Gianfranco Alicandro

Identification of insulin secretory defects and insulin resistance during oral glucose tolerance test in a cohort of cystic fibrosis patients.

BACKGROUND Cystic fibrosis (CF)-related diabetes is a leading complication of CF and is associated with pulmonary and nutritional deterioration, years before an evident hyperglycemia, possibly because of insulin deficiency and resistance. AIM To evaluate glucose tolerance, insulin secretion, and insulin sensitivity by a widely applicable method suitable for accurate and prospective measurements in a CF population. METHODS A total of 165 CF subjects (80 females) aged 17±5 years and 18 age- and sex-matched healthy controls (CON) received an oral glucose tolerance test with glucose, insulin and C-peptide determinations. Insulin sensitivity was defined on the basis of glucose and insulin concentrations using the oral glucose insulin sensitivity index, whereas β-cell function was determined on the basis of a model relating insulin secretion (C-peptide profile) to glucose concentration. RESULTS Fifteen percent of CF patients had glucose intolerance and 6% had diabetes without fasting hyperglycemia and 3% had diabetes with fasting hyperglycemia. β-cell function was reduced in CF patients compared with CON (70.0±4.1 vs 117.9±11.6  pmol/min per m(2) per mM, P<0.001) and decreased significantly with age by -2.7  pmol/min per m(2) per mM per year (confidence interval (CI) -4.5 to -0.82), i.e. almost 4% yearly. The early insulin secretion index was also reduced. Insulin sensitivity was similar to CON. CF patients who attained glucose tolerance comparable to CON had lower β-cell function and higher insulin sensitivity. CONCLUSION The major alteration in insulin secretion and insulin sensitivity of CF patients is slowly declining β-cell function, consisting of delayed and reduced responsiveness to hyperglycemia, that in CF patients with normal glucose tolerance may be compensated by an increased insulin sensitivity.

Validation of a predictive survival model in Italian patients with cystic fibrosis

BACKGROUND In 2001 Liou published a 5-year survival model using CFF Registry data. AIMS To evaluate its validity in predicting survival in Italian CF patients. METHODS In a retrospective study on 945 patients, the 9 variables selected by Liou were analyzed, vital status on December 2008 recorded and observed and expected deaths compared. To develop a new model, patients were randomly divided into a derivation (n=475) and a validation sample (n=470). RESULTS A significant difference was found between observed and expected deaths based on Lious model (62 vs 94), with a 34% reduction in mortality (p<0.05). A new model (based on FEV1, Staphylococcus aureus and Burkholderia cepacia complex infection, number of pulmonary exacerbations/year) was generated, that correctly predicted survival in the validation sample (31 observed vs 29 expected deaths, p=0.660). CONCLUSIONS The Liou model did not adequately predict 5-year survival in our CF population that, compared to the one in which it was originally tested, could benefit from 10 years of improvement in treatments and practice patterns. A new generated model, based on only four variables, was more accurate in predicting 5-year survival in Italian CF patients.

Influenza A/H1N1 in patients with cystic fibrosis in Italy: a multicentre cohort study

The clinical consequences of influenza are severe in cystic fibrosis (CF), but the impact of A/H1N1 virus infection remains poorly defined.1 2 Pandemic influenza A/H1N1 started in Italy in September 2009 and CF patients were included among those at risk of complications and recommended to receive A/H1N1 vaccine. Better characterisation of the impact of influenza A/H1N1 in comparison with other flu-like illnesses in CF would provide a rational basis for antiviral treatment and vaccination strategies for the next flu season. Within the Italian Cystic Fibrosis Society, we sent a questionnaire to 30 centres to collect follow-up data for all patients with influenza-like symptoms consecutively seen between November 2009 and March 2010. Realtime RTPCR test was performed to define A/H1N1 status.3 Continuous variables are reported as medians, IQR (see online supplement for details of study methods). Nineteen centres reported data from 127 patients: 68 were ‘A/H1N1+ve’ and 59 were ‘A/H1N1–ve’ for the RT-PCR test. Symptom …

A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis (CF) patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100 mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA:DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skinfold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (α-tocopherol and retinol). Compared to the control group plasma AA:DHA ratio decreased in the intervention group after 6 months (median percentage changes: -73% in the intervention group vs. -10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes. Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients.

Cystic fibrosis mortality trend in Italy from 1970 to 2011

BACKGROUND Survival in cystic fibrosis (CF) has progressively improved and the female-gender disadvantage first described many years ago remains controversial. OBJECTIVES To describe the mortality trend due to CF in Italy over the last decades; to verify the female-mortality disadvantage; to compare the comorbidities reported in death certificates of CF patients with those of the general population. METHODS Mortality data were extracted from the database of underlying cause of death (1970-2011) and multiple causes of death (2003-2011) of the Italian National Institute of Statistics. Age-standardized mortality ratio (SMR) was calculated to compare the mortality between genders. The association between CF and other contributing causes of death was verified by calculating the age- and gender-adjusted proportional mortality ratio (PMR). RESULTS During the study period, 1947 death certificates reported CF as the underlying cause of death. Mortality rate due to CF decreased in newborns and children and by the end of the 1990s also in adolescents and young adults. Adult mortality started to increase in the early 1990s. Over the whole period an excess in mortality was observed in young CF females (1-29 years). The multiple causes of death database included 531 certificates with CF listed as cause of death. Pneumonia, chronic lower respiratory diseases, pulmonary heart disease and diseases of pulmonary circulation, aspergillosis, sepsis, renal failure, diabetes, malnutrition and amyloidosis were more frequently reported in CF death certificates compared to those of the general population (PMR>1). CONCLUSIONS This mortality trend provides evidence of a consistent improvement in survival, although the excess female-mortality persists despite aggressive treatment of CF lung disease. Several extra-pulmonary conditions associated with CF contributed to the morbidity leading to death.

Recurrent pulmonary exacerbations are associated with low fat free mass and low bone mineral density in young adults with cystic fibrosis

BACKGROUND In cystic fibrosis (CF), systemic inflammation and pulmonary infections sustain a catabolic response leading to fat free mass (FFM) depletion. OBJECTIVES To investigate the association between recurrent pulmonary exacerbations and alteration in body composition in young adults with CF. METHODS In a retrospective study we collected body composition data, obtained by DXA scan, on 85 young adults with CF (44 males, mean age 23±4years). Whole body and appendicular FFM were divided by height squared to obtain FFM indices (FFMI). Number of pulmonary exacerbations occurred in the year preceding DXA scan were computed and patients were defined as frequent exacerbators if they experienced more than 2 pulmonary exacerbations/year. Body composition data were compared between frequent and infrequent exacerbators. RESULTS Male patients classified as frequent exacerbators had lower total body bone mineral density (Z-score -1.44±1.22 vs. -0.66±0.92, P=0.033), whole body FFMI (18.0±1.9kg/m(2) vs. 19.3±1.4kg/m(2), P=0.024) and appendicular FFMI (7.8±1.0kg/m(2) vs. 8.8±0.8kg/m(2)P=0.004) compared to infrequent exacerbators. The reduced FFM found in frequent exacerbators was not uniformly distributed and involved mainly appendicular FFM (mean difference: -11% compared to infrequent exacerbators, P=0.016), whereas trunk FFM was not significantly affected by pulmonary exacerbations (mean difference -3% compared to infrequent exacerbators, P=0.34). These differences were not found in female patients. CONCLUSIONS Recurrent pulmonary exacerbations are associated with reduced appendicular FFM and bone mineral density in young male adults with CF. The gender-dependent relationship between pulmonary exacerbations and body composition alteration needs to be further investigated.

Efficacy and tolerability of a new nasal spray formulation containing hyaluronate and tobramycin in cystic fibrosis patients with bacterial rhinosinusitis

BACKGROUND Chronic rhinosinusitis is common in cystic fibrosis (CF), as CFTR defects equally affect the airway and sinonasal mucosa. However, therapeutic strategies for CF-associated chronic rhinosinusitis lag behind current approaches for pulmonary disease. OBJECTIVE To assess the tolerability and efficacy of a nasal spray formulation containing 0.2% sodium hyaluronate and 3% tobramycin compared to a control formulation containing 0.2% sodium hyaluronate alone in the treatment of bacterial rhinosinusitis in patients with CF. METHODS In a double-blind controlled study, 27 patients with an established diagnosis of CF and a documented nasal infection with Pseudomonas aeruginosa and/or Staphylococcus aureus [22 males (81%), median age of 15 years (range 5-26 yrs)], were randomized to receive the nasal spray formulation containing hyaluronate and tobramycin (N=14) or hyaluronate alone (N=13) for 14 days. Efficacy and local tolerability of the treatments were assessed by ear, nose and throat (ENT) examination and related symptoms. RESULTS The formulation containing hyaluronate and tobramycin was more effective than hyaluronate alone in improving the status of the nasal mucosa, in reducing the mucopurulent secretion at the level of the osteomeatal complex and in improving ENT symptoms (hyposmia/anosmia and headache/facial pain). The treatment was well tolerated without relevant side effects. CONCLUSIONS The present study suggests that the combination therapy with hyaluronate plus tobramycin was more effective than hyaluronate alone in the treatment of bacterial rhinosinusitis in CF. TRIAL REGISTRATION NUMBER EudraCT 2007-003628-39.

Coffee and cancer risk: a summary overview

We reviewed available evidence on coffee drinking and the risk of all cancers and selected cancers updated to May 2016. Coffee consumption is not associated with overall cancer risk. A meta-analysis reported a pooled relative risk (RR) for an increment of 1 cup of coffee/day of 1.00 [95% confidence interval (CI): 0.99–1.01] for all cancers. Coffee drinking is associated with a reduced risk of liver cancer. A meta-analysis of cohort studies found an RR for an increment of consumption of 1 cup/day of 0.85 (95% CI: 0.81–0.90) for liver cancer and a favorable effect on liver enzymes and cirrhosis. Another meta-analysis showed an inverse relation for endometrial cancer risk, with an RR of 0.92 (95% CI: 0.88–0.96) for an increment of 1 cup/day. A possible decreased risk was found in some studies for oral/pharyngeal cancer and for advanced prostate cancer. Although data are mixed, overall, there seems to be some favorable effect of coffee drinking on colorectal cancer in case–control studies, in the absence of a consistent relation in cohort studies. For bladder cancer, the results are not consistent; however, any possible direct association is not dose and duration related, and might depend on a residual confounding effect of smoking. A few studies suggest an increased risk of childhood leukemia after maternal coffee drinking during pregnancy, but data are limited and inconsistent. Although the results of studies are mixed, the overall evidence suggests no association of coffee intake with cancers of the stomach, pancreas, lung, breast, ovary, and prostate overall. Data are limited, with RR close to unity for other neoplasms, including those of the esophagus, small intestine, gallbladder and biliary tract, skin, kidney, brain, thyroid, as well as for soft tissue sarcoma and lymphohematopoietic cancer.

Cost of Cystic Fibrosis: Analysis of Treatment Costs in a Specialized Center in Northern Italy

IntroductionAdvances in cystic fibrosis (CF) therapy have resulted in improved survival and increasing treatment burden and costs. The economic impact of current treatment strategies for CF is poorly defined.MethodsThe authors prospectively assessed direct medical costs (including hospitalizations, outpatient interventions, drugs, devices, dietetic products) in 165 consecutive CF patients (aged 5–39 years) seen between March and July 2009.ResultsThe mean annual cost/patient increased with age and lung disease severity from yy4,164 in children aged ≤5 years to yy30,123 in patients aged >5 years with severe lung disease (forced expiratory volume in 1 second [FEV1] <40% of predicted). The increase in costs involved all items, with a progressive increase in cost attributed to hospitalizations.ConclusionTreatment of CF is associated with relevant cost for the Italian National Healthcare Service. Costs of illness tend to increase progressively with age, suggesting that increasing economic resources should be allocated to the treatment of CF, given the increasing number of patients surviving into adulthood.

Estimating body composition from skinfold thicknesses and bioelectrical impedance analysis in cystic fibrosis patients

BACKGROUND The accuracy of body composition estimates based on skinfold thickness measurements and bioelectrical impedance analysis (BIA) is not yet adequately explored in cystic fibrosis (CF). Using DXA as reference method we verified the accuracy of these techniques and identified predictors of body composition specific for CF. METHODS One hundred forty-two CF patients (age range: 8-31 years) underwent a DXA scan. Body fat percentage (BF%) was estimated from skinfolds, while fat free mass (FFM) from single-frequency 50 kHz BIA. RESULTS Bland-Altman analysis showed poor intra-individual agreement between body composition data provided by DXA and BF% estimated from skinfolds or FFM estimated from BIA. The skinfolds of the upper arm were better predictors of BF% than BMI, while compared to other BIA measurements the best predictor of FFM was the R-index (Height(2)/Resistance). CONCLUSIONS Due to poor accuracy at individual level, the estimates of body composition obtained from these techniques cannot be part of the standard nutritional assessment of CF patients until reliable CF-specific equations will become available. BMI has limited value in predicting body fatness in CF patients and should be used in combination with other predictors. Skinfolds of the upper arm and R-index are strongly related to BF% and FFM and should be tested in a large CF population to develop specific predictive equations.