A new screening programme for cystic fibrosis (CF) in on the cards for South Africa which, it is hoped, will diagnose cases in newborns and lead to earlier treatment of the disease.
CF has been in the headlines recently because of a court case about access to new treatments, and while it’s one of the most common genetic disorders inherited from parents, actual cases in South Africa are rare, with fewer than 600 cases having being diagnosed.
However, writes Catherine Tomlinson in Spotlight, experts believe this is only a fraction of the actual number of people with the condition – that most babies born with CF are never diagnosed and die in infancy from CF-related complications and infections.
A new screening programme may, however, help change this.
Who can get cystic fibrosis?
While it’s more common in people with European ancestry, it can affect anyone. Lingering misbeliefs in developed countries that it’s a “white disease” and Euro-centric testing tools have led to under-diagnosis in other ethnic groups – including in people with African ancestry living in the developed world.
In South Africa, it has long been known among CF specialists that the illness is not limited to the white population. The first diagnosis of CF in a black child occurred in 1959.
Yet, an ongoing lack of awareness about CF among healthcare workers, the absence of a newborn screening programme, geographical barriers to diagnostic services, and the similarities of CF’s presentation in infants with more common conditions – such as TB, HIV, and poverty-related malnutrition – means that most babies born with CF in South Africa might never be diagnosed before they succumb in infancy to malnutrition-related complications caused by untreated CF.
Extrapolating from available genetic and population data, Professor Marco Zampoli, a paediatric pulmonologist from the University of Cape Town, estimates that between 2 000 and 3 000 babies may have been born with CF in South Africa since 1999 – including more than 1 000 black African babies.
Sadly, based on data from the national CF registry, which to date has recorded 53 black people with CF (10% of all cases), very few of these babies were ever diagnosed with CF and linked to appropriate care. And when diagnosis does occur, it often occurs late after CF has already done irreparable harm to one’s body and health.
The CF registry and its importance
South Africa’s national cystic fibrosis registry was established in 2018, and includes demographic and health data for everyone diagnosed with the disease who consents to be included in the registry (only one known patient has not consented to date).
Registries of people living with CF have long been used in developed countries. They allow for monitoring of outcomes and the comparison of outcomes across different demographic groups and treatment centres.
Since the establishment of SA’s registry in 2018, two annual reports have been published compiling and explaining the data collected. The most recent annual report, published in 2020, provides data on 525 people diagnosed with cystic fibrosis who are receiving care in public or private care facilities.
More than half of the patients are under 18; 16% are pre-school aged, 69% are white, 19% of mixed race, 10% are black, and 1% Indian.
How is CF diagnosed?
Consensus guidelines were published by the South African Cystic Fibrosis Association (SACFA) and the CF Medical and Scientific Advisory Committee (formed under SACFA) in 2017. These outline the steps for diagnosing CF using a combination of different diagnostic tools – sweat tests, genetic tests and faecal pancreatic elastase tests (which test stool to determine whether the pancreas is functioning properly).
Without a newborn screening programme for CF, most people are only diagnosed after showing clinical symptoms. In newborns, symptoms may include intestinal obstructions, failure to thrive, malnutrition and recurrent infections. In older children, symptoms often include a chronic cough, wheezing and recurrent infections requiring periods of hospitalisation.
Early diagnosis of CF is key to slowing the progression of the disease and ensuring that patients can access therapies to manage CF’s potentially fatal symptoms.
Zampoli said the “sweat test” is typically the first test offered to patients suspected of having CF. CF impedes the normal movement of salt and water across cell membranes throughout the body, including sweat glands and a hallmark symptom is salty sweat.
“This involves a small instrument… with two probes which are attached to the forearm… which stimulate small electric currents to stimulate the sweat glands to produce sweat”.
Then, he says, a device collects a small sweat sample which is sent to the laboratory to measure the salt content. High salt content (chloride > 60 mmol/L) is diagnostic of CF.
Why is genetic testing important for people with CF?
A startlingly high number of people carry the genetic coding for cystic fibrosis in their DNA. In South Africa, it is estimated that one in 27 people from Caucasian ancestry, one in 55 people from mixed race ancestry, and one in 90 people from black African ancestry carry the gene.
While carriers of the CF gene are not affected by CF diseases, when two carriers of the cystic fibrosis gene have a baby together, that baby has a one in four chance of having cystic fibrosis. The baby must inherit two copies of the CF gene, one from each parent, to be affected by CF.
It important for people with CF to know what genes they have, as these are a good predictor of the severity of the disease they will have.
CF disease has a broad spectrum in terms of how it can present. In fairly mild cases in men, its only symptom may be infertility. In severe cases, it is debilitating and life-shortening. There are more than 2 000 different cystic fibrosis-causing gene mutations and these have different prevalence levels across different racial groups.
Knowing what CF-causing genes one has is essential to determining eligibility for new effective CF medicines, known as CFTR modulator therapies. While these are not yet available in South Africa, cystic fibrosis patients are taking legal action to address this.
How is genetic testing performed?
According to CF guidelines used in South Africa, patients who receive two positive sweat test results should be referred for genetic screening – both to confirm their CF diagnosis and to identify what genes they have.
The usual genetic test performed in South Africa is a commercial screening test kit that can detect the presence of up to 50 known CF-causing genes.
Zampoli said commercial tests were designed to suit European populations and while they can identify the genes carried by most people with cystic fibrosis of Caucasian descent, they can only identify the CF-causing genes in around 60% of black Africans with CF.
Patients whose gene mutations cannot be identified using existing commercial screening kits require full sequencing of their CF-causing genes. Full sequencing allows for detection of any CF-causing genes, including uncommon and unknown genes. Unknown genes are genes whose reporting may be new and whose clinical significance is not yet known.
While full sequencing is not available in the public sector, CF clinicians are often able to find ways to have it done when needed for public sector patients – including through using research funds – as the costs of this type of sequencing are coming down, says Zampoli.
Full gene sequencing must be done if routine commercial kit testing does not identify two CF genes when CF is suspected in someone based on symptoms and abnormal sweat test results.
How can CF detection be improved in SA?
While universal newborn screening is not available in South Africa, it is used in most developed countries to screen for genetic and metabolic diseases.
Professor Chris Vorster, director of the Centre for Human Metabolomics and clinical pathologist at North-West University, said newborn screening efforts should target “those conditions that by the time the clinician makes the diagnosis, typically the damage done is already irreversible”.
Vorster’s lab has developed the capacity to undertake newborn screening for a range of genetic and metabolic conditions which, in the absence of government funds for a national screening programme, it now offers through a fee-for-service model, with a company called NextBiosciences in Gauteng.
NextBiosciences’ currently available newborn screening test screens for multiple genetic and metabolic conditions, including conditions for which dietary interventions early in life can prevent serious mental disabilities.
While the government does not offer universal newborn screening for CF and other genetic and metabolic conditions, in November 2021, the Department of Health published Clinical Guidelines for Genetics Services. These recommend “newborn screening for congenital disorders where newborn screening prevents significant and irreversible morbidity and/or mortality” and that “more studies are needed to determine which congenital disorders must be included in the programme”.
“However, an initial screening programme should at (a) minimum include congenital hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis, classical galactosemia, glutaric aciduria type 1, and propionic academia.”
Vorster said further research is needed to inform the roll-out of universal screening in South Africa, including gaining an understanding of the earliest points at which newborn screening can be performed. He noted that in the public sector, most women leave the hospital six hours after giving birth.
In response to Spotlight about the Health Department’s timeline for introducing newborn screening (including CF screening), spokesperson Foster Mohale said: “The department continues to commit to implement(ing) the newborn screening …there are processes between the approval of the guideline and actual implementation …which include preparing the service delivery platform to adapt to the new guidelines. The approval of the guideline came during the pandemic, which delayed the triggering of implementation.”
He said an implementation study on the feasibility of the programme’s roll-out should be completed in the 2023/24 financial year.
How is newborn screening for CF done here?
Newborn screening tools, like other CF diagnostic tools, are Euro-centric and have lower success rates in identifying CF in black and Hispanic Americans, as they test for CF-causing genes more common in the European population, according to US research.
Vorster said the approach currently used in South Africa by NextBiosciences and North-West University avoids this pitfall, since rather than screening for CF-causing genes, the process involves “immuno-reactive trypsinogen screening”, which looks at whether a chemical made by the pancreas is abnormally high.
Unlike in the developed world, genetic screening only occurs at a later stage in South Africa after an initial positive CF diagnosis is made via a sweat test or a faecal pancreatic elastase test.
CF guidelines
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