History: Cystic Fibrosis, Yesterday and Tomorrow: Memories of an Old Clinician

My intention in this article is not to present you with highly scientific elements, but rather the thoughts of a pediatrician at a cystic fibrosis clinic who feels a bit like the old soldier returning from war. The one who has seen the atrocities, but who has also participated in several hard-won battles, without having achieved the ultimate goal, which is to win the final victory against cystic fibrosis.

It can sometimes be beneficial to look back to appreciate the road already traveled and the gains made, and thus better assess the steps to be taken before arriving at the discovery of the final solution, which is now imminent.

The Stone Age

The disease “cystic fibrosis of the pancreas” was officially described in 1938 by Dr. D.H. Andersen who observed, at the autopsy, that several infants who died before the age of one year from malnutrition and/or pneumonia had a pancreas full of cysts. This is where the name “pancreatic cystic fibrosis” comes from. Now we all know that cystic fibrosis is not just a problem with the pancreas, but a disease that affects all the mucus glands, called exocrine glands, such as the bronchi, sinuses, intestines, intestines, liver, and genitals.

Quickly, researchers discovered that the basic problem of cystic fibrosis was abnormal mucus, which was too thick, which interfered with the proper functioning of these secretory organs. From the start, people were desperate to improve the health of these children who were dying very early.

They first thought of treating abnormal mucus with mucolytics: they even quickly tried dornase alfa (yes, the same thing as the Pulmozyme® that we are currently using!).
Except that at the time, it was of animal origin and caused allergies so significant that
treatment has been abandoned. Only very recently did researchers realize that human-made dornase alfa (Pulmozyme®) could be very useful without causing allergies.

As an alternative for thick mucus, treatment with N-acetylcysteine by prolonged inhalation in a croupet all night was recommended: unfortunately, this approach was not very effective and caused a great deal of inconvenience to children who had to sleep all night in these wet and sticky croupettes.

It was also noted that all patients' stools contained far too much fat. To alleviate this very important symptom, the researchers first recommended cutting fat in the diet: children then had to stick to a very restrictive fat-free diet. This proved to be effective in reducing fatty diarrhea, but it was not the ideal solution since all patients already suffered from severe malnutrition that could only be made worse by such a diet.

Despite all the attempts at treatments invented, in 1960, the life expectancy of fibrocystic patients was only five to six years.

The years 60-70

In the early 1960s, several Canadian parents and volunteers decided to join forces and create an organization to promote the cause of cystic fibrosis in Canada: the Canadian Cystic Fibrosis Foundation (CFK) (now called Cystic Fibrosis Canada). The FCFK had two priorities: to support cystic fibrosis research, and to encourage the creation and maintenance of multidisciplinary teams specialized in the care of cystic fibrosis patients. As we will see later, this foundation will become a key element in the evolution of the fight against cystic fibrosis in Canada.

I started my career as a pediatrician at CHUL in 1975 and, in 1976, I was lucky enough to join the team at the CHUL Cystic Fibrosis Clinic. Significant progress has been made in previous years, and the average age at death is now 16 to 17. At the CHUL, there was only one adult patient in 1976, but quickly, there was a very rapid growth in the number of adult cystic fibrosis patients in Quebec, as everywhere in Canada. We are then confronted with a new problem, which in my opinion is very interesting: the need to create cystic fibrosis clinics adapted to the needs of adults.

Interesting breakthroughs are being made in terms of treatments:

• We are definitely stopping the use of croupettes with mucolytics at night.

• We have understood the importance of treating infections early and are using antibiotics much more aggressively, and over the longer term, especially for the youngest children.

• We are always looking for any form of treatment that can benefit our cystic fibrosis patients. Some Canadian pediatricians, like us, have the crazy idea of administering antibiotics against Pseudomonas in aerosols to send them to where they are most useful: in the bronchi. This idea was not widely accepted and was highly controversial at the beginning. But over time, research has shown the effectiveness of this method, which has now become the
treatment of choice against Pseudomonas.

• We are also benefiting from a significant improvement in treatment on the digestive side: patients can take pig pancreatic enzymes that replace missing enzymes and better digest all foods. There is a marked improvement in nutrition with this treatment. However, it has major drawbacks: the drugs are powdered, in poorly concentrated capsules and heavily destroyed by stomach liquid. Patients should therefore take a very large quantity at each meal (10 to 15 capsules or 1 to 2 handfuls per meal).

However, we are making slow progress, and the median age of survival is now over 25 years.

The years 80-90s

During these years, research has experienced a very significant boom. The FCFK becomes the largest funding agency for cystic fibrosis research in Canada. Canadian researchers have earned a global reputation and have contributed very actively to major discoveries in the world of cystic fibrosis, including the discovery of the cystic fibrosis gene in 1989 by a team of three researchers, including two Canadians. This great discovery is of great importance because it will make it possible to:

• better understand the mechanisms of the disease;

• make a transgenic animal model of cystic fibrosis;

• study gene therapy;

• establish molecular confirmation of a diagnosis;

• implement prenatal diagnosis and neonatal screening;

• discover medications that can correct the basic defect of cystic fibrosis.

We are witnessing the multiplication of cystic fibrosis clinics in Canada: there were 32 in 1990 (and 38 now, including 11 in Quebec!). The FCFK, now called Cystic Fibrosis Canada, and its Quebec counterpart, Cystic Fibrosis Quebec, are key elements in the evolution of the care of cystic fibrosis patients in Canada. It is these organizations that have allowed the creation and maintenance of specialized cystic fibrosis clinics. Without their contribution, these clinics, now essential to the care of cystic fibro-cystic patients, would never have been possible in the care model in Quebec and Canada. They are an exceptional care organization model and ensure that each patient is provided with all the necessary services and care. Here, I would like to pay tribute to all the members of cystic fibrosis clinics.
(directors, doctors, nurse coordinators, dietitians, physiotherapists, respiratory therapists, social workers, psychologists, pharmacists) from the CHUL (obviously), but also from other clinics in Quebec and Canada.

These years also marked a significant increase in knowledge about the causes and complications of cystic fibrosis. Once again, the Canadian cystic fibrosis community is innovative and distinguishes itself by recognizing the importance of nutrition in improving patients' quality of life and prognosis factors. To this end, the emphasis is on the need to provide caloric intakes in excess of 150% of the basic needs of the Canadian population, either through hypercaloric diets or even by force-feeding if necessary.

Antibiotics are becoming more varied and effective. We can administer them intravenously once or twice a day, making it possible to start home treatments (ATIVAD) and reduce hospital stays.

Tobramycin is now administered regularly by aerosol therapy. This practice, which was initially empirical, is now officially recognized as effective for treating Pseudomonas. In my opinion, this strategy is another major element in improving disease control over time.

Pancreatic enzymes are now available in enteric-soluble formulas, which protects them against destruction by the stomach and allows the number of capsules needed to be reduced by three to four times. In addition, there are concentrated forms that make it possible to further reduce the number of capsules to be ingested: 2 concentrated enteric-soluble capsules are now as effective, if not more, than the 15 ordinary powdered capsules.

Lung transplantation is becoming available for cystic fibrosis patients. The beginnings are difficult, and
the initial results are not very encouraging. But, rapidly, techniques and treatments improved considerably, and lung transplantation became a very interesting option for the most severely affected patients. Unfortunately, it is not available for everyone, and we are still facing the limitations imposed by the number of donors.
We continue to make progress and the median age of survival in Canada is now close to 35. All the better, but it's not enough. You have to rush very aggressively into the 2000s.

From the 2000s to the present

Research is constantly intensifying. Its main objective: to find the solution that could correct the basic defect. Gene therapy (correction of the defective gene by the transfer of normal genes) was the first solution hoped for: unfortunately, it is almost impractical, in particular because of absolutely unacceptable and unsolvable side effects.

The search for the correction of the basic defect of cystic fibrosis is also oriented towards interventions on the biomolecular functions of cells. This strategy is much more promising: laboratory tests are multiplying, and the results have made it possible to undertake clinical trials in cystic fibro-cystic patients in recent years. Even better, there is now a new drug available that fixes the basic defect in a particular cystic fibrosis mutation. Unfortunately, this medication is only effective for patients who have this very specific mutation, and few Canadians are eligible. But clinical trials are already under way to develop similar drugs that will address the most common mutations, such as ∆F508, which is the most common mutation in Canada.

It is essential that all patients with cystic fibrosis be identified as early as possible to ensure the management and control of the disease before symptoms appear and complications develop. For this purpose, neonatal screening is very widely used in the Western world and was officially recommended by the FCFK a few years ago. It is already offered in several Canadian provinces and is unanimously desired by all the directors of
cystic fibrosis clinics in Quebec. We continue to very strongly hope that it will be offered very soon in Quebec.

Finally, we are witnessing the mandatory phenomenon of rejuvenation and consolidation of teams specialized in cystic fibrosis: old soldiers must make way for fresh, young and dynamic forces, just as dedicated to the cause of cystic fibrosis and filled with energy to continue the fight.

In summary, after more than 50 years of intensive struggle, the clinical situation of the Canadian cystic fibrosis population has improved significantly:

• The median age of survival increased from 5-6 years in 1960 to nearly 48 years in 2010 (note that this statistic improves by about 10 months for each year of intensive struggle).

• There are now more adults than children living with cystic fibrosis in Canada. Children reach adulthood in better condition.

• The quality of life of patients with cystic fibrosis is constantly improving: better respiratory condition, better nutritional status, better work tolerance, better accessibility to family life and professional careers.

But it remains an unacceptable situation: cystic fibrosis still causes too many deaths, and too early. Far too many cystic fibrosis patients die before the age of 30.

Of course, over the past 50 years, we have made enormous progress, we have won several battles, the average age at death has increased by more than 40 years and the quality of life just as much.

But the war is not over. Let's continue all together to devote all our energies to our cystic fibrosis population until discovery (very imminent now!) of a correction of the defective mechanism of cystic fibrosis.

Thank you to all those who have worked near me over all these years, doctors, nurses and workers at cystic fibrosis clinics, of course those at the CHUL, but also those at other cystic fibrosis clinics in Quebec and Canada.

Thanks to all the local, provincial and national administrators, and especially to those of Cystic Fibrosis Quebec, the Provincial Committee for Adult Fibrocystic Fibrosis and Cystic Fibrosis Canada.

And above all... Thank you to all our cystic fibrosis patients!

In short, thank you to those who continue the fight “for a better breath of life”!

Dr Georges Rivard Pediatrician
Ex (!) co-director of the
Cystic Fibrosis Clinic Hospital Center
University of Quebec (CHUQ)
Quebec (Quebec) Canada

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