Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis

Data derived from a cross-sectional analysis of 7,566 patients stratified into six age groups were used to compare lung function, body mass index (BMI), and weight for age in patients with and without cystic fibrosis-related diabetes mellitus (CFDM). The presence of CFDM was tightly linked to poor lung function, regardless of age. The mean value of FEV(1) % predicted in the age groups < 10, 10-< 15, 15-< 20, 20-< 25, 25-< 30, and 30 years or older were 87%, 77%, 69%, 58%, 55%, and 53% in the nondiabetic cystic fibrosis (CF) patients as compared to 79%, 66%, 55%, 49%, 46%, and 44% in the diabetic CF patients. BMI and weight for age were also lower in diabetic than nondiabetic CF patients in all age groups, except for BMI in the youngest patients. The difference in lung function and in nutritional parameters between diabetic and nondiabetic CF patients was not linked to presence or absence of any specific pathogen in the lower respiratory tract. These results confirm and extend those of earlier studies in smaller numbers of patients, and they clearly identify CFDM as a powerful determinant of severe lung disease and reduced survival in patients with CF and diabetes mellitus.     

Conventional measures underestimate glycaemia in cystic fibrosis patients.

AIMS: Diabetes mellitus is an increasingly important complication of cystic fibrosis (CF). The association with increased morbidity of cystic fibrosis-related diabetes (CFRD) has emphasized the need for accurate monitoring of glycaemia in all CF patients. The diagnosis has relied on conventional thresholds in an oral glucose tolerance test (OGTT) derived from epidemiological studies in non-CF subjects. However, it has not been established if these values are equivalent in CF and non-CF populations. METHODS: We compared glycaemia in 21 non-diabetic CF subjects with 21-age and BMI-matched non-CF controls using HbA(1c), OGTT and a subcutaneous continuous glucose monitoring system (CGMS) that measures interstitial glucose levels. RESULTS: All conventional measures of glycaemia were similar in the two groups: HbA(1c) mean CF vs. controls (5.5 vs. 5.3%P = 0.4), fasting glucose (4.8 vs. 4.7 mmol/l P = 0.7) and 2-h glucose (5.8 vs. 5.7 mmol/l P = 0.8). However, these conventional measures did not accurately reflect glycaemia 30-, 60- and 90-min. Glucose values and area under the curve in OGTT were all higher in CF subjects than controls (P = 0.01-0.0001). Mean CGMS value [5.9 (0.8) vs. 5.1 (0.5) mmol/l, P = 0.004], and the proportion of subjects with peak CGMS values > 11.1 mmol/l (33 vs. 5%P = 0.00001) were also higher in CF subjects than controls. These results remained significantly different when only subjects with normal glucose tolerance in the two groups were studied. CONCLUSIONS: We have shown that overall glycaemia, as shown by both the response during an OGTT and CGMS, is higher in CF subjects who have similar HbA(1c), fasting and 2-h glucose values. These results question whether it is appropriate to use the diagnostic thresholds and OGTT time points derived from the non-CF population for a diagnosis of diabetes in patients with cystic fibrosis.     

Lumacaftor/ivacaftor therapy is associated with reduced hepatic steatosis in cystic fibrosis patients

BACKGROUND Hepatic steatosis is a common form of cystic fibrosis associated liver disease(CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis(CF).The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown.In the general population,hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes.Cystic fibrosis related diabetes(CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance.We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.AIM To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.METHODS Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study.Only pancreatic insufficient patients with CFRD or normal glucose tolerance(NGT) were included.Patients with established CFLD,end stage lung disease,or persistently elevated liver enzymes were excluded.Mean magnetic resonance imaging(MRI) proton density fat fraction(PDFF) was obtained for all participants.Clinical characteristics [age,sex,body mass index,percent predicted forced expiratory volume at 1 s(FEV1),lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis.Hepatic steatosis was defined as a mean MRI PDFF 5%.Patients were grouped by diabetes status(CFRD,NGT) and cystic fibrosis transmembrane conductance regulator(CFTR) modulator use(lumacaftor/ivacaftor,no lumacaftor/ivacaftor) to determine between group differences.Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher's exact test.RESULTS Twenty subjects were included in the final analysis.The median age was 22.3 years(11.3-39.0) and median FEV1 was 77%(33%-105%).Twelve subjects had CFRD and 8 had NGT.Nine subjects were receiving lumacaftor/ivacaftor.The median PDFF was 3.0%(0.0%-21.0%).Six subjects(30%) had hepatic steatosis defined as PDFF 5%.Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor(median,range)(2.0%,0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor(4.1%,2.7-21.0%),P = 0.002.Though patients with CFRD had lower PDFF(2.2%,0.0%-14.5%) than patients with NGT(4.9%,2.4-21.0%) this did not reach statistical significance,P = 0.06.No other clinical characteristic was strongly associated with hepatic steatosis.CONCLUSION Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis.No association between CFRD and hepatic steatosis was found in this cohort.     

Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease

AIM To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis(CF) patients with hepatic steatosis as compared to normal CF controls.METHODS We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging(ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls.RESULTS Data was collected on 114 patients meeting inclusion criteria. Seventeen patients(14.9%) were found to have hepatic steatosis on imaging. Being overweight(BMI 25)(P = 0.019) and having a higher pp FEV1(75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level(27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.CONCLUSION Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher pp FEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.     

Association of body composition and lung function in children with cystic fibrosis

Survival in cystic fibrosis has improved significantly in the last 30 years, with major therapeutic goals of delaying the progressive loss of pulmonary function and maintaining normal growth. Dual-energy X-ray absorptiometry (DEXA) was performed in children with cystic fibrosis (CF) to assess both bone mineral density and body composition. We hypothesised that there would be an association between body composition and pulmonary function in children with CF. Fifty subjects with CF (28 males), mean age 12.7 years, participated in the study. Body composition was determined by DEXA. Body mass index (BMI) was calculated from the ratio of weight/height2 (kg/m2). Lung function was assessed by spirometry. Most patients (78%) had mild lung disease. The mean forced expired volume in 1 sec percent predicted (FEV1% predicted) for the 50 patients was 79.2% (range, 24-117%). There was a strong association between FEV1% predicted and BMI (R=0.59, P=0.0001). Fat-free mass had positive association with pulmonary function tests (R=0.30, P=0.03). Although fat mass showed a positive correlation with pulmonary function, this association did not reach statistical significance. In our group of children with CF and mild lung disease, pulmonary function was more strongly associated with BMI than with fat and fat-free mass.     

Cold air provocation of airway hyperreactivity in patients with cystic fibrosis

Thirty-four patients with cystic fibrosis (CF) were assessed for baseline pulmonary functions before, and 5 and 15 minutes after cold air challenge (CACh). Most of the patients had no change in forced expiratory volume in 1 second (FEV1) and maximum expiratory flow at 25% vital capacity (Vmax25%VC) post-CACh. Five patients responded with reduced FEV1 and 13 with reduced Vmax25%VC. However, paradoxical increases were noted in 10 patients for FEV1 and in 5 for Vmax25%VC. Paradoxical responses were most frequent in patients with severe lung disease. The explanation for this variability may lie in the varying degrees of airway instability and volume of airway contribution (VAC) to early flows, resulting from the damage caused by chronic infection. Conventional challenges may be useless in determining the true incidence of bronchial hyperreactivity in patients with CF.     

Changes in spirometry during consecutive admissions for infective pulmonary exacerbations in adolescent and adult cystic fibrosis.

Changes in spirometry during consecutive admissions for treatment of pulmonary infective exacerbations were studied in 45 patients (24 males, 21 females) with cystic fibrosis (CF) who had required five or more such admissions. Over the overall study period there was a mean (SD) decline in FEV1 of -112.1 (188.0) ml yr-1 (P less than 0.001) and in FVC of -47.9 (82.4) ml yr-1 (P less than 0.001). FEV1 and FVC increased during each admission with treatment; however, the magnitude of this change became less over consecutive admissions by a mean value of -33.3 ml (45.0) (P less than 0.001) for FEV1, and -26.0 (72.2) ml (P less than 0.05) for FVC. In the majority of patients that died or underwent transplantation, FEV1 at the time of the last admission did not rise above 800 ml despite full treatment.     

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis

Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.     

Predictors of mortality in adults with cystic fibrosis

Assessment of prognostic indicators in patients with cystic fibrosis (CF) is important. The study's aim was to assess the relative contribution of gender, genetics and microbiology on survival in adults with CF. Adult patients were studied from 1995 to 2005 and data collected included FEV(1) (%predicted), body mass index (BMI), genetics, and microbiology. Data was available on 183 patients in 1995. Forty-five patients died in the subsequent 10 years. Patients who died during the study had lower mean (SD) FEV(1) %predicted in 1995 when compared to those remaining alive, 41.5 (15.2)% versus 69.8 (23.2)% predicted, respectively, P<0.001 and they had lower mean (SD) BMI in 1995, 19.2 (3.3) kg/m(2) in comparison to those remaining alive, 20.7 (3.4) kg/m(2), P=0.008. The proportion of patients infected with Pseudomonas aeruginosa and Burkholderia cepacia complex was higher in the group who died during the study compared to those remaining alive, odds ratio 20.9 P<0.0001 and 7.1 P<0.0001, respectively. The presence of the Delta F508 homozygous mutation did not alter survival, P=0.3. Patients infected with either P.aeruginosa or B.cepacia complex had reduced survival compared to those without infection, P=0.01 and P<0.0001, respectively. FEV(1)% (P<0.0001), infection with P.aeruginosa (P=0.005) or B.cepacia complex (P=0.03) were the only significant predictors of mortality. This study demonstrates adults who died were more likely to have worse lung function and be infected with either P.aeruginosa or B.cepacia complex. FEV(1)% and infection with P.aeruginosa or B.cepacia complex were the most significant predictors of survival in adults with CF.     

Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis.

Many children with cystic fibrosis (CF), receiving modern, aggressive CF care, have normal spirometry results. This study aimed to see if homogeneity of ventilation distribution is impaired early in the course of CF lung disease, and if ventilation inhomogeneity is a more frequent finding than abnormal spirometry in children benefiting from modern CF care. The study compared spirometry findings to two indices of ventilation inhomogeneity (mixing ratio (MR) and lung clearance index (LCI)) from multiple-breath inert gas washout in 43 children with CF, aged 3-18 yrs, and 28 healthy children. In total, 10/43 CF subjects (23%) had reduced forced expiratory volume in one second (FEV1) and 14/34 (41%) showed abnormal maximum expiratory flow at 25% of forced vital capacity (MEF25). In contrast, MR was abnormal in 31/43 (72%) and LCI in 27/43 (63%). MR was abnormal in 22/33 CF subjects with normal FEV1, versus 0/28 controls (p<0.001), and abnormal MR was found in 10/20 CF subjects with normal MEF25, versus 0/22 controls (p<0.001). Nine of the 10 CF subjects with reduced FEV1 and 12/14 with abnormal MEF25 showed abnormal MR. Inert gas washout discloses airway dysfunction in the majority of children with cystic fibrosis with normal lung function judged by spirometry. These findings suggest that multiple-breath inert gas washout is of greater value than spirometry in detecting early cystic fibrosis lung disease.     

Nasal and exhaled nitric oxide is reduced in adult patients with cystic fibrosis and does not correlate with cystic fibrosis genotype

STUDY OBJECTIVES: Inducible nitric oxide synthase (iNOS) is upregulated in a number of inflammatory lung conditions, and exhaled nitric oxide (NO) concentration is increased. However, previous studies in children with cystic fibrosis (CF) have shown that exhaled NO is reduced. The purpose of this investigation was to study exhaled NO concentration in adults with CF, and to investigate the effect of CF genotype and respiratory tract infection on this measurement. DESIGN: Exhaled and nasal NO levels were measured in 54 adult CF subjects and 37 healthy nonsmoking age-matched subjects using a chemiluminesence analyzer. Spirometry (FEV(1) and FVC), CF genotype, and bacterial colonization were also recorded. SETTING: This study was conducted at a national CF center. RESULTS: The mean age of patients was 26.9 years, and the mean FEV(1) was 50.5% predicted (range, 17 to 104%). Nasal NO in the CF patients (mean, 520 parts per billion [ppb]; confidence interval [CI], 452 to 588) was significantly lower (p < 0.001) than in control subjects (987 ppb; CI, 959 to 1,015). Exhaled NO was significantly lower (p < 0. 001) in CF patients (5.0 ppb; CI, 4.1 to 6.1) than in control subjects (7.3 ppb; CI, 6.8 to 7.8). FEV(1) did not correlate with nasal or exhaled NO. No association was observed between genotype and NO values or colonization with Pseudomonas aeruginosa. CONCLUSIONS: Despite the airway inflammation that is characteristic of CF, both nasal and exhaled NO were reduced. There was no association with genotype or infection status. As NO has bacteriostatic effects and may augment mucociliary clearance, this observation may be of clinical importance.     

Symptoms, lactate and exercise limitation at peak cycle ergometry in adults with cystic fibrosis.

The purpose of this study was to investigate symptoms, lactate accumulation and limiting factors at peak exercise in cystic fibrosis (CF) patients. In total, 104 CF adults attending an adult CF centre and 27 controls performed progressive cycle ergometry to a symptom-limited maximum. Measurements taken at peak exercise included: heart rate, ventilation, oxygen uptake, carbon dioxide output, oxygen saturation and blood lactate. Symptom scores of perceived breathlessness and muscle effort were recorded using Borg scales. The CF subjects had a lower mean body mass index, forced expiratory volume in one second (FEV(1)) and peak oxygen uptake than controls. Peak lactate concentrations were very similar to controls (mean+/-sd 6.8+/-2.0 mmol x L(-1) versus 7.4+/-1.0 mmol x L(-1)). Symptom scores were no different to controls for either breathlessness (4.5+/-2.0 versus 4.3+/-1.0) or perceived muscle effort (6.1+/-2.0 versus 6.5+/-1.0), with higher scores for muscle effort than breathlessness in both groups. In addition, peak ventilation was lower than the predicted maximum, and high peak heart rates were recorded supporting nonpulmonary factors as important in limiting peak exercise. Peak oxygen uptake was correlated with FEV(1). Comparison of CF subjects with mild or moderate pulmonary disease and controls revealed similar exercise responses. In contrast, those CF patients with severe lung disease (FEV(1) <40% predicted) had significantly higher breathlessness, lower muscle effort scores, lower peak lactate, lower peak heart rate and a mean ventilation exceeding predicted, thus confirming that ventilation was the major factor limiting exercise. In conclusion, cystic fibrosis subjects have a reduced peak exercise capacity, but their exercise response is similar to controls in generating high blood-lactate concentrations and symptoms of muscle effort in excess of dyspnoea. Nonpulmonary factors influence peak performance more in those without severe disease.     

Effects of postural drainage, incorporating the forced expiration technique, on pulmonary function in cystic fibrosis

Detailed pulmonary function tests were performed on 12 patients with cystic fibrosis (CF) before and after 3 days treatment with postural drainage incorporating the forced expiration technique. The results following treatment showed a statistically significant improvement in FEV1 (P less than 0.001), FVC (P less than 0.001), PEFR(P less than 0.001), PIFR (P less than 0.001), and VEmax50 (P less than 0.025). The study demonstrates objective benefit from this form of physiotherapy in cystic fibrosis patients with copious bronchial secretions.     

Pregnancy in cystic fibrosis. Fetal and maternal outcome

OBJECTIVE: To assess the effect of pregnancy on pulmonary function and survival in women with cystic fibrosis (CF) and to assess the fetal outcome. DESIGN: Cohort study. The data analyzed were collected from the Toronto CF database, chart review, and patient questionnaire. SETTING: Tertiary-care center. PATIENTS: All women with CF who, at the time of diagnosis or pregnancy, attended the Toronto Cystic Fibrosis Clinics between 1961 and 1998. RESULTS: From 1963 to 1998, there were 92 pregnancies in 54 women. There were 11 miscarriages and 7 therapeutic abortions. Forty-nine women gave birth to 74 children. The mean follow-up time was 11 +/- 8 years. One patient was lost to follow-up shortly after delivery, and one was lost after 12 years. The overall mortality rate was 19% (9 of 48 patients). Absence of Burkholderia cepacia (p < 0.001), pancreatic sufficiency (p = 0.01), and prepregnancy FEV(1) > 50% predicted (p = 0.03) were associated with better survival rates. When adjusted for the same parameters, pregnancy did not affect survival compared to the entire adult female CF population. The decline in FEV(1) was comparable to that in the total CF population. Three women had diabetes mellitus, and seven developed gestational diabetes. There were six preterm infants and one neonatal death. CF was diagnosed in two children. CONCLUSIONS: The maternal and fetal outcome is good for most women with CF. Risk factors for mortality are similar to those for the nonpregnant CF population. Pregnancies should be planned so that there is opportunity for counseling and optimization of the medical condition. Good communication between the CF team and the obstetrician is important.     

The relationship between insulin secretion, the insulin-like growth factor axis and growth in children with cystic fibrosis

OBJECTIVE: Cystic fibrosis-related diabetes mellitus (CFRD) is an increasingly common complication of cystic fibrosis. CFRD is preceded by a progressive decline in insulin secretion but there is no accepted definition of the prediabetic state in CFRD. This prediabetic state appears to have adverse effects on clinical status, nutrition and lung function, but there is no direct evidence that the impaired glucose homeostasis is the cause of these deteriorations. This study examined the prevalence of glucose intolerance and impaired insulin secretion in a population of children with CF without CFRD. Severe CF lung disease is often associated with poor weight gain and slower growth but the mechanism for this is still unclear. The relationships between the current state of glucose homeostasis, insulin secretion and the insulin-like growth factor axis, height velocity, nutrition status and lung function were therefore studied. DESIGN AND PATIENTS: Eighteen children with cystic fibrosis aged 9.5-15 years had oral glucose tolerance tests and 14 of these also had intravenous glucose tolerance tests (four refused). Blood samples were collected for insulin, C-peptide, glucose, HbA1c, insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3. Data on height, weight, puberty status, clinical score (Shwachman score) and lung function were recorded. Height velocity, height and weight standard deviation scores (SDS) were calculated using WHO/CDC data. RESULTS: The mean height SDS (-0.52 +/- 0.17) was less than the normal population (P = 0.007) and the mean height velocity was 4.6 +/- 0.5 cm/year, 39% with a height velocity less than the third percentile for age. The weight SDS and body mass index (BMI) were similar to the normal population. Four children had impaired glucose tolerance. The first-phase insulin response (FPIR) was below the first percentile of normal population values in nine (65%). Impaired FPIR or impaired glucose tolerance did not correlate with the Shwachman score, nutritional status or pulmonary function. There was a significant positive correlation between insulin secretion (area under the curve) and height velocity (P = 0.001) and serum IGFBP-3 levels (P = 0.001). CONCLUSIONS: Impaired glucose tolerance was present in 20% of children with cystic fibrosis. Impaired insulin secretion was common (65%) even in children with normal glucose tolerance. The mean height SDS for the group was low and the height velocity was abnormally slow in 39%, yet nutritional status as measured by BMI was appropriate for age. Relative insulin deficiency rather than nutritional deprivation or poor clinical status thus appears to be implicated in the poor linear growth of these children with relatively stable lung disease. This was a small study and firm conclusions on this chronic suppurative disease as to the cause of poor growth are not possible. The causes of poor growth are likely to be complex; nevertheless, the apparent decrease in insulin secretion combined with the expected increased demands on insulin production during pubertal growth raises the question as to whether insulin therapy should be considered in children with cystic fibrosis before the onset of cystic fibrosis-related diabetes mellitus.     

Association of common haplotypes of surfactant protein A1 and A2 (SFTPA1 and SFTPA2) genes with severity of lung disease in cystic fibrosis

Most individual cystic fibrosis transmembrane conductance regulator (CFTR) mutations appear not to correlate directly with severity of lung damage in cystic fibrosis (CF). Components of innate immunity, namely, mannose-binding lectin (MBL2), and surfactant protein A1 and A2 genes (SFTPA1 and SFTPA2), were shown to be critical in pulmonary host defenses. A pilot association study was conducted to identify genetic modifiers of lung disease in adult patients with CF. The structural and promoter (-221x/y) variants of MBL2, variants at codons 19, 50, 62, and 219 of SFTPA1, and at codons 9, 91, and 223 for SFTPA2, were studied in 135 adults with CF and compared to their forced expired volume in 1 sec (FEV1), diffusion of CO (DLCO), and other pulmonary scores. Predicted FEV1 was significantly lower in adults with the SFTPA1 6A3 allele and SFTPA2 1A1) allele (P = 0.01 and 0.009, respectively). The extended haplotype 6A3/1A1, which includes SFTPA1 and SFTPA2, was associated with lower pulmonary function, using FEV1 (P = 0.005) and poor pulmonary scores which were determined by American Medical Association, American Thoracic Society, and modified Shwachman-Kulczycki scores. Lower FEV1 and DLCO values were associated with MBL2 coding variants in those who had the DeltaF508 CFTR mutation (P = 0.03 and 0.004, respectively). These results support the current hypothesis that variants in pulmonary host defense molecules are potentially genetic modifiers of pulmonary disease in CF. Further work in larger populations is required to provide important new insights into the pathogenesis of CF.     

Increased arginase activity in cystic fibrosis airways

RATIONALE: Airway nitric oxide concentrations are reduced in cystic fibrosis (CF). Arginases compete for L-arginine, the substrate of nitric oxide synthesis. OBJECTIVES: We hypothesized that increased arginase activity may be one factor contributing to nitric oxide deficiency in CF. MEASUREMENTS: We therefore studied sputum arginase activity, exhaled nitric oxide, and pulmonary function in patients with cystic fibrosis. RESULTS: Mean (+/- SEM) sputum arginase activity was significantly higher in patients admitted for pulmonary exacerbation compared with patients with stable disease (1.032 +/- 0.148 vs. 0.370 +/- 0.091 U/mg protein, p = 0.004). Fourteen days of intravenous antibiotic treatment resulted in significantly decreased sputum arginase activity in all patients (p = 0.0002). However, arginase activity was still significantly (p = 0.0001) higher in CF sputum after treatment for exacerbation compared with induced sputum from healthy control subjects (0.026 +/- 0.006 U/mg protein). Negative correlations were found for sputum arginase activity at admission with FEV1 (r = -0.41, p = 0.01), as well as changes in arginase activity with percent change in FEV1 during antibiotic therapy (r = -0.4, p < 0.01) in CF. Exhaled nitric oxide in CF was positively correlated to FEV1 (r = 0.34, p = 0.007), and in patients admitted for pulmonary exacerbation negatively correlated to sputum arginase activity (r = -0.45, p = 0.03). CONCLUSIONS: These data suggest that increased sputum arginase activity contributes to nitric oxide deficiency in CF lung disease and may be relevant in the pathogenesis of CF airway disease.     

Changes in lung function measured by spirometry and the forced oscillation technique in cystic fibrosis patients undergoing treatment for respiratory tract exacerbation

Objective measures of lung function are critical for the treatment and study of lung diseases such as cystic fibrosis (CF). Spirometry is the most widely used and accepted method of pulmonary function testing in CF, but not all patients can perform the maneuvers required to obtain valid results from spirometry. The forced oscillation technique (FOT) requires less cooperation than spirometry. The goals of this study were to determine if FOT could detect changes in lung function in CF patients receiving inpatient treatment of respiratory tract exacerbations (RTEs), and to gather preliminary data on the magnitude of these changes and the variability of FOT data in such patients. We performed a retrospective chart review of CF patients admitted to the hospital for RTEs. We identified 14 patients who had both spirometry and FOT performed at the beginning and end of their treatment course. Their mean age was 15.9 years (range, 8-18). The mean forced expiratory volume in 1 sec (FEV1) on admission was 62.57% predicted. FEV1 increased by 27.1 +/- 33.15% (mean +/- SD, P = 0.008). The absolute value of reactance at 5 Hz (X5) decreased by 22.3 +/- 25.1% (P = 0.005), while resistance at 5 Hz decreased by 11.6 +/- 17.3% (P = 0.025). There was a significant relationship between changes in FEV1 and X5 (P = 0.003, r2 = 0.54). Our study demonstrates that FOT can detect significant changes in lung function in CF patients receiving treatment for RTEs. We speculate that FOT can serve as an alternative method to measure lung function in CF patients unable to perform spirometry, such as young children.     

The effect of pregnancy on survival in women with cystic fibrosis

STUDY OBJECTIVES: Patients with cystic fibrosis (CF) are currently living to their fourth decade and are making reproductive decisions. Information concerning the reproductive health of women with CF has been limited to small or single-center studies. DESIGN: We conducted a matched parallel-cohort study to assess the impact of pregnancy on the survival of women with CF. PARTICIPANTS: A parallel-cohort study included all women > 12 years of age who were enrolled in the US Cystic Fibrosis Foundation National Patient Registry from 1985 to 1997. MEASUREMENTS AND RESULTS: Six hundred eighty of the 8,136 women in the cohort became pregnant. These 680 women were matched on an index year to 3,327 control women with CF. At the inception of entry into the cohort, women who reported pregnancy were more likely to have had a higher percentage of predicted FEV(1) (67.5% predicted vs 61.7% predicted, respectively; p < 0.001) and a higher weight (52.9 vs 46.4 kg, respectively; p < 0.001). Using Kaplan-Meier survival curves, the 10-year survival rate in pregnant women (77%; 95% confidence interval [CI], 71 to 82%) was higher than in those women who did not become pregnant (58%; 95% CI, 55 to 62%). A separate analysis, matching pregnant patients on FEV(1) percent predicted, age, Pseudomonas aeruginosa colonization, and pancreatic function, obtained similar results. Using Cox proportional hazard modeling to adjust for baseline age, FEV(1) percent predicted, weight, height, and pulmonary exacerbation rate per year, pregnancy was not associated with an increase risk of death. Pregnancy was not harmful in any subgroup including patients with FEV(1) < 40% of predicted or diabetes mellitus. CONCLUSIONS: Women with CF who became pregnant were initially healthier and had better 10-year survival rates than women with CF who did not become pregnant. After adjustment for the initial severity of illness, women who became pregnant did not have a significantly shortened survival.     

Annual lung function changes in young patients with chronic lung disease.

Reference equations for ventilatory function that use different statistical models may introduce artifacts that affect the estimated change of lung function during growth in young subjects. The effect of differently modelled reference equations on the estimated annual change of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in young patients with chronic lung disease was assessed. Four frequently used reference equations were used to describe the longitudinal changes of FEV1 and FVC in 52 patients (23 females) with cystic fibrosis (CF) during a mean follow-up of 3.9 yrs. Choice of reference equations directly affected value and, most importantly, estimated annual change of FVC and FEV1. Mean+/-SD annual change of FEV1 varied from 2.2+/-6.2 to -2.2+/-3.6% of predicted. For two reference equations the estimated individual changes of FEV1 and FVC in CF were positively correlated with mean individual age. This probably reflects underestimation of deteriorating lung function. Variability of annual change was independent of age only when reference equations that were designed to accurately predict lung function during the pubertal growth spurt were used. These findings have implications for patient care and clinical research.