities available, should be the test of choice for detecting ototoxicity in children with CF receiving IV AG.

Aminoglycoside antibiotics cochleotoxicity in paediatric cystic fibrosis (CF) patients: A study using extended high-frequency audiometry and distortion product otoacoustic emissions

Abstract 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. Objective: To document the incidence of hearing loss in cystic fibrosis (CF) children. Design: Hearing function of 45 children from Great Ormond Street Hospital was assessed using pure-tone audiometry up to 20kHz and DPOAEs up to 8kHz. Study Sample: 39/45 of participants had received intravenous (IV) AGs, 23 of which received repeated IV AGs every 3 months. Results: 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. Conclusions: 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. Sumario A pesar de los conocidos efectos ototóxicos de los antibióticos aminoglucósidos (AG), en el Reino Unido no se lleva a cabo de rutina una evaluación audiológica en los pacientes con fibrosis quística (CF); consecuentemente, la incidencia de hipoacusia no está bien establecida. Objetivo: Documentar la incidencia de trastornos auditivos en niños con fibrosis quística (CF). Diseño: Se evaluó la función auditiva de 45 niños del Hospital Great Ormon Street, usando audiometría de tonos puros hasta 20kHz y DPOAE hasta 8 kHz. Muestra Del Estudio: 39/45 participantes habían recibido AG intravenosos (IV), 23 de los cuáles los recibieron repetidamente por vía IV, cada 3 meses. Resultados: En este grupo de alta exposición, 8 niños (21%) mostraban claros signos de ototoxicidad; los umbrales promedio de 8-20 kHz estaban elevados por ∼50dB y las amplitudes de las DPOAE estaban >10dB más bajas en f2 3.2-6.3 kHz. Los restantes 31/39 (79%) pacientes expuestos a AG tenían una audición normal e incluso, excepcionalmente buena. La incidencia de ototoxicidad del 21% que observamos es sustancial y es más alta de lo previamente reportado. Sin embargo, nuestro hallazgo de audición normal en niños con exposición equivalente a AG sugiere fuertemente que otros factores desconocidos, posiblemente la susceptibilidad genética, influyen en los resultados. Conclusiones: Recomendamos evaluaciones auditivas similares en todos los pacientes con CF con alta exposición a AG. El análisis genético puede ayudar a explicar la dicotomía encontrada en cuanto a la respuesta a AG.

Growth in Children With Cystic Fibrosis-Related Diabetes

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 FEV1 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. Pediatr Pulmonol. 2009; 44:1223–1225.

Dual energy x-ray absorptiometry and quantitative ultrasound are not interchangeable in diagnosing abnormal bones

Objective To evaluate whether dual energy x-ray absorptiometry (DXA) and quantitative ultrasound (QUS) classify the same children as ‘abnormal’ (SD (z) score (SDS) ≤−2). Methods 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. Results BMD SDS positively (p<0.001) and tibia SOS SDS negatively correlated with size (p<0.05). Disagreement between DXA and QUS for ‘abnormal’ 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. Conclusions DXA and QUS identify different individuals as ‘abnormal’. Agreement between BMD and tibia SOS is lower in obese subjects. Without a gold-standard, it is difficult to determine which technique is more ‘correct’.

A cost-effectiveness analysis of rhDNase in children with cystic fibrosis

OBJECTIVES This study compared the relative cost-effectiveness of daily recombinant human deoxyribonuclease (rhDNase), with alternate day rhDNase and hypertonic saline (HS) for treating children with cystic fibrosis (CF). METHODS A randomized controlled trial with a crossover design allocated 40 CF children consecutively to 12 weeks of daily rhDNase, alternate day rhDNase, or HS. The primary outcome measure was forced expiratory volume in 1 second (FEV1), a measure of lung function. All health resource use was prospectively documented for each patient and multiplied by unit costs to give a total health service cost for each 12-week treatment period. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves and net benefit statistics for each treatment comparison, for various hypothetical levels of the decision makers ceiling ratio. RESULTS Compared with HS, there was a 14% improvement in FEV1 for daily rhDNase (95% Cl, 5% to 23%), and a 12% improvement (95% Cl, 2% to 22%) for alternate day rhDNase. For a ceiling ratio of 200 pounds sterling per 1% gain in FEV1, the mean net benefits of daily and alternate day rhDNase compared with HS were 1,158 pounds sterling (95% Cl, -621pounds sterling to 2,842) and 1,188 pounds sterling (95% Cl, -847 to 3,343), respectively; the mean net benefit of daily compared with alternate day rhDNase was -30 pounds sterling (95% Cl, -2,091 pounds sterling to 1,576). CONCLUSIONS If decision makers are prepared to pay 200 pounds sterling for a 1% gain in FEV1 over a 12-week period, then on average either rhDNase strategy is cost-effective.

Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?

The mtDNA m.1555A>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>G genetic testing in similar clinical scenarios.

The role of endoscopy and biopsy in the management of severe gastrointestinal disease in cystic fibrosis patients.

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. Pediatr Pulmonol. 2013; 48:1181–1189.