TWO YEARS OF NEWBORN SCREENING FOR CYSTIC
FIBROSIS IN NORTH MACEDONIA: FIRST EXPERIENCE
Fustik S1,*, Anastasovska V2, Plaseska-Karanfilska D3, Stamatova A1,
Spirevska L1, Pesevska M2, Terzikj M3, Vujovic M3
*Corresponding Author: Professor Stojka Fustik, M.D., Ph.D., Department for Cystic Fibrosis,
University Clinic for Pediatrics, Faculty of Medicine, University “Ss. Cyril and Methodius,” Vodnjanska
17, 1000 Skopje, Republic of North Macedonia. Tel.: +389-23-147-716; +389-75-705-369. Fax: +389-
23-129-027. E-mail: stojkaf@yahoo.com
page: 41
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DISCUSSION
Cystic fibrosis is a multisystem genetic disease resulting
in complicationsin multiple organs, but especially involving
the lungs and pancreas. Since the discovery of the CFTR
gene associated with CF, there has been à great progress in
understanding and in the care of patients with this disease.
Cystic fibrosis has been changed from a fatal early childhood
disease to a chronic disorder in which most patients with
CF are expected to live into adulthood. Early diagnosis by
NBS, multidisciplinary care in specialized CF centers, and optimized and preventive treatments are the most important
factors that have changed the face of CF [10].
Today, NBS is considered an essential component in the
standards of care for CF [2]. The vast majority of newborns
in North America, Europe, Australia and New Zealand, and
a growing number in South America, are screened for CF
[5]. Newborn screening and early appropriate treatment
(pancreatic enzyme replacement, fat-soluble vitamins, salt
supplementation) has a beneficial effect on growth and nutritional
status, and prevent deficiency of fat-soluble vitamins
and protein malnutrition [3,11-13]. Cystic fibrosis patients
diagnosed with NBS have a lower burden of treatment and
fewer hospitalizations for intravenous antibiotic therapy due
to exacerbation of lung disease [12,13]. Children diagnosed
with CF by NBS are expected to have better lung function
and lower incidence of Pseudomonas aeruginosa infection,
in particular delayed onset of chronic Pseudomonas
aeruginosa infection [12,14,15]. Newborn screening for CF
leads to improved long-term health outcomes and survival
for the CF population [12,16]. Screening is a cost-effective
public health strategy [17]. In the era of CFTR modulator
therapies that correct the basic underlying molecular defect,
early diagnosis with NBS will enable the timely introduction
of this therapy in the future.
Considering the confirmed benefits from the early
diagnosis of CF by NBS, which was introduced in our
country as a national program on all newborn poputation
from 2019, after a previous pilot study. We performed a
two-step IRT-IRT algorithm, and then a sweat test for confirmation/
exclusion of the CF diagnosis when IRT values
are both above the cutoff values. In cases of positive or
borderline sweat tests, mutation analysis of CFTR gene
was performed.
However, the screening protocols are varied, and
there are many different NBS protocols for CF across
Europe. Most programs use DNA analysis as a second-tier
test, due to the fact that the IRT-1/IRT-2 protocol is not
sufficiently sensitive [18]. While five CF screening protocols
in Europe (Austria, Portugal, Russia, Slovakia and
Turkey) still rely exclusively on biochemical tests, either
a repeat IRT measurement at days 14-21 or measurement
of PAP in parallel to IRT-1 plus IRT-2 measurement in/
after the third week [5,19]. The IRT values decrease in
infants without CF over the first 4 weeks of life, but remain
high in those with CF. The IRT-1/IRT-2 protocol improves
positive predictive value by reducing the number of infants
who are referred for a sweat test. Biochemical screening
protocols also avoid the issues raised by CFTR mutation
analysis as a second step such as carrier detection and
limited the number of cases with equivocal diagnosis of
CF. Cystic fibrosis screen positive, inconclusive diagnosis
(CFSPID), also known as CFTR-related metabolic syndrome
(CRMS) in the USA, are infants detected by NBS
with a normal sweat test and two CFTR mutations, at least
one of which has unclear phenotypic consequences and
infants with intermediate sweat test and one or no CFTR
mutations [7,20,21]. Infants with an uncertain diagnosis
of CF (CFSPID/ CRMS) require further investigation that
should be undertaken with close liaison of the CF Center
with the service for molecular genetics. A number of these
children will remain free of symptoms throughout their
life, but some of them may develop clinical features suggestive
of CFTR-related disorder (CFTR-RD) or clinical
features of CF later in life [21,22]. Many more CFSPID/
CRMS cases are found if DNA analysis is a second-tier
test in screening protocol, especially if protocols include
large panel of CFTR mutations [22].
During the screening period, one CF case with meconium
ileus was missed on screening, that is, the NBS test
for CF was false negative. It is well recognized that infants
with meconium ileus usually have IRT-1 values below the
cutoff and false negative NBS results [23,24]. Therefore,
any case of meconium ileus should be considered as CF
until proven otherwise.
The incidence of CF in the Republic of North
Macedonia, estimated in the short observation period
while the NBS program was being implemented, is one
of the highest in Europe, on average 1:2500 [11]. North
Macedonia is a multiethnic country. In the newborn population,
Macedonians of Slavic origin are in the majority,
contributing 53.0%, 30.0% are ethnic Albanians, 7.0% are
Romas, 5.0% are Turks and 5.0% are of other ethnicities.
The NBS for CF revealed a huge difference in disease
incidence between the two largest newborn populations in
the country, Macedonian (1:4530) and Albanian (1:1284).
The closedness of the Albanian population over the centuries,
including consanguineous marriages, has contributed
to the greater frequency of the pathological CF gene in
this population. Further years of NBS would give us a
more accurate assessment of the incidence of CF in our
geographic area and between the different ethnic groups.
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