- Email: [email protected]
Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al
ARTICLE IN PRESS
JID: JCF
[m5G;October 31, 2019;5:58]
Journal of Cystic Fibrosis xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf
Original Article
Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al Hanne V Olesen a,∗, Pavel Drevinek b, Vincent A Gulmans c, Elpis Hatziagorou d, Andreas Jung e, Meir Mei-Zahav f, Natasa Stojnic g, Muriel Thomas h, Anna Zolin i , on behalf of the ECFSPR Steering Group a
Dept of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Denmark Department of Medical Microbiology, Motol University Hospital and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic c Dutch Cystic Fibrosis Foundation (NCFS), Baarn, The Netherlands d Paediatric Pulmonology and CF Unit, Hippokration Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece e Paediatric Pulmonology, University Children‘s Hospital Zurich, Zurich, Switzerland f Pulmonary Institute, Schneider Children’s Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Israel g Department of Pulmonology, Mother and Child Healthcare Institute of Serbia, Belgrade, Serbia h Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy i Belgian Cystic Fibrosis Registry, Sciensano, Belgium b
a r t i c l e
i n f o
Article history: Received 21 August 2017 Revised 17 September 2019 Accepted 1 October 2019 Available online xxx Keywords: Cystic fibrosis Diabetes Lung function Body mass index Gender
a b s t r a c t Background: Cystic fibrosis related diabetes (CFRD) has implications for morbidity and mortality with several risk factors identified. We studied the epidemiology of CFRD in the large dataset of the European Cystic Fibrosis Society Patient registry. Methods: Data on CF patients were investigated for the prevalence of CFRD as well as for any association with suggested risk factors and effects. Results: CFRD increased by approximately ten percentage points every decade from ten years of age. Prevalence was higher in females in the younger age groups. CFRD was associated with severe CF genotypes (OR = 3.11, 95%CI: 2.77–3.48), pancreatic insufficiency (OR = 1.46, 95%CI: 1.39–1.53) and female gender (OR = 1.28, 95%CI: 1.21–1.34). Patients with CFRD had higher odds of being chronically infected with Pseudomonas aeruginosa, Burkholderia cepacia complex and Stenotrophomonas maltophilia than patients without CFRD, higher odds of having FEV1% of predicted <40% (OR = 1.82, 95%CI: 1.70–1.94) and higher odds of having BMI SDS ≤−2 than patients without CFRD (OR = 1.24, 95%CI: 1.15–1.34). Conclusions: Severe genotype, pancreatic insufficiency and female gender remain considerable intrinsic risk factors for early acquisition of CFRD. CFRD is associated with infections, lower lung function and poor nutritional status. Early diagnosis and aggressive treatment of CFRD are more important than ever with increasing life span. © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Background Cystic fibrosis related diabetes (CFRD) remains a frequent extrapulmonary complication of cystic fibrosis (CF) – adding considerably to the treatment burden [1,2]. CFRD is primarily caused by insulin deficiency based on destruction of islet cells in the pancreas, although recent research suggests that CFTR in itself interferes with insulin secretion and glycaemic control [3,4]. Glucose ∗
Corresponding author. E-mail addresses: [email protected] (H.V. Olesen), [email protected] (P. Drevinek), [email protected] (V.A. Gulmans), [email protected] (A. Jung), [email protected] (M. Thomas), [email protected] (A. Zolin).
metabolism impairment in CF starts from early infancy and continues during life with variable progression, primarily in pancreatic insufficient patients [5–7]. Initially, the decreasing number of betacells leads to delayed and eventually insufficient insulin release, as impaired glucose tolerance changes into overt diabetes with fasting hyperglycaemia. CF patients with CFRD are insulin resistant to a mild degree, but this increases with exacerbations and progression of lung disease. Whether this resistance is also present in nondiabetic CF patients is disputed [7,8,9]. CFRD has been associated with poor lung function, poor BMI and higher mortality [10–13] The aim of this study was to evaluate the prevalence of CFRD in the European Cystic Fibrosis Society Patient Registry (ECFSPR), and
https://doi.org/10.1016/j.jcf.2019.10.009 1569-1993/© 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 2
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
to analyse the influence of genotype, pancreatic status and gender, as well as the association between CFRD and lung function, nutritional status and chronic infections. The number of patients and years of follow-up in the ECFSPR will improve the validity of the findings.
3. Statistics
2. Methods
3.1. Longitudinal analysis
The European Cystic Fibrosis Patient Registry (ECFSPR) collects demographic and clinical data of CF patients from the following countries: Austria, Belgium, Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg, Republic of Macedonia, Republic of Moldova, the Netherlands, Portugal, Romania, Russian Federation, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, Ukraine and United Kingdom (for coverage per country, see [1]). For the purpose of this study, data of years 2008–2015 (the most updated data at the time of the analysis) were considered. Only patients with confirmed diagnosis of CF according to ECFSPR criteria [14] and seen at the CF centre for the years of follow-up were included in the study. The structure of the ECFSPR and the methods of collection and management of data are described elsewhere [15]. For collecting information on CFRD, the ECFSPR uses the variable “daily insulin use”. Patients with e.g. pathological oral glucose tolerance test (OGTT), but not on insulin are thus not captured by the ECFSPR. For simplicity patients with “daily insulin use = yes” will be named as CFRD. The following variables were used for analyses (for ECFSPR definitions see [14]): country; age at follow up; gender; both CFTR mutations; use of pancreatic enzymes as a proxy for pancreatic status; Stenotrophomonas maltophilia (SM) infection, chronic Pseudomonas aeruginosa (PA) and Burkholderia cepacia complex (BCC) infection;1 FEV1% of predicted (best in year2 ; Global Lung Function Initiative equations described by Quanjer PH et al. [16]., BMI z-score (CDC references [17]); lung transplantation. Since the ECFSPR does not collect the information of the date of diagnosis of CFRD, age at diagnosis of CFRD was computed as difference between the year of follow up in which the patient used insulin for the first time and the year of birth. Genotype was classified according to De Boeck et al. [18]. The patients were grouped as “two severe mutations (class I, II or III)”, “at least one mild mutation (class IV, V)” and “unclassifiable” (one severe and one unclassifiable mutation or two unclassifiable mutations). CFRD classification for patients with missing values were performed as follows: If information on CFRD was missing for a year, but the status of CFRD (yes or no) was the same for the previous and the subsequent year, the information for the missing year was set to that value (only 1% of the records). If information on the CFRD status was not consistent through the years, e.g. a patient was free of CFRD for 2 years, then the patient was diagnosed as CFRD patient, but the subsequent years the patient was negative for CFRD, that patient was not included into the analysis (only 6% of patients). For patients who died during the study period all years were included. Lung transplanted patients were omitted from FEV1 analysis after the year of the transplant, since FEV1 after transplant would not reflect the natural progression of the disease.
Longitudinal analysis was performed on data from 2008–2015. Patients from countries with percentage of missing data on CFRD status higher than 15% for more than two years and problems with the patients’ linkage through the years were excluded. A Student’s t-test was used to assess any difference in age at CFRD diagnosis between males and females. To investigate which intrinsic risk factors (gender, genotype and pancreatic status) are associated to CFRD, a multivariable logistic regression model, accounting for repeated measures, was used with adjustment for country and age. The method of generalized estimating equations with an unstructured covariance matrix was used to account for correlations among observations from the same subject. Records with missing values for a patient were not used. [19,20]. To investigate if CFRD is a risk factor associated to microbiology infections, lung function and growth, multivariable logistic regression models, accounting for repeated measures, were used. All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) were considered into the model with adjustment for country and age. Records with missing values for a patient were not used. [19,20]. Data were analysed both including and excluding pancreatic sufficient (PS) patients, because of the much lower prevalence of diabetes in these patients, who, generally, have milder lung disease. All analyses were conducted using SAS version 9.4 (SAS Institute Inc).
1 for the UK the definition of chronic infection is slightly different but judged to cover the same population. 2 The following countries reported last FEV1 or FEV1 at annual review instead: France, Germany, Sweden and UK.
Prevalence was calculated from the 2015 data set. Patients from countries with percentage of missing data on CFRD status higher than 15% were excluded. For prevalence comparisons, with a descriptive purpose, Chi-square test was used for all variables.
4. Results A total of 40,096 patients with confirmed diagnosis of CF and seen at a CF centre were recorded in the 2015 data set. Belgian data for 2014 and 2015 were not submitted at time of analysis, therefore the data from 2008–2013 were only included in the longitudinal analyses. Germany had more than 30% of patients with unknown status of CFRD. They furthermore had linkage issues due to change of software during the study period, therefore this country was not considered, leaving 34,733 patients for further analysis. 4.1. Prevalence of CFRD The prevalence varied by age group: < 10 year olds 0.8%; 10–19 year olds 9.7%; 20–29 year olds 24.1%; and ≥30 year olds 32.7%. Due to very low prevalence and suspected overrepresentation of type 1 diabetes in that age group, the < 10 year age group was omitted from further analyses (9590 patients) leaving 25,143 patients as the new basis for further analyses. The total prevalence of CFRD was 21.6%. The country specific prevalence varied both overall and in the specific age groups (Table 1). Some countries had the highest prevalence in some age groups and the lowest prevalence in others (Table 1). The prevalence of CFRD was significantly higher in patients with pancreatic insufficiency (PI) overall (25.8 vs 3.5%) and through all age groups (11.2 vs 1.4% in 10–19 year olds; 28.0 vs 2.5% in 20– 29 year olds; 42.6 vs 5.4% in ≥30 year olds – with a factor of 8 to 11 – all p < 0.0 0 01).
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
ARTICLE IN PRESS
JID: JCF
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
3
Table 1 Prevalence of CFRD by country and age group (year 2015). Three highest prevalences in each age group (bold/large) and the three lowest (underscore/petite) are marked. Countries with < 20 patients in the age group not ranked (grey background). 1 For the age group ≥ 30 yrs, Greece has a percentage of missing information on CFRD > 10%. 2 For the age group 20–29 yrs, Serbia has a percentage of missing information on CFRD > 10%.
Austria Bulgaria Czech Republic Denmark France Greece1 Hungary Ireland Israel Italy Latvia Lithuania Luxembourg Rep. Macedonia Rep. Moldova The Netherlands Portugal Romania Russian Fed. Serbia Slovak Republic Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom Total
Overall Age group 10-19 yrs Age group 20-29 yrs Age group ≥ 30 yrs Missing/ Prev of N of Missing/ Prev of N of Missing/ Prev of N of Missing/ Prev of N of Unknown CFRD pts Unknown CFRD pts Unknown CFRD pts Unknown CFRD pts 1.18 18.31 508 1.38 8.76 217 0.60 20.36 167 1.61 32.26 124 2.44 6.06 0.00 7.78 90 0.00 41 0.00 33 0.00 25.00 16 0.00 28.97 397 0.00 182 0.00 126 0.00 37.08 89 19.23 37.30 0.00 31.90 373 0.00 7.02 114 0.00 119 0.00 140 34.45 50.00 0.00 19.92 4959 0.00 8.24 1783 0.00 22.77 1537 0.00 29.96 1639 4.78 16.03 418 1.17 8.19 171 4.35 18.12 138 11.01 25.69 109 1.67 13.88 418 0.48 6.19 210 2.21 19.12 136 4.17 26.39 72 0.89 17.98 784 0.00 6.84 307 0.82 21.81 243 2.14 28.63 234 1.14 23.57 437 1.89 10.69 159 1.39 29.86 144 0.00 32.09 134 0.93 19.36 3998 0.54 7.57 1307 0.90 19.23 1113 1.27 29.21 1578 13.64 4.55 22 7.14 0.00 14 16.67 0.00 6 50.00 50.00 2 0.00 7.14 14 0.00 0.00 1 0.00 9.09 11 0.00 0.00 2 0.00 22.22 18 0.00 16.67 6 0.00 0.00 4 0.00 37.50 8 0.00 15.38 65 0.00 9.30 43 0.00 31.58 19 0.00 0.00 3 0.00 10.53 19 0.00 8.33 12 0.00 14.29 7 0.00 31.10 1058 0.00 337 0.00 29.43 333 0.00 388 21.36 40.98 8.51 5.16 9.86 213 6.36 9.09 110 5.36 12.50 56 2.13 47 0.00 0.00 14 0.00 0.00 14 6.71 8.09 4.43 5.15 1399 4.00 3.75 801 3.90 462 8.82 136 13.76 17.43 109 7.81 15.63 64 22.58 19.35 31 21.43 21.43 14 1.61 8.70 17.78 0.65 8.50 153 0.00 62 0.00 46 2.22 45 0.00 20.31 64 0.00 35 0.00 21.05 19 0.00 20.00 10 20.00 7.76 18.69 1225 9.33 9.51 536 3.88 24.27 309 8.68 27.11 380 0.00 22.66 512 0.00 9.93 141 0.00 17.22 151 0.00 34.55 220 1.97 21.71 608 1.00 8.46 201 2.53 24.75 198 2.39 31.58 209 0.00 4.76 21 0.00 5.56 18 0.00 0.00 2 0.00 0.00 1 3.51 1.52 3.03 66 1.75 57 0.00 0.00 8 0.00 0.00 1 0.00 27.68 7181 0.00 13.09 2323 0.00 0.00 31.02 2373 38.15 2485 1.12 21.55 25143 1.23 9.70 9266 0.90 24.12 7791 1.21 32.65 8086
Table 2 Prevalence of CFRD by genotype group and age group (year 2015). The prevalence was statistically different between genotype groups in all age groups (all p < 0.0 0 01). Genotype class
Mild (at least one class IV-V) Severe (both mutations class I-III) Unclassifiable (one class I-III and one unclassifiable mutation or two unclassifiable)
Age group ≥ 30 yrs
Age group 10–19 yrs
Age group 20–29 yrs
Number of pts
Prevalence of CFRD
Number of pts
Prevalence of CFRD
Number of pts
403 5451 3177
0,50 12,05 7,43
374 4690 2609
2,41 29,79 17,86
788 3893 3238
Almost all (99.9%) of the patients have data on CFTR mutation: 1585 (6.4%) patients had genotype classified as “at least one mild mutation”, 14,131 (56.7%) patients had genotype classified as "two severe mutations” and 9179 (36.9%) patients had “unclassifiable genotype” [18]. The distribution of CFRD by the genotype class is presented in Table 2. The percentage of male patients was 51.5% in 10–19 year olds and increased to 55.1% in the ≥30 year olds. The prevalence of CFRD was significantly higher in females for the two youngest age groups (11.6% females vs 8.1% males for 10–19 year olds; 27.8 vs 21.2% for 20–29 year olds, p < 0.0 0 01), whereas there was no significant difference in the ≥30 year age group (33.3 vs 32.3%). 24,339, 24,454 and 24,112 patients (96.8%, 97.2% and 95.6%) had data on chronic PA, chronic BCC and SM infection, respectively. For chronic PA, the prevalence of chronic infection was higher in all age groups in the CFRD patients (Fig. 1A). For chronic
Prevalence of CFRD 9,90 47,88 21,09
BCC infection, the prevalence was significantly higher in CFRD patients in the youngest age group (10–19 year), whereas there was no difference in the older age groups (Fig. 1B). For SM infection, the prevalence was significantly higher in CFRD patients in the youngest age group (10–19 year), but was significantly higher in non- CFRD patients in the oldest age group (≥30 year) (Fig. 1C). Among the 23,284 patients without a lung transplant, 20,167 (86.6%) patients had data on FEV1 (the 3117 patients without data on FEV1 was primarily from the UK (1592), Italy (483) and Russia (448), the rest were evenly distributed). Patients with CFRD had a higher percentage of low or moderately low lung function (< 40 and 40–80% of predicted) in all age groups (Fig. 2). The difference between CFRD and non-CFRD patients was smaller when comparing only PI patients, but still highly significant in all age groups (Fig. 1 suppl).
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 4
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
Hungary were excluded from the analysis due to linkage problems between the oldest and newest data sets. The mean age at diagnosis of CFRD was significantly lower for females than males in all years (2009: 25.1 years for females vs 28.7 years for males; 2010: 25.7 years vs 27.6 years, 2011: 23.7 years vs 27.8 years, 2012: 23.5 years vs 26.8 years, 2013: 23.4 years vs 27.2 years, 2014: 25.0 years vs 26.9 years, 2015: 25.0 years vs 27.1 years, all p < 0.05). Using a multivariable logistic regression model, accounting for repeated measures, to investigate the risk factors associated with CFRD, we observed that PI patients had a slightly higher odds of having CFRD than PS patients (OR = 1.46, 95%CI: 1.39–1.53). Patients with severe genotype had an increased odds of having CFRD compared to patients with mild genotype (OR = 3.11, 95%CI: 2.77– 3.48) and patients with unknown genotype had a higher odds of having CFRD than patients with mild genotype (OR = 1.94, 95%CI: 1.75–2.15). Female patients had slightly higher odds of having CFRD than male patients (OR = 1.28, 95%CI: 1.21–1.34). The results of the multivariable logistic models to investigate if CFRD is a risk factor associated to microbiology infections are reported in Table 3. Patients with CFRD had slightly higher odds of being chronically infected with PA than patients without CFRD (OR = 1.32, 95%CI: 1.26–1.39), had slightly higher odds of being chronically infected with BCC than patients without CFRD (OR = 1.12, 95%CI: 1.00–1.24); and had slightly higher odds of being chronically infected with SM than patients without CFRD (OR = 1.10, 95%CI: 1.01–1.20). The results of the multivariable logistic models to investigate if CFRD is a risk factor associated to lung function and growth are reported in Table 4. Patients with CFRD had higher odds of having FEV1 percent of predicted <40% than patients without CFRD (OR = 1.82, 95%CI: 1.70–1.94). Patients with CFRD had slightly higher odds of having BMI SDS ≤−2 than patients without CFRD (OR = 1.24, 95%CI: 1.15–1.34). 5. Discussion
Fig. 1. Chronic Pseudomonas aeruginosa (1A), chronic Burkholderia cepacia complex (1B) and Stenotrophomonas maltophlia (1C) infections and CFRD by age group. ∗ p < 0.0 0 01 compared to no CFRD patients.
Among the 25,143 patients, 23,672 (94.1%) patients had information on BMI (the 1471 patients without data were primarily from Italy (508), UK (193) and Russia (158), the rest were evenly distributed). Patients with CFRD had a higher percentage of low BMI (z-score ≤ −2) in all age groups: for the 10–19 year olds 13.0% of CFRD patients vs 7.9% in non-CFRD (p < 0.0 0 01); 20–29 year olds 15.6% vs 11.2% (p < 0.0 0 01) and ≥30 year olds 9.7% vs 5.1% (p = 0.0 0 01). When excluding the PS patients, the percentage of patients with low BMI remained significantly higher in patients with CFRD in all the age groups (Fig. 2 suppl). 4.2. Longitudinal analysis Data from Italy where excluded from the longitudinal analysis due to high percentages of missing values in some years. Data from
This manuscript presents a very large registry based epidemiological study on CFRD, exploring risk factors as well as outcomes. We confirmed that CFRD is still a common complication to CF with increasing prevalence with age, thus constituting an increasing problem with the increasing life span of CF patients. Severe CF genotype, pancreatic insufficiency and female gender were confirmed as risk factors for acquisition of CFRD, whereas CFRD was still associated with poorer lung function, poorer BMI, and increased prevalence of chronic infections. The prevalence of CFRD does not appear to have increased considerably in the last couple of decades. In 1994, the Danish CF cohort showed prevalence of 1% at 10 years and 15% at 20 years [21]. In 2005, the US Epidemiologic Study of Cystic Fibrosis showed a prevalence of seven percent in teenagers, 20% in 18–25 year olds and 25% in 26+ year olds (use of insulin or oral antidiabetics) [10]. In 2009, in a smaller UK study, the prevalence of CFRD with fasting hyperglycaemia was five percent in 10–19 year olds, 18% in 20– 29 year olds and 25% in 30–39 year olds (higher for CFRD without fasting hyperglycaemia) [22]. Our study showed an increase in prevalence of ten percent per decade from ten to forty years. The ECFSPR registers CFRD as “daily insulin – yes/no”, thus reaching a very high specificity, but a lower sensitivity, especially for patients with impaired OGTT without fasting hyperglycaemia, who may not yet be on insulin treatment. The prevalence varies considerably between countries (Table 1). With our definition, national differences in registration of CFRD is not a likely cause of the variation, since most national registries capture insulin use, even if they also have other variables defining CFRD. The ECFSPR requires registration of either yes, no or unknown for this variable, so unknown is clearly
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
5
Table 3 Odds ratios and 95% confidence intervals of multivariable logistic regression models, accounting for repeated measures, to investigate if CFRD is a risk factor associated to microbiology infections (grey). All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) are considered into the model with adjustment for country and age. Genotype, gender, chronic PA and SM did not contribute to the chronic BCC model. Genotype and BMI did not contribute to the SM model.
enzymes yes vs no genotype severe vs mild genotype unclassifiable vs mild gender F vs M age ≥ 30 vs 10-19 age 20-29 vs 10-19 CFRD yes vs no Chronic Pseudomonas aeruginosa yes vs no Chronic Burkholderia cepacia complex yes vs no Stenotrophomonas maltophilia yes vs no BMI SDS≤-2 vs SDS>-2 FEV1% of predicted 40-80% vs >80% FEV1% of predicted <40% vs >80%
Chronic Pseudomonas Chronic Burkholderia aeruginosa cepacia complex OR 95% CI OR 95% CI 1.65 1.55 1.75 1.43 1.27 1.62 1.89 1.70 2.10 1.38 1.24 1.53 1.14 1.08 1.19 2.27 2.16 2.39 1.35 1.20 1.52 1.87 1.79 1.95 1.31 1.19 1.44 1.32 1.26 1.39 1.12 1.01 1.24 - 0.88 0.82 0.95 0.77 0.70 0.85 0.87 0.83 0.91 1.07 1.02 1.12 1.21 1.12 1.32 1.52 1.47 1.58 1.26 1.18 1.35 2.41 2.29 2.54 1.55 1.39 1.73
Stenotrophomonas maltophilia OR 95% CI 1.47 1.33 1.62
1.34 0.67 0.79 1.11 0.69 0.66 -
1.25 0.61 0.73 1.02 0.65 0.56 -
1.44 0.74 0.85 1.22 0.74 0.78 -
1.33 1.58
1.25 1.42
1.42 1.75
Table 4 Odds ratios and 95% confidence intervals of multivariable logistic regression models, accounting for repeated measures, to investigate if CFRD is a risk factor associated to low lung function (FEV1 < 40%) and growth (BMI < −2SD) (grey). All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) are considered into the model with adjustment for country and age. Gender did not contribute to the FEV1 model. .
enzymes yes vs no genotype seve vs mild genotype ukno vs mild gender F vs M Age ≥30 vs 10-19 age 20-29 vs 10-19 CFRD yes vs no Chronic Pseudomonas aeruginosa yes vs no Chronic Burkholderia cepacia complex yes vs no BMI SDS≤-2 vs SDS>-2 FEV1% of predicted 40-80% vs >80% FEV1% of predicted <40% vs >80%
defined as unknown, but may not be so in the national registry. This possible inconsistency in coding will be investigated as part of the ECFSPR Data Quality Programme. Diagnosis of CFRD at the clinic level may vary, depending on practice of diagnosing by routine OGTT, HbA1c, random blood glucose levels, or only at symptoms. Finally, the difference may be due to percentage of PI patients in the countries which varies between five and 25% [1]. As expected, CFRD was associated with PI, with prevalence 8 to 11 times higher than in PS patients. However, the frequency of CFRD in PS patients is 2–3 times higher than the prevalence of type 1 diabetes in young adults reported in e.g. the UK (one to two percent in 16–44 y olds) [23]. CFRD may evolve in the course of chronic pancreatitis, a known complication to PS, but the ECFSPR does not capture this complication, so the question of aetiology in PS and PI patients remains unsolved. However, regular OGTT should be performed in all CF patients, regardless of pancreatic status [24,25]. For genotype classification, we chose to group our mutations using De Boeck et al. [18], which classify the 30 most common genotypes. For genotype, the pattern of CFRD is very much the same as for PI/PS but with lower prevalence in PS patients than in the mild mutation group. The unclassifiable group seems
OR 1.49 1.35 1.36 4.32 2.60 1.82 1.63 1.54 0.36 -
FEV1 95% CI 1.37 1.62 1.14 1.59 1.15 1.61 3.99 2.44 1.70 1.56 1.38 0.33 -
4.67 2.78 1.94 1.71 1.72 0.39 -
OR 1.66 1.16 1.51 0.55 0.53 1.07 1.24 1.06 1.30 2.13 5.76
BMI 95% CI 1.49 1.85 0.93 1.45 1.22 1.88 0.50 0.59 0.48 0.59 1.00 1.14 1.15 1.34 1.00 1.12 1.16 1.47 1.99 2.27 5.27 6.30
closer to the severe mutations in CFRD prevalence than the group with at least one mild mutation (Table 2), implying that most of the unclassified mutations are indeed severe mutations. The CFTR2 project has now classified 322 mutations, so further classification could be performed [26]. Previously, female CF patients have had poorer survival with CFRD, [12], although the poorer survival is not seen in more recent studies [13]. Females have a higher prevalence [10] with a trend towards earlier onset than in male patients [27]. Our study showed a significantly earlier onset of CFRD in females. The prevalence was higher in females in the younger age groups, but was equal in the ≥30 year olds. Considering the findings of lower FEV1, lower BMI and more chronic infections associated with CFRD, the female CFRD patients are, thus, exposed to these known risk factors for early death at a younger age and in a higher proportion [28]. The increasing proportion of males with increasing age implies an excess mortality in females which may account for the equalising of CFRD prevalence in the older age groups. CFRD remains associated with poorer lung function and nutrition. The proportion of patients with low or moderately low FEV1 was significantly higher in all age groups, including the 10–19 year olds, quite recently diagnosed with CFRD. The proportion of very
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 6
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
Fig. 2. FEV1 groups with or without CFRD in three age groups. FEV1 grouped as > 80%, 40–80% and < 40% of predicted value. P-value for all age groups < 0.0 0 01.
low BMI z-score was also higher in CFRD patients in all age groups. Some of this deterioration may be reversible with treatment [29], but the CFRD patients continued to have lower lung function than their peers and thus, consequently, reach end stage lung disease earlier (Table 4; Fig. 2): a UK registry study found a hazard ratio (HR) of death with diabetes of 1.31 (CI) [11]. In the Canadian registry, the hazard ratio was 1.81 (CI) of death for females with diabetes, whereas CFRD did not increase the HR for males [12]. Chronic infection with PA was more frequent with CFRD in all age groups. As opposed to genotype, gender and pancreatic status, which are all intrinsic factors associated with CFRD, lung function, BMI and chronic infections are factors that may interact with CFRD.CFRD is often diagnosed during periods of deterioration, and increased glucose levels may be seen during exacerbations, returning to normal when the exacerbation subsides. Changes in glucose tolerance may be seen very early in life, when lung disease is still minimal and no chronic infections are established, but the majority of patients are diagnosed with CFRD in their teens or later [30]. Most of the epidemiological research has been focused on patients already diagnosed with CFRD compared to patients without CFRD. A small retrospective case-control study (36 patients), showed that patients who later developed CFRD had lower FEV1 and BMI than matched controls six years prior to diagnosis [29]. The ECFSPR data set represents a very large real-life dataset including a wide variety of CF patients across Europe. Considering the number of patients included from many countries and centres, the latest datasets have very few missing values (< 6%) for most of the variables, which makes the data analysis highly valid. Only the FEV1 variable has a higher number of missing values (13.4%), which makes the results a little less robust. However, the missing data were primarily from three countries and analysis of age, gender, genotype or other risk-factors in patients with or without FEV1 showed no bias in recording (data not shown). We chose to exclude some countries entirely from the analysis instead of using country as a factor in multivariable analysis. This exclusion was done due to specific and rather severe data issues. We found that the large total number of patients made the data analysis less vulnerable to country specific bias by this exclusion. Another limitation to the study is our exclusion of patients in the longitudinal
analysis not coded as insulin yes for two years or more, even if they were later coded as yes again. One could argue that these patients still had CFRD, just off insulin for a while. However, because our only registry variable is insulin and we used that as definition for all the other analyses we decided to exclude patients off insulin for two years or more from our case definition. CFRD is becoming a common complication with the increasing life span of CF patients, thus not only requiring early diagnosis, but also evidence based treatment regimens to avoid long-term complications. With longer life expectancy and the increasing access to lung transplantation, diabetic kidney disease is now of concern [31]. International guidelines, not only on diagnosis, but also on treatment, were published in 2010 and 2014 [24,25], but the implementation of these guidelines may not be satisfactory [32,33]. Being diagnosed with CFRD imposes a substantial addition to the already imposing treatment burden associated with CF. Blood sugar measurements, insulin injections, and carbohydrate counting are added to the daily treatment plan, along with additional controls at the CF centre, often with a new endocrinology team. Our job as clinicians must be to diagnose, treat and further investigate this complication effectively, in order to hopefully counteract the deleterious defects presented here. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2019.10.009. References [1] Orenti A, Zolin A, Naehrlich L, van Rens J. et al. ECFSPR Annual Report 2017. 2019. https://www.ecfs.eu/sites/default/files/general-content-images/ working- groups/ecfs- patient- registry/ECFSPR_Report2017_v1.3.pdf. [2] Cystic Fibrosis Foundation Patient Registry. 2014 Annual Data Report. Cystic Fibrosis Foundation, Bethesda, Maryland, 2015. [3] Guo JH, Chen H, Ruan YC, Zhang XL. Glucose-induced electrical activities and insulin secretion in pancreatic islet b-cells are modulated by CFTR. Nat Commun 2014;5:4420. [4] Uc A, Olivier A, Griffin M, Meyerholz D, Yao J, Abu-el-Haija M. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci 2015;128:131–42. [5] Iannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis. Hum Pathol 1984;3(15):278–84.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx [6] Couce M, O’Brien TO, Moran A, Roche PC, Butler PC. Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. J Clin Endocrinol Metab 1996;3(81):1267–72. [7] Street ME, Spaggiari C, Ziveri MA, Rossi M, Volta C, Viani I, et al. Insulin production and resistance in cystic fibrosis: effect of age, disease activity and genotype. J Endocrinol Invest 2012;35:246–53. [8] Lanng S, Thorsteinsson B, Røder ME, Nerup J, Koch C. Insulin sensitivity and insulin clearance in cystic fibrosis patients with normal and diabetic glucose tolerance. Clin Endocrinol 1994;41:217–23. [9] Hardin DS, LeBlanc A, Para L, Seilheimer DK. Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis. Diabetes 1999;5(48):1082–7. [10] Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005;146:681–7. [11] Adler AI, Shine B, Haworth C, Leelarathna L, Bilton D. Hyperglyceamia and death in cystic fibrosis-related diabetes. Diabetes Care 2011;34:1577–8. [12] Stephenson AL, Tom M, Berthiaume Y, Singer LG, Aaron SD, Whitmore GA, et al. A contemporary survival analysis of individuals with cystic fibrosis: a cohort study. Eur Respir J 2015;45:670–9. [13] Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med 2015;191(2):194–200. [14] European Cystic Fibrosis Society Patient Registry, “Registry variables and definitions,” 2016. https://www.ecfs.eu/sites/default/files/images/ VariablesDefintions3.14.pdf. [15] Viviani L, Zolin A, Mehta A, Olesen HV. The European cystic fibrosis society patient registry: valuable lessons learned on how to sustain a disease registry. Orphanet J Rare Dis 2014;9:81–95. [16] Quanjer P, Stanojevic S, Cole TGlobal Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95 years age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–43. [17] Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 20 0 0 CDC growth charts for the United States: methods and development. Vital Health Stats 11 2001;246:1–190. [18] De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros 2014;13:403–9. [19] Lipsitz SR, Kim K, Zhao L. Analysis of repeated categorical data using generalized estimating equations. Stat Med 1994;13:1149–63.
7
[20] Liyang K-Y, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22. [21] Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiøtz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complication. Acta Pæd 1994;83:72–7. [22] Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W. Cystic fibrosis–related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009;32(9):1626–31. [23] Diabetes UK. Diabetes in the UK 2010: key statistics on diabetes. Diabetes UK 2010:5. [24] Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis–related diabetes. Diabetes Care 2010;12(33):2697–708. [25] Moran A, Pillay K, Becker DJ, Acerini CL. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2014;15(S20):65–76. [26] The Clinical and Functional TRanslation of CFTR (CFTR2)[Online] http://cftr2. org 2018. [27] Milla CE, Billings J, Moran A. Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis. Diabetes Care 2005;28:2141–4. [28] Olesen HV, Pressler T, Hjelte L, Mared L, Lindblad A, Knudsen PK, et al. Gender differences in the Scandinavian cystic fibrosis population. Pediatr Pulm 2010;45:959–65. [29] Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, et al. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Respir J 2014;43:125–33. [30] Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Pæd Scand 1994;83:949–53. [31] Ode KL, Moran A. New insights into cystic fi brosis-related diabetes in children. Lancet Diabetes Endocrinol 2013;1:52–8. [30] Quon BS, Mayer-Hamblett N, Aitken ML, Smyth AR, Goss CH. Risk factors for chronic kidney disease in adults with cystic fibrosis. Am J Respir Crit Care Med 2011;184:1147–52. [33] Scheuing N, Berger G, Bergis D, Gohlke B, Konrad K, Laubner K, et al. Adherence to clinical care guidelines for cystic fibrosis-related diabetes in 659 German/Austrian patients. J Cyst Fibros 2014;13:730–6.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF
[m5G;October 31, 2019;5:58]
Journal of Cystic Fibrosis xxx (xxxx) xxx
Contents lists available at ScienceDirect
Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf
Original Article
Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al Hanne V Olesen a,∗, Pavel Drevinek b, Vincent A Gulmans c, Elpis Hatziagorou d, Andreas Jung e, Meir Mei-Zahav f, Natasa Stojnic g, Muriel Thomas h, Anna Zolin i , on behalf of the ECFSPR Steering Group a
Dept of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Denmark Department of Medical Microbiology, Motol University Hospital and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic c Dutch Cystic Fibrosis Foundation (NCFS), Baarn, The Netherlands d Paediatric Pulmonology and CF Unit, Hippokration Hospital of Thessaloniki, Aristotle University of Thessaloniki, Thessaloniki, Greece e Paediatric Pulmonology, University Children‘s Hospital Zurich, Zurich, Switzerland f Pulmonary Institute, Schneider Children’s Medical Center of Israel, Sackler Faculty of Medicine, Tel Aviv University, Israel g Department of Pulmonology, Mother and Child Healthcare Institute of Serbia, Belgrade, Serbia h Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy i Belgian Cystic Fibrosis Registry, Sciensano, Belgium b
a r t i c l e
i n f o
Article history: Received 21 August 2017 Revised 17 September 2019 Accepted 1 October 2019 Available online xxx Keywords: Cystic fibrosis Diabetes Lung function Body mass index Gender
a b s t r a c t Background: Cystic fibrosis related diabetes (CFRD) has implications for morbidity and mortality with several risk factors identified. We studied the epidemiology of CFRD in the large dataset of the European Cystic Fibrosis Society Patient registry. Methods: Data on CF patients were investigated for the prevalence of CFRD as well as for any association with suggested risk factors and effects. Results: CFRD increased by approximately ten percentage points every decade from ten years of age. Prevalence was higher in females in the younger age groups. CFRD was associated with severe CF genotypes (OR = 3.11, 95%CI: 2.77–3.48), pancreatic insufficiency (OR = 1.46, 95%CI: 1.39–1.53) and female gender (OR = 1.28, 95%CI: 1.21–1.34). Patients with CFRD had higher odds of being chronically infected with Pseudomonas aeruginosa, Burkholderia cepacia complex and Stenotrophomonas maltophilia than patients without CFRD, higher odds of having FEV1% of predicted <40% (OR = 1.82, 95%CI: 1.70–1.94) and higher odds of having BMI SDS ≤−2 than patients without CFRD (OR = 1.24, 95%CI: 1.15–1.34). Conclusions: Severe genotype, pancreatic insufficiency and female gender remain considerable intrinsic risk factors for early acquisition of CFRD. CFRD is associated with infections, lower lung function and poor nutritional status. Early diagnosis and aggressive treatment of CFRD are more important than ever with increasing life span. © 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
1. Background Cystic fibrosis related diabetes (CFRD) remains a frequent extrapulmonary complication of cystic fibrosis (CF) – adding considerably to the treatment burden [1,2]. CFRD is primarily caused by insulin deficiency based on destruction of islet cells in the pancreas, although recent research suggests that CFTR in itself interferes with insulin secretion and glycaemic control [3,4]. Glucose ∗
Corresponding author. E-mail addresses: [email protected] (H.V. Olesen), [email protected] (P. Drevinek), [email protected] (V.A. Gulmans), [email protected] (A. Jung), [email protected] (M. Thomas), [email protected] (A. Zolin).
metabolism impairment in CF starts from early infancy and continues during life with variable progression, primarily in pancreatic insufficient patients [5–7]. Initially, the decreasing number of betacells leads to delayed and eventually insufficient insulin release, as impaired glucose tolerance changes into overt diabetes with fasting hyperglycaemia. CF patients with CFRD are insulin resistant to a mild degree, but this increases with exacerbations and progression of lung disease. Whether this resistance is also present in nondiabetic CF patients is disputed [7,8,9]. CFRD has been associated with poor lung function, poor BMI and higher mortality [10–13] The aim of this study was to evaluate the prevalence of CFRD in the European Cystic Fibrosis Society Patient Registry (ECFSPR), and
https://doi.org/10.1016/j.jcf.2019.10.009 1569-1993/© 2019 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 2
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
to analyse the influence of genotype, pancreatic status and gender, as well as the association between CFRD and lung function, nutritional status and chronic infections. The number of patients and years of follow-up in the ECFSPR will improve the validity of the findings.
3. Statistics
2. Methods
3.1. Longitudinal analysis
The European Cystic Fibrosis Patient Registry (ECFSPR) collects demographic and clinical data of CF patients from the following countries: Austria, Belgium, Bulgaria, Czech Republic, Denmark, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Lithuania, Luxembourg, Republic of Macedonia, Republic of Moldova, the Netherlands, Portugal, Romania, Russian Federation, Serbia, Slovak Republic, Slovenia, Spain, Sweden, Switzerland, Turkey, Ukraine and United Kingdom (for coverage per country, see [1]). For the purpose of this study, data of years 2008–2015 (the most updated data at the time of the analysis) were considered. Only patients with confirmed diagnosis of CF according to ECFSPR criteria [14] and seen at the CF centre for the years of follow-up were included in the study. The structure of the ECFSPR and the methods of collection and management of data are described elsewhere [15]. For collecting information on CFRD, the ECFSPR uses the variable “daily insulin use”. Patients with e.g. pathological oral glucose tolerance test (OGTT), but not on insulin are thus not captured by the ECFSPR. For simplicity patients with “daily insulin use = yes” will be named as CFRD. The following variables were used for analyses (for ECFSPR definitions see [14]): country; age at follow up; gender; both CFTR mutations; use of pancreatic enzymes as a proxy for pancreatic status; Stenotrophomonas maltophilia (SM) infection, chronic Pseudomonas aeruginosa (PA) and Burkholderia cepacia complex (BCC) infection;1 FEV1% of predicted (best in year2 ; Global Lung Function Initiative equations described by Quanjer PH et al. [16]., BMI z-score (CDC references [17]); lung transplantation. Since the ECFSPR does not collect the information of the date of diagnosis of CFRD, age at diagnosis of CFRD was computed as difference between the year of follow up in which the patient used insulin for the first time and the year of birth. Genotype was classified according to De Boeck et al. [18]. The patients were grouped as “two severe mutations (class I, II or III)”, “at least one mild mutation (class IV, V)” and “unclassifiable” (one severe and one unclassifiable mutation or two unclassifiable mutations). CFRD classification for patients with missing values were performed as follows: If information on CFRD was missing for a year, but the status of CFRD (yes or no) was the same for the previous and the subsequent year, the information for the missing year was set to that value (only 1% of the records). If information on the CFRD status was not consistent through the years, e.g. a patient was free of CFRD for 2 years, then the patient was diagnosed as CFRD patient, but the subsequent years the patient was negative for CFRD, that patient was not included into the analysis (only 6% of patients). For patients who died during the study period all years were included. Lung transplanted patients were omitted from FEV1 analysis after the year of the transplant, since FEV1 after transplant would not reflect the natural progression of the disease.
Longitudinal analysis was performed on data from 2008–2015. Patients from countries with percentage of missing data on CFRD status higher than 15% for more than two years and problems with the patients’ linkage through the years were excluded. A Student’s t-test was used to assess any difference in age at CFRD diagnosis between males and females. To investigate which intrinsic risk factors (gender, genotype and pancreatic status) are associated to CFRD, a multivariable logistic regression model, accounting for repeated measures, was used with adjustment for country and age. The method of generalized estimating equations with an unstructured covariance matrix was used to account for correlations among observations from the same subject. Records with missing values for a patient were not used. [19,20]. To investigate if CFRD is a risk factor associated to microbiology infections, lung function and growth, multivariable logistic regression models, accounting for repeated measures, were used. All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) were considered into the model with adjustment for country and age. Records with missing values for a patient were not used. [19,20]. Data were analysed both including and excluding pancreatic sufficient (PS) patients, because of the much lower prevalence of diabetes in these patients, who, generally, have milder lung disease. All analyses were conducted using SAS version 9.4 (SAS Institute Inc).
1 for the UK the definition of chronic infection is slightly different but judged to cover the same population. 2 The following countries reported last FEV1 or FEV1 at annual review instead: France, Germany, Sweden and UK.
Prevalence was calculated from the 2015 data set. Patients from countries with percentage of missing data on CFRD status higher than 15% were excluded. For prevalence comparisons, with a descriptive purpose, Chi-square test was used for all variables.
4. Results A total of 40,096 patients with confirmed diagnosis of CF and seen at a CF centre were recorded in the 2015 data set. Belgian data for 2014 and 2015 were not submitted at time of analysis, therefore the data from 2008–2013 were only included in the longitudinal analyses. Germany had more than 30% of patients with unknown status of CFRD. They furthermore had linkage issues due to change of software during the study period, therefore this country was not considered, leaving 34,733 patients for further analysis. 4.1. Prevalence of CFRD The prevalence varied by age group: < 10 year olds 0.8%; 10–19 year olds 9.7%; 20–29 year olds 24.1%; and ≥30 year olds 32.7%. Due to very low prevalence and suspected overrepresentation of type 1 diabetes in that age group, the < 10 year age group was omitted from further analyses (9590 patients) leaving 25,143 patients as the new basis for further analyses. The total prevalence of CFRD was 21.6%. The country specific prevalence varied both overall and in the specific age groups (Table 1). Some countries had the highest prevalence in some age groups and the lowest prevalence in others (Table 1). The prevalence of CFRD was significantly higher in patients with pancreatic insufficiency (PI) overall (25.8 vs 3.5%) and through all age groups (11.2 vs 1.4% in 10–19 year olds; 28.0 vs 2.5% in 20– 29 year olds; 42.6 vs 5.4% in ≥30 year olds – with a factor of 8 to 11 – all p < 0.0 0 01).
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
ARTICLE IN PRESS
JID: JCF
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
3
Table 1 Prevalence of CFRD by country and age group (year 2015). Three highest prevalences in each age group (bold/large) and the three lowest (underscore/petite) are marked. Countries with < 20 patients in the age group not ranked (grey background). 1 For the age group ≥ 30 yrs, Greece has a percentage of missing information on CFRD > 10%. 2 For the age group 20–29 yrs, Serbia has a percentage of missing information on CFRD > 10%.
Austria Bulgaria Czech Republic Denmark France Greece1 Hungary Ireland Israel Italy Latvia Lithuania Luxembourg Rep. Macedonia Rep. Moldova The Netherlands Portugal Romania Russian Fed. Serbia Slovak Republic Slovenia Spain Sweden Switzerland Turkey Ukraine United Kingdom Total
Overall Age group 10-19 yrs Age group 20-29 yrs Age group ≥ 30 yrs Missing/ Prev of N of Missing/ Prev of N of Missing/ Prev of N of Missing/ Prev of N of Unknown CFRD pts Unknown CFRD pts Unknown CFRD pts Unknown CFRD pts 1.18 18.31 508 1.38 8.76 217 0.60 20.36 167 1.61 32.26 124 2.44 6.06 0.00 7.78 90 0.00 41 0.00 33 0.00 25.00 16 0.00 28.97 397 0.00 182 0.00 126 0.00 37.08 89 19.23 37.30 0.00 31.90 373 0.00 7.02 114 0.00 119 0.00 140 34.45 50.00 0.00 19.92 4959 0.00 8.24 1783 0.00 22.77 1537 0.00 29.96 1639 4.78 16.03 418 1.17 8.19 171 4.35 18.12 138 11.01 25.69 109 1.67 13.88 418 0.48 6.19 210 2.21 19.12 136 4.17 26.39 72 0.89 17.98 784 0.00 6.84 307 0.82 21.81 243 2.14 28.63 234 1.14 23.57 437 1.89 10.69 159 1.39 29.86 144 0.00 32.09 134 0.93 19.36 3998 0.54 7.57 1307 0.90 19.23 1113 1.27 29.21 1578 13.64 4.55 22 7.14 0.00 14 16.67 0.00 6 50.00 50.00 2 0.00 7.14 14 0.00 0.00 1 0.00 9.09 11 0.00 0.00 2 0.00 22.22 18 0.00 16.67 6 0.00 0.00 4 0.00 37.50 8 0.00 15.38 65 0.00 9.30 43 0.00 31.58 19 0.00 0.00 3 0.00 10.53 19 0.00 8.33 12 0.00 14.29 7 0.00 31.10 1058 0.00 337 0.00 29.43 333 0.00 388 21.36 40.98 8.51 5.16 9.86 213 6.36 9.09 110 5.36 12.50 56 2.13 47 0.00 0.00 14 0.00 0.00 14 6.71 8.09 4.43 5.15 1399 4.00 3.75 801 3.90 462 8.82 136 13.76 17.43 109 7.81 15.63 64 22.58 19.35 31 21.43 21.43 14 1.61 8.70 17.78 0.65 8.50 153 0.00 62 0.00 46 2.22 45 0.00 20.31 64 0.00 35 0.00 21.05 19 0.00 20.00 10 20.00 7.76 18.69 1225 9.33 9.51 536 3.88 24.27 309 8.68 27.11 380 0.00 22.66 512 0.00 9.93 141 0.00 17.22 151 0.00 34.55 220 1.97 21.71 608 1.00 8.46 201 2.53 24.75 198 2.39 31.58 209 0.00 4.76 21 0.00 5.56 18 0.00 0.00 2 0.00 0.00 1 3.51 1.52 3.03 66 1.75 57 0.00 0.00 8 0.00 0.00 1 0.00 27.68 7181 0.00 13.09 2323 0.00 0.00 31.02 2373 38.15 2485 1.12 21.55 25143 1.23 9.70 9266 0.90 24.12 7791 1.21 32.65 8086
Table 2 Prevalence of CFRD by genotype group and age group (year 2015). The prevalence was statistically different between genotype groups in all age groups (all p < 0.0 0 01). Genotype class
Mild (at least one class IV-V) Severe (both mutations class I-III) Unclassifiable (one class I-III and one unclassifiable mutation or two unclassifiable)
Age group ≥ 30 yrs
Age group 10–19 yrs
Age group 20–29 yrs
Number of pts
Prevalence of CFRD
Number of pts
Prevalence of CFRD
Number of pts
403 5451 3177
0,50 12,05 7,43
374 4690 2609
2,41 29,79 17,86
788 3893 3238
Almost all (99.9%) of the patients have data on CFTR mutation: 1585 (6.4%) patients had genotype classified as “at least one mild mutation”, 14,131 (56.7%) patients had genotype classified as "two severe mutations” and 9179 (36.9%) patients had “unclassifiable genotype” [18]. The distribution of CFRD by the genotype class is presented in Table 2. The percentage of male patients was 51.5% in 10–19 year olds and increased to 55.1% in the ≥30 year olds. The prevalence of CFRD was significantly higher in females for the two youngest age groups (11.6% females vs 8.1% males for 10–19 year olds; 27.8 vs 21.2% for 20–29 year olds, p < 0.0 0 01), whereas there was no significant difference in the ≥30 year age group (33.3 vs 32.3%). 24,339, 24,454 and 24,112 patients (96.8%, 97.2% and 95.6%) had data on chronic PA, chronic BCC and SM infection, respectively. For chronic PA, the prevalence of chronic infection was higher in all age groups in the CFRD patients (Fig. 1A). For chronic
Prevalence of CFRD 9,90 47,88 21,09
BCC infection, the prevalence was significantly higher in CFRD patients in the youngest age group (10–19 year), whereas there was no difference in the older age groups (Fig. 1B). For SM infection, the prevalence was significantly higher in CFRD patients in the youngest age group (10–19 year), but was significantly higher in non- CFRD patients in the oldest age group (≥30 year) (Fig. 1C). Among the 23,284 patients without a lung transplant, 20,167 (86.6%) patients had data on FEV1 (the 3117 patients without data on FEV1 was primarily from the UK (1592), Italy (483) and Russia (448), the rest were evenly distributed). Patients with CFRD had a higher percentage of low or moderately low lung function (< 40 and 40–80% of predicted) in all age groups (Fig. 2). The difference between CFRD and non-CFRD patients was smaller when comparing only PI patients, but still highly significant in all age groups (Fig. 1 suppl).
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 4
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
Hungary were excluded from the analysis due to linkage problems between the oldest and newest data sets. The mean age at diagnosis of CFRD was significantly lower for females than males in all years (2009: 25.1 years for females vs 28.7 years for males; 2010: 25.7 years vs 27.6 years, 2011: 23.7 years vs 27.8 years, 2012: 23.5 years vs 26.8 years, 2013: 23.4 years vs 27.2 years, 2014: 25.0 years vs 26.9 years, 2015: 25.0 years vs 27.1 years, all p < 0.05). Using a multivariable logistic regression model, accounting for repeated measures, to investigate the risk factors associated with CFRD, we observed that PI patients had a slightly higher odds of having CFRD than PS patients (OR = 1.46, 95%CI: 1.39–1.53). Patients with severe genotype had an increased odds of having CFRD compared to patients with mild genotype (OR = 3.11, 95%CI: 2.77– 3.48) and patients with unknown genotype had a higher odds of having CFRD than patients with mild genotype (OR = 1.94, 95%CI: 1.75–2.15). Female patients had slightly higher odds of having CFRD than male patients (OR = 1.28, 95%CI: 1.21–1.34). The results of the multivariable logistic models to investigate if CFRD is a risk factor associated to microbiology infections are reported in Table 3. Patients with CFRD had slightly higher odds of being chronically infected with PA than patients without CFRD (OR = 1.32, 95%CI: 1.26–1.39), had slightly higher odds of being chronically infected with BCC than patients without CFRD (OR = 1.12, 95%CI: 1.00–1.24); and had slightly higher odds of being chronically infected with SM than patients without CFRD (OR = 1.10, 95%CI: 1.01–1.20). The results of the multivariable logistic models to investigate if CFRD is a risk factor associated to lung function and growth are reported in Table 4. Patients with CFRD had higher odds of having FEV1 percent of predicted <40% than patients without CFRD (OR = 1.82, 95%CI: 1.70–1.94). Patients with CFRD had slightly higher odds of having BMI SDS ≤−2 than patients without CFRD (OR = 1.24, 95%CI: 1.15–1.34). 5. Discussion
Fig. 1. Chronic Pseudomonas aeruginosa (1A), chronic Burkholderia cepacia complex (1B) and Stenotrophomonas maltophlia (1C) infections and CFRD by age group. ∗ p < 0.0 0 01 compared to no CFRD patients.
Among the 25,143 patients, 23,672 (94.1%) patients had information on BMI (the 1471 patients without data were primarily from Italy (508), UK (193) and Russia (158), the rest were evenly distributed). Patients with CFRD had a higher percentage of low BMI (z-score ≤ −2) in all age groups: for the 10–19 year olds 13.0% of CFRD patients vs 7.9% in non-CFRD (p < 0.0 0 01); 20–29 year olds 15.6% vs 11.2% (p < 0.0 0 01) and ≥30 year olds 9.7% vs 5.1% (p = 0.0 0 01). When excluding the PS patients, the percentage of patients with low BMI remained significantly higher in patients with CFRD in all the age groups (Fig. 2 suppl). 4.2. Longitudinal analysis Data from Italy where excluded from the longitudinal analysis due to high percentages of missing values in some years. Data from
This manuscript presents a very large registry based epidemiological study on CFRD, exploring risk factors as well as outcomes. We confirmed that CFRD is still a common complication to CF with increasing prevalence with age, thus constituting an increasing problem with the increasing life span of CF patients. Severe CF genotype, pancreatic insufficiency and female gender were confirmed as risk factors for acquisition of CFRD, whereas CFRD was still associated with poorer lung function, poorer BMI, and increased prevalence of chronic infections. The prevalence of CFRD does not appear to have increased considerably in the last couple of decades. In 1994, the Danish CF cohort showed prevalence of 1% at 10 years and 15% at 20 years [21]. In 2005, the US Epidemiologic Study of Cystic Fibrosis showed a prevalence of seven percent in teenagers, 20% in 18–25 year olds and 25% in 26+ year olds (use of insulin or oral antidiabetics) [10]. In 2009, in a smaller UK study, the prevalence of CFRD with fasting hyperglycaemia was five percent in 10–19 year olds, 18% in 20– 29 year olds and 25% in 30–39 year olds (higher for CFRD without fasting hyperglycaemia) [22]. Our study showed an increase in prevalence of ten percent per decade from ten to forty years. The ECFSPR registers CFRD as “daily insulin – yes/no”, thus reaching a very high specificity, but a lower sensitivity, especially for patients with impaired OGTT without fasting hyperglycaemia, who may not yet be on insulin treatment. The prevalence varies considerably between countries (Table 1). With our definition, national differences in registration of CFRD is not a likely cause of the variation, since most national registries capture insulin use, even if they also have other variables defining CFRD. The ECFSPR requires registration of either yes, no or unknown for this variable, so unknown is clearly
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
5
Table 3 Odds ratios and 95% confidence intervals of multivariable logistic regression models, accounting for repeated measures, to investigate if CFRD is a risk factor associated to microbiology infections (grey). All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) are considered into the model with adjustment for country and age. Genotype, gender, chronic PA and SM did not contribute to the chronic BCC model. Genotype and BMI did not contribute to the SM model.
enzymes yes vs no genotype severe vs mild genotype unclassifiable vs mild gender F vs M age ≥ 30 vs 10-19 age 20-29 vs 10-19 CFRD yes vs no Chronic Pseudomonas aeruginosa yes vs no Chronic Burkholderia cepacia complex yes vs no Stenotrophomonas maltophilia yes vs no BMI SDS≤-2 vs SDS>-2 FEV1% of predicted 40-80% vs >80% FEV1% of predicted <40% vs >80%
Chronic Pseudomonas Chronic Burkholderia aeruginosa cepacia complex OR 95% CI OR 95% CI 1.65 1.55 1.75 1.43 1.27 1.62 1.89 1.70 2.10 1.38 1.24 1.53 1.14 1.08 1.19 2.27 2.16 2.39 1.35 1.20 1.52 1.87 1.79 1.95 1.31 1.19 1.44 1.32 1.26 1.39 1.12 1.01 1.24 - 0.88 0.82 0.95 0.77 0.70 0.85 0.87 0.83 0.91 1.07 1.02 1.12 1.21 1.12 1.32 1.52 1.47 1.58 1.26 1.18 1.35 2.41 2.29 2.54 1.55 1.39 1.73
Stenotrophomonas maltophilia OR 95% CI 1.47 1.33 1.62
1.34 0.67 0.79 1.11 0.69 0.66 -
1.25 0.61 0.73 1.02 0.65 0.56 -
1.44 0.74 0.85 1.22 0.74 0.78 -
1.33 1.58
1.25 1.42
1.42 1.75
Table 4 Odds ratios and 95% confidence intervals of multivariable logistic regression models, accounting for repeated measures, to investigate if CFRD is a risk factor associated to low lung function (FEV1 < 40%) and growth (BMI < −2SD) (grey). All the intrinsic (gender, genotype, pancreatic status) and extrinsic variables (infections, lung function and growth) are considered into the model with adjustment for country and age. Gender did not contribute to the FEV1 model. .
enzymes yes vs no genotype seve vs mild genotype ukno vs mild gender F vs M Age ≥30 vs 10-19 age 20-29 vs 10-19 CFRD yes vs no Chronic Pseudomonas aeruginosa yes vs no Chronic Burkholderia cepacia complex yes vs no BMI SDS≤-2 vs SDS>-2 FEV1% of predicted 40-80% vs >80% FEV1% of predicted <40% vs >80%
defined as unknown, but may not be so in the national registry. This possible inconsistency in coding will be investigated as part of the ECFSPR Data Quality Programme. Diagnosis of CFRD at the clinic level may vary, depending on practice of diagnosing by routine OGTT, HbA1c, random blood glucose levels, or only at symptoms. Finally, the difference may be due to percentage of PI patients in the countries which varies between five and 25% [1]. As expected, CFRD was associated with PI, with prevalence 8 to 11 times higher than in PS patients. However, the frequency of CFRD in PS patients is 2–3 times higher than the prevalence of type 1 diabetes in young adults reported in e.g. the UK (one to two percent in 16–44 y olds) [23]. CFRD may evolve in the course of chronic pancreatitis, a known complication to PS, but the ECFSPR does not capture this complication, so the question of aetiology in PS and PI patients remains unsolved. However, regular OGTT should be performed in all CF patients, regardless of pancreatic status [24,25]. For genotype classification, we chose to group our mutations using De Boeck et al. [18], which classify the 30 most common genotypes. For genotype, the pattern of CFRD is very much the same as for PI/PS but with lower prevalence in PS patients than in the mild mutation group. The unclassifiable group seems
OR 1.49 1.35 1.36 4.32 2.60 1.82 1.63 1.54 0.36 -
FEV1 95% CI 1.37 1.62 1.14 1.59 1.15 1.61 3.99 2.44 1.70 1.56 1.38 0.33 -
4.67 2.78 1.94 1.71 1.72 0.39 -
OR 1.66 1.16 1.51 0.55 0.53 1.07 1.24 1.06 1.30 2.13 5.76
BMI 95% CI 1.49 1.85 0.93 1.45 1.22 1.88 0.50 0.59 0.48 0.59 1.00 1.14 1.15 1.34 1.00 1.12 1.16 1.47 1.99 2.27 5.27 6.30
closer to the severe mutations in CFRD prevalence than the group with at least one mild mutation (Table 2), implying that most of the unclassified mutations are indeed severe mutations. The CFTR2 project has now classified 322 mutations, so further classification could be performed [26]. Previously, female CF patients have had poorer survival with CFRD, [12], although the poorer survival is not seen in more recent studies [13]. Females have a higher prevalence [10] with a trend towards earlier onset than in male patients [27]. Our study showed a significantly earlier onset of CFRD in females. The prevalence was higher in females in the younger age groups, but was equal in the ≥30 year olds. Considering the findings of lower FEV1, lower BMI and more chronic infections associated with CFRD, the female CFRD patients are, thus, exposed to these known risk factors for early death at a younger age and in a higher proportion [28]. The increasing proportion of males with increasing age implies an excess mortality in females which may account for the equalising of CFRD prevalence in the older age groups. CFRD remains associated with poorer lung function and nutrition. The proportion of patients with low or moderately low FEV1 was significantly higher in all age groups, including the 10–19 year olds, quite recently diagnosed with CFRD. The proportion of very
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF 6
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx
Fig. 2. FEV1 groups with or without CFRD in three age groups. FEV1 grouped as > 80%, 40–80% and < 40% of predicted value. P-value for all age groups < 0.0 0 01.
low BMI z-score was also higher in CFRD patients in all age groups. Some of this deterioration may be reversible with treatment [29], but the CFRD patients continued to have lower lung function than their peers and thus, consequently, reach end stage lung disease earlier (Table 4; Fig. 2): a UK registry study found a hazard ratio (HR) of death with diabetes of 1.31 (CI) [11]. In the Canadian registry, the hazard ratio was 1.81 (CI) of death for females with diabetes, whereas CFRD did not increase the HR for males [12]. Chronic infection with PA was more frequent with CFRD in all age groups. As opposed to genotype, gender and pancreatic status, which are all intrinsic factors associated with CFRD, lung function, BMI and chronic infections are factors that may interact with CFRD.CFRD is often diagnosed during periods of deterioration, and increased glucose levels may be seen during exacerbations, returning to normal when the exacerbation subsides. Changes in glucose tolerance may be seen very early in life, when lung disease is still minimal and no chronic infections are established, but the majority of patients are diagnosed with CFRD in their teens or later [30]. Most of the epidemiological research has been focused on patients already diagnosed with CFRD compared to patients without CFRD. A small retrospective case-control study (36 patients), showed that patients who later developed CFRD had lower FEV1 and BMI than matched controls six years prior to diagnosis [29]. The ECFSPR data set represents a very large real-life dataset including a wide variety of CF patients across Europe. Considering the number of patients included from many countries and centres, the latest datasets have very few missing values (< 6%) for most of the variables, which makes the data analysis highly valid. Only the FEV1 variable has a higher number of missing values (13.4%), which makes the results a little less robust. However, the missing data were primarily from three countries and analysis of age, gender, genotype or other risk-factors in patients with or without FEV1 showed no bias in recording (data not shown). We chose to exclude some countries entirely from the analysis instead of using country as a factor in multivariable analysis. This exclusion was done due to specific and rather severe data issues. We found that the large total number of patients made the data analysis less vulnerable to country specific bias by this exclusion. Another limitation to the study is our exclusion of patients in the longitudinal
analysis not coded as insulin yes for two years or more, even if they were later coded as yes again. One could argue that these patients still had CFRD, just off insulin for a while. However, because our only registry variable is insulin and we used that as definition for all the other analyses we decided to exclude patients off insulin for two years or more from our case definition. CFRD is becoming a common complication with the increasing life span of CF patients, thus not only requiring early diagnosis, but also evidence based treatment regimens to avoid long-term complications. With longer life expectancy and the increasing access to lung transplantation, diabetic kidney disease is now of concern [31]. International guidelines, not only on diagnosis, but also on treatment, were published in 2010 and 2014 [24,25], but the implementation of these guidelines may not be satisfactory [32,33]. Being diagnosed with CFRD imposes a substantial addition to the already imposing treatment burden associated with CF. Blood sugar measurements, insulin injections, and carbohydrate counting are added to the daily treatment plan, along with additional controls at the CF centre, often with a new endocrinology team. Our job as clinicians must be to diagnose, treat and further investigate this complication effectively, in order to hopefully counteract the deleterious defects presented here. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jcf.2019.10.009. References [1] Orenti A, Zolin A, Naehrlich L, van Rens J. et al. ECFSPR Annual Report 2017. 2019. https://www.ecfs.eu/sites/default/files/general-content-images/ working- groups/ecfs- patient- registry/ECFSPR_Report2017_v1.3.pdf. [2] Cystic Fibrosis Foundation Patient Registry. 2014 Annual Data Report. Cystic Fibrosis Foundation, Bethesda, Maryland, 2015. [3] Guo JH, Chen H, Ruan YC, Zhang XL. Glucose-induced electrical activities and insulin secretion in pancreatic islet b-cells are modulated by CFTR. Nat Commun 2014;5:4420. [4] Uc A, Olivier A, Griffin M, Meyerholz D, Yao J, Abu-el-Haija M. Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass. Clin Sci 2015;128:131–42. [5] Iannucci A, Mukai K, Johnson D, Burke B. Endocrine pancreas in cystic fibrosis. Hum Pathol 1984;3(15):278–84.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009
JID: JCF
ARTICLE IN PRESS
[m5G;October 31, 2019;5:58]
H.V. Olesen, P. Drevinek and V.A. Gulmans et al. / Journal of Cystic Fibrosis xxx (xxxx) xxx [6] Couce M, O’Brien TO, Moran A, Roche PC, Butler PC. Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. J Clin Endocrinol Metab 1996;3(81):1267–72. [7] Street ME, Spaggiari C, Ziveri MA, Rossi M, Volta C, Viani I, et al. Insulin production and resistance in cystic fibrosis: effect of age, disease activity and genotype. J Endocrinol Invest 2012;35:246–53. [8] Lanng S, Thorsteinsson B, Røder ME, Nerup J, Koch C. Insulin sensitivity and insulin clearance in cystic fibrosis patients with normal and diabetic glucose tolerance. Clin Endocrinol 1994;41:217–23. [9] Hardin DS, LeBlanc A, Para L, Seilheimer DK. Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis. Diabetes 1999;5(48):1082–7. [10] Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005;146:681–7. [11] Adler AI, Shine B, Haworth C, Leelarathna L, Bilton D. Hyperglyceamia and death in cystic fibrosis-related diabetes. Diabetes Care 2011;34:1577–8. [12] Stephenson AL, Tom M, Berthiaume Y, Singer LG, Aaron SD, Whitmore GA, et al. A contemporary survival analysis of individuals with cystic fibrosis: a cohort study. Eur Respir J 2015;45:670–9. [13] Lewis C, Blackman SM, Nelson A, Oberdorfer E, Wells D, Dunitz J, et al. Diabetes-related mortality in adults with cystic fibrosis. Role of genotype and sex. Am J Respir Crit Care Med 2015;191(2):194–200. [14] European Cystic Fibrosis Society Patient Registry, “Registry variables and definitions,” 2016. https://www.ecfs.eu/sites/default/files/images/ VariablesDefintions3.14.pdf. [15] Viviani L, Zolin A, Mehta A, Olesen HV. The European cystic fibrosis society patient registry: valuable lessons learned on how to sustain a disease registry. Orphanet J Rare Dis 2014;9:81–95. [16] Quanjer P, Stanojevic S, Cole TGlobal Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95 years age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–43. [17] Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 20 0 0 CDC growth charts for the United States: methods and development. Vital Health Stats 11 2001;246:1–190. [18] De Boeck K, Zolin A, Cuppens H, Olesen HV, Viviani L. The relative frequency of CFTR mutation classes in European patients with cystic fibrosis. J Cyst Fibros 2014;13:403–9. [19] Lipsitz SR, Kim K, Zhao L. Analysis of repeated categorical data using generalized estimating equations. Stat Med 1994;13:1149–63.
7
[20] Liyang K-Y, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22. [21] Lanng S, Thorsteinsson B, Lund-Andersen C, Nerup J, Schiøtz PO, Koch C. Diabetes mellitus in Danish cystic fibrosis patients: prevalence and late diabetic complication. Acta Pæd 1994;83:72–7. [22] Moran A, Dunitz J, Nathan B, Saeed A, Holme B, Thomas W. Cystic fibrosis–related diabetes: current trends in prevalence, incidence, and mortality. Diabetes Care 2009;32(9):1626–31. [23] Diabetes UK. Diabetes in the UK 2010: key statistics on diabetes. Diabetes UK 2010:5. [24] Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, et al. Clinical care guidelines for cystic fibrosis–related diabetes. Diabetes Care 2010;12(33):2697–708. [25] Moran A, Pillay K, Becker DJ, Acerini CL. Management of cystic fibrosis-related diabetes in children and adolescents. Pediatr Diabetes 2014;15(S20):65–76. [26] The Clinical and Functional TRanslation of CFTR (CFTR2)[Online] http://cftr2. org 2018. [27] Milla CE, Billings J, Moran A. Diabetes is associated with dramatically decreased survival in female but not male subjects with cystic fibrosis. Diabetes Care 2005;28:2141–4. [28] Olesen HV, Pressler T, Hjelte L, Mared L, Lindblad A, Knudsen PK, et al. Gender differences in the Scandinavian cystic fibrosis population. Pediatr Pulm 2010;45:959–65. [29] Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, et al. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Respir J 2014;43:125–33. [30] Lanng S, Thorsteinsson B, Nerup J, Koch C. Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Pæd Scand 1994;83:949–53. [31] Ode KL, Moran A. New insights into cystic fi brosis-related diabetes in children. Lancet Diabetes Endocrinol 2013;1:52–8. [30] Quon BS, Mayer-Hamblett N, Aitken ML, Smyth AR, Goss CH. Risk factors for chronic kidney disease in adults with cystic fibrosis. Am J Respir Crit Care Med 2011;184:1147–52. [33] Scheuing N, Berger G, Bergis D, Gohlke B, Konrad K, Laubner K, et al. Adherence to clinical care guidelines for cystic fibrosis-related diabetes in 659 German/Austrian patients. J Cyst Fibros 2014;13:730–6.
Please cite this article as: H.V. Olesen, P. Drevinek and V.A. Gulmans et al., Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome; Olesen et al., Journal of Cystic Fibrosis, https://doi.org/10.1016/j.jcf.2019.10.009