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Dutch

Cystic Fibrosis

Registry

Data on people with cystic fibrosis in the Netherlands

Annual report for 2018

Published in 2019

Copyright NCFS © 2019 The data from this report may be used for publications and presentations, but only with reference to the source:

Dutch CF Registry 2018 www.ncfs.nl

http://www.ncfs.nl/

Dutch CF Registry Report 2018

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Foreword

This online report of the Dutch CF Registry for 2018 has been realised with the cooperation of almost all people with Cystic Fibrosis (CF) and the efforts of many people working in the seven CF centres and at the Dutch Cystic Fibrosis Foundation (NCFS).

The report provides information and trends on many aspects of CF diagnostics and treatment, complications of CF and some aspects of living with CF.

The summary is shown as an infographic. Online, the topics from the infographic are linked to the information from the report.

The report also presents the information for each centre separately and at a national level. It also includes information on indicators that say something about the quality of CF care.

The CF centres have each received an overview of their own data in relation to the national averages. Every year, the NCFS organises meetings with the centres’ paediatric pulmonary specialists, chest physicians, paediatric gastroenterologists and paediatric nutritionists. At these meetings, the treatment, results and differences between the centres are discussed in an open and positive atmosphere, and points for improvement are determined.

The Registry is also of increasing importance for the research into and the development, reimbursement and evaluation of new medicines.

The joint ambition of the CF centres and the NCFS remains unchanged: better care that results in a better and longer life for people with CF.

September 2019

Jacquelien Noordhoek, chair of the steering group of the Dutch CF Registry

https://ncfs.nl/onderzoek/dutch-cf-registry-2018/


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Table of Contents

Foreword ................................................................................................................................................................................ 2

Table of Contents ................................................................................................................................................................. 3

1. Summary ........................................................................................................................................................................ 5

2. Demographic data ....................................................................................................................................................... 6 The numbers ......................................................................................................................................................................................................... 6 Age ........................................................................................................................................................................................................................... 7 Death ....................................................................................................................................................................................................................... 8 CF centres ............................................................................................................................................................................................................. 9

3. Diagnosis ..................................................................................................................................................................... 11 Symptoms leading to a CF diagnosis ........................................................................................................................................................ 12 Age CF diagnosis .............................................................................................................................................................................................. 13 Heel prick screening ....................................................................................................................................................................................... 14 Mutations ........................................................................................................................................................................................................... 15

4. Pulmonary function ................................................................................................................................................. 18 Pulmonary function and age ....................................................................................................................................................................... 18 Distribution per centre ................................................................................................................................................................................. 20 Pulmonary function over the years .......................................................................................................................................................... 21

5. Micro-organisms ...................................................................................................................................................... 23 Presence of micro-organisms ..................................................................................................................................................................... 23

6. Height and weight .................................................................................................................................................... 25 BMI in children ................................................................................................................................................................................................. 25 Height-to-weight ratio in children ............................................................................................................................................................ 26 BMI in adults ..................................................................................................................................................................................................... 28

7. Comorbidity ............................................................................................................................................................... 30 Presence of other diseases or conditions .............................................................................................................................................. 30 CF-related diabetes ........................................................................................................................................................................................ 31

8. Treatment ................................................................................................................................................................... 32 CFTR modulators ............................................................................................................................................................................................ 32 Respiratory tract ............................................................................................................................................................................................. 34 Treatment of Pseudomonas infection ....................................................................................................................................................... 36 IV antibiotics ..................................................................................................................................................................................................... 37 Digestive system .............................................................................................................................................................................................. 38 Transplants ........................................................................................................................................................................................................ 39

9. Work and family ....................................................................................................................................................... 40 Work and education ....................................................................................................................................................................................... 40 CF and having children .................................................................................................................................................................................. 40

10. Over-50s and CF ................................................................................................................................................. 41


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Age ........................................................................................................................................................................................................................ 41 Mutations ........................................................................................................................................................................................................... 41 Other properties .............................................................................................................................................................................................. 42

11. Quality of care ..................................................................................................................................................... 43 Visits to the outpatient clinic ...................................................................................................................................................................... 43 Pulmonary function test ............................................................................................................................................................................... 44 Sputum culture ................................................................................................................................................................................................. 44 Glucose tolerance test ................................................................................................................................................................................... 45

Annex 1. Methods ............................................................................................................................................................. 46 International harmonisation ....................................................................................................................................................................... 46 Calculations ....................................................................................................................................................................................................... 46 Concepts ............................................................................................................................................................................................................. 47 Abbreviations.................................................................................................................................................................................................... 47

Annex 2. Registry Steering Group ............................................................................................................................... 48 Steering Group ................................................................................................................................................................................................. 48


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1. Summary


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2. Demographic data

How many people with CF and CF-related diseases are there in the Netherlands? What is the age distribution? How many hospitals provide specialist CF care? These and other demographic characteristics are described in this chapter.

The demographic data include all people who were registered in the Dutch CF Registry in 2018. These are people with CF, but also people with a CF-related disease (i.e. without a confirmed CF diagnosis) or people who have undergone a lung transplant.

Want to know more about CF? Go to the NCFS website.

The numbers

In 2018, 1,487 people were included in the Dutch CF Registry: 594 children and 893 adults. The total number of people in the Registry is somewhat lower than in previous years. The reason for this reduction is that, when the General Data Protection Regulation (GDPR) entered into force in 2018, explicit attention was paid to the fact that people first signed for agreement for their data to be included in the Dutch CF Registry. For approximately 110 people, the letter of agreement was not completed/received by the time the data was submitted.

It is estimated that in the Netherlands, there are 1,500 people with CF and another 100 people with CF-related diseases.

Figure 1 shows how many people have been included in the Dutch CF Registry since 2009. The numbers per year are also broken down into adults and children.

Figure 1: Number of people in the Dutch CF Registry in the period 2009-2018. All registered people were included, irrespective of a confirmed CF diagnosis or lung transplant. Adults are aged 18 and over, children are under 18 years of age.

* This year, fewer people are included in the Registry. More than 100 people had not (yet) signed for inclusion of their data in the Registry.

https://www.ncfs.nl/


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The division of the people included in the Registry into men and women has been stable for years, as can be seen in Figure 2. The percentage of men is slightly above 50% and the percentage of women slightly below.

Figure 2: Division men/women in the Dutch CF Registry in the period 2009-2018.

Age

The average age of people with CF or a CF-related disease is going up (Figure 3). In 2018, the average age was 24. In 2018, half of the people in the Registry were younger and the other half older than 22 years. That number is the median value. This age has also been increasing over the years, as shown in Figure 3.

The median age is always slightly lower than the average age. This means that some people are relatively old.

Figure 3: Average and median age of the people in the Dutch CF Registry in the period 2009-2018. The median value is the middle value of all values together. Half of the people are older and the other half younger than the median age.


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Figure 4 shows how many people were of a certain age in 2018. In terms of age distribution, adults are in the majority, 50% of people were aged 22 or over.

Figure 4: Age distribution of the people in the Dutch CF Registry in 2018. For all ages, the number of people is shown. Children up to the age of 18 are depicted in light green, adults in dark green. The orange dotted line indicates the cumulative percentage: the percentage of people up to the respective age of the total group.

Death

Unfortunately, a number of people with CF die every year. Fortunately, that number seems to be decreasing (Figure 5).

Every year, the median age of death is calculated: half of the people who die are younger than this age, and the other half are older. This age varies, but has been going up over the years, partly due to the better treatment of CF. Unfortunately, a number of young people with CF died in 2018, which explains the sharp drop in the median age for that year. This value has been calculated with the data of only eight people, which is why the difference with previous years is so significant.

When displaying the number (and age) of deceased people, no distinction is made between deaths due to CF and deaths due to other causes.

Figure 5: Number of people who died in the period 2009-2018. The number of people who died in a certain year is shown here. The orange line shows the calculated median age of death.


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CF centres

There are seven hospitals in the Netherlands that provide CF care to both children and adults. The map and table below show where these hospitals can be found and how many people they have treated in recent years (map of the Netherlands and Table 1).


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Table 1. CF centres in the Netherlands and the number of people they treat. *The total is lower than in previous years because a number of people have not (yet) signed for their data to be included in the Registry.

  2014 2015 2016 2017 2018 UMC Utrecht           Children 206 196 190 191 158

Adults 231 245 260 281 251

Erasmus MC Rotterdam           Children 149 143 140 149 135

Adults 121 120 139 138 122

HagaZiekenhuis           Children 55 63 59 55 55

Adults 210 210 217 215 200

Amsterdam UMC           Children 102 105 104 100 104

Adults 100 106 109 116 118

UMC Groningen           Children 69 73 74 72 65

Adults 88 84 83 80 83

Radboud UMC Nijmegen           Children 47 49 52 58 67

Adults 50 57 56 56 57

Maastricht UMC           Children 34 28 26 27 29

Adults 37 42 40 40 43

Total 1,499 1,521 1,549 1,578 1,487*


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3. Diagnosis

How many children with CF are born every year? What symptoms are seen and what is the role of the heel prick screening? What about CF and mutations? All these questions, related to the diagnosis of CF, are discussed in this chapter. Therefore, this chapter will only use data from people with a confirmed CF diagnosis, whether or not they have had a lung transplant.

The diagnosis of CF can be made in different ways and at different times. It can be done before the birth, immediately after or in the first weeks or months. But it also happens that people do not find out that they have CF until they reach adulthood. Want to find out more? Read more on the website.

In the past five years, approximately 25 children with CF were born per year (Figure 6). In 2018, 19 children with CF were born. This number may go up somewhat, as children may have been born in the last weeks of the year 2018 who were only diagnosed in the first weeks of 2019.

Figure 6: Children with CF born in the period 2014-2018.

https://ncfs.nl/over-cf/diagnose/


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Symptoms leading to a CF diagnosis

Before the heel prick screening for CF was introduced, the diagnosis of CF was usually made on the basis of a number of symptoms. The Registry records which symptoms led to a diagnosis and these data are carefully recorded for children.

In some cases, it is already clear that an unborn baby has CF (prenatal screening). Immediately after birth, it can also be clearly apparent, if a baby has meconium ileus. Meconium is the first (black) stool that a baby excretes in the first days after birth. In some babies, this meconium is so concentrated that it is stuck (meconium ileus) and sometimes has to be surgically removed. In most cases, this is caused by CF.

Figure 7 shows the percentage of children born with meconium ileus. The second green bar shows the percentage of children who had symptoms leading to a CF diagnosis. This percentage does not add up to 100%, because some babies do not yet have any symptoms while the heel prick screening shows that they have CF. To the right of the dotted line, a breakdown is given of the type of symptoms that may occur. In particular, respiratory complaints and problems with nutrition and growth are common.

Figure 7: Symptoms children with CF have at their time of diagnosis. All children in the Registry with a confirmed CF diagnosis are included. The symptoms are specified to the right of the dotted line. Electrolyte imbalance means a shortage of, for example, sodium or chloride. Rectal prolapse means a piece of rectum is protruding.


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Age CF diagnosis

The age at which the diagnosis of CF is made varies greatly, also in the Netherlands (Figure 8). Still, half of the people who were under the age of 40 in 2018 were diagnosed with CF well before their first birthday. Half of the children/young adults aged 19 and under were less than one month old at the time of diagnosis. For the group of over-40s, the age of diagnosis is much higher: half of them were younger than 12 years at the time of diagnosis.

12% of adults were only diagnosed with CF when they were aged 18 or over.

Figure 8: Age at the time of CF diagnosis, shown by age group.


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Heel prick screening

Since 2011, in principle, all new-borns in the Netherlands are screened for CF by means of the heel prick screening. Figure 9 shows, for the period 2012-2018, how many children were diagnosed with CF as a result of this screening. In most children, the diagnosis of CF is made as a result of the heel prick screening.

Sometimes the screening indicates that a child does not have CF, but the diagnosis is confirmed at a later date (a so-called false negative result). There are also a number of situations every year in which screening is not carried out. This can be because the diagnosis of CF is known before birth, or because a baby is born with meconium ileus, clearly indicating that it has CF.

Figure 9: Number of children with CF diagnosed by means of the heel prick screening or in some other way in the period 2012-2018. Meconium ileus means that a new-born baby has a blocked intestine. In most cases, the child will then have CF and sometimes the heel prick screening for CF will not be done.


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Since 2012, 144 children with CF were diagnosed by means of the heel prick screening and 39 children were diagnosed in a different way. If both groups are compared in terms of symptoms leading to the CF diagnosis (Figure 10), it appears that children with CF, who were not diagnosed by means of the heel prick screening, had more symptoms.

Figure 10: Symptoms at the time of the CF diagnosis by means of the heel prick screening or in another way. To the right of the dotted line, the various symptoms are specified.

Mutations

CF is caused by mutations in the DNA, on the CFTR gene. If both parents pass on a CFTR mutation to their child, the child has CF. It should be noted that not all CFTR mutations cause CF. There are more than 2,000 known mutations, of which at least 346 cause CF (source: cftr2.org).

The most common mutation worldwide is F508del. F508del is also the most common one in the Netherlands, as can be seen in Figure 11, which shows the mutation distribution for all people with CF in 2018. 90% of all people with CF in the Netherlands have at least one F508del mutation.

Figure 11: Mutation distribution for people with CF with F508del or other mutations. For a small part of the people no mutation analysis was carried out.


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Table 2 shows the most common mutations. The numbers and percentages are not calculated per person, but per gene. Everyone inherits a set of genes, one from each parent. In 2018, 1,424 people with a confirmed CF diagnosis were registered. The total of all genes therefore results in a number that is twice as high: 2,848.

The most common mutation after F508del is A455E. In other countries this is not the most common ‘second mutation’, which is why A455E is also called the Dutch mutation.

Table 2. The 15 most common CF mutations in the Netherlands in 2018. These numbers are calculated with the mutations of 1,424 people with CF. Because everyone with CF has a mutation on two sets of genes (one from each parent), the total sum of the genes is twice as high as the number of people: 2,848.

Mutation Number Percentage (%)

F508del 2,065 72.5 A455E 120 4.2 G542X 50 1.8 1717-1G->A 45 1.6 S1251N 35 1.2 R1162X 34 1.2 3272-26A->G 33 1.2 N1303K 31 1.1 R117H 28 1.0 R553X 27 0.9 2789+5G->A 24 0.8 3849+10kbC->T 18 0.6 E60X 16 0.6 711+1G->T 15 0.5 W1282X 14 0.5 Unknown 25 0.9 Not done 18 0.6 Other 250 8.8 Total 2,848 100.0


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For the 63 people in the Registry without a confirmed CF diagnosis, the distribution of mutations is different again (Figure 12). Almost 60% has one F508del mutation, the rest has two other mutations or the analysis was not carried out.

Figure 12: Mutation distribution for people with a CF-related disease without a confirmed CF diagnosis.


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4. Pulmonary function

Pulmonary function is one of the most important parameters in CF. Because of the tough mucus, the lungs, but also the nose and other parts of the respiratory tract, often suffer from (bacterial) infections and inflammation, which makes the pulmonary function deteriorate further and further. This process has a major impact on the life expectancy of a person with CF. This is why the pulmonary function is often measured.

In this chapter, the pulmonary function measurements are given, including the best measurement of 2018 for each person with CF. These measurements are compared between different age groups, between different CF centres and over time.

Pulmonary function and age

From the age of six, the pulmonary function of a person with CF is tested several times a year. The pulmonary function is usually measured as the volume that a person can force out of their lungs in one second, the FEV1. The measurement is given as a percentage of the so-called healthy population: peers of the same age, height and sex, without CF or other pulmonary disease. We call this the FEV1% of predicted.

Figure 13 shows the progression of pulmonary function by age group. The height of the bars indicates that half of the people in that age group had a better pulmonary function and the other half a worse pulmonary function. The number of people used for the calculation for that age group is given at the top of the bar.

Pulmonary function deteriorates gradually with age. The strongest deterioration is seen until approx. 20 years of age. From the age of 30 onwards, the deterioration in pulmonary function is no longer as evident. This can be explained by the fact that from this age onwards, more people die and the people with a relatively better pulmonary function continue to live.

Figure 13: Pulmonary function by age group. The median FEV1% of predicted is shown for each period of 3-6 years. The FEV1% of predicted is a measure of pulmonary function: the volume that a person can force out of their lungs in one second, compared to their peers without CF. The median value indicates that half of the people had a better pulmonary function and the other half a worse pulmonary function. The number of people used to calculate the value is given above each bar.


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In order to have a better overview of all pulmonary function values, the pulmonary function values are often divided into groups, which is also done internationally. In Figure 14 below the pulmonary functions for 2016-2018 are divided into four groups: less than 40%, between 40 and 70%, between 70 and 90% and greater than 90%. A pulmonary function of 90% or higher is considered normal.

The differences between children and adults are significant. More than half of the children had a normal pulmonary function of at least 90% in the past years, while less than a quarter of adults had a normal pulmonary function.

Figure 14: Pulmonary function values of people with CF for the period 2016-2018. Divided into four pulmonary function groups and shown separately for children and adults.


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Distribution per centre

Figure 15 shows the pulmonary function values of children for the year 2018. Between the CF centres there are minor differences in pulmonary function values. One of the possible reasons for this variation is a difference in the number of seriously ill children with CF treated at a centre.

The pulmonary functions are converted to Z-scores to correct for age and gender. A Z-score of 0 means an average pulmonary function and 95% of healthy children in the Netherlands have a Z-score between -2 and 2. A Z-score lower than -2 or higher than 2 is considered to be strongly deviating.

Figure 15: Pulmonary function of children with CF per centre. The pulmonary function value of the children is compared to their peers with a healthy pulmonary function. The Z-scores are then calculated. A Z-score of 0 is normal, higher than 2 or lower than -2 is considered to be strongly deviating. The median value is the middle value: half of the group of children at a centre has a higher Z-score, the other half a lower one. See Annex 1 for an explanation of this type of chart.


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Figure 16 shows the pulmonary function values of the adults. Here, too, the differences between the CF centres are small. However, the Z-scores are much lower than for the children, which corresponds to the pulmonary function groups in Figure 14.

Figure 16: Pulmonary function of adults per centre. The pulmonary function value of the adults is compared to their peers with a healthy pulmonary function. The Z-scores are then calculated. A Z-score of 0 is normal, higher than 2 or lower than -2 is considered to be strongly deviating. The median value is the middle value: half of the group of adults at a centre has a higher Z-score, the other half a lower one. See Annex 1 for an explanation of this type of chart.

Pulmonary function over the years

In recent years, there has been little progression in pulmonary function, also looking at each CF centre individually. Figure 17 shows the pulmonary function values for the children’s departments of the CF centres for the period 2016-2018. At all centres, (at least) half of the children had a pulmonary function greater than 90%.

Figure 17: Pulmonary function of children per centre, for the period 2016-2018. The bars indicate the median value: half of the children has a better pulmonary function and the other half a worse pulmonary function.


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For the adult departments, the pulmonary function values are much lower, as can be seen in Figure 18. Here too, the changes in the past three years were minimal.

Figure 18: Pulmonary function of adults per centre, for the period 2016-2018.


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5. Micro-organisms

Micro-organisms are living creatures (organisms) that are only visible under the microscope (micro). Examples include bacteria and fungi. Micro-organisms can be useful; bacteria in the intestine, for instance, break down food and strengthen our immune system. However, there are also micro-organisms that cause disease.

People with CF can suffer more from infections with ‘bad’ micro-organisms, because the tough mucus in the lungs is less able to remove these pathogens. That is why we pay close attention to whether, and if so which, bacteria and fungi are detected in the respiratory tract.

Infections are treated with antibiotics; more information can be found in the chapter ‘Treatment’.

Presence of micro-organisms

At each stage of their life, different micro-organisms can be found in the respiratory tract of a person with CF. Figure 19 shows the percentage of people who had a certain bacterium or fungus, per age group.

Figure 19 shows, for example, that infections with the fungus Aspergillus fumigatus and the bacterium Pseudomonas aeruginosa become more frequent with age.

Figure 19: Presence of micro-organisms. The calculations are done by age group (per 6-year age bracket and the group aged 54 and over).


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Figure 19 shows the data for 2018. The presence of micro-organisms has been fairly stable over the years, as shown in Figure 20 with data from the period 2013-2018.

Figure 20: Presence of micro-organisms, period 2013-2018.


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6. Height and weight

The relationship between body height and weight says something about a person’s nutritional status. ‘Nutritional status’ is the medical term for the balance between the intake of energy and nutrients and their consumption. It is important to have a good nutritional status, among other things to ensure a healthy immune system. This is all the more true for people with CF, who have problems with the digestion of fats. For this reason, height and weight are measured every time a person visits the outpatient clinic.

BMI in children

The Body Mass Index (BMI) is an important measure to gain insight into a person’s nutritional status. For children, these values are converted to Z-scores to correct for age and gender. A Z-score of 0 is average, and 95% of healthy children in the Netherlands have a Z-score between -2 and 2. A Z-score lower than -2 or higher than 2 is considered to be strongly deviating.

In 2018, the BMI values at the centres were very similar (Figure 21). The median Z-score of all children together was around average (0): half of the children have a lower value, the other half a higher one.

Figure 21: BMI of children with CF in 2018. The BMI values are converted to Z-scores to correct for age and gender. A Z-score with a value of 0 is average. A BMI Z-score lower than -2 or higher than 2 is considered to be strongly deviating. The median value is the middle one of all the values measured: half of the people have a higher BMI Z-score and the other half a lower score.


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The BMI of all children together went up slightly for a number of years, so that the median Z-score was above 0 from 2011 onwards (Figure 22). In 2016 and 2017, the BMI fell slightly. In 2018, the Z-score went up and is now again around 0, which indicates a normal BMI.

Figure 22: BMI of children with CF for the period 2008-2018. The BMI values are converted to Z-scores to correct for age and gender. A Z-score with a value of 0 is normal. A BMI Z-score lower than -2 or higher than 2 is considered to be strongly deviating. The median value indicates that half of the children had a lower BMI and the other half a higher one.

Height-to-weight ratio in children

Another way to look at the differences in nutritional status is to divide the Z-score into groups. This visualises how often the nutritional status is good and when it deviates significantly. A Z-score lower than -2 or higher than 2 is considered to be strongly deviating. In this section, the BMI, height-by-age, and weight-by-age are assigned to these Z-score groups.

Figure 23 shows the BMI values divided into groups and broken down by centre. This shows that only a few children have a BMI that is strongly deviating

Figure 23: BMI values of children in 2018, divided into three BMI Z-score groups. Z-scores higher than 2 or lower than -2 indicate that the BMI deviates significantly from the normal value (too high or too low).


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By calculating the height-for-age in relation to the healthy population of children, it appears that the height is lagging behind in 7.2% of the children (Figure 24).

Figure 24: Height-for-age of children with CF in 2018. Divided into three groups and broken down by CF centre. Z-scores higher than 2 or lower than -2 indicate that the BMI deviates significantly from the normal value (higher than normal or too low).

Comparing the weight of children with CF to age, and in relation to peers without a pulmonary disease, shows that the weight of most children is healthy. However, for almost 6% of the children the weight strongly deviates (Figure 25).

Figure 25: Weight-for-age of children with CF in 2018. Divided into three groups and broken down by CF centre. Z-scores higher than 2 or lower than -2 indicate that the BMI deviates significantly from the normal value (too high or too low).


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BMI in adults

The nutritional status of adults with CF is calculated using the BMI. Figure 26 shows the median BMI for each age group (half of the people have a higher BMI, the other half a lower one).

As people age, their BMI goes up bit by bit. The median BMI remains in the healthy area between 18.5 and 25.

Figure 26: BMI of adults with CF in 2018. Divided into age groups. The green bars indicate the median BMI value of the age groups. Half of the people in that age group have a higher BMI, the other half a lower one.

Over the years, the BMI in adults does not change that much, and there is little difference between centres (Figure 27).

Figure 27: BMI in adults with CF for the period 2016-2018. The median BMI is shown by centre: half of the people have a higher BMI, the other half a lower one.


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Figure 28 also shows the BMI values of adults in three groups: a BMI that is too low (below 18.5), a healthy BMI (between 18.5 and 25) or a BMI that is too high (above 25). The percentage of significantly deviating BMI values is about 23% for adults, with the highest impact due to the excessively high BMI values.

Figure 28: BMI in adults in 2018, divided into three groups. The percentage of people with a healthy BMI (18.5-25), a low BMI and a high BMI is shown per centre.


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7. Comorbidity

Comorbidity is the generic term for other diseases or conditions that patients that have a particular disease, such as CF, can also have. This chapter shows how often people with CF suffer from comorbidity and zooms in on CF-related diabetes.

Presence of other diseases or conditions

There are many different conditions that a person with CF can get, varying from liver disease to nasal polyps. Figure 29 shows how often each disorder occurs in children and in adults. Almost all comorbidities are more prevalent in adults than in children.

Figure 29: Comorbidity in children and adults with CF in 2018. Comorbidity is an ‘extra’ disorder or disease, and the figure shows the percentage of children (C) and adults (A) with a comorbidity in 2018. For some people, the Registry does not give comorbidity details, which is specified as ‘unknown’. * List of abbreviations: ABPA stands for allergic bronchopulmonary aspergillosis, CFRD for CF-related diabetes and DIOS for distal intestinal obstruction syndrome.


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CF-related diabetes

One comorbidity which has been specifically monitored in recent years in people with CF is CF-related diabetes (CFRD). CFRD can be caused by pancreatic scarring, due to years of obstruction of that organ by tough mucus. The production of insulin takes place in the pancreas and can deteriorate due to scarring. CFRD therefore resembles diabetes (type 1 and type 2) but is not exactly the same. Want to know more about CFRD? Click here for the website with more information.

In principle, people with CF who are at risk of developing CFRD are tested every year; see Chapter 11, ‘Quality of care’. The percentage of people who actually have CFRD has gone up in the past two years compared to previous years (Figure 30).

Figure 30: CF-related diabetes (CFRD) in people with CF in the period 2013-2018. Every year, we can see what percentage of people with CF have CFRD.

https://ncfs.nl/over-cf/symptomen-en-gevolgen/verminderde-vetvertering-en-suikerziekte/


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8. Treatment

CF can be treated in various ways.

This chapter shows how many people with CF are prescribed a CFTR modulator. CFTR modulators are drugs that address the cause of CF. Unfortunately, not everyone is eligible for such a drug yet, because it depends on the mutations that someone has.

People with CF have to deal with various problems of their respiratory tract, intestines or pancreas. How many people take medication for these problems is described in this chapter. It also contains information on organ transplants in the year 2018.

CFTR modulators

The first CFTR modulator available in the Netherlands is ivacaftor (Kalydeco). This drug is now available for people with CF with one of nine specific mutations and who are aged 1 and over. People who have an R117H mutation and are aged 18 and over are also eligible for ivacaftor (Kalydeco).

Figure 31 shows that approximately 50 people have now been prescribed this drug. Of the people with one of the nine mutations officially eligible for ivacaftor (Kalydeco), 94.4% were prescribed this drug in 2018. Within the group of people with an R117H mutation, that was one person.

Figure 31: The number of people prescribed ivacaftor (Kalydeco) in the period 2014-2018.


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Ivacaftor/lumacaftor (Orkambi) is the second modulator that can be prescribed in the Netherlands to people with CF. This drug may now be prescribed to people aged 2 and over with two F508del mutations. About three quarters of these people were prescribed ivacaftor/lumacaftor (Orkambi) in 2018, about 76%. In total, almost 600 people received ivacaftor/lumacaftor (Orkambi) (see Figure 32).

Figure 32: The number of people prescribed ivacaftor/lumacaftor (Orkambi) in the period 2015-2018.

Halfway through 2019, ivacaftor/tezacaftor (Symkevi) was approved as the third modulator in the Netherlands for people with CF with a double F508del mutation, but (still) only for patients aged 12 and over. However, a few people already used ivacaftor/tezacaftor (Symkevi) in 2017 and 2018, by participating in a clinical study (Figure 33).

Figure 33: The number of people prescribed ivacaftor/tezacaftor (Symkevi) in 2017 and 2018.


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Respiratory tract

With CF, it is important to keep the respiratory tract as clean as possible and prevent infections. There are several drugs available that can help, such as the expectorant dornase alpha (Pulmozyme) or medicines that dilate the airways. Other respiratory treatment methods may help in case of severe lung function impairment, such as extra oxygen through a nasal tube or mask, or extra support when breathing with a mask (non-invasive ventilation).

Figure 34 shows the percentage of children and adults who received respiratory drugs or treatment in 2018.

It appears that dornase alpha (Pulmozyme) and airway dilators are the most commonly used. It is also becoming apparent that adults were prescribed drugs more often than children, which is also to be expected on the basis of their pulmonary function (see Chapter 4, ‘Pulmonary function’). When anti-inflammatory drugs (corticosteroids) are needed, the variants that need to be inhaled are more often prescribed than the corticosteroids that are taken in pill form.

Figure 34: Treatment of respiratory problems in people with CF in 2018. The percentage of children and adults is shown for each medication or treatment prescribed.


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Figure 35 further zooms in on the different types of inhaled antibiotics in order to treat or prevent infections. About 20% of children used inhaled antibiotics in 2018, in particular tobramycin and colistin. As far as the group of adults is concerned, more than half of them took antibiotics and all five drugs were prescribed approximately the same number of times.

Figure 35: Inhaled antibiotics used by people with CF in 2018. The percentage of children and adults prescribed inhaled antibiotics is shown, as a total and also broken down by drug (to the right of the dotted line). The antibiotics are inhaled liquids using a nebulizer, dry powder can be tobramycin or colistin.


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Treatment of Pseudomonas infection

The chapter on micro-organisms (Chapter 5) shows how many people with CF have had a chronic infection with the Pseudomonas Aeruginosa bacterium in recent years. In Figure 36 below these data are linked to the treatment of this infection with antibiotics that were inhaled into the lungs (inhaled antibiotics). The data are shown per CF centre and for each centre for children and adults separately.

Pseudomonas infections are much less common in children than in adults. Most people are then treated with inhaled antibiotics. However, there are also differences between the centres. One of the reasons is that a person sometimes immediately receives intravenous (IV) antibiotics.

Figure 36: Percentage of people with a chronic Pseudomonas aeruginosa infection and how many of them were treated with inhaled antibiotics. Broken down per centre and for children (C) and adults (A). Abbreviations for the centres: Ams, Amsterdam; DeHa, The Hague; Gron, Groningen; Maas, Maastricht; Nijm, Nijmegen; Rott, Rotterdam; Utr, Utrecht. * No data


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IV antibiotics

If inhaled antibiotics or antibiotics in pill form do not work sufficiently, and someone with CF still has a bacterial or fungal infection, antibiotics are administered directly into the blood stream, by infusion. This is called an intravenous (IV) treatment.

IV antibiotics are usually administered in the hospital, but it can also often be done at home (after first starting treatment in the hospital). Data are available for 1,182 people.

Figure 37 shows the percentage of people receiving IV antibiotics in 2018, broken down by age group and for home or hospital treatment. The treatment usually took place in the hospital. It also shows that the percentage of people who received treatment is highest among young adults (18-29 years).

Figure 37: IV antibiotics administered to people with CF in 2018. Per age group, we can see what percentage of people were given IV antibiotics.

Figure 38 zooms in on the number of days that people with CF were treated with IV antibiotics. Here, too, the data are broken down by age group and it can be seen that older children and young adults (12-23 years) were treated the most often.

Figure 38: Number of days of IV antibiotics administered to people with CF in 2018. For each age group, we can see how many days all people, added together, were given such a treatment.


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Whether or not IV antibiotics are prescribed has been recorded in the Dutch CF Registry for many years. Figure 39 shows that the percentage of children and adults remains fairly stable over the years.

Figure 39: IV antibiotics administered to people with CF in the period 2009-2018. Percentage of children and adults receiving IV antibiotics, at home or in the hospital, per year.

Digestive system

In addition to respiratory problems, people with CF often also suffer from a poorly functioning digestive system (such as the intestines, the liver and the pancreas). Figure 40 shows which drugs were prescribed to people with CF in 2018 in order to treat digestive problems. There are small differences between children and adults. It also appears that pancreatic enzymes (which digest food and thus also improve the absorption of food) are by far the most commonly used.

Figure 40: Treatment of problems of the digestive system in people with CF in 2018. The percentage of children and adults is shown for each medication or treatment prescribed. Pancreatic enzymes digest the food, so that it is better absorbed by the body, proton pump inhibitors help against heartburn. Oral supplemental feeding, gavage or a gastric colostomy help gain/maintain weight. Ursodeoxycholic acid may improve bile function.


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Transplants

In people with CF, the function of some organs often deteriorates with time. They may become eligible for a transplant if the lungs, liver or kidneys have almost stopped working.

In people with CF, lung transplants are the most common, liver transplants are much less common and kidney transplants are very rare (kidney transplants are not recorded in the Registry).

In the Netherlands, transplants are carried out at three hospitals: Groningen, Utrecht and Rotterdam. This year, the data from one centre are missing. According to the data in the Registry, seven people underwent a lung transplant in 2018. Sixteen people were still waiting for new lungs on 31/12/2018.

The Dutch Transplant Foundation collects transplant data from all transplanted people every year. According to their data, ten people with CF received new lungs in 2018.

Liver transplants are less common than lung transplants. In 2018, one person underwent a liver transplant and four people with CF were still on the waiting list.


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9. Work and family

For those who have CF, work and study are not self-evident. How many adults with CF are capable of hold down a job or go to school or university? We also discuss pregnancies in women with CF.

Work and education

Social participation is not only reserved for people who work or study. This also includes volunteering or helping/caring for friends/family. The Dutch CF Registry keeps general data about the social participation of adults with CF in 2018.

Based on the data in the Registry, approximately half of the people have a job, at home or elsewhere (Figure 41). 17% were in school, college or university in 2018.

Figure 41: Various roles of adults with CF in society.

CF and having children

The Dutch CF Registry records the number of women with CF who are pregnant and/or had a child. It does not track whether men with CF have become a father.

In 2018, twelve women with CF were pregnant. That’s almost 5% of all women with CF aged 18 and over. Of the group of women with CF aged 18 and over in 2018, almost a quarter of the women had been pregnant in previous years (87 women).

Want to know more about CF and having children? The website gives more information and also contains references to other websites.

https://ncfs.nl/leven-met-cf/kinderwens/


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10. Over-50s and CF

According to the 2018 Registry, there are 109 people in the Netherlands who have CF or a CF-related disease and who are aged 50 and over. Of this group, 97 people had a confirmed CF diagnosis. More information about these people can be found in this chapter on the age distribution and mutations.

Age

Of the people aged 50 and over with CF, almost three-quarters are between the ages of 50 and 60 (Figure 42). The oldest person with CF turned 77 in 2018.

Figure 42: Age distribution of people with CF aged 50 and over. Each green bar and the left Y-axis indicate how many people fall into the age group. The orange line and the right Y-axis show the cumulative percentage: the percentage of people up to the respective age group in relation to the group as a whole.

Mutations

The mutation distribution within the group of people aged 50 and over is different from that for the entire group of people with CF (Figure 43). The most common mutation is still F508del. But when we look at the mutation combination, the double F508del mutation is no longer the most common, but F508del with another (often milder) mutation.

Figure 43: Mutation distribution of over-50s with CF, divided into four groups.


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Other properties

Of the 97 people with CF aged 50 or over, 12 had a lung transplant. These 12 people were not included in the description of properties such as hearing loss, bone weakness or chronic bacterial infections. The reason is that after a lung transplant, both the treatment and the symptoms often change dramatically.

Of the 85 people aged 50 or over with CF who did not undergo a lung transplant, almost 45% use pancreatic enzymes (38 people) and over 40% have (had) a chronic infection with the Pseudomonas bacterium (35 people). Regarding the condition of the lungs, 42 people use inhaled antibiotics and the median pulmonary function is 68%. A third of people have been prescribed a CFTR modulator. The infographic in Figure 44 shows many more properties for the group of over-50s in the Dutch CF Registry.

Figure 44: Infographic of over-50s in the Dutch CF Registry in 2018.


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11. Quality of care

How good is the quality of CF care in hospitals? The National Health Care Institute [Zorginstituut Nederland] tries to establish this every year by collecting data, the so-called indicators. One indicator, for example, is how many people with CF visited the CF centre four times or more in a year.

The indicators are published in an online database, the Transparency Calendar [Transparantiekalender]. It also contains information about the quality of care in other areas of healthcare, such as home care, maternity care and physiotherapy.

The Dutch CF Registry’s annual report (such as this year’s report) also gives the indicators for CF. This will continue to be the case in the future, as the Transparency Calendar will no longer be published.

Visits to the outpatient clinic

In principle, people with CF visit the outpatient clinic of the CF centre four times a year for a check-up. During this check-up, a number of things are measured, such as pulmonary function and height and weight. A sputum sample is also taken.

A large number of people with CF, or a CF-related disease, have few symptoms and have arranged fewer check-ups with the CF centre. Figure 45 shows that 80-90% of people visited the outpatient clinic four times or more in 2018.

Figure 45: Number of times people with CF visited the outpatient clinic in 2018. For each centre, we can see what percentage of children and adults visited the outpatient clinic at least four times for a check-up.

https://www.zorginzicht.nl/openbare-data


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Pulmonary function test

In principle, pulmonary function is also tested during the regular (four) visits to the outpatient clinic. Figure 46 shows that on average 70% of adults and about 75% of children (aged 6 years or over) underwent four pulmonary function tests in 2018.

Figure 46: Pulmonary function tests of people with CF in 2018. For each centre, we can see what percentage of children (aged 6 years or over) and adults underwent at least four pulmonary function tests.

Sputum culture

Taking a sample of the sputum (the mucus deep in the lungs) is also a standard part of a regular outpatient clinic check-up. The sputum is then tested for bacteria and fungi (micro-organisms, see Chapter 5). Figure 47 shows that almost 90% of the children had at least four sputum samples taken in 2018, to test for the presence of micro-organisms. For adults, the average percentage is about 60%.

Figure 47: Sputum sampling of people with CF in 2018. Sputum is mucus deep in the lungs and is sampled to test for the presence of bacteria and fungi. For each centre, we can see what percentage of children and adults had at least four sputum samples taken and tested. *Data for the children in Utrecht are missing.


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Glucose tolerance test

Some people with CF have an increased risk of CF-related diabetes (CFRD). The production of insulin can be affected by the scarring of the pancreas. For this reason, the Dutch guideline stipulates that all people with CF who take pancreatic enzymes undergo a glucose tolerance test every year from the age of ten. This glucose tolerance test shows whether someone is developing CFRD or not.

Want to know more about CFRD? Check out the website for more information.

Figure 48 shows the percentage of people at risk who underwent a glucose tolerance test in 2018. The figures vary from centre to centre, but the totals show that more than 80% of children and almost 60% of adults at risk were tested for CFRD in 2018.

Figure 48: Glucose tolerance test performed on people with CF who are at risk of CF-related diabetes (CFRD). Distribution per centre.

https://ncfs.nl/over-cf/symptomen-en-gevolgen/verminderde-vetvertering-en-suikerziekte/


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Annex 1. Methods

For this report, seven CF centres collected the medical data on almost all people with CF in the Netherlands. This data was then sent to the NCFS, that manages the Registry, does the calculations and prepares the report. The data is encrypted and cannot be identified or traced back to individuals by the NCFS. In total, about 160 different data or variables are collected per person. The data has been collected in this way for 10 years.

How is this coordinated with other countries? How are the calculations made and what assumptions are used? This chapter explains the methods and process. It also explains a number of the terms and abbreviations used.

International harmonisation

Every year, a part of the data from the Dutch Registry is forwarded to the European CF Society Patient Registry (ECFSPR). The European database now comprises data on more than 48,000 people with CF from 35 countries. Want to know more about the ECFSPR? Read more here.

For years, data from people with CF have also been collected in America, Canada, and Australia. In order to compare the data properly, all countries have to collect the data in the same way as far as possible. An example is that the highest pulmonary function value of every year and the height and weight of the same day are collected. Or that an infection with the Pseudomonas bacterium is classed as chronic if three of the four sputum cultures come back positive.

The way data is recorded is becoming more and more standardised internationally, which also makes the data more reliable.

Calculations

In addition to chapter 2, ‘Demographic data’, the analyses in this report have only used data on people with CF who did not undergo a lung transplant.

Two calculations were carried out for the data in this report, which are explained below:

1. Pulmonary function: the centres entered the highest value (before broncho-dilating medication) per person of all measurements done in 2018. The relationship between this data and the reference group with international reference values was then examined (Global Lung Initiative 2012).

2. The height and weight of children were converted to Z-scores in order to be able to combine the different age groups (and boys and girls). These Z-scores were calculated using the Growth Analyser programme of the Foundation for Child and Growth [Stichting Kind en Groei] in Rotterdam. The reference values used are those of the Dutch, Turkish and Moroccan populations from 2010.

https://www.ecfs.eu/ecfspr

https://erj.ersjournals.com/content/early/2012/06/27/09031936.00080312.abstract?papetoc

https://erj.ersjournals.com/content/early/2012/06/27/09031936.00080312.abstract?papetoc


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Concepts

This report makes use of and explains various terms:

- The median value is the middle value of all values together. Half of the people have a higher value and the other half has a lower value than the median value. The average value is calculated differently: the sum of all values is divided by the total number of values.

- Z-score: In some cases, the pulmonary function and height-weight values are converted to Z-scores to correct for age and gender. A Z-score of 0 means an average value and 95% of healthy children in the Netherlands have a Z-score between -2 and 2. A Z-score lower than -2 or higher than 2 is considered to be strongly deviating.

- In Chapter 4, ‘Pulmonary function’, so-called box plots are used (Figures 15 and 16) to display all pulmonary function values. Figure A1 explains how such a box plot should be read.

Figure A1. An example of a box plot, with explanation of the lines and symbols.

Abbreviations

The abbreviations used in this report are explained again here.

- ABPA is an allergic respiratory reaction to the fungus Aspergillus fumigatus, and stands for allergic bronchopulmonary aspergillosis

- BMI stands for body mass index, and says something about the ratio of weight to height: the weight (in kilograms) is divided by the square of the height (in metres).

- CF is short for cystic fibrosis. - CF-related disease is a disease where a person has CFTR mutations but not a confirmed CF

diagnosis, for example because they have a normal sweat test or because one of the CFTR mutations does not cause CF

- CFRD CF-related diabetes - DIOS stands for distal intestinal obstruction syndrome, a severe obstruction of the last part of

the small intestine - FEV1% of predicted is a measure of pulmonary function The FEV1 is the amount of air a person

can force out in one second (Forced Expiratory Volume in the first (1) second). This value is displayed in litres. In order to be able to compare the values of people with CF with peers of the same age, height and sex without a lung disease, the volumes are converted into percentages. These percentages are called FEV1% of predicted.


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Annex 2. Registry Steering Group

Representatives of all seven CF centres and the NCFS together form the Dutch CF Registry Steering Group. The Steering Group determines the policy of the Registry and determines which data will be included in the Registry, in consultation with the European CF Registry. The results are discussed every year to improve CF care in the Netherlands.

Steering Group

NCFS

Drs. J.J. Noordhoek-van der Staay, director NCFS, chair of the Steering Group

Dr. V.A.M. Gulmans, Head of Research and Quality of Care NCFS, secretary of the Steering Group

Dr. D.D. Zomer-van Ommen, coordinator CF Registry NCFS

CF centres

Prof. Dr. H.G.M. Heijerman, chest physician, UMC Utrecht

Dr. K.M. de Winter-de Groot, paediatric pulmonologist, UMC Utrecht

Dr. H.M. Janssens, paediatric pulmonologist, Erasmus MC Rotterdam

Drs. R. van der Meer, chest physician, HagaZiekenhuis, The Hague

Dr. M. Nuijsink, paediatric pulmonologist, HagaZiekenhuis, The Hague

Dr. C.M. Majoor, chest physician, Amsterdam UMC

Dr. S.W.J. Terheggen-Lagro, paediatric pulmonologist, Amsterdam UMC

Dr. H. van der Vaart, chest physician, UMC Groningen

Prof. Dr. G.H. Koppelman, paediatric pulmonologist, UMC Groningen

Dr. P.J.F.M. Merkus, paediatric pulmonologist, Radboud UMC Nijmegen

Dr. J.J.E. Hendriks, paediatric pulmonologist, Maastricht UMC

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