Insulin production and resistance in cystic fibrosis: effect of age, disease activity, and genotype.

AIM: To assess the major determinants of glucose tolerance between age, genotype, and clinical status in cystic fibrosis (CF) patients, and study if defects of insulin secretion and insulin sensitivity were associated with the onset of CF-related diabetes (CFRD). SUBJECTS AND METHODS: One hundred and nineteen patients, in stable clinical condition were studied. They were subdivided into 3 groups based on age, and 2 groups based on Schwachman-Kulczycki clinical score. All patients were genotyped, and subsequently divided into 3 groups. Ninety-four healthy normal-weight controls, comparable for sex and age were also studied. All subjects had baseline blood samples taken for glucose and insulin, C-peptide, and glycated hemoglobin. Homeostasis model assessment of insulin resistance (HOMA-IR), fasting glucose/insulin ratio (FGIR) were calculated as indices of IR and insulinogenic index as a marker of pancreatic ß-cell function. All patients underwent an oral glucose tolerance test, and 57 underwent an IVGTT for the calculation of first-phase (FPIR) and acute insulin responses (AIR). RESULTS: The F508del homozygous patients had an increased chance of developing impaired glucose tolerance (IGT) and significantly lower FPIR, decreased HOMA-IR, and insulinogenic index. Heterozygote F508del patients had an increased chance of having normal glucose tolerance. HOMA-IR, FGIR, and insulinogenic index did not change with age or clinical score. HOMAIR correlated with FPIR. FPIR correlated positively with insulinogenic index. AIR correlated negatively with FGIR, and positively with C-reactive protein. In multiple linear regression analyses, glucose tolerance was related to the agegroup, and to the HOMA-IR and insulinogenic indexes. CONCLUSIONS: IGT and CFRD were related mainly to genotype, although, as expected, the prevalence increased with age. The data suggested a possible combined contribution of insulin deficiency, ß-cell function, and reduced insulin sensitivity to the onset of CFRD; however, further studies are warranted to better elucidate this aspect.

Three-dimensional quantitative assessment of lung parenchyma in cystic fibrosis: preliminary results.

PURPOSE: The aim of this study was to assess the feasibility of three-dimensional (3D) reconstructions and quantitative analysis of the volume of each component of the lung with cystic fibrosis (CF). MATERIALS AND METHODS: Twenty-two patients with CF (mean age 17+/-8 years) were included in the study. The patients underwent an unenhanced single-slice spiral computed tomography (CT) chest scan with the following parameters: collimation 3 mm, table feed 6 mm x rot(-1), reconstruction interval 1 mm, soft tissue reconstruction kernel. Four image data sets were obtained: native axial slices, cine-mode display, virtual bronchographic volume-rendered images with algorithm for tissue transition display and virtual endoluminal views. The lungs were segmented manually from the hilum to the visceral pleura on the axial images, and the entire lung volume was calculated. A histogram was generated representing the fractional volume of tissues, the density of which was within a preset range. A curve was then obtained from the histogram. RESULTS: Native axial images and cine-mode display allowed complete evaluation of lung volumes. Virtual bronchography allowed a better assessment of the distribution of bronchiectasis. Virtual bronchoscopy was limited by the fact that it visualised only the surface, without differentiating mucus from the bronchial wall. Manual segmentation and generation of density-volume curves required 41+/-7 min for each lung. Three curve patterns were identified depending on disease severity. CONCLUSIONS: Volume-density analysis of lungs with CF is feasible. Its main advantage is that image analysis is not analogical, as the assessment is not performed using scoring systems or similar ordinal scales. This technique cannot differentiate acute from chronic findings, and the predictive value of the curve should be assessed.

Six-minute walking test in cystic fibrosis adults with mild to moderate lung disease: comparison to healthy subjects.

The six-minute walking test (6MWT) has been widely utilized to evaluate global exercise capacity in patients with cystic fibrosis. The aim of this study was to assess the exercise capacity by 6MWT, measuring four outcome measures: walk distance, oxygensaturation and pulse rate during the walk, and breathlessness perception after the walk, in a group of cystic fibrosis adults with mild to moderate lung disease, and in healthy volunteers, as the control group. Moreover, the study examined the relationship between 6MWT outcome measures and pulmonary function in patients. Twenty-five adults (15 females, age range 18-39 years) with cystic fibrosis and 22 healthy volunteers (14 females, age range 20-45 years) performed a 6MWT following a standard protocol. Walk distance, oxygen saturation (SpO2) and pulse rate at rest and during walk, and breathlessness perception after walk assessed by visual analogue scale (VAS) were measured. Cystic fibrosis patients did notdiffer from healthy volunteers in walk distance (626 +/- 49 m vs. 652 +/- 46 m) and pulse rate. Patients significantly differed from healthy volunteers in SPO2 during the walk (mean SpO2) (P < 0.0001) and VAS (P < 0.0001). In patients, SPO2 during the walk significantly correlated with forced expiratory volume in 1 sec (FEV1) (P < 0.0001), residual volume (RV) (P < 0.001), resting SPO2 (base SpO2) (P < 0.001), and inspiratory capacity (IC) (P < 0.01). In addition, VAS significantly correlated with resting SPO2 (P < 0.01) and IC (P < 0.01). On the basis of regression equations by stepwise multiple regression analysis, SpO2 during walk was predicted by FEV1 (r2 = 0.60) and VAS by IC (r2 = 0.31), whereas walk distance was not reliably predicted by any assessed variables. This study showed that cystic fibrosis adults with mild to moderate lung disease covered a normal walk distance with unimpaired cardiac adaptation, but experienced a significant fall in oxygen saturation and an increased breathlessness perception during exercise. Resting pulmonary function was related to oxygen saturation and breathlessness perception during walk, but contributed significantly only tothe prediction of oxygen saturation. We suggest that 6MWT could be valuable for identifying patients who might experience oxygen desaturation and dyspnoea during demanding daily activities.

Comparison of two enteric coated microsphere preparations in the treatment of pancreatic exocrine insufficiency caused by cystic fibrosis.

BACKGROUND: Pancreatic exocrine insufficiency is a common condition in patients with cystic fibrosis. Large amounts of pancreatic enzyme supplements are required to reduce malabsorption but patient compliance is not always optimal. AIMS: To compare patients' preference and the efficacy of two enteric coated microsphere preparations in patients with cystic fibrosis. PATIENTS: Patients with pancreatic exocrine insufficiency due to cystic fibrosis. METHODS: Patients were assigned to the crossover treatment with Creon or Pancrease for 1 week and then to the alternative treatment. Patients had to follow a fixed diet (at least 2 g fat/kg) and had to assume 1000 units lipase/g fat. The evaluation parameters were: patients' preference, acceptance of therapy, stool fat excretion, stool weight, gastrointestinal symptoms, and tolerance. RESULTS AND CONCLUSIONS: Of the 33/60 patients who expressed a preference for one of the two treatments, 30 preferred Creon while only 3 patients preferred Pancrease (p<0.001). No difference between the two treatments was observed regarding stool characteristics, gastrointestinal symptoms and tolerance. The mean number of capsules taken daily was reduced by 35% with Creon. The results of this study showed a preference in favour of Creon probably due to the reduction of daily capsule intake of 35%, supporting digestion as well as Pancrease.

[Thirty years of activity at the center for cystic fibrosis in Parma]. / Trenta anni di attività del Centro per la fibrosi cistica di Parma.

One hundred fourteen patients (52 males, age range 1 to 40 yr, median age 16 yr) affected by Cystic Fibrosis (CF) are currently followed by the CF Centre of Parma. Forty two percent of them are adults. Most patients live in Emilia Romagna (59%) and Lombardia (19%). With respect to CF genotype, delta F508 mutation has been found in 54% of patients. Despite of the improvement in knowledge of CF, its diagnosis is still based on the clinical features and sweat test is usually used to confirm the diagnosis. Recent diagnostic tools, such as the genetic analysis and the potential difference measurement, could also be helpful in ambiguous situations. In the CF Centre of Parma, in agreement with the literature, the disease is now diagnosed earlier than in the past. Particularly, in the last year the median age of diagnosis was seven months, while it was 20 months in the 1980s. The early diagnosis and the improvement in the treatment of lung disease has significantly increased the median survival age of our patients, changing from 7.5 years in 1975 to 20 years in 1999. A significant improvement in CF prognosis could be further achieved by potential investigational agents, such as "protein-repair" addressed to CFTR activation. However, the gold standard for CF therapy is represented by gene therapy, although it is not yet available.

[Response to bronchodilator administered directly with spray or with spacer]. / La risposta al broncodilatatore spray somministrato direttamente e con distanziatore.

If we assume that the only function of a spacer is that to facilitate the esecution of a spray, its use is limited to small children who do not collaborate (below age 6-7 years). However, spacers seem to improve the effectiveness of drugs and reduce both directly and indirectly the side effects. The assess if these characteristics have a role in clinical practice, the response to 100 micrograms of salbutamol administered directly by Autohaler was compared to that obtained with the same dose administered with three different spacers, Aerochamber, Babyhaler, Volumatic. A series of 88 asthmatic subjects with a FEF 25-75 less than 70% of the predicted value was considered. Overall patients provided 118 responses to the bronchodilator: 17 using the Aerotec (Autohaler), 38 the Aerochamber, 33 the Babyhaler, 30 the Volumatic. The response was evaluated considering the parameters obtained by spirometry just before, 5 and 20 minutes after the inhalation of salbutamol. Heart rate was also measured at the same time points. Heart rate, but not spirometric parameter were increased by the use of the Autohaler, proving that the drug had been inhaled. All the spacers determined a significant increase in the parameters considered. No significant difference was detected among spacers, although the smallest (Aerochamber, Babyhaler) showed a trend to a better response, in particular before age 7 years. The complete ineffectiveness of direct inhalation and the excellent response to inhalation with spacers show the indispensability of the latter, independent of age. Although no substantial difference among spacers was detected, the trend to obtain a better response with smaller spacers inclines us to use them in particular between 4 and 7 years of age. The negative correlation between the increase in spirometric parameters and the age of the patient would allow to have doses aimed to age or to body weight.

Prolonged bronchodilating effect of formoterol versus procaterol in bronchial asthma.

The tolerability and the duration of effect of 12 micrograms of formoterol and 25 micrograms of procaterol administered via metered-dose aerosol to 12 stable asthmatic patients were evaluated in a double-blind, placebo controlled trial. FEV1, pulse rate, and blood pressure were measured at baseline and every two hours after dosing for 12 hours. The bronchodilation peak was observed after two hours for both drugs. Formoterol induced a significant bronchodilating effect for 12 hours compared with both baseline and placebo values. With procaterol, significant bronchodilation occurred for six hours compared with baseline values and four hours compared with placebo. No significant changes were observed in pulse rate and blood pressure with either drug. Four subjects complained of muscle tremor after procaterol administration. We conclude that in subjects with stable asthma, inhaled formoterol at a dose of 12 micrograms maintains significant bronchodilation for 12 hours after dosing and is very well tolerated. Further studies are required to evaluate effectiveness and tolerability of high dose formoterol treatment in acute severe asthma therapy.

[New clinico-therapeutic directions in upper airway pathology]. / Nuovi orientamenti clinico-terapeutici nella patologia delle prime vie aeree.

The main issues regarding the pathology of the primary airways in children, such as persistent rhinitis, recurrent disease of the pharynx and laryngitis, have been re-examined and updated on the basis of the latest findings regarding immunology and respiratory physiopathology as well as recent technological progress in the field of diagnosis. As far as rhinitis is concerned, recently demonstrations that nasal mucosa, like bronchial mucosa, responds to different kinds of stimuli with the same type of inflammation, have led to a new nosographic viewpoint: apart from classic allergic rhinitis, multifactorial forms are now recognised. They have been defined as nonallergic persistent rhinitis having a particular subgroup: nonallergic rhinitis with eosinophils. The fact that different factors contribute to bringing about the same inflammatory process is also confirmed by a personal study carried out on 132 asthmatic children with rhinitis: the results showed, in fact, that there are no differences regarding the nasal mucosa of allergic children (positive prick) and nonallergic children (negative prick). This observation therefore diminishes the importance of rhinoscopy in the etiologic diagnosis of rhinitis. As far as the obstructive syndrome caused by adenotonsillar hypertrophy is concerned, extremely polymorphic clinical pictures can be identified: from the slightest nocturnal hypoventilation to the apnea syndrome during sleep, even to the most severe forms with cardiocirculatory insufficiency. Personal data on 42 children helped to define both the anamnestic and objective findings necessary for making the diagnosis. It was therefore found that the most indicative and specific observations were those made either by the mothers (heavy breathing noises) or by the physician (inspiratory retractions) while the children were sleeping. Clinical data are therefore usually sufficient for making the diagnosis; however, in the first two years of life, a period in which surgical operations are usually delayed if possible, it is necessary to make an instrumental evaluation of the degree of hypoventilation. By means of radiological examination, pharyngoscopy and capnography, it is possible to record the degree of obstruction and therefore decide whether or not to delay surgery. Apart from the obstructive respiratory syndrome with hypoventilation, that requires surgery at all costs, other conditions were examined that can profit by adenoidectomy, such as affections of the middle ear, chronic sinusitis and craniofacial dysmorphisms. As far as laryngitis is concerned, the importance of radiology and endoscopy in rapidly diagnosing epiglottic laryngitis is reported. This in turn sometimes facilitates quick pharmacological treatment so as to avoid more invasive interventions, such as tracheostomy.

[Tuberculosis in children in the early 90's]. / La tubercolosi del bambino agli inizi degli anni '90.

The natural history of tuberculosis was re-examined, and especially the relation between contagion and first infection on one side and, on the other, primary tuberculosis (in children) and secondary tuberculosis in adult. With regard to the primary tuberculosis, the different clinical pictures were taken into consideration and it was reported how symptoms change as years go by (see miliary tuberculosis). As for the diagnostic aspect the importance of a quantitative interpretation of Mantoux reaction, was emphasized. In the final judgement, all factors that may change the results can therefore by considered: from the intercurrent viral infection to the patient's age, to the spreading of atypical mycobacteria in that area. The screening performed with the multi-injections technique is necessary to control the diffusion of the infection in the general population. In Italy, 1-2% of children aged 6 to 14 years old, are skin positive but the percentage varies widely in the different areas. However, it was higher than that observed in other European countries and far from the 1% incidence for 14 year olds, as hoped by the World Health Organization. After re-examining the characteristics of the four most important anti-tubercular drugs with particular attention to possible hepatotoxic effects of the isoniazid-rifampicin association, the authors analyses new therapeutic strategies, especially the one that tends to shorten treatment periods. This approach is effective in adults but has not yet been definitively confirmed in children. The surgical approach is more standardized in superficial adenitis where extirpation is indicated in atypical mycobacteria infections rather than in those due to Koch's bacillus. As far as indications of chemoprophylaxis are concerned it would seem that an international arrangement has now been reached that on the whole extends the indications to this type of treatment. The only uncertainty is whether adults, with intradermal reactions to tuberculin should undergo chemoprophylaxis if the time of contagion is unknown and the subject does not show any particular risk factors. On the grounds of data from literature, the results of vaccination are contrasting. Many factors could be responsible for this, especially the use, till a few years ago, of a non-standardized vaccine. However, vaccination remains an efficient method in populations at risk, listed in Italian law too. Nevertheless, according to the law, the subjects who would most benefit by vaccination are excluded (children under the age of 5 years and over the age of 15 years). However vaccination is getting less important in the general population.(ABSTRACT TRUNCATED AT 400 WORDS)

[Circadian variations of bronchoconstriction in asthmatic children]. / Variazioni circadiane della broncoostruzione nel bambino asmatico.

In order to determine the magnitude of circadian variations in bronchoconstriction, we examined modifications of the spirometry observed during the 24-hr in a group of asthmatic (31 males, mean age = 8 years, 6 months). Particular attention was paid to the forced expiratory volume in 1 sec. (FEV1) and the forced vital capacity (FVC). We were thus able to compare in single patients 43 spirometry pairs between morning (between 8 and 10 am) and early afternoon (between 1 and 4 pm), 46 pairs between morning and evening (between 6 and 10 pm) and 54 between 2 consecutive mornings. The results of this study, substantially similar for the FEV1 and the FVC, show that the mean values obtained at different hours during the day and in two consecutive mornings were almost superimposable. On the other hand, the mean values and the standard deviations of the differences between two determinations in single patients are high. The percentage of patients who present significant modifications (greater than 10%) of FEV1 or of FVC at different hours of the day is also quite high. Moreover these variations seem directly related to the baseline spirometric value. Although the literature frequently outlines the existence of a circadian rhythm in the modifications or airways patency (maximum bronchoconstriction in the morning and minimum in the evening), in the asthmatic, however, the fast variations in the bronchial tone can be such as to mask this cyclic rhythm.(ABSTRACT TRUNCATED AT 250 WORDS)

[Respiratory physio-kinesitherapy in cystic fibrosis: the parents' viewpoint]. / La fisiochinesiterapia respiratoria nella fibrosi cistica vista dai genitori.

The aim of this study was to evaluate the problems found in performing chest physiotherapy (PKT) by patients with Cystic Fibrosis (CF) and by their families. The research has been based upon processing 389 questionnaires (46 items) that were compiled by the families. Thirteen CF centers all over the nation have participated in this study. Patients' mean age was 7.4 years (range 2 months to 14 years). Data about the socio-economic status and illness severity were available for every patient. Many graphs (line connects points with a line = n. 8; bar charts = n. 17; pie charts = n. 13) show the results and their statistical processing. Our purpose was to solve the following problems: 1) What is the extent of the compliance? 2) Who perform, or should perform, PKT in the family environment? 3) What is the kind and extent of the help request? 4) What are the mistakes made in executing PKT? 5) What is the usefulness of precursors and aerosol therapy? 6) What is the link between physical activity and PKT? 7) What are the main difficulties in performing PKT? 8) How effective is PKT? 9) What is the extent of the parents' faith in their capabilities? 10) Are there any prejudices against PKT? Three major findings emerge from this study: 1) the compliance appeared good; 2) the average family understood the meaning of PKT correctly and 3) PKT is usually executed properly. As for negative results are concerned, it is to be noted that the burden of performing PKT is usually up to the mother. This finding is linked both to the socio-economics status of the family and to the severity of the illness. On the other hand, a home PKT service is only asked in very extreme situations such as sudden worsening of the patient's illness. The difficulties met in performing PKT range from the patient's refusal to logistical and organization problems, which are correlated with the socio-economic status of the family. The relationship between PKT and sport is understood well and there is a high percentage of patients doing regular physical activity, even if it is often hindered by the severity of the disease. In conclusion, although there are many problems, there are also many methods to use in order to improve the acceptance and the effectiveness of the PKT.