Neonatal screening for cystic fibrosis in Quebec: soon to be a reality?

Policy — Neonatal screening for cystic fibrosis in Quebec: soon to be a reality?

Over the past few decades, remarkable progress has been made in the life expectancy and quality of life of patients with cystic fibrosis. During this time, the median age of survival increased from less than 10 years to nearly 50, and adult patients now represent nearly 60% of all people with cystic fibrosis in the country.

Unfortunately, the diagnosis of cystic fibrosis is still too often made late. This situation can lead to significant nutritional delays (weight and height) at diagnosis that are difficult to recover later, permanent lung disease that could have been avoided, and a break in trust with the health system when parents have to consult multiple times before getting a diagnosis.

Over time, it has been shown that early interventions could lead to better quality of life, decreased morbidity, and extended life expectancy in these patients. This is why programs to screen for cystic fibrosis from birth (neonatal screening) are present in almost all Western countries and have been implemented in most Canadian provinces in recent years. In this article, we will see how and why these protocols were put in place and we will discuss the relevance of such a program in Quebec.

Cystic Fibrosis in Canada

Year after year, between 120 and 140 new cases of cystic fibrosis are diagnosed in Canada. The median age at diagnosis is around seven months; that is, half of patients are diagnosed before that age and half later. Among the new patients, some will have milder forms of the disease and will be diagnosed in adulthood — often men in whom the condition results in infertility. In newborns, 15 to 20% of diagnoses are made in children with intestinal obstruction at birth: meconium ileus. Excluding these, the number of children with cystic fibrosis who can be detected at birth is just under 100 cases per year in Canada, including about 30 in Quebec.

Neonatal screening

In Quebec, universal neonatal screening — performed on all newborns — includes several important diseases such as congenital hypothyroidism, phenylketonuria, tyrosinemia and a few other even rarer conditions. These diseases all require rapid detection and treatment to avoid serious complications or deaths. In addition, there is a strong desire to add screening for deafness (hearing test) and sickle cell anemia. Apart from the hearing exam, these tests are all carried out on two samples: a few drops of dried blood placed on blotting paper taken in the nursery and a urine sample sent to 21 days of life by the parents.

For several decades, many countries have chosen to add neonatal screening for cystic fibrosis to the diseases sought from birth in the entire population. The first studies that looked at this question date back to the mid-1970s, but often encountered the difficulties of obtaining a reliable and inexpensive test that could be easily generalized to all newborns.

The first regions that decided to move forward during the 1970s were Australia and New Zealand, parts of Italy, the Netherlands and the American state of Colorado. At the same time, a Quebec geneticist, Dr. Richard Gagné, had shown great interest in these new techniques, but could not convince the Quebec government to follow in the footsteps of these precursors. Although the first published studies that wanted to demonstrate the benefits of such screening were of poor quality, some of them confirmed that patients who were screened at birth had better nutritional status and better lung function than patients diagnosed later.

Subsequently, beginning in 1985, the state of Wisconsin (in the United States) began a study involving more than 650,000 newborns. This research compared children diagnosed through newborn screening at the outset to those diagnosed later.
according to their clinical condition. To date, it is the largest study of its kind to have been conducted. In the decades that followed, Dr. Philip Farrell contributed to the publication of dozens of articles demonstrating the benefit for cystic fibrosis patients of getting a diagnosis as soon as possible. These benefits include a reduction in the need for intravenous antibiotics, fewer hospitalizations, fewer hospitalizations, fewer early childhood complications, better growth, better levels of vitamins that influence intellectual abilities (vitamin E), and better estimated survival, although the data on this subject is still debated. From that point on, no study was able to continue such work since it became difficult to justify it as the previous results were convincing.

Several types of protocols (the process in which tests are done to screen) have been put in place to ensure that the diagnosis of cystic fibrosis in newborns is made in the safest, least disturbing and least expensive way possible, while avoiding missing diagnoses and making false diagnoses. Initial screening attempts required two separate samples a few weeks apart, which had obvious disadvantages. Subsequently, and the state of Wisconsin was still at the forefront, the protocols were all able to be carried out on a single blood sample, i.e. the same dried drops of blood already used to screen for other diseases.

Today, almost all neonatal screening protocols for cystic fibrosis work the same way. A first measurement, called “immunoreactive trypsin” (TIR, or IRT in English), is carried out. If this value is high, a second test is done on the same sample. This second test is generally a search for the most frequent cystic fibrosis mutations. If at least one mutation is found (even if two mutations are required to have the disease), the family is advised that a sweat test should be scheduled, as the child is “at risk” for cystic fibrosis. Screening officials then spring into action and meet with parents at the time of the sweat test to offer them full explanations, whether the test results are abnormal or not.

Despite everything, this protocol remains imperfect since it requires genetic tests and finds not only patients with cystic fibrosis, but also some carriers of a single mutation — as in more than 5% of Quebecers. This is problematic, because this result is only important when this newborn baby wants children himself, a few decades later. Some rules even prohibit the disclosure of these results until the main person concerned is old enough to understand their implications.

Other types of protocols have also been studied and could prove useful if Quebec decided to follow suit and adopt a neonatal screening program. These, like the “TIR/ PAP”, have been studied in France and Germany, and could prove to be interesting solutions since they avoid the initial search for mutations in all “possible diagnoses”.

How do these programs work?

In France, all newborns have been screened for “cystic fibrosis” for ten years now, even though several regional programs had been put forward previously. Currently, blood drops are collected on the third day of life since newborns and mothers remain hospitalized longer at birth than in Quebec. The protocol uses the measurement of TIR (as mentioned above), then the search for mutations if this first value is high. The French are currently reviewing their program and may choose to add a step to limit the possibility of discovering carriers of the disease.

If these initial examinations raise the possibility of a diagnosis of cystic fibrosis, the file is sent to the Cystic Fibrosis Resource and Skills Center (CRCM) closest to the child's home. He will be responsible for organizing the sweat test, answering parents' questions and ensuring the patient's care if the test is positive.

From that moment on, the operation was very similar to what was generally done in Quebec during the first management of a patient with cystic fibrosis. An initial assessment is often carried out during a hospitalization of a few days during which the parents meet with members of the multidisciplinary team, learn the basics of treatment and begin to know the essential elements of the disease. Treatment with pancreatic enzymes is started quickly in the 85-90% of patients who need it, vitamin supplements are started and respiratory physiotherapy treatments are put in place. In France, these are usually performed by physiotherapists, and the techniques used are sometimes different from what is done in North America.

Afterwards, outpatient clinic visits follow one another fairly quickly during the first year of life to ensure optimal growth, quickly identify complications and build a relationship of trust with the family. Clinics try as much as possible to avoid the contact of newborns with cystic fibrosis with older patients to avoid contamination by problem bacteria such as Pseudomonas or B.cepacia for example.

This type of care is typical of neonatal screening programs around the world, except for a few variations.

The current situation: elsewhere in the world, in Canada, in Quebec

Elsewhere in the world, the majority of Western countries have implemented or are on the verge of implementing programs to screen newborns for cystic fibrosis. Since 2009, all American states have programs in place, the last on the list being Texas. As mentioned earlier, France has had a program for ten years now; Great Britain (England, Scotland, Wales) has been doing the same for a few years now and Ireland has just been added; most regions of Italy, Australia and New Zealand, as well as many smaller European countries, as well as many smaller European countries, also have their own programs; even several regions of Brazil have screening programs. For the time being, Germany remains on the sidelines while working on research projects aimed at circumventing the problem of detecting carriers of the disease since tougher laws on this subject hinder this possibility.

In 2005, the Canadian Cystic Fibrosis Foundation (now Cystic Fibrosis Canada) issued an opinion on neonatal screening to encourage provinces (which are solely responsible for the screening programs they establish) to consider the possibility of adding cystic fibrosis to the diseases detected in all newborns. In this opinion, members of the Foundation said that patients diagnosed late (1 to 12 months) showed growth retardation and that the data suggested evidence of lung disease in patients diagnosed at that age. Therefore, early diagnosis could identify and treat the condition before growth was affected or lung disease set in. All things considered, the potential benefits outweighed the individual harms of a well-managed screening program, and the Canadian Cystic Fibrosis Foundation therefore encouraged Canadian provinces to move forward and begin neonatal screening programs for cystic fibrosis.

As a result of this report and the efforts of Dr. Mark Montgomery, the first neonatal cystic fibrosis screening project in Canada was established in the Calgary region in 2005-2006 to assess the feasibility of such a program, estimate its costs, and set up the communication networks required for such a project. As the program was a success, Alberta then agreed to implement a universal screening program as early as 2006-2007. In the following years, Ontario followed suit beginning in April 2008, and then British Columbia, Saskatchewan and shortly thereafter Manitoba also implemented such programs. These are now well-established and constantly updated to ensure the best possible path for newly diagnosed patients.
In Quebec, the directors of numerous clinics, as well as members of the Canadian Cystic Fibrosis Foundation and other specialized advisors met for the first time in April 2006 to explore the possibility of implementing such a program in our province.

Following this meeting, meetings took place and letters were exchanged with officials from the Ministry of Health and Social Services (MSSS) in an attempt to convince them of the importance of supporting the establishment of such a program. Unfortunately, these efforts were not successful until recently. In June 2010, initial discussions took place until the announcement of the establishment of a committee of the National Institute of Public Health of Quebec (INSPQ) responsible for making recommendations to the MSSS on neonatal screening for cystic fibrosis. This committee was implemented, and the Deliberative Forum on Cystic Fibrosis took place in Montreal in November 2011, under the aegis of the INSPQ. These two-day meetings bringing together clinic directors, geneticists, geneticists, parents and patients, and numerous other specialists focused on all aspects of the diagnosis of cystic fibrosis. Following these meetings, a detailed report was prepared and was due to be submitted to the National Director of Public Health this fall. It must take a decision and issue recommendations in the coming months. It is therefore possible that a resolution is just around the corner, even if the decision to conduct such a screening will not lead to
necessarily its immediate implementation.

Over the past few decades, many regions have made the decision to screen all newborns for cystic fibrosis. Such programs have several advantages, including: the establishment of early follow-up and management as well as genetic counseling that can, among other things, prevent the birth of affected siblings if the parents do not want it; the prevention of malnutrition and growth retardation, which can be irreversible and which are common in children diagnosed late; the prevention of deficiencies in vitamins, essential fatty acids and proteins; the prevention of hospitalizations. Serious for problems undiagnosed respiratory tract, for digestive problems or for dehydration; and finally the possibility of avoiding the diagnostic odyssey, that is to say the numerous urgent visits, consultations, hospitalizations that are sometimes necessary before the correct diagnosis is made. Finally, it should be expected that the treatments currently being studied in research projects will increasingly focus on a very early approach to the disease in order to prevent complications before they occur — which is why it is important to make a diagnosis as soon as possible.

To conclude, it should be noted that a neonatal screening protocol for cystic fibrosis ensures that all affected patients start on an equal footing. Despite awareness-raising campaigns and training offered to medical personnel, the diagnosis is too often delayed, so that growth retardation and irreversible lung damage can occur in the absence of adequate follow-up in a specialized clinic. Such a screening program in Quebec could be set up quite quickly if a decision is made to move forward, since the stakeholders are already well identified in the various multidisciplinary clinics in the province, and their enthusiasm for providing this care is acquired. However, neonatal screening is not a panacea since several factors are taken into account in determining the long-term severity of the disease in a given patient. Any program can run into difficulties, and no measure can replace patient and family education, and good collaboration with the treatment team (in both directions!) and healthy lifestyles.

Dr Patrick Daigneault Pediatrician-pulmonologist
Director of the Pediatric Pulmonology Department Mother and Child Center Hospital Center
University of Quebec (CHUQ)
Quebec (Quebec) Canada

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