Introduction

Cystic Fibrosis (CF), the most common life-threatening autosomal recessive and multisystemic disease, is due to alterations in CF Transmembrane Conductance Regulator ( CFTR ) gene that encodes a membrane glycoprotein . Such protein acts as a transmembrane channel by regulating chloride and sodium transport and its alteration or reduction leads to the production of thick secretions within the affected organs, causing progressive lung damage, pancreatic injury and multiorgan involvement . Furthermore, there is a growing number of individuals diagnosed as CFTR-related disorders (CFTR-RD), a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF .

The introduction of newborn screening (NBS) allowed early diagnosis of CF and, consequently, the opportunity to commence specific treatments with an improvement of clinical outcome, quality of life and survival . Different NBS protocols are used in different countries even within the same country . All protocols start with the measurement of blood immunoreactive trypsinogen (b-IRT) on dried blood spots at 49–72 h after birth. The second level may include either molecular analysis of CFTR with techniques that explore a limited panel of variants or with the whole gene scanning by next generation sequencing (NGS), or a repeated measurement of b-IRT concentration at the age of 4–6 weeks followed or not by molecular analysis. The sweat test (ST), the gold standard for the diagnosis of CF, is offered to all children positive for NBS and it is considered pathological for levels of sweat chloride (SC) ≥ 60 mmol/L . In most patients with CF the SC is pathological and CFTR gene analysis shows two CFTR causing variants ( https://cftr2.org/ ), however such genotype may be observed even in patients with a SC value in the intermediate (30–59 mmol/l) or normal (<30 mmol/L) range .

Following the enhancement of diagnostic techniques, particularly NGS for CFTR gene scanning, and the increase of the number of subjects screened, a growing and variable number of positive NBS subjects with an inconclusive diagnosis of CF has been identified over years . This cluster of asymptomatic subjects, firstly designated in USA as CFTR-related metabolic syndrome (CRMS), and then in Europe as CF Screen Positive, Inconclusive Diagnosis (CFSPID) , shows elevated b-IRT with persistently intermediate SC levels and fewer than 2 CF causing CFTR variants; or normal SC concentration (<30 mmol/L) and 2 CFTR variants with 0 to 1 known to be CF-causing .

The two terms have been harmonised introducing the definition of CRMS/CFSPID to improve indefinite diagnosis, international communications, and analysis of clinical outcomes . Here, we preferred the shorter term CFSPID throughout the rest of the paper. The number of such subjects (and the ratio between CF and CFSPID cases) revealed by NBS is widely different between countries depending on the different protocols used for NBS and on genetic differences between populations . Over time, a variable percentage of CFSPIDs will be diagnosed as CF owing to a positive ST, a re-classification of CFTR variants as CF causing, or onset of CF-related symptoms (CFSPID > CF) . However, the most probable risk for these children seems the evolution in the CFTR-RD label . Even with the published revised guidance from the European Cystic Fibrosis Society (ECFS) neonatal screening working group , one of most important aspect concerning management and monitoring of CFSPIDs is to early identify those at greatest risk of transitioning in CF. This could avoid overmedicalization of healthy subjects or healthy carriers and properly provide more information to the families of these children, as persistence of an inconclusive diagnosis may cause a negative psychological impact for families, increasing parents’ distress .

Here, we performed a systematic literature review to investigate possible biochemical, genetic and microbiological criteria, which could early identify CFSPIDs who deserve a closer follow-up for the high chance of developing a CF phenotype.

Material and Methods

Results

Included manuscripts’ characteristics

The electronic search resulted in 85 articles that were reduced by 63 after duplicates were removed. Therefore, a total of 22 studies focusing on CFSPID who progressed to CF (CFSPID > CF) were included in this review ( Appendix 2 , Fig. 1 , Table 1 ): 10/22 multicentre retrospective studies, 4/22 multicentre prospective studies, 2/22 monocentre retrospective studies, 1/22 monocentre prospective studies, 3/22 retrospective cross-sectional studies, 2/22 case series. 19/22 studies were performed on children and 3/22 both children and adults. 11/22 papers focused on CFSPID and IRT values ( Table 3 ); 17/22 studies on CFSPID and CFTR gene analysis ( Table 4 ); 16/22 studies on CFSPID and SC values ( Table 5 ); 9/22 studies on CFSPID and Pseudomonas aeruginosa (Pa) isolation ( Table 6 ); 4/22 studies on CFSPID and lung clearance index (LCI) ( Table 7 ) and 5/21 on CFSPID follow-up.

Flow chart of the literature research for two independent reviewers.

Table 1

Population and number of CF, CFSPID patients included in the selected papers.

Authors	Year	Enrolled population	Nr. CF	Nr. CFSPIDs	Ref.
Ren CL et al. §	2015	1.962	1.540	309
Ooi et al.	2015	162	80	82
Groves T et al.	2015	29	0	29
Levy et al.	2016	376	300	57
Şaşihüseyinoğlu1 et al.	2019	66	12	54
Munck A et al.	2019	126	63	63
Ooi et al.	2019	218	120	98
Terlizzi V et al.	2019	82	32	50
Terlizzi V et al.	2020	43	0	43
Kasi AS et al.	2020	54	19	17
Terlizzi V et al.	2020	19	0	19
Terlizzi V et al.	2021	593	257	336
Ginsburg D et al.	2021	10	0	10
Hatton A et al.	2021	23	0	23
Bauer SE et al.	2021	2.613	45	145
Gonska T et al.	2021	115	0	115
Dolce D et al.	2022	217	0	217
Tosco A et al.	2022	129	30	58
McGarry M et al. §	2022	51.941	46.729	5.212
Fingerhut R et al.	2022	815.899	232	27
Salinas DB et al.	2022	112	53	59
Gunnett MA et al.	2023	1.346	129	63

 

§ Data from US CFF Registry.

Table 2

Percentage of CFSPID > CF/CFSPID in the different populations.

Authors	Year	CFSPID > CF/CFSPID	%	Ref.
Terlizzi V et al.	2021	18/336	5.3 %
Tosco A et al.	2022	6/58	10.3 %
Ooi CY et al.	2015	11/82	11.0 %
Ooi CY et al. §	2019	14/98	14.3 %
Gunnett MA et al.	2023	11/63	17.5 %
Salinas DB et al.	2022	12/59	20.3 %
Gonska T et al.	2021	24/115	21.0 %
Munck A et al.	2020	28/63	44.0 %
Groves T et al.	2015	14/29	48.0 %

 

§ also includes patients from the same authors’ 2015 paper.

Table 3

List of the papers focusing on b-IRT in CF, CFSPID > CF or CFSPID-P.

Authors	Year	Study	Nr. CFSPID	Aim	Main findings	Ref.
Ooi et al.	2015	Multicenter prospective case control	82	To identify CFSPIDs and evaluate outcomes	b-IRT value was significantly higher in CF than CFSPIDs
Levy et al.	2016	Two-center retrospective cross sectional	57	To evaluate the concordance between physician diagnoses and consensus guidelines	CF and CFSPIDs significantly differed in b-IRT levels
Ooi CY et al.*	2019	Multicenter Prospective study	98	To identify CFSPIDs at risk of developing CF	Infants CFSPID > CF had significantly higher b-IRT levels than CFSPID-P
Munck A et al.	2019	Prospective study	63	To characterize the genotypic expression of CFSPIDs	No differences in b-IRT value between CFSPID > CF and CFSPID-P
Terlizzi V et al.	2020	Multicenter retrospective study	43	To define the role of the second CFTR variant as a predictive factor of CF evolution in CFSPIDs carrying the D1152H variant	IRT values were higher in CFSPIDs with D1152H/CF-causing genotypes
Terlizzi V et al.	2021	Multicenter retrospective study	336	To evaluate the prevalence, clinical data, management, and outcome for Italian CFSPIDs	No differences in b-IRT value between CFSPIDs > CF and CFSPID-P
Gonska T et al.	2021	Multicenter prospectivelongitudinal study	115	To describe the clinical course of CFSPIDs	No differences in b-IRT value between CFSPIDs > CF and CFSPID-P
Fingerhut R et al.	2022	Multicenter retrospective study	27	To compare b-IRT levels between healthy newborns, CF and CFSPIDs	No evaluation of b-IRT levels in CFSPID > CF
Salinas DB et al.	2022	Multicenter retrospective study	59	To describe the progression to a CF diagnosis in CFSPIDs	No differences in b-IRT value between CFSPIDs > CF and CFSPID-P

 

CF = Cystic Fibrosis; CFSPID = Cystic Fibrosis Screen Positive Inconclusive Diagnosis; CFSPID > CF = subjects who progressed to CF; CFSPID > P = subjects who remained CFSPID b- IRT = Immunoreactive Trypsinogen.

Table 4

List of the papers focusing on CFSPIDs and CFTR gene analysis.

Authors	Year	Type of study	CFSPID > CF	Aims	CFTR genetic profile of CFSPID > CF	Length of follow up (months)	Ref.
Groves et al.	2015	Retrospective case control	14	To describe the clinical course of CFSPIDs with intermediate sweat chloride values	7/14: F508del/unknown variant; 4/14: F508del/R117H	14
Ooi CY et al.	2015	Multicenter prospective case control	9	To identify and evaluate infants with CFSPID	most frequent genotypes were CF causing/R117C or L206W	36
Munck A et al.	2019	Prospective study	63	To characterize the genotypic expression of children with CFSPID	5/28 had at least one R117H;7T CFTR complex allele	90
Ooi C Y et al.	2019	Prospective study	98	To define a correlation between CF level and the degree of CFTR dysfunction to identify CFSPID at risk of developing CF	9/14 reassigned according to genotype; 2/14 had R117H/7T	120
Terlizzi V et al.	2019	Monocenter retrospective study	50	To evaluate prevalence and clinical outcome of CFSPID infants	all with CF causing variant/VVCC or S737F, variant typical in Tuscany region	6.6
Terlizzi V et al.	2020	Retrospective analysis	19	To illustrate prevalence, SC trend and outcome of patient with VVCC	all with CF causing variant/R117H/7T; D1152H or 5 T;TG12	3.1
Ginsburg D et al.	2021	Case series	10	To illustrate evolution from CFSPID to CF	7/10 had CF causing variant/ 5 T;TG12, 5 T;TG13 or D1152H	NS
Terlizzi V et al.	2020	Multicenter retrospective study	43	To define the role of the second CFTR variant as a predictive factor of disease evolution in CFSPID carrying the D1152H variant	all with D1152H/CF causing variant	40.6
Terlizzi V et al.	2021	Multicenter retrospective study	336	To evaluate the prevalence, management and outcome of Italian CFSPID subjects	16/18 had CF causing/VVCC, such as 5 T;TG12 or D1152H	40
Hatton A et al.	2021	Case series	23	To describe a CFSPID population performing in vivo and in vitro functional studies	4/23 (17.4 %) CFSPID > CF; three with CF causing variant/D1152H; one 5 T;TG12/5T;TG13	84.7
Gonska T et al.	2021	Multicenter prospective, longitudinal study	115	To describe the clinical course of CFSPID	12/24 reassigned according to genotype; most frequent genotypes were F508del/VVCC, such as R117H;7T or poly T tract	84.7
Tosco A et al.	2022	Multicenter retrospective study	58	To describe the progression to a CF diagnosis for subjects with F508del/5T;TG12	6/58 (10.3 %) CFSPID > CF	72.7
Salinas DB et al.	2022	Multicenter retrospective study	59	To describe the progression to a CF diagnosis	8/12 with one causing variant/5T;TG12, 5 T;TG13 or D1152H	NS
Gunnett MA et al.	2023	Multicenter retrospective study	63	To identify features of progression from CFSPID to CF	2/11 reassigned according to genotype; 2/11 with CF causing/R117H/7T	NS

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