In recent weeks, cystic fibrosis (CF) has been in the headlines because of a court case about access to new treatments for the genetic condition. CF is one of the most common genetic disorders inherited from one's parents, but actual cases of the disease in South Africa are rare.
There are under six hundred people who have been diagnosed with CF in the country - experts believe this is only a fraction of the actual number of people with the condition. Most babies born with CF, it is believed, are never diagnosed and die in infancy due to CF-related complications and infections. A new screening programme may, however, help change this.
Who can get cystic fibrosis?
While CF is more common in people with European ancestry, it can affect people of any ethnic background. Lingering misbeliefs in developed countries that cystic fibrosis is a 'White disease' and Euro-centric testing tools have led to under-diagnosis of cystic fibrosis in other ethnic groups - including in people from 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 in South Africa occurred in 1959. Yet, an ongoing lack of awareness about CF among healthcare workers in the country, 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 two and three thousand babies may have been born with CF in South Africa since 1999 - including over a thousand black African babies. Yet, based on data from the national CF registry, which to date has recorded 53 Black Africans 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.
What is the national cystic fibrosis registry and why is it important?
South Africa's national cystic fibrosis registry was established in 2018. The registry includes demographic and health data for all people diagnosed with cystic fibrosis in South Africa who consent 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 CF outcomes across the country and the comparison of outcomes across different demographic groups and treatment centres. Registries can be used to identify where there are positive health outcomes and successes, as well as where there are challenges and gaps. And, in the case that a pharmaceutical company seeks to undertake a CF-related clinical trial, registries enable clinicians and researchers to identify eligible patients who may be interested in participating in trials.
Since the establishment of South Africa's registry in 2018, two annual reports have been published compiling and explaining the data collected in the registry. The most recent annual report, published in 2020, provides data on 525 people diagnosed with cystic fibrosis in the country who are receiving care in public or private care facilities.
According to the registry, more than half of CF patients in the country are under the age of 18. Sixteen percent of patients are pre-school aged. Among patients diagnosed with CF in South Africa, 69% identified as white, 19% identified as mixed race, 10% identified as Black, and 1% identified as Indian.
How is cystic fibrosis diagnosed in South Africa?
Consensus guidelines for the management of CF were published by the South African Cystic Fibrosis Association (SACFA) and the CF Medical and Scientific Advisory Committee (formed under SACFA) in 2017. These guidelines 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 with CF 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 explains that 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 one's body, including sweat glands and one of its hallmark symptoms is salty sweat. According to Zampoli, the sweat test "is a small instrument... it has two probes which are attached to the forearm... which stimulate small electric currents to stimulate the sweat glands to produce sweat. Then," he says, "there's a little device which collects a small sample of the sweat and that is sent to the laboratory to measure the salt content of that little bit of sweat. High salt content in sweat (chloride > 60 mmol/L) is diagnostic of CF."
Zampoli, however, cautions that conducting sweat tests requires a high level of technical skill and experience and that these skills only exist within tertiary hospitals in city centres in the public sector and private sector laboratories that are also largely limited to city centres.
"In rural areas and in the Eastern Cape, Northern Cape, Limpopo, and Mpumalanga, there are no facilities to do sweat tests. So, if a doctor suspects CF, they must either refer patients to a lab in one of the major centres," says Zampoli. Patients who receive two positive sweat test results should then have their cystic fibrosis confirmed through genetic testing.
Why is genetic testing important for people with cystic fibrosis?
A startlingly high number of people carry the genetic coding for cystic fibrosis in their DNA. In South Africa, it is estimated that 1 in 27 people from Caucasian ancestry, 1 in 55 people from mixed race ancestry, and 1 in 90 people from black African ancestry carry the cystic fibrosis 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, then their 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.
According to Zampoli, it is important for people with CF to know what genes they have, as these genes are a good predictor of the severity of the disease that they will have. Zampoli explains that 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. Yet, in severe cases, it is debilitating and life-shortening. There are over two thousand different cystic fibrosis-causing gene mutations and different gene mutations have different prevalence levels across different racial groups.
Zampoli explains that knowing what CF-causing genes one have is essential to determining one's eligibility for new highly effective CF medicines, known as CFTR modulator therapies. While these medicines are not yet available in South Africa, cystic fibrosis patients are taking legal action to address this (Spotlight reported on those efforts here).
JUST IN: Landmark SA court case takes on US maker of #cysticfibrosis drugs. @SECTION27news @HealthZA @MSF_SApress @MSF_southafrica @HealthJusticeIn @_HassanF @VertexPharma @CF_Foundation @RareGenomicsRSA @rarediseasessa @HumGen_UCT @irdirc @kellyrare https://t.co/Px2wCRntp9
-- Spotlight (@SpotlightNSP) March 7, 2023
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 explains, however, that commercial tests were designed to suit the needs of 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 percent 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. He adds that 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 South Africa?
While universal newborn screening is not available in South Africa, it is broadly 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, explains that newborn screening efforts should target "those conditions that by the time the clinician makes the diagnosis, then 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 together with a company called NextBiosciences, located in Midrand, 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.
Their newborn screening test, which includes CF screening, is available to private patients at a cost of R 1 646.16 (excluding collection, courier, and administration costs). It is not typically covered by medical aid schemes.
While the South African government does not currently offer universal newborn screening for CF and other genetic and metabolic conditions, it is moving in this direction. In November 2021, the Department of Health published 'Clinical Guidelines for Genetics Services'. The guidelines recommend "newborn screening for congenital disorders where newborn screening prevents significant and irreversible morbidity and/or mortality" and adds 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 notes that further research is required to inform the rollout of universal screening in South Africa, including gaining an understanding of the earliest points at which newborn screening can be performed. He also notes that in South Africa's public sector, most women leave the hospital six hours after giving birth.
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In response to a question from Spotlight regarding the National Department of Health's timeline for introducing newborn screening (including CF screening) in South Africa, spokesperson Foster Mohale told Spotlight, "The department continues to commit to implement[ing] the newborn screening in South Africa. There are processes between the approval of the guideline and actual implementation of the guidelines. Such processes include preparing the service delivery platform to adapt to the new guidelines. The approval of the guideline came during the COVID-19 pandemic, which delayed the triggering of guidelines implementation," says Mohale.
Mohale says it is envisaged that an implementation study on the feasibility of a rollout of the programme will be completed in the 2023/24 financial year. Depending on the results of that feasibility study, he says the country rollout plan will then be developed.
How is newborn screening for CF done in South Africa?
Recent research published in the United States has demonstrated that 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.
Vorster notes that the approach currently used in South Africa for newborn screening by NextBiosciences and North-West University avoids this pitfall since rather than screening for CF-causing genes in newborns, the screening offered involves "immuno-reactive trypsinogen screening" - which looks to see whether a chemical made by the pancreas is abnormally high. Vorster says that 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.
Zampoli says that while access to new transformative medicines for CF remains critical to improving CF patients' outcomes, early diagnosis can also save lives and prevent the progression of CF by allowing patients to begin currently available therapies needed to treat symptoms and prevent the progression of the disease but adds that there are large geographical barriers for many people born outside of city centres to accessing required specialised CF care.
Either way, critically important as it is, diagnosis is always only a first step. Kelly du Plessis, founder of Rare Diseases South Africa says, "If we're going to start the newborn screening process... where you are you're actually identifying cystic patients early, you also have to have the interventions in place to help them once they've been identified."
Whether those interventions are indeed in place will be the subject of the next article in this Spotlight special series on CF.
