To prospectively study infants with an inconclusive diagnosis of cystic fibrosis (CF) identified by newborn screening (NBS; “CF screen positive, inconclusive diagnosis” [CFSPID]) for disease manifestations.
Infants with CFSPID and CF based on NBS from 8 CF centers were prospectively evaluated and monitored. Genotype, phenotype, repeat sweat test, serum trypsinogen, and microbiology data were compared between subjects with CF and CFSPID and between subjects with CFSPID who did (CFSPID→CF) and did not (CFSPID→CFSPID) fulfill the criteria for CF during the first 3 years of life.
Eighty-two subjects with CFSPID and 80 subjects with CF were enrolled. The ratio of CFSPID to CF ranged from 1:1.4 to 1:2.9 in different centers. CFTR mutation rates did not differ between groups; 96% of subjects with CFSPID and 93% of subjects with CF had 2 mutations. Subjects with CFSPID had significantly lower NBS immunoreactive trypsinogen (median [interquartile range]:77 [61–106] vs 144 [105–199] μg/L; P < .0001) than did subjects with CF. Pseudomonas aeruginosa and Stenotrophomonas maltophilia were isolated in 12% and 5%, respectively, of subjects with CFSPID. CF was diagnosed in 9 of 82 (11%) subjects with CFSPID (genotype and abnormal sweat chloride = 3; genotype alone = 4; abnormal sweat chloride only = 2). Sweat chloride was abnormal in CFSPID→CF patients at a mean (SD) age of 21.3 (13.8) months. CFSPID→CF patients had significantly higher serial sweat chloride (P < .0001) and serum trypsinogen (P = .009) levels than did CFSPID→CFSPID patients.
A proportion of infants with CFSPID will be diagnosed with CF within the first 3 years. These findings underscore the need for clinical monitoring, repeat sweat testing at age 2 to 3 years, and extensive genotyping.
Comments
Re:Stratifying Cystic Fibrosis Risk for Newborn Screen Infants with Equivocal Sweat Chloride Levels
We thank Groves et al. [1] for their interest in our study in infants with "Cystic Fibrosis (CF) Screen Positive, Inconclusive Diagnosis" (CFSPID) [2]. In our study, both repeat sweat testing and extensive genotyping helped clarify the diagnosis of CF (CFSPID->CF). At initial evaluation cross-sectionally, the sweat chloride levels were significantly higher in CFSPID->CF than CFSPID->CFSPID subjects (mean [SD]: 43.1 [8.3] vs. 28.7 [11.5] mmol/L; P=0.0005). However, unlike the cohort by Groves et al. [3], our CFSPID cohort included children with two CFTR mutations and normal sweat chloride (n=39). When we only compared CFSPID- >CF and CFSPID->CFSPID subjects with intermediate sweat chloride values, there were no differences in sweat chloride levels between the two groups (43.1 [8.3] vs. 39.0 [6.6] mmol/L; P=0.13). Furthermore, there was no significant increased risk of developing CF among CFSPID subjects with initial intermediate sweat chloride values based on initial sweat chloride concentrations of 30-39 mmol/L vs. 40-59 mmol/L (odds ratio = 0.62; 95% CI: 0.14-2.8; P=0.71). These findings highlight the importance of repeat sweat testing rather than predicting the risk of future CF, on an individual basis, according to an initial or single sweat test result.
In our study, 11% (9/82) of subjects with CFSPID were subsequently diagnosed with CF [2], while Groves et al. reported 48% (14/29) of their subjects who were later diagnosed with CF [3]. There may be several reasons for this large discrepancy. The study by Groves et al. extended over at least 15 years whilst ours followed subjects for only three years. Furthermore, we conducted a prospective study as a retrospective study can be associated with the risk of ascertainment and differential selection biases. Finally, as the diagnosis of CF can be a challenging [4, 5], we adhered strictly to the diagnostic criteria to allow comparisons between different studies and centres. Only 6 of 29 (20.1%) patients had a CF diagnosis based on elevated sweat chloride (n=3) and two CF-causing mutations (n=3) in the cohort described by Groves et al. [3], which more closely matches our finding in our CFSPID cohort [2].
Groves et al. also commented on our previous publication on older children and adults with a CF-like phenotype [4]. Both our prospective studies [2, 4] highlight two different populations of individuals who pose diagnostic challenges in CF; the former being asymptomatic infants with positive newborn screening but inconclusive diagnosis of CF [2] and the latter relate to symptomatic individuals who present later in life with a single-organ manifestation of CF [4]. It is currently unknown whether the two cohorts represent the same population at different time points. A prospective follow-up study into adulthood of infants with CFSPID will ultimately be necessary to determine their natural history, and to determine to what extent they overlap with individuals who present with single-organ manifestations of CF later in life.
References:
1. Groves TM, Robinson P, Wiley V, et al. Stratifying Cystic Fibrosis Risk for Newborn Screen Infants with Equivocal Sweat Chloride Levels [E-letter], Pediatrics (July 10, 2015).
2. Ooi CY, Castellani C, Keenan K, et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics 2015;135(6):e1377-85.
3. Groves T, Robinson P, Wiley V, et al. Long-term outcomes of children with intermediate sweat chloride values in infancy. J Pediatr 2015;166(6):1469-1474.
4. Ooi CY, Dupuis A, Ellis L, et al. Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? Thorax 2012;67(7):618-24.
5. Ooi CY, Dupuis A, Ellis L, et al. Does extensive genotyping and nasal potential difference testing clarify the diagnosis of cystic fibrosis among patients with single-organ manifestations of cystic fibrosis? Thorax 2014;69(3):254-60.
Conflict of Interest:
None declared
Stratifying Cystic Fibrosis Risk for Newborn Screen Infants with Equivocal Sweat Chloride Levels
We read with interest the recent study by Ooi et al. (2015) [1], which adds significantly to the recent literature guiding physicians on how to manage infants with equivocal sweat chlorides (30-59 mmol/L, termed CF screen positive, inconclusive diagnosis, CFSPID) identified through newborn screening (NBS). Nine of 82 (11%) subjects with CFSPID were subsequently diagnosed with CF during the three-year follow-up period. The findings are in agreement with our recent publication, analyzing a similar cohort retrospectively, where 48% (14/29) were later diagnosed with CF over a longer follow up period [2].
In the current study by Ooi et al. (2015), four of the nine (44%) CFSID infants presented with initial sweat chloride levels between 30-39 mmol/L, while the remainder were between 40-59 mmol/L. The risk of later CF diagnosis, based on the level of the initial sweat chloride would be of great interest, but was not presented.
We considered this within our cohort of 29 patients with an elevated NBS immunoreactive trypsinogen level, heterozygous for the p.F508del mutation, and an intermediate initial sweat chloride level between 30-59 mmol/L. Comparing two cohorts based on initial sweat chloride level (30-39 mmol/L vs. 40-59 mmol/L), the incidence of a later CF diagnosis was less in patients from the 30-39 mmol/L vs. 40-59 mmol/L cohort (3/14, 21% vs. 11/15, 73%, p=0.009). The mean age of CF diagnosis was older in patients from the 30-39 mmol/L vs. 40-59 mmol/L cohort (2.9 vs. 0.26 years, p=0.0001). Amongst the 30-39 mmol/L cohort, two patients were diagnosed based on proven pancreatic insufficiency at 1.5 and 2.5 years, with initial sweat chloride levels of 38 and 32 mmol/L at 1.5 and two months, respectively. Identification of the second gene mutation (p.Val470Met) confirmed diagnosis in the former patient at 2.5 years. The latter patient had follow-up sweat chlorides of 33 and 55 mmol/L at nine months and 2.5 years, respectively. One patient was diagnosed based on a respiratory clinical course consistent with CF at 4.5 years. This patient had follow- up sweat chloride levels of 45, 29, and 35 mmol/L at three months, four years, and fourteen years, respectively, along with significant CT bronchiectasis from six years of age, with resistant non-mucoid pseudomonas aeruginosa from repeated sputa subsequently.
Our data, with the CFSPID infants of Ooi et al (2015), illustrate potential relative risk stratification between initial sweat chloride values and later CF diagnosis. In fact, the current North American guidelines [3], which use a cut-off of 40 mmol/L over six months of age to assess indeterminate sweat chloride values, would have missed a CF diagnosis in two patients (14%) within our cohort. This is higher than the estimated 5% discordance between diagnosis in such infants comparing North American and European lower sweat chloride cut-off limits in infancy reported by Ooi et al. (2012) [4]. We support the consistent use of the lower cutoff of 30 mmol/L as outlined in the European guidelines [5]. It would be of great interest to know if the data of Ooi et al. (2015) also support this stance.
References:
1. Ooi, C. Y., Castellani, C., Keenan, K., Avolio, J., & Volpi, S. (2015). Inconclusive Diagnosis of Cystic Fibrosis After Newborn Screening, Pediatrics.
2. Groves, T., Robinson, P., Wiley, V., & Fitzgerald, D. A. (2015). Long-Term Outcomes of Children with Intermediate Sweat Chloride Values in Infancy. The Journal of Pediatrics.
3. Farrell, P. M., Rosenstein, B. J., White, T. B., Accurso, F. J., Castellani, C., Cutting, G. R., Campbell, P. W. (2008). Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. The Journal of Pediatrics, 153(2), S4-S14.
4. Ooi, C. Y., Dupuis, a., Ellis, L., Jarvi, K., Martin, S., Gonska, T., Durie, P. R. (2012). Comparing the American and European diagnostic guidelines for cystic fibrosis: same disease, different language? Thorax, 67(7), 618-624.
5. De Boeck, K., Wilschanski, M., Castellani, C., Taylor, C., Cuppens, H., Dodge, J., & Sinaasappel, M. (2006). Cystic fibrosis: terminology and diagnostic algorithms. Thorax, 61(7), 627-635.
Conflict of Interest:
None declared