Background: Many studies have shown that CFRD has a negative impact on CF prognosis. Current guidelines advise to screen for CFRD with an OGTT yearly from the age of 10 - 12. In our center we do not routinely screen for CFRD because the OGTT is cumbersome and not an ideal screening test. We therefore want to exclude unfavourable clinical evolution due to late diagnosis. Methods: 23 CF patients with diagnosis of CFRD < 18 years old were matched to a control patient. Clinical evolution (BMI, lung function, and chronic infection treatment burden) was analyzed starting 2 years before until 2 years after diagnosis of CFRD. Results: In the 2 years before diagnosis of CFRD, BMI and LF were similar for both groups while need for IV AB treatment was higher in the CFRD group. In the 2 years following diagnosis and treatment, LF decline was worse in the CFRD despite more IV AB treatments. BMI was still comparable. We conclude that clinical status was comparable between cases and controls in the 2 years preceding the diagnosis of CFRD. However, the need for IV antibiotic treatment seems to precede the faster lung function decline after CFRD diagnosis.
Cystic fibrosis (CF) is a life-shortening, multi-organ disease, caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. This gene encodes an ion channel highly expressed in the apical membrane of epithelial cells [
CF related diabetes (CFRD) is one of the most common comorbidities of this disease [
The pathophysiology of CFRD is complex. Thick viscous secretions cause obstruction of the exocrine pancreatic ducts with secondary pancreatic fibrosis and fatty infiltration [
Current guidelines [
In our center, we do not perform yearly CFRD screening with OGTT but rather use this test as a low threshold for diagnostic purposes whenever a patient with CF between the age of 10 and 18 years old has an unstable evolution. In order to evaluate the impact of this practice on patient evolution, we decided to study the clinical evolution before and after diagnosis of CFRD in our pediatric cohort.
This is a retrospective case-control study using the hospital patient registry from the pediatric CF database. Patients born between 1-1-1997 to 31-12-2012, diagnosed with CFRD and treated with insulin before the age of 18 years were included. Each patient diagnosed with CFRD patients was matched with a CF patient without CFRD based on gender, genotype, year of birth, age at CF diagnosis and chronic P. aeruginosa infection. Exclusion criteria were death within the follow up period, and lung transplantation before time zero.
Possible indications for OGTT apart from diabetic symptoms are: insufficient growth or weight gain increased respiratory symptoms or increased treatment need, vague complaints of fatigue or malaise. The pediatric CF cohort in our center counted 127 children (<18 years old) in 1997 and decreased to 118 children in 2012 (excluding transplanted CF patients).
We collected patient data two years before the start of insulin treatment (=time zero), until two years after. For the matched group, time zero was set at the same age as time zero of the index case. For CFRD patients receiving a lung transplant within the two year period after start of insulin, data after the transplantation were excluded.
The following parameters were used. For lung function, FEV1 was expressed as % predicted (FEV1%pred) according to Wang et al. [
Infection status was registered for Pseudomonas aeruginosa (PA), other Gram negative bacteria (for example Achromobacter xylosoxidans), Methicillin Resistant Staphylococcus aureus (MRSA] and Aspergillus spp in each year. Chronic Pseudomonas infection was defined according to the Leeds criteria [
Corticosteroid use was classified as “any” systemic steroids versus no systemic steroids over the year. Intravenous (IV) antibiotic use was counted as the number of days IV antibiotics per year, and the number of IV treatment courses per year.
Biometric data are given as BMIz-score. Best, worst and mean BMI z-score per year were included.
Diagnosis of CFRD was based on OGTT (glycaemia after 120 minutes > 200 mg/dl) or on a typical clinical presentation with polyuria, polydipsia, glycosuria, in the face of fastinghyperglycaemia.
For all patients the highest HbA1c value for each year was registered. For the OGTT fasting glycaemia and glycaemia after two hours were registered.
The Ethics Committee of the University Hospitals Leuven acknowledged that the study is carried out according to the prevailing ethical standards.
Data were analysed with the non-parametric independent samples median test, using SPSS (IBM Corp., Released 2011, IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY). Categorical parameters like gender, transplantation and death were assessed using chi square test. Statistical significance was considered at p-values < 0.05. Lung function decline was calculated as a linear regression through the best value of FEV1 of each quarter of a year. No decline was calculated if only 2 consecutive lung function values were available, in order to avoid falsely steep regression lines.
Data were analysed for 23 CFRD patients and the same number of matched non CFRD patients. All patients were pancreatic insufficient. Baseline characteristics are presented in
All control patients had at least one OGGT excluding CFRD in the study period (Year − 2 to Year + 2): 6/11 patients had at least 1 OGTT in the J-2 to time 0 period and 9/11 patients at least one test in the period time 0 to Year + 2 (median glycaemia at 2 hours 126 mg/dl IQR 106 - 160).
Best FEV1 % predicted of each quartile of the four years’ timeline did not significantly differ between CFRD and control patients (see figure 1). Lung function declinetwo years before start of insulin treatment was not different: a median (IQR) of −0.85% (−1.44% - −0.16%) for the CFRD group and −0.33% (−1.40% - 0.13%) for the controls (p = 1.00). Despite start of insulin treatment, we notice a significantly faster lung function decline in the CFRD group compared to the control group (median (IQR) −0.67% (−1.62 - 0.11%) versus 0.10% (−0.91 - 0.46%) over a period of 2 years.
The incidence of chronic infection with Pseudomonas aeruginosa or with other Gram negative bacteria was similar for both groups because this was one of the matching criteria (
CFRD N = 23 | Matched controls N = 23 | p-value | |
---|---|---|---|
Current age | 21.2 years (16.7 - 23.6) | 20.7 years (16.0 - 23.5) | 1.00 |
Gender F/M | 14/9 | 14/9 | 1.00 |
Age at CF diagnosis | 0.1 years (0 - 0.5) | 0.1 years (0 - 0.1) | 0.167 |
Age at CFRD diagnosis | 14.0 years (13.4 - 17.0) | / | / |
FEV1 % predicted at time zero | 71.6 (59.2 - 89.2) | 82.3 (57.8 - 92.5) | 0.095 |
BMI Z-score at diagnosis | −0.89 (−2.23 - 0.42) | −0.71 (−1.29 - 0.16) | 0.628 |
HbA1c at diagnosis | 6.30 % (6.2% - 6.7%) | 5.75% (5.5% - 6.1%) | <0.001 |
OGTT at time zero: fasting glycaemia | 96 mg/dl (85 - 106) | / | / |
OGTT at time zero: glycaemia at 120’ | 214 mg/dl (192 - 233) | / | / |
F508 Homozygote | 17/23 | 15/23 | 0.522 |
F508 Heterozygote/class I-III | 5/23 | 8/23 | 0.326 |
No F508 deletion | 1/23 | 0/23 | 0.321 |
CFRD + | CFRD − | p-value | |||||||
---|---|---|---|---|---|---|---|---|---|
Non chronic | Chronic | Non chronic | Chronic | ||||||
Y − 2 | P. aeruginosa | 11 | 12 | 15 | 8 | 0.234 | |||
Other Gram-bacteria | 10 | 13 | 14 | 9 | 0.238 | ||||
Y − 1 | P. aeruginosa | 14 | 9 | 16 | 7 | 0.536 | |||
Other Gram-bacteria | 10 | 13 | 13 | 10 | 0.376 | ||||
Y + 1 | P. aeruginosa | 12 | 11 | 14 | 9 | 0.552 | |||
Other Gram-bacteria | 8 | 15 | 12 | 11 | 0.234 | ||||
Y + 2 | P. aeruginosa | 14 | 9 | 18 | 5 | 0.200 | |||
Other Gram-bacteria | 11 | 12 | 16 | 7 | 0.134 |
The number of IV antibiotic days per year increased in both groups over the years but was always significantly higher in the CFRD group (
The number of patients treated with oral steroids varied significantly from year to year in the CFRD group (between 4/23 or 17.4% to 6/23 or 26.1%), as well as in the control group (from 1/23 or 4.5% to 4/23 or 18.2%) in the control group. This was not different between groups. All years combined, 18/92 (19.6%) of CFRD group used steroids which is higher than the control group: 8/88 (9%) (p = 0.0458).
The median BMI z-score per year was comparable in both groups for each year (−0.77, −0.88, −0.89, −1.18 for the CFRD group, −0.94, −0.73, −0.72, −0.90 for the control group).
Median HbA1c rose in the CFRD group from 6.1% in year −2, to 6.4% in the fourth year. In the control group median HbA1 increased from 5.75% to 5.9%. The highest HbA1cper patient was significantly higher in the
CFRD+ | CFRD- | p-value | ||
---|---|---|---|---|
Median (IQR) of IV antibiotic days | Y − 2 | 18 (12 - 43) | 5 (0 - 16) | 0.072 |
Y − 1 | 26 (13 - 58) | 1.5 (0 - 15) | 0.022 | |
Y + 1 | 40 (15 - 58) | 7 (0 - 18) | 0.004 | |
Y + 2 | 33 (15 - 64) | 0 (0 - 36) | 0.016 | |
Y − 2 and Y − 1 | 45 (18 - 101) | 7 (0 - 24) | 0.002 | |
Y + 1 and Y + 2 | 59 (44 - 122) | 15 (0 - 59) | 0.016 |
CFRD group compared to the control group for the first three years of the timeline: medians in year −2 were 6.1% vs. 5.75% (p = 0.03), in year −1 6.2% vs. 5.8% (p < 0.001), and in year +1 6.3% vs. 5.75% (p<0.001). Only in the fourth year-that is the second year after start of insulin treatment-this difference was no longer significantly different (medians 6.4% vs. 5.9%; p = 0.10).
There was no significant difference in transplantation between cases and controls (4 out of 23 for the CFRD group, 3 out of 23 for the controls, p = 0.681). Concerning mortality: 3 out of 23 in the CFRD group died (at 4, 9 and 10 years after time zero), 1 out of 23 for the controls died 7 years after time zero (p = 0.295).
Since we do not systematically screen for CFRD with OGTT, we decided to study the clinical evolution of CF patients diagnosed with CFRD before the age of 18 years in our CF clinic using a case control approach. FEV1 (expressed as best FEV % predicted per quartile) did not significantly differ between the two groups over a time period starting 2 years before up to the diagnosis of CFRD. Despite start of insulin treatment FEV1 decreased faster in the CFRD group in the 2 years after the diagnosis. In a large data set from the European Epidemiologic Registry of Cystic Fibrosis (ERCF) (7566 CF patients), mean FEV1 % was significantly lower in pediatric patients diagnosed with CFRD [
Chronic infection with P. aeruginosa and other gram negative bacteria was overall rare in the CFRD group and control patients were matched for this. Isolation of MRSA and Aspergillus spp were rather infrequent and not significantly different. We did not find literature to compare these data with.
Biometric evolution did not differ between both groups and this is in agreement with other recent data [
Our study cohort was not appropriate to estimate mortality. An extensive retrospective multicentre cohort study of 4234 CF patients showed that diabetes is a clear determinant of mortality [
The only difference between patients and controls in the years preceding the CFRD diagnosis was burden of therapy which may be an indication of disease severity. Higher need for therapy is one of the clinical reasons to plan an OGTT in our clinic. However, higher need for IV antibiotic treatment persisted after start of insulin treatment. We did not find other data on need for antibiotic treatment in CFRD to compare our data with.
Prescription of oral steroids(which in our centre reflects mostly occurrence of allergic bronchopulmonary aspergillosis) was higher in the CFRD patients only when grouping all the years. Oral steroid use may increase insulin resistance and therefore worsen glucose intolerance.
European (2005) as well as American guidelines (2010] [
The rationale to screen is that CFRD has a negative impact on disease course and increases mortality [
There are little data on the benefit of treating the prediabetic status with insulin [
So the arguments pro screening are the following: no early or specific symptoms and treatment improves prognosis. Arguments against screening are: OGTT is cumbersome and time consuming, OGTT is not a good screening test (OGGT fluctuates over time and normal OGTT does not rule out post prandial hyperglycaemia), respiratory decline may occur already before abnormal OGTT. Additionally, no firm data are available that earlier therapy based on screening (ideally with CGM) in otherwise stable CF patients improves prognosis. Finally, there is a cost issue: at the age of 12 years, CFRD prevalence is around 7%. Therefore in 93% of children this test is futile. The cost of this test in a day care setting in our center is 330 euros.
In our CF clinic, we do not screen annually and the OGTT is used as diagnostic instead of screening tool. We do realise that because diabetes symptoms are often mild and a specific, diagnosis may be made too late. A recent study form Brazil suggested that from 52 screened patients, 10 had CFRD based on the OGTT while only 8 had a diagnosis based on clinical suspicion [
Limitations of our study are the small cohort, the retrospective design, and the fact that we did not always find a perfect match for each CFRD patient fulfilling all of the matching criteria. The strengths of our study are the homogenous treatment of the patients and the extensive documentation of clinical status including airway pathogens and therapy burden.
Based on the results presented here we have no indication that the diagnosis of CFRD is made too late since lung function and weight are comparable for cases and controls. However, the higher treatment burden with IV antibiotics in the CFRD group and faster decline of lung function at follow-up might be avoided by earlier diagnosis.
These data are presented as a plead for more studies into optimized screening tests together with more studies on when and how to treat (pre) CFRD. As soon as more data are available on how to use continuous glucose monitoring as a screening tool for CFRD diagnosis and treatment decision, we are keen to change or clinical practice in order to optimise the treatment of our CF patients [
AnJacobs,FrancoisVermeulen,Krisde Boeck,KristinaCasteels,MarijkeProesmans, (2016) Clinical Outcome of CF Patients with CF Related Diabetes: Do We Need to Change Our Policy?. Open Journal of Pathology,06,32-40. doi: 10.4236/ojpathology.2016.61006