Cystic fibrosis?

Question

Dear expert team,

My daughter is 8 years old and has the R1162X – R1084G mutation. We received the cystic fibrosis diagnosis when she was still a baby. At that time, we went to a CF clinic. The first years of her life were unsuspicious. The sweat test was negative. We were told she had CF, but that is was a form without symptoms. At the age of three, she had infections repeatedly so that the CF clinic considered therapy options. From then on, she got Zithromax® (azithromycin) every other day and we did breathing therapy twice daily. When she was six years old, we switched to a different CF clinic because we felt that the therapy up to then in no way compared to our daughter’s health status. She did have recurring infections, but we did not understand why we had to give her antibiotics continuously. In the new clinic, again sweat tests were done. The values were between 15, 22 and 43. We were now told here that our daughter did not have CF because the tests were negative. We were advised to refrain from any kind of therapy since she is a healthy child. This is what we did. Unfortunately, she got worse over time. She got short of breath, could not do sports as usual, and had (slight) infections repeatedly. Over the course of five months, two spirometries were done, both of which were significantly below her usual values. We subsequently resumed breathing therapy (saline solution inhalation once daily, flutter, autogeneous drainage). She got significantly better and the spirometry values were excellent again. During our last consultation at the CF clinic, we were again reassured that she does not have CF. My question now is: does the sweat test alone indicate CF, or does a blood test also reveal something? Could it be that she shows CF symptoms despite a negative sweat test? We are confused because we got two completely contradictory statements from CF specialists. Some say she has CF and want to do a complete therapy; others, on the other hand, think she is completely healthy and that it is only necessary to do a sweat test once a year.

Answer

Dear questioner,

I would like to answer your questions in several steps.

1. Does just the sweat test alone indicate CF?
No, just the sweat test alone does only indicate CF if it is positive (i.e., >60). There are enough CF-mutation-genotypes which show a negative sweat test (i.e. below 60). CFTR, the protein affected in CF, is a chloride channel (casually speaking, chloride is one half of common salt). This feature can be measured: if CFTR does not work, there is more salt in the perspiratory gland. Apart from the sweat test, there are two other diagnostic approaches (see also below): intestinal current measurement (ICM) and nasal potential difference test (NPD) are considered sensitive measures in order to determine how well CFTR works.

2. …or does a blood test also reveal something?
Yes, but only if the doctor has treated enough patients with the same CFTR mutation genotype. R1162X – R1048G is a very rare, perhaps even unique combination worldwide. A lot is known about R1162X – there are enough patients so that we know it is a CF mutation. As for R1048G, without having further data, unfortunately one can only guess (which, unfortunately, is what your doctors did with the diagnosis).

3. Could she show CF symptoms despite negative sweat tests?
Yes. There are further intermediate forms between “healthy“ and “affected by CF“ in which only part of the spectrum of symptoms is developed. The data you describe (increased proneness to infections as a toddler, sweat test value in the threshold range at 40, respiratory tract problems at school age) suggest that your daughter possesses less functional CFTR than you or your husband. Now whether this is CF or one of the rare CFTR-related intermediate forms (atypical CF or CFTRopathy) can be determined with certainty through further measurements (NPD, ICM).

In summary: for a definite diagnosis, please refer to a centre that is certified for CF basic defect diagnostics and apart from sweat tests also offers nasal potential difference testing (NPD) and diagnosis via ICM (in Germany, at this point, these centres are: Berlin, Bochum, Hannover, Heidelberg). There, one will measure how well the CFTR works in your daughter’s respiratory tracts and intestinal tissue, and afterwards will be able to tell you with certainty whether your daughter has mild CF, CFTRopathy, atypical CF, or none of these. This will surely help your treating doctor a lot, as he must systematically treat the symptoms, not the yes/no diagnosis after CFTR gene test and sweat test. The following is particularly important: problems such as “proneness to infections during toddlerhood” and “respiratory tract problems at school age” also occur in children with two healthy CFTR genes (i.e. without CF). These other clinical pictures will then have to be treated differently than CF, of course.

Finally, a historical digression – why do doctors contradict each other?
The approach of classifying your daughter’s symptoms accurately now with the help of ICM and NPD is consistent with the current European guidelines for the diagnosis of CF (J Cyst Fibros. 2011 Jun;10 Suppl 2:S53-66.) as well as the atypical courses of the disease (Cyst Fibros. 2011 Jun;10 Suppl 2:S86-102). As you can see, these guidelines from 2011 are rather new, so that word about the new options for detailed diagnostics may not have gotten around to all doctors yet. This also explains your doctors’ contradictory statements, as the state of knowledge has changed radically during the past few years: around ten years ago, it was still automatically assumed that each sequential variation in the CFTR gene causes a disease (hence your daughter’s diagnosis based on the blood test as a baby). Afterwards, it became known that therapy is better determined by the clinical symptoms, not by the CFTR genetics which in some cases is not very conclusive (hence the intensive therapy of your daughter’s infections during toddlerhood). Some centres attach only secondary importance to the CFTR gene test but have relied on the unfortunately not-so-sensitive sweat test (hence the statement that your daughter is healthy and does not need therapy). By now, it is known that some sequential variations in the CFTR gene cause classic CF – and fortunately, with NPD and ICM, there are tools available that are better suited to detect this better than the sweat test.

All the best for the future to you and your family,
Frauke Stanke

15.01.2013