Neonatal Screening – all aspects. CF-related metabolic syndrome (CRMS) and CF screen positive inconclusive diagnosis (CFSPID)

See also Lung Function Topic for early respiratory function studies on screened infants

1952 Buchanan DJ, Rapoport S. Chemical comparison of normal meconium and meconium from a patient with meconium ileus. Pediatrics 1952; 9:304-310. [PubMed]

This is the first report of increased protein content in the meconium of an infant with meconium ileus when compared with meconium from three non-CF infants. Normal meconium contained less nitrogen than the meconium from the CF infant with meconium ileus. This observation would eventually form the basis of the BM Meconium screening test for cystic fibrosis (also Green et al, 1958 below; Green & Shwachman, 1968 below; Schutt & Isles, 1968 below).

1958 Green MN, Clarke JT, Shwachman H. Studies in cystic fibrosis of the pancreas: protein pattern in meconium ileus. Pediatrics 1958: 21:635-641. [PubMed]

This study confirmed the presence of large amounts of protein in the meconium from patients with meconium ileus. The meconium of subsequent newborn siblings of known patients with CF was examined in a later study (Green & Shwachman, 1968 below).

1964 Wiser WC, Beier FR. Albumin in the meconium of infants with cystic fibrosis: a preliminary report. Pediatrics 1964; 33:115-118. [PubMed]

Although an unusual protein content in the meconium of infants with meconium ileus had been described by a number of authors (Glanzmann E, Berger H. Ann Paediat 1950; 175:33 above; Buchannan & Rapoport Pediatr 1952:9:304 above; Green M et al. Pediatr 1958; 21:635 above), the present study was to determine if meconium from infants with CF who did not have meconium ileus also had an abnormal protein content as perhaps this could be “used in a predictive manner” i.e. for neonatal CF screening.
In this study, using immunoelectrophoresis, the meconium from five infants with a family history of CF (1 – 5) was examined for increased protein. The three of these infants with CF (1,2,& 4) had obviously raised albumin levels which did not occur in the two unaffected infants (3 & 5) nor in two healthy control infants (6 & 7) .(figure in reference in main Sixties  text)
This study, from Salt Lake City, was the first to demonstrate increased albumin in the meconium of all CF infants and to suggest the finding could be used in a “predictive manner”. Later Schutt & Isles (Arch Dis Child 1968; 43:178 below) from Bristol in the UK showed that the increased albumin could be recognised very simply by using the Albustix dipstick test designed for testing urine for albumin; this method eventually formed the basis of the BM Meconium test used in several neonatal CF screening studies during the Seventies (In Europe by Stephan U, et al. Pediatrics 1975; 55:35-38 below; in Wales by Ryley HC, et al. Arch Dis Child 1979; 54:92-97 below; in the UK by Evans et al, 1983 below).

1968 Schutt WH, Isles TE. Protein in meconium from meconium ileus. Arch Dis Child 1968; 43:178-181. [PubMed]

A really memorable little cameo presentation by Dr Werner Schutt of Bristol at the UK Paediatric Research Society. The authors state “we have found a simple side room technique helpful in detecting the presence or absence of albumin in significant quantities in meconium”.
The authors proposed, for the first time, a simple test using the Albustix, a urine dipstick test that turned blue in the presence of the protein, to detect the increased albumin in the CF meconium. A solution of a few drops of water and a little CF meconium was mixed on a white tile, and the Albustix was laid on the tile with the tip in the solution. There was an impressive blue coloration when there was excess albumin present.
The authors observed that the test “Could provide the basis for a screening test” – which it did – the BM Meconium test! Wiser & Beier (above) were the first to describe the excessive amount of albumin in the meconium of CF infants who did not have meconium ileus (Pediatrics 1964; 33:115-118 above).

1968 Green MN, Shwachman H. Presumptive tests for cystic fibrosis based on serum protein in meconium. Pediatrics 1968; 41:989-992. [PubMed]

An early suggestion of neonatal screening from detection of increased protein in meconium, a finding which was first described by Buchanan & Rapoport, 1952 (above). Wiser & Beier, 1964 (above) had described raised albumin in the meconium of infants who did not have meconium ileus. Meconium from 49 of 196 siblings of people with CF tested who also had CF and only 4 gave a negative protein reaction (trichloracetic acid ring test and a slide agglutination test); 1600 control meconium specimens were negative.
The test was suggested as screening test for CF with 90% reliability. The authors stated – “It is strongly recommended that mass surveys be undertaken only with accompanying facilities for the clinical investigation and treatment of the patients found”. This was very sound advice and lack of centre care for infants with CF detected eventually proved to be a main reason that a large UK Wales & West Midlands neonatal screening study in the Eighties (Chatfield et al. 1991) failed to show benefit for the screened infants. It is a basic principle that the means of treating the infants detected by screening must be available before neonatal screening is introduced.

1971 Davidson AG, Anderson CM. Diagnosis of cystic fibrosis. Br Med J 1971; 4:362 (letter). [PubMed]

A short letter from Birmingham UK warning that the meconium test for CF may be negative if pancreatic sufficient and tested by the Green and Shwachman technique. An infant with CF was missed in this manner and subsequently proved to have CF but be pancreatic sufficient.

1972 Cain ARR, Deall AM, Noble TC. Screening for cystic fibrosis by testing meconium for albumin. Arch Dis Child 1972; 47:131-132. [PubMed]

One of the earliest reports from the paediatricians in Newcastle and Ashington in the North of England of meconium screening using the Labstix (Ames) urine test strip for albumin as suggested by Werner Schutt et al 1968 (above). A small smear of meconium was mixed with few drops of water on a glass slide and the Labstix placed on the edge. In this study one infant with CF was detected in 6200 newborns among whom there were also 2 with meconium ileus – the expected incidence of around 1 in 2000 births.

1974 Prosser R, Owen H, Bull F, Parry B, Smerkinich J, Goodwin HA, Dathan J. Screening for cystic fibrosis by examination of meconium. Arch Dis Child 1974; 49:597-601. [PubMed]

Dr Prosser, a paediatrician from Newport in Wales, considered the BM Meconium screening test gave too many false negative results. In Wales 34,228 samples were examined over 4 years; 12 infants with CF were detected – only a 60% detection rate. The paper was generally quoted and accepted as showing BM meconium test was unsuitable for neonatal CF screening due to the unacceptable false negative rate. Also, at that time, the standard of treatment of most children with CF in the UK in general paediatric clinics was such that early diagnosis was of little advantage to most infants with CF in terms of long term survival.

So BM screening was evaluated in Wales and abandoned on the grounds of an unacceptable false negative rate (Prosser et al. 1974 above; Bray et al, 1979 below). However, it is likely that their poor results were related to the tests being carried out (or perhaps not being carried out!) by the busy midwives on the wards.

Despite the discouraging observations from Wales, in one of the Leeds maternity units for which I was responible (St Mary’s in Leeds) I introduced BM screening for CF in 1975. We used the method continuously at St Marys and then at St James’s, when the maternity services moved there, until a change to IRT was made in 1995 when funding became available. When the BM test was done in the St James’s laboratory (rather than by the overworked midwives on the wards!!) we achieved an acceptable false negative rate of only some 12% (Evans et al, 1981 below).

The practicalities of busy midwives being responsible for carrying out the tests on meconium in the maternity unit were a major problem. However, at St Mary’s Maternity Hospital in Leeds, where we had 3000 births per year in the Seventies, we used the BM test with success from 1975 for many years. However this was only because our laboratory agreed to do the tests on small specimens of meconium sent to them rather than asking the overworked midwives to perform the tests on the wards (Evans et al, 1981 below).

Neonatal screening for CF was delayed until 1995 in the other maternity units in Leeds as the two paediatricians responsible for neonatal care were opposed to it.

1975 Antonowicz I, Ishida S, Shwachman H. Studies in meconium: Disaccharidase activities in meconium from cystic fibrosis patients and controls. Pediatrics 1975; 56:782-787. [PubMed]

The enzymatic activities of disaccharidases in meconium from infants with CF and controls were found to be significantly increased in the infants with CF. The test was suggested as an alternative method for screening for CF or a method of interpreting borderline BM tests but the test did not become widely used and interest waned.

1975 Stephan U, Busch E-W, Kollberg H, Hellsing K. Cystic fibrosis detection by means of a test strip. Pediatrics 1975; 55:35-38. [PubMed]

The main review of the results of neonatal CF screening at various European centres by detecting raised levels of albumin in the meconium. The test was later abandoned on the grounds of an unacceptable number of false positives and negatives. In this study BM-Test Meconium had been applied to (approximately) 69,000 meconium specimens and detected 60 infants with CF – but some were known high risk infants; three of 14 neonates with subsequently proven CF had negative albumin tests.

This is really an anecdotal study and as described in this paper is quite difficult to follow.

1976 Robinson PG, Elliott RB. Cystic fibrosis screening in the newborn. Arch Dis Child 1976; 51:301-304. [PubMed]

Using a method of measuring the stool enzyme activity (chymotrypsin) in dry faecal specimens from newborn infants, three infants with CF were detected. The test was proposed as suitable for neonatal CF screening and the specimens could be sent to the laboratory by post. However, the test was soon to be replaced by the blood immunoreactive trypsin test developed in the same Auckland laboratory (Crossley et al, 1977 below; Crossley et al, 1979 below).

1977 Crossley JR, Berryman CC, Elliott RB. Cystic fibrosis screening in the newborn. Lancet 1977; ii: 1093-1095. [PubMed]

Screening the stools of newborn infants for low trypsin content indicated the possibility of their having cystic fibrosis. Trypsin releases a yellow colour with benzyl-arginine-p-nitroanilide. The same group in Auckland later described the immunoreactive trypsin test (IRT) performed on Guthrie blood spots – this latter proved to be a really major advance in neonatal CF screening (see Crossley et al, 1979 below; also Robinson & Elliott, 1976 above) and was subsequently adopted around the world for neonatal CF screening.

1978 Bray PT, Clark GC, Moody GL, Thomas G, Thomas JD. Sweat testing for cystic fibrosis. Diagnostic screening with a combination chloride ion-selective electrode. Arch Dis Child 1978; 53: 483-486. [PubMed]

Screening of newborns using an Orion Skin Chloride Measuring System incorporating some innovations. There were a number of potential possibilities for errors with this test (Bray PT et al. Clin Chem Acta 1977; 80:333-338) and it was never introduced into routine care. There was more interest in Meconium screening at the time in Wales.

1979 Ryley HC, Neale LM, Brogan TD, Bray PT. Screening for cystic fibrosis in the newborn by analysis of meconium. Arch Dis Child 1979; 54:92-97. [PubMed]

Percy Bray of Cardiff, was one of the few paediatricians in the UK with a special interest in CF at the time. This final report of BM Meconium screening between 1973-1977 showed the test failed to identify 25% of infants with CF when performed in Wales by midwives in maternity units.

Dr Henry Riley is a microbiologist in Cardiff and closely involved  with cystic fibrosis in Cardiff, particularly the early work on neonatal screening. He has continued his interest in CF with involvement with the ECFS for many years. In 2023 he produces a regular  list of all the publications concerning CF – a formidable task but very helpful.

In East Leeds we started neonatal screening in 1975 in one of our maternity units (St Mary’s, Bramley) with this test. However, after repeatedly finding small pots of meconium on ward window sills, I soon realized that overworked midwives were not the people to do this test!! The laboratory kindly offered to do the tests with proper laboratory standard control so meconium specimens were sent to the laboratory in small bottles where the test was done more professionally. We later reported better results when the test was performed by our laboratory colleagues (Evans et al, 1981). However, Crossley and Elliott (1979 below) were about to describe their IRT blood test for neonatal CF screening which was a far better test and was soon taken up and used with success by neonatal CF screening enthusiasts making the BM tests redundant. Yet, for financial and administrative reasons (and because with the BM test performed in the laboratory, rather than on the ward, we seemed to be identifying the infants with CF!) we continued to use the BM test with reliable results until the well into the Nineties until it was replaced by the IRT method (Littlewood JM et al. 20 years continuous neonatal screening in one hospital: progress of the 37 patients and their families. Pediatr Pulmonol 1995; Suppl 12: Abstr 372 p.284).

1979 Crossley JR, Elliott RB, Smith PA. Dried blood spot screening for cystic fibrosis in the newborn. Lancet 1979; i: 472-474. [PubMed]

This study was from Auckland, New Zealand. Serum-immunoreactive-trypsin (IRT) was measured in children with CF and a variety of controls. In the first few months of life all the children with CF had a raised serum-IRT. A dried blood-spot assay for IRT was established using double antibody radioimmunoassay kit (Hoechst Research Laboratories) and presented as having potential as a screening test for CF in the newborn. There were none of the disadvantages of stool trypsin screening as infants with residual pancreatic function (“pancreatic sufficient” infants) also has a raised IRT (Figure 24).

In New Zealand Crossley and colleagues further evaluated the test (Crossley JR et al. Clin Chim Acta 1981; 113:111-121; Lyon IC et al. NZ Med J 1983; 96:673-675). Neonatal IRT screening was soon adopted in New Zealand and some states in Australia where Bridget Wilcken of Sydney has been a champion of neonatal screening since the early Eighties. The IRT test now forms the basis of most neonatal CF screening programmes throughout the world – now usually combined with DNA examination for CF-causing mutations when the IRT is positive.

This was a really important landmark paper for neonatal CF screening.

Neonatal IRT screening had the great practical advantage of using the same neonatal blood spots already collected by the heel prick in the first week of life for phenylketonuria and later hypothyroidism.

In the UK, Dr Anthony Heeley, the biochemist in Peterborough, UK started IRT neonatal screening in East Anglia in 1981 (Heeley et al, 1982 below). In 2009 he kindly commented as follows – “Your summaries of our early papers are excellent. A point to emphasise was that Crossley & Elliott’s seminal work in 1979 required 2 x 12 mm blood spots for the assay. We realised that was unrealistic for routine screening and in our paper in the Lancet the same year (King DN. Heeley AF. Walsh MP. Kuzemko JA. Sensitive trypsin assay for dried-blood specimens as a screening procedure for early detection of cystic fibrosis. Lancet 1979; 2(8154):1217-1219) we showed that their results could be confirmed using 4 mm blood spots which was a much more practical size for routine prospective screening trials. These trials were quickly underway in the Antipodes, here and elsewhere, but we have ascertained that the first case of CF to be detected in a prospective screening trial with IRT was in East Anglia in 1980, a girl born one month before the first case detected prospectively by the New Zealanders. Even better, although homozygous Delta F 508, to my knowledge she led a robust and active life up to late teenage when I lost contact. Her paediatrician could not recall any exacerbation of her condition requiring hospital admission. I still treasure a slide of her as a healthy teenager and I was proudly able to show it at a National Neonatal Screening Seminar in Newcastle a couple of years ago (dragged out of retirement for the historical story!)”.

In 2009 Dr Jeanette Crossley (figure) kindly commented for me as follows –

“We were fortunate that our 1979 Lancet paper robustly established the potential of blood spot IRT for CF newborn screening, using the Hoechst-Behring Riagnost Trypsin Kit
The kitset as supplied required a relatively large sample size [we used 2 x 12mm discs from a 5-day Guthrie card], so our next step was modifying that method. We achieved 10-fold greater sensitivity, enabling one 3mm disc as sample, left in the tube throughout the stages of the assay. In a retrospective study of 23 known CFs using this optimized assay [unpublished], each CF was clearly distinguishable from two controls from the same batch of Guthrie cards, despite the Guthrie cards having been stored at room temperature for up to seven years.
For several reasons, economics being a main one, we did not conduct an extensive prospective trial using the Hoechst-Behring reagents. Rather, we developed our own Auckland radioimmunoassay ‘from scratch’ [reported in detail in the Clin Chim Acta paper1981]. Its validation included repeating the retrospective study, again clearly distinguishing all the known CFs from controls. We established that the molecular species assayed in blood is trypsinogen. Our ‘Auckland assay’ was more sensitive, and had better linearity for serially diluted samples, than our optimization of the Hoechst-Behring kitset assay. Also, knowing what was in all our reagents gave us confidence – we had been unable to obtain from Hoechst the exact make-up of their assay.
Our team effort launched dried bloodspot CF screening in NZ, first as a pilot, and then nationally – and also enabled Bridget Wilcken to get started in NSW, Australia. I’ve been told that our original purified trypsin and antisera were used in the National CF Screening Programme until about 1990, when changing health and safety policies required a move away from radio-labelled methods.
It had been a delight to be invited to present our experience with our ‘Auckland IRT assay’ and with our optimisation of the Hoechst-Behring Riagnost kitset, at an international meeting ‘Immunoreactive Trypsine’ sponsored by Hoechst France in Caen, 25 October 1980. We were very pleased to see the quick and thorough progress being made in several countries with validation of IRT as a CF newborn screening method. The first UK symposium on neonatal screening for cystic fibrosis, for example, sponsored by CIS (UK) Ltd and Sorin Biomedica SpA, was held in London 10 days after the Caen meeting”.

1981 Evans RT, Little AJ, Steel AE, Littlewood JM. Satisfactory screening for cystic fibrosis with the BM meconium procedure. J Clin Path 1981; 34:911-913. [PubMed]

Dr Robert Evans, at the time the consultant biochemist at St James, Leeds agreed to perform our BM Meconium tests in the laboratory when it became obvious the midwives on the maternity wards were far too busy looking after the mothers. Here he reported favourable results since we started BM screening in 1975. Although by 1981 most paediatricians had either never started or by this time rejected the BM Meconium test for neonatal CF screening, in one hospital East Leeds we had continued to use the test from 1975. We had more success than in some other places with a false negative rate of only 12% – but we found, as had the people in Veneto, that the test had to be done in the laboratory and not by midwives who, it was soon realised, had their hands full looking after the mothers and babies!
The test was used continuously in East Leeds until the early 1990s when we changed to immunoreactive trypsin (now IRT/DNA/IRT) and involved the whole city.

I thought our continuous CF neonatal screening in Leeds from 1975 to the present was a world record; however it appears to have been just preceded by Professor Gianni Mastella’s regional CF neonatal screening in Veneto Italy from 1974!! (Mastella et al, 1981 below)

1981 Mastella G, Borgo G, Castellani E, Ferro I, Pederzini F. Results and praxis for cystic fibrosis neonatal screening, steps in a regional program and some evaluation of the prophylactic treatment (A story of 8 year cystic fibrosis screening in Veneto). In: Warwick WJ (ed.) 1000 Years of Cystic Fibrosis. Minnesota University, 217-232.

When many people were arguing about the possible benefits of neonatal screening (as occurred in the UK until 2001 and even more recently by some) some paediatricians introduced screening as it seemed a commonsense idea to diagnose early and treat vigorously an eventually fatal condition where survival depended almost entirely on the success of the treatment!
Gianni Mastella (figure) was one such paediatrician – since 1960 he produced 177 publications – 122 on CF and has been one of the outstanding pioneers of European CF care (for which he was awarded the Rossi Medal of the European CF Society), a pioneer of neonatal CF screening and one of the senior doctors of Italian CF.
This report concerns five stages of the Veneto programme from 1974 to 1981, screening 200,000 infants in 81 hospitals. Stages 1 to 3 used the BM test. As we also discovered in Leeds, the BM test was acceptable only if performed in the laboratory but not when performed by many different nurses. Stages 4 and 5 used an immunodiffusion technique for albumin when there were only 9.5% false negatives. Finally IRT in blood spots (as described by Crossley et al, 1979) was introduced. Nutritional parameters and clinical scores were significantly better in the screened infants.

1982 Heeley AF, Heeley ME, King DN, Kuzemko JA, Walsh MP. Screening for cystic fibrosis by dried blood spot trypsin assay. Arch Dis Child 1982; 57:18-21. [PubMed]

The first detailed report of immunoreactive trypsin neonatal CF screening in East Anglia in the UK by Anthony Heeley (figure) the biochemist in

Peterborough and his wife Mary (figure) and colleagues. The Heeleys were pioneers of neonatal immunoreactive trypsin CF screening in the UK. Dr Jan Kuzemko was their paediatric colleague n Peterborough and also involved in a number of early CF publications from the UK including the use of continuous IV ceftazidime (1989), resistance with ceftazidime monotherapy (1988) and home intravenous antibiotic treatment (1988).
In the present study 14,000 infants were screened, 0.2% required a second test and five infants with CF were detected. A satisfactory method which has continued to the present time and resulted in a number of subsequent publications from East Anglia (Green MG et al. Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history. Arch Dis Child 1993;68: 464-467; Green MR & Weaver LT, J R Soc Med 1994; 87 suppl 21:5-10; Weaver LT et al Arch Dis Child 1994; 70:84-89 be low. This last was an important controlled trial on the effect of long term flucloxacillin during the first 2 years).

In the longer term it was unfortunate that many of these screened infants in East Anglia did not receive specialist CF centre care, as was usual at the time, and so many did not achieve their full health potential (see Crossley & Elliott, 1979 above for Dr Heeley’s comments).

A recent 30 year follow-up of this programme was published in 2012 and Anthony and Mary Heeley were among the authors (Calvin J et al. Thirty-years of screening for cystic fibrosis in East Anglia. Arch Dis Child 2012; 97:1043-1047. [PubMed]). During the 30 years 582,966 infants were screened by IRT-IRT and 147,764 by IRT-DNA-IRT (total 730,730 infants) resulting in 296 screen positve cases of CF and 29 false negatives (including 10 with meconium ileus).

1983 Wilcken B, Brown AR, Urwin R, Brown DA. Cystic fibrosis screening by dried blood spot trypsin assay: Results in 75,000 newborn infants. J Pediatr 1983; 102:383-387. [PubMed]

An early report of neonatal CF screening from New South Wales, Australia where CF was confirmed in 35 of 38 infants with persistently raised immunoreactive trypsin (IRT) levels; only 37% of the infants would have been diagnosed by having a family history of CF or by their having meconium ileus. There were further publications from Bridget Wilcken providing further evidence for the value of neonatal CF screening (Wilcken et al, Arch Dis Child 1983; 58:863-866; Wilcken & Chalmers. Lancet 1985; ii: 1319-1321 and others).

Prof. Bridget Wilcken, from Sydney, (figure) has been and remains a pioneer and constant vocal advocate of neonatal CF screening since the early Eighties. Bridget Wilcken and her colleagues were one of the first groups to introduce neonatal CF screening in New South Wales using the IRT method described by Crossley and Elliott in 1979 (above), even though there was still considerable discussion as to the benefits which continued into the next Millennium!

Screened children in Australia did well compared to non-screened as most had CF Centre care, in contrast to the UK where most were treated at their local hospitals – almost certainly accounting for the lack of benefit from neonatal CF screening in a study in Wales and West Midlands during the Eighties (Chatfield et al, 1991 below). After considerable pressure, national neonatal screening for CF was approved by the UK Government in 2001 and eventually introduced throughout the UK by 2007.

1984 Reardon MC, Hammond KB, Accurso FJ, Fisher CD, McCabe ER, Cotton EK, Bowman CM. Nutritional deficits exist before 2 months of age in some infants with cystic fibrosis identified by screening test. J Pediatr 1984; 105:271-274. [PubMed]

Data on the first 20 infants identified in the Colorado neonatal CF screening programme. Although birth weights were normal, by a mean age of 5.5 weeks nine infants had a weight more than 20 percentile points less than birth although their dietary intake was normal. Albumin and pre-albumin levels were low in thirteen. Eight had elevated alkaline phosphatase levels; five had low cholesterol levels and stool trypsin was undetectable in nine, low in four and normal in three.

The very early onset of nutritional and weight gain problems, even when diagnosed early by neonatal screening, has been observed in a number of series of screened CF infants. Also the catch up growth period may last for the whole of the first year even with expert dietetic support (Wolfe et al, 2005)

1985 Wilcken B, Chalmers G. Reduced morbidity with cystic fibrosis detected by neonatal screening. Lancet 1985; ii: 1319-1321. [PubMed]

Cystic fibrosis-related morbidity was evaluated by comparing hospital admissions for CF-related illness in the first two years of life in 40 patients detected by means of neonatal screening and 56 patients born in the three years before screening began. Unscreened patients without meconium ileus had a mean of 27.25 hospital days for CF-related illness, and screened patients a mean of only 3.9 days. There was no trend with time towards fewer days spent in hospital: the change was sudden following the introduction of neonatal screening. The difference was significant and could not be attributed to non-comparability of groups, changes in admission policy, or changes in management. So in Australia neonatal screening significantly reduced CF morbidity in the first two years of life.

The impressive improvement in the outlook for the screened infants, quite obviously related to the introduction of neonatal CF screening, was not accepted by Cochrane reviewers as historical controls were used. However, the advantages of screening were obvious and acceptable to most experienced CF clinicians who, before neonatal screening, had seen so many CF infants sustain severe irreversible and ultimately fatal lung damage and malnutrition before eventually being diagnosed.

1991 Laroche D, Travert G. Abnormal frequency of delta F508 mutation in neonatal transitory hypertrypsinaemia Lancet 1991; 337:55. [PubMed]

Neonatal CF screening programmes that involve DNA testing for CF mutations identify some infants who are CF carriers. There was much discussion as to whether parents should be told their infant is a carrier of one CF mutation – most clinicians were quite firmly in favour of informing the parents. Most generally agreed that it was acceptable to detect CF carriers provided adequate genetic advice was provided to the parents and child bearing relatives for planning future pregnancies now it was known that one of them may be a CF carrier.

1991 Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. N Eng J Med 1991; 325:769-774. [PubMed]

Keith Hammond (figure) was one of the early enthusiasts for neonatal CF screening and was the biochemist involved with these screening studies from Denver, Colorado on 278,399 infants from 1982 to 1987, using immunoreactive trypsin. They confirmed that the method was feasible and could be implemented with acceptable rates of repeat testing and false positives and false negatives. 95% of infants with CF who did not have meconium ileus could be identified by the screening method.

Many subsequent valuable reports have resulted from this Denver screening programme including the early bacteriologic and clinical course (Abman SH et al. J Pediatr 1991; 119:211-217.[PubMed]), early respiratory course (Accurso FJ et al. Pediatr Pulmonol Suppl 1991; 7:42-45.[PubMed]), fat soluble vitamin status (Sokol RJ et al. Pediatr Pulmonol Suppl 1991; 7:52-55. [PubMed]) and pancreatic and nutritional state (Bronstein MN et al. J Pediatr 1992; 120:533-540.[PubMed]).

1991 Chatfield S, Owen G, Ryley HC, Williams J, Alfaham M, Goodchild MC, Weller P. Neonatal screening for cystic fibrosis in Wales and the West Midlands: clinical assessment after five years of screening. Arch Dis Child 1991; 66:29-33. [PubMed]

A UK neonatal CF screening study, funded by the Cystic Fibrosis Trust, using measurement of immunoreactive trypsin, was undertaken in Wales (Mary Goodchild) and the West Midlands (Peter Weller) screening on alternate weeks for five years from 1985. Fifty eight infants, not considered to be at risk of CF (i.e. they did not present with meconium ileus and did not have a sibling with cystic fibrosis) were detected by screening and were compared with 44 children born on the non-screening weeks whose CF was diagnosed clinically. The false negative rate in the screened group was a disappointing 13.4%. Predictably, the screened group were diagnosed earlier and spent less time in hospital. In other respects the groups were similar to the age of 4 years.

Treatment of CF in 1985 in the UK was often undertaken at the local hospitals (Littlewood et al, 1984 above, 1988 above and 1993 below) and half these children were only seen at their local hospitals by general paediatricians who had no particular expertise in CF – this was the major flaw of this Wales & West Midlands study. However, the study did show that if clinical care was not of a high standard there was no advantage in neonatal diagnosis. Subsequently this study was not considered to provide support for the introduction of national neonatal CF screening by the UK National Screening Committee.

There was a final report of this data from Cardiff by Iolo Doull (Doull IJ et al. Pediatr Pulmonol 2001; 31:363-366.[PubMed]). Eligible children with CF who died in the first five years of life were identified from the local paediatricians and from the National UK CF Survey. In all, 230,076 infants had been screened and 234,510 unscreened. 176 children with CF were identified, of whom seven died in the first five years of life, three having presented with meconium ileus. Median age of diagnosis in the screened group was eight weeks (this would not be regarded as acceptable now but DNA testing was not available in addition to IRT until after 1990). On an intention to treat analysis, all four non-meconium ileus-related deaths occurred in the unscreened group; however, the clinical presentation of two of these infants led to their being diagnosed prior to eight weeks, i.e., earlier than would have been likely by screening as practiced in the study. The authors concluded that newborn screening has the potential to decrease infant CF deaths, but if it is to be successful, identification and treatment must occur as soon as possible after birth.

Eventually neonatal CF screening was agreed by the UK government in 2001 after Mrs Rosie Barnes, Chief Executive of the CF Trust, and Dr Jim Littlewood, Chair of the CF Trust’s Medical Advisory Committee, made personal representation to Ms Yvette Cooper the then Health Minister.

As a result of the overwhelming pressure from the CF Trust and the whole CF professional and lay communities rather than on the advice of the National Screening Committee that, even then, still considered the evidence for screening inadequate even after the Government recommendation! The 2001 Farrell paper, which showed a long term nutritional advantage in the screened infants (Farrell et al, 2001; 107:1-13 below), was important in finally convincing the government to introduce national neonatal CF screening.

The major lessons from all this being that, of course neonatal diagnosis is essential but must be followed by good CF care from the start to prevent irreversible malnutrition and chronic respiratory infection.

1992 Heeley AF, Bangert SK. The neonatal detection of cystic fibrosis by measurement of immunoreactive trypsin in blood. Ann Clin Biochem 1992; 29:361-376. [PubMed]

Anthony Heeley has been a pioneer of neonatal CF screening in the UK. This is a detailed review of the situation at this time (also Green et al, 1993 below for Heeley’s East Anglian results; also Crossley et al, 1979 above).(Also comments after Crossley & Elliott 1979 above; Heeley et al, 1982 above).

1993 Green MR, Weaver LT, Heeley AF, Nicholson K, Kuzemko JA, Barton DE, McMahon R, Payne SJ, Austin S, Yates JR, et al. Cystic fibrosis identified by neonatal screening: incidence, genotype, and early natural history. Arch Dis Child 1993; 68:464-467. [PubMed]

This is the main report of the East Anglian neonatal CF screening programme. The incidence of cystic fibrosis over the 10 years in East Anglia (a region of the United Kingdom with a population of 2.1 million) had halved. Neonatal screening allowed early diagnosis, genetic counselling of parents and relatives, and more recently the option of prenatal diagnosis in subsequent pregnancies. One hundred and seven children were born with cystic fibrosis between 1981 and 1990, eight of whom were siblings. The Guthrie blood spots of the 82 infants detected by neonatal immunoreactive trypsin screening between 1981 and 1990 were examined for the presence of the most common cystic fibrosis gene mutation (delta F508). It was present in 135 (82%) of the 164 cystic fibrosis genes analysed with 54 (66%) cases being homozygous and 27 (33%) heterozygous. Sixty nine per cent of infants were symptomatic at the time of diagnosis regardless of genotype. No association was found between the early clinical or biochemical features of the disease and homozygosity or heterozygosity for this mutation.

Screening for CF using the blood immunoreactive trypsin assay alone remains an effective method of identifying infants with the CF within the first weeks, thereby allowing early therapeutic intervention. Genetic counselling and prenatal diagnosis have contributed to a reduction in the number of children born with CF, but may not entirely explain the decreasing incidence of the disease (also Heeley AF et al, 1982 above).

1994 Green MR, Weaver LT. Early and late outcome of cystic fibrosis screening. J R Soc Med 1994; 87 (Suppl 21): 5-10. [PubMed]

More data from the East Anglian screened CF infants. During the decade although the birth rate in the region had increased, the incidence of CF had halved. Early detection of CF by neonatal screening allows genotyping of infant and family. It also offers parents of an affected child the opportunity of counselling before further pregnancies and if desired subsequent antenatal testing. So both neonatal and antenatal CF screening (Cunningham et al, 1998 below) appear to reduce the incidence of CF. This has been the experience in a number of regions but not all – for example Colorado.

1995 Dankert-Roelse JE, te Meerman GJ. Long term prognosis of patients with cystic fibrosis in relation to early detection by neonatal screening and treatment in a cystic fibrosis centre. Thorax 1995; 50:712-718. [PubMed]

Comparative clinical follow up in three birth cohorts of patients with CF was performed at the Cystic Fibrosis centre in Groningen. The first birth

cohort (n = 19) was detected by screening and the two other cohorts were detected clinically, one (n = 30) consisting of patients born during the screening programme and the other (n = 32) of patients born during the six years immediately after the screening programme ended. Patients born during the screening programme but detected clinically appeared to have a reduced life expectancy compared with patients detected by screening. The patients detected by screening showed less deterioration in lung function, a smaller increase in immunoglobulin levels, and minimal catch-up growth compared with the non-screened birth cohort of the same age.
Expert management when started immediately after an early diagnosis of CF by neonatal screening results in important beneficial effects on the outcome and clinical course of the condition. The institution of very early treatment may be critical for the outcome and long term prognosis for most patients with cystic fibrosis. The authors believe that neonatal screening programmes for cystic fibrosis should be introduced more widely.

Jeanette Dankert-Roelse (figure) from the Netherlands has been a tireless advocate of CF neonatal screening since the early Eighties and is still, in 2009, is involved in the European CF Society neonatal CF screening programme. It is a relief that the obvious benefits of neonatal screening are now accepted and supported by studies that are acceptable to virtually everyone.

1999 Waters DL, Wilcken B, Irwing L, Van Asperen P, Mellis C, Simpson JM, Brown J, Gaskin KJ. Clinical outcomes of newborn screening for cystic fibrosis. Arch Dis Child 1999; 80: F1-F7. [PubMed]

An important long term observational study from Sydney of 10 year follow-up of screened infants with CF, showing significant nutritional and respiratory benefits from neonatal CF screening first introduced in 1981 in New South Wales. Fifty seven unscreened CF children (born 1978-1981) are compared with 60 screened infants (born 1981-1984). Height and weight of screened are consistently better (SDs of 0.3 and 0.4 better respectively) and respiratory function is higher – FEV1 difference of 9.4% and FVC 8.4% in favour of the screened infants.

In New South Wales a more progressive attitude to neonatal CF screening has prevailed over the years than in the UK. Although Cochrane reviewers considered this paper unsatisfactory as the controls were historical, most people accepted that the results were predictable and and provided further supportive evidence for neonatal CF screening.

2000 Massie RJ, Olsen M, Glazner J, Robertson CF, Francis I. Newborn screening for cystic fibrosis in Victoria: 10 years’ experience (1989-1998). Med J Aust 2000; 172:584-587. [PubMed]

Of 635,157 babies born in Victoria in the 10 years 1989-1998, 191 were diagnosed with CF. A further 30 cases were detected antenatally, giving an incidence of 1/2874. CF was detected early in 182 babies (95.3% of affected babies in the screened cohort)–136 by screening, 35 because they had meconium ileus, and 11 because they were siblings of older children with CF. Nine cases (4.7%) of CF were missed by screening. Of these nine babies, four did not have an elevated neonatal IRT level, one had a normal IRT level at repeat testing at 4-6 weeks (1989-1990), three did not have a delta F508 mutation (1991-1998), and one had a false negative sweat test result. Nevertheless 6 of the 9 missed babies (67%) were diagnosed within four months of birth.

These are excellent figures and the authors justifiably concluded that newborn screening for CF in Victoria had proved effective in detecting most babies with CF in the newborn period. However, they stressed that a sweat test should still be requested by doctors when the clinical features suggested the diagnosis of CF, even if the child had been screened as a neonate.

2000 Massie J, Gaskin K, Van Asperen P, Wilcken B. Sweat testing following newborn screening for cystic fibrosis. Pediatr Pulmonol 2000; 29:452-456. [PubMed]

Thirty-nine of 85 DeltaF508 homozygous and 270 of 274 DeltaF508 heterozygous infants had sweat tests reported to the screening program. There were 6 DeltaF508 heterozygous infants with sweat chloride concentrations of 40-60 mmol/L and subsequently 4 of the 6 had CF confirmed. Infants with sweat chloride levels of 40-60 mmol/l require further investigation and review, but they almost certainly have CF. The chloride/sodium ratio previously recommended in evaluating marginal sweat test results (Green A, et al. Ann Clin Biochem 1985; 22:171-174 4004107; Henderson MJ, et al. Ann Clin Biochem 1986; 23:109 3767251) was not useful in establishing a diagnosis of CF in these infants.

This paper is helpful and important confirmation that sweat chloride results can be well below the traditional level of 60 meq/l for a positive diagnosis in young infants with CF. In a later study of young non-CF infants the sweat chloride was inversely related to age at testing. For example, chloride values for infants aged between 3-7 days were 23.3 +_5.7 mmol/l, 8-14 days 17.6 +_5.6 mmol/l, 15 – 42 days 14.8+_ 5.9 mmol/l, and more than 42 days 13.1 +_ 7.4mmol/l (Eng W et al. Pediatr Pulmonol 2005; 40:64-67 ). [PubMed]

Prof John Massie (figure) trained in Sydney (from where this paper originated) and is now head of Education and Training at the Royal Children’s Hospital Melbourne.

2000 Scotet V, de Braekeleer M, Roussey M, Rault G, Parent P, Dagorne M, Journel H, Lemoigne A, Codet JP, Catheline M, David V, Chaventre A, Dugueperoux I, Verlingue C, Quere I, Mercier B, Audrezet MP, Ferec C. Neonatal screening for cystic fibrosis in Brittany, France: assessment of 10 years’ experience and impact on prenatal diagnosis. Lancet 2000; 356:789-794. 11022925 [PubMed

A report of 10 years of neonatal CF screening in Brittany, France, and its impact on prenatal screening of subsequent pregnancies in couples with one affected child. From Jan 1, 1989, to Dec 31, 1998 118 children with CF were identified – an incidence of 1/ 2913. Thirty nine (34%) of the families identified by neonatal screening opted for subsequent prenatal diagnosis at least once in future pregnancies. Twelve couples would have benefited from this procedure while their first child was still symptom-free. Forty two healthy children were born, and 18 pregnancies were terminated (therapeutic abortion rate of 100%).

The authors showed the feasibility of neonatal screening for CF in Brittany. Through the detection of a large range of mutations, neonatal screening provides the opportunity for more reliable prenatal diagnosis and cascade screening of other family members. It is somewhat surprising that the time when this paper appeared, in 2000, the UK National Screening Committee still did not consider there was sufficient evidence to recommend national CF neonatal screening.

2000 Dudding T, Wilcken B, Burgess B, Hambly J, Turner G. Reproductive decisions after neonatal screening identifies cystic fibrosis. Arch Dis Child Fetal 2000; 82:F124-127. [PubMed]

The extensive New South Wales experience of neonatal CF screening from 1981 to 1996 indicated that two thirds of women who had a CF infant chose to avoid having another child with CF. In subsequent pregnancies 66% had antenatal diagnosis of whom 69% terminated or would have terminated had the fetus been affected. The 59% who decided against further pregnancies did so to avoid having a further child with CF.

As was also shown in East Anglia UK and Brittany, France the presence of a neonatal CF screening programme appears to have an overall effect of reducing the future incidence of CF in the newborns in that region. A similar effect was shown following the introduction of antenatal screening in Edinburgh (Cunningham S, Marshall T. Arch Dis Child 1998; 78:345-348.[PubMed] above). Similar findings re. antenatal diagnosis and termination were reported in the large neonatal CF screening programme from Brittany (Scotet et al, 2000 . [PubMed] above). However, it may be that with the steadily improving prognosis termination will become increasingly unacceptable to potential parents – this was said to be one factor in discontinuing the successful antenatal CF screening in Edinburgh.

Doull IJ, Ryley HC, Weller P, Goodchild MC. Cystic fibrosis-related deaths in infancy and the effect of newborn screening. Pediatr Pulmonol 2001; 31:363-366, 2001 [PubMed]

Between 1985-1989 infants, born in Wales and the West Midlands were randomized to newborn CF screening by heel-prick immunoreactive trypsin (IRT) measurement or diagnosis by clinical presentation. Eligible children with CF who died in the first 5 years of life were identified from the local pediatricians and from the National UK CF Survey. In all, 230,076 infants were randomized to be screened, while 234,510 were unscreened. One hundred seventy-six CF children were identified, of whom 7 died in the first 5 years of life, 3 having presented with meconium ileus. Median age of diagnosis in the screened group was 8 weeks. On an intention to treat analysis, all 4 non meconium ileus-related deaths occurred in the unscreened group (Fisher’s exact test, P < 0.05). However, the clinical presentation of 2 of these infants led to them being diagnosed prior to 8 weeks, i.e., earlier than would have been likely by screening. In conclusion, newborn screening has the potential to decrease infant CF deaths, but if it is to be successful, identification and treatment must occur as soon as possible after birth.

This is the last report of data from the Wales West Midlands neonatal CF screening study funded by the CF Trust during the mid-Eighties. The lessons from this study were that neonatal screening is of no advantage if the diagnosis of the infants is delayed and also if they do not also receive CF centre care once diagnosed.

2001 Mastella G, Zanolla L, Castellani C, Altieri S, Furnari M, Giglio L, Lombardo M, Miano A, Sciuto C, Pardo F, Magazzu G. Neonatal screening for cystic fibrosis: long-term clinical balance. Pancreatology 2001; 1:531-537. [PubMed]

Very few studies have been performed on the long-term clinical advantages of neonatal screening programs for CF and many of these have been inconclusive. This is a preliminary report of two observational cohort studies on this subject from Italy where neonatal CF screening has been pioneered in Europe since the mid-Seventies. In the first study, CF patients born between 1973 and 1981 in North Eastern Italy were divided into four groups according to the method of diagnosis: either screening by meconium test (58 patients); meconium ileus (45 patients); symptoms and pancreatic insufficiency (PI; 75 patients), or symptoms and pancreatic sufficiency (PS; 19 patients). The patients were followed for up to 26 years by three CF centres sharing common treatment protocols.

In this first study, the patients detected by newborn screening (PI) showed better survival and nutritional status compared to patients diagnosed through meconium ileus or symptom presentation with PI. PS patients diagnosed by symptoms showed the best outcome as would be expected as most of them had a mild genotype. In the second study, two cohorts of CF patients born between 1983 and 1992 were compared. Patients from one cohort (126 patients) were born in the Veneto region, where a neonatal screening program had been established based on immunoreactive trypsinogen. Patients from the other cohort (152 patients) were born in Sicily, where an intensive program of early diagnosis by symptoms was implemented. The cohorts were comparable for CF incidence, CFTR genotypes, gender proportion and common treatment protocols.

In this second study, the Veneto neonatal screened cohort showed better outcome with regard to survival and nutritional status over 16 years of follow-up.

Observational cohort studies cannot give definitive evidence of the clinical benefit of neonatal CF screening; however, data have been accumulated which strongly suggest a better clinical outcome for CF patients born in an area where a screening program is performed – always provided they receive good care after diagnosis.

The Italians, in particular astute clinicians such as Gina Mastella, deserve the credit for having pioneered effective neonatal CF screening in Europe since 1973.

2001 Farrell PM, Kosorok MR, Rock MJ, Laxova A, Zeng L, Lai HC, Hoffman G, Laessig RH, Splaingard ML. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001; 107:1-13. [PubMed]

Follow-up of the Wisconsin screened infants showing significantly better long term growth and nutritional state in the screened group.

This particular trial and this particular paper were influential in the eventual recommendation for national neonatal CF screening by the UK Government in May 2001 when Yvette Cooper, the Health Minister at the time, agreed to the introduction of nationwide neonatal screening wisely ignoring the advice of the National Screening Committee.

Previously the Child Health Subgroup of the UK National Screening Committee (NSC) had considered the evidence of long term benefit was insufficient to recommend national neonatal CF screening including a paper from Wisconsin (Farrell et al, N Eng J Med 1997; 337:963-969) which

was considered by Professor NJ Wald, to “provide no evidence of any benefits of screening”.
Even after the UK Government’s decision in 2001, following the present 2001 paper, the National Screening Committee remained

unconvinced. As recently as 2002, Dr David Elliman, a community paediaitrician and then Chair of the Child Health Subgroup of the UK National Screening Committee, wrote “The National Screening Committee concluded that there was currently insufficient evidence of longer term benefit, specifically in relation to pulmonary function, to support implementation of newborn screening” and then adds without any comment “Subsequently a ministerial decision was made in July 2001 to formally introduce screening in England followed shortly by a similar decision in Scotland” (Elliman DAC, et al. Arch Dis Child 2002; 87:6-9). Even in 2003 the Child Health Subgroup of the National Screening Committee reported to the National Screening Committee “that on the evidence available a national neonatal screening programme should not be introduced”. However as one fifth of babies were already being screened in the UK, considerations of equity could not be ignored. The Minister of State for Health decided that screening should be introduced. However, already the Minister, Yvette Cooper (figure), had agreed to screening in 2001!
Fortunately this 2001 trial from Wisconsin had resulted in the agreement of the UK Government and was the culmination of a 7 year, at times traumatic and heated, campaign by the UK CF Trust – the introduction of national neonatal CF screening was undoubtedly one of the major clinical advances, if not the major advance, of the decade in the UK. In this writer’s opinion the whole issue revealed serious flaws in the NHS advisory system.

Professor Philip M. Farrell (figure)  is Professor of Pediatrics and Population Health Sciences at the University of Wisconsin School of Medicine and Public Health and initiated the Wisconsin neonatal CF screening programme from 1985. He worked with Paul di Sant’Agnese at the NIH before moving to Wisconsin in 1977.

2003 Parsons EP. Clarke AJ. Bradley DM. Implications of carrier identification in newborn screening for cystic fibrosis. Arch Dis Child Fetal & Neonat 2003; 88:F467-471. [PubMed].
The dire psychological consequences of discovering an infant to be a CF carrier predicted by some are not born out by this small study. Six months after disclosure to the parents carrier identification of their infant was not perceived by parents to be problematic.

2002 McCormick J. Green MW. Mehta G. Culross F. Mehta A. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet 2002; 10:583-590. [PubMed].

The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.

2004 Koscik RL. Farrell PM. Kosorok MR. Zaremba KM. Laxova A. Lai HC. Douglas JA. Rock MJ. Splaingard ML. Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition. Pediatrics 2004; 113:1549-1558. [PubMed]

The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

This was another important study from the Wisconsin screening group adding further evidence of the need for neonatal screening and of great importance of adequate nutritional management once diagnosed by neonatal screening.

2005 Armstrong DS, Hook SM, Jamsen KM, Nixon GM, Carzino R, Carlin JB, Robertson CF, Grimwood K. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol 2005; 40:500-510. [PubMed]

Controversy exists over whether the lower airway inflammation that characterizes cystic fibrosis (CF) is initiated primarily by the genetic defect. To determine if inflammation precedes infection, we examined bronchoalveolar lavage (BAL) fluid cytology, cytokines (interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha), and free neutrophil elastase activity from 70 CF (aged 1.5-71 months) children detected by newborn screening and 19 (aged 2.0-48 months) controls with chronic stridor. CF subjects were selected and categorized as pristine (13 aged </= 6 months, lacking prior respiratory symptoms and exposure to antibiotics, and without respiratory pathogens on BAL), infected (42 with viruses or >/= 10(5) colony-forming units/ml of pathogenic bacteria in BAL), and uninfected (15 aged > 6 months, asymptomatic, not taking antibiotics at bronchoscopy, and free of pathogens in their BAL). To further resolve if inflammation develops without infection, inflammatory mediators in paired annual BAL samples from 38 CF subjects were measured, and results were grouped according to whether BAL showed persistence (n = 6), acquisition (n = 8), clearance (n = 13), or absence (n = 11) of infection. While pristine, uninfected, and control subjects had similar BAL profiles, infected patients showed elevated inflammatory indices, including increased IL-10 (P < 0.001). Pristine subjects had the fewest signs of inflammation. Analysis of BAL pairs found differences between the four infection groups for changes in neutrophil percentages, IL-8 (P < 0.001), and free neutrophil elastase (P = 0.009). Infection was associated with elevated inflammatory mediators in BAL fluid. In contrast, minimal or reduced signs of inflammation accompanied absence of eradication of infection from BAL fluid. We conclude that in CF, infection initiates and sustains airway inflammation.

This provides further evidence that infection usually precedes inflammation in the CF airways – this does not necessarily exclude the probability that the degree and duration of inflammation, when it occurs, is excessive in CF.

2005 Koscik RL, Lai HJ, Laxova A, Zaremba KM, Kosorok MR, Douglas JA, Rock MJ, Splaingard ML, Farrell PM. Preventing early, prolonged vitamin E deficiency: an opportunity for better cognitive outcomes via early diagnosis through neonatal screening. J Pediatr 2005; 147:S51-6. [PubMed]

The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Significantly lower cognitive scores correlated with indicators of malnutrition and un favourable family factors such as single parents, lower socioeconomic status, and less parental education. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, following neonatal screening, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

Thus important evidence that diagnosis via newborn screening may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy which is the majority. Another important positive in favour of newborn screening for CF from the Wisconsin study.

2005 Sims EJ, McCormick J, Mehta G, Connett G, Mehta A. UK CF Database Steering Committee. Newborn screening for cystic fibrosis is associated with reduced treatment intensity. J Pediatr 2005; 147:306-311. [PubMed]

To determine whether the improved clinical status of children with CF diagnosed after newborn screening was associated with reduced need for treatment compared with a clinical diagnosis. Those diagnosed after neonatal screening received significantly fewer and less demanding therapies. So CF populations diagnosed by newborn screening are associated with reduced treatment requirements compared with age- and genotype-matched control subjects.

This is one of a number of important papers by written by Erika Sims (figure) using data from the UK CF Database managed at the time by Anil and Gita Mehta. Although the condition of children diagnosed by neonatal screening was similar to those diagnosed clinically it took a great deal more expensive and time consuming treatment to keep them in good condition.

2005 Sims EJ. McCormick J. Mehta G. Mehta A. Steering Committee of the UK Cystic Fibrosis Database. Neonatal screening for cystic fibrosis is beneficial even in the context of modern treatment. J Pediatr 2005; 147(3 Suppl):S42-46. [PubMed]

To determine whether early identification of babies with cystic fibrosis (CF) improves outcome in the current environment of new improved treatments, considering the criticism that there may be only marginal benefit gained by CF newborn screening (NBS). STUDY DESIGN: We tested whether CF NBS in the setting of modern CF center care still afforded benefit using the UK CF Database (UKCFD; ) to compare clinical outcomes in infants who underwent NBS and control subjects who were clinically diagnosed (CD). With Mann-Whitney rank tests, 184 patients who underwent NBS aged 1 to 9 years in 2002 (excluding meconium ileus) were compared with matched patients who were CD in 3-year age groups (950 control subjects).

RESULTS: Patients as old as 6 years who underwent NBS had significantly greater median height z-scores, less severe Northern chest radiography scores, better Shwachman-Kulczycki scores, and lower rates of chronic Pseudomonas aeruginosa infection. No difference was found for weight z-score or % predicted forced expiratory value in 1 second or forced volume capacity. Nutritional benefit was demonstrated in patients who underwent NBS and were homozygous for the DeltaF508 mutation.

The authors concluded that NBS segregates with better outcomes in patients as old as 6 years compared with age- and gene-matched control subjects who are CD. This cross-sectional study shows that infants who undergo screening derive nutritional benefit in improved median height and reduced morbidity.

2005 Bolhuis PA, Page-Christiaens GC. The advisory report ‘Neonatal screening’ from the Health Council of The Netherlands]. [Dutch] Nederlands Tijdschrift voor Geneeskunde 2005; 149:2857-2860. [PubMed]

The Health Council of the Netherlands published an advisory report on neonatal screening in view of developments in diagnostics, therapy and the prevalence of neonatal diseases. Despite recommending neonatal screening for many rare metabolic disorders the council decided that a “better detection method for cystic fibrosis must be developed before it is included in screening to restrict the number of sweat-test referrals of unaffected newborns”.

This is really a rather surprising conclusion and out of keeping with both experience and the published evidence. This report must have been particularly frustrating for Dr Jeanette Dankert-Roelse of the Netherlands who has campaigned for CF screening for many years and first published on the subject in 1983. [PubMed]. After further study to improve the test properties a four step protocol (IRT [immunoreactive trypsi], PAP [pancreatitis associated protein], screening for mutation panel and sequencing of the CFTR gene) was eventually introduced nationwide in the Netherlands in May 2010 (Cornel MC et al. J Inherit Metab Dis 2012; 35:635-640.[PubMed])n.

2005 Bolhuis PA, Page-Christiaens GC. The advisory report ‘Neonatal screening’ from the Health Council of The Netherlands]. [Dutch] Nederlands Tijdschrift voor Geneeskunde 2005; 149:2857-2860. [PubMed]

The Health Council of the Netherlands published an advisory report on neonatal screening in view of developments in diagnostics, therapy and the prevalence of neonatal diseases. Despite recommending neonatal screening for many rare metabolic disorders the council decided that a “better detection method for cystic fibrosis must be developed before it is included in screening to restrict the number of sweat-test referrals of unaffected newborns”.

This is really rather surprising conclusion and quite out of keeping with both experience and good published evidence. This report must be particularly frustrating for Dr Jeanette Dankert-Roelse of the Netherlands who has campaigned for CF screening for many years and first published on the subject back in 1983 ([PubMed]).

2007 Hilliard TN, Sukhani S, Francis J, Madden N, Rosenthal M Balfour-Lynn I, Bush A, Davies JC. Bronchoscopy following diagnosis with cystic fibrosis. Arch Dis Child 2007; 92:898-899. [PubMed]

The authors recently changed their practice and performed bronchoscopy following a diagnosis of cystic fibrosis. On a retrospective review of 25 children, Pseudomonas aeruginosa was detected in bronchoalveolar lavage for the first time in five children (20%) and Staphylococcus aureus in four (16%). Lavage culture was positive in eight of the 18 children without respiratory symptoms. The authors suggest that these findings highlight the potential of bronchoscopy following diagnosis, even in asymptomatic children.

Whether to recommend bronchoscopy in an asymptomatic screened infant with CF is dependent on many factors, not least, where the infant was born and the facilities and skill available for paediatric respiratory investigation. Also, the treatment policy of the unit responsible for the care of the infants. Also there is the potential danger of infecting an, as yet uninfected, infant with the instrument if sterilisation has been faulty; also hospitalisation does present a definite infection risk to infants with CF. If the infants were started on prophylactic flucloxacillin from diagnosis (as is recommended by the UK CF Trust’s expert Antibiotic Group 2009), it is very unlikely that S. aureus would have been cultured. Also units where screening has been routine for many years, such as Leeds, have managed to achieve very low levels of chronic Pseudomonas infection using only frequent throat cultures, cough swabs and serum antibody levels to recognise and treat early P. aeruginosa infection. If an infant with CF had repeatedly negative upper respiratory tract cultures and negative Pseudomonas antibody levels it would be very unlikely there would be positive bronchial cultures. So “bronchoscopy for all at diagnosis”, although it may be decided is desirable, is definitely a policy that needs careful discussion before being applied generally.

The recent multicentre study completed in 2009 comparing regular bronchoscopy with routine care led by Claire Wainwright of Brisbane does not show a significant advantage for those who have regular bronchoscopies (Wainwright CE et al. JAMA 2011; 306:163-171.[PubMed]).

2007 Sims EJ, Clark A, McCormick J, Mehta G, Connett G, Mehta A, on behalf of the UK Cystic Fibrosis Database Steering Committee. Cystic fibrosis diagnosed after 2 months of age leads to worse outcomes and requires more therapy. Pediatrics 2007; 119:19-28. [PubMed]

Another important paper by Erika Sims using data from the UK CF database then in Dundee. Homozygous DF508 infants aged one to 10 years born between 2000 and 2002 were stratified into “newborn screened”, “early diagnosed” or “late diagnosed”. Newborn screening was associated with greater height Z scores, higher Shwachman-Kulczycki scores, lower likelihood of a height less than tenth centile and fewer long term therapies compared with late clinically diagnosed patients.

This is really hard data further supporting the case for newborn screening which the UK National Screening Committee were so reluctant to agree to until the Wisconsin paper of 2001 showed a definite long term advantage in terms of growth (Farrell et al, Pediatrics 2001; 107:1-13 above).

Unfortunately it is still true that the need for evidence-based medicine delayed the introduction of newborn CF screening in the UK by a decade when the need was so blatantly obvious to most experienced paediatricians and families many of whom had children with CF whose chests were severely damaged before they were eventually diagnosed. Apologies for mentioning this more than once but the delay in introducing national screening had a disastrous effect on the ultimate survival of a minority of children with CF who were not diagnosed until their chests were irretrievably damaged; paediatricians working in large CF centres saw many such children

2008 Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, et al. Guidelines for diagnosis of cystic fibrosis in newborns through older adults: Cystic Fibrosis Foundation consensus report. J Pediatr 2008; 153:S4-S14. [PubMed]

The diagnosis of infants detected by neonatal CF screening is not always straightforward and this report gives advice to employ a combination of clinical presentation, laboratory testing and genetics to confirm a diagnosis of CF.
A European CF Society consensus report also dealt with problem of equivocal diagnosis after neonatal CF screening and dealt with sweat testing, further assessment and investigations, review arrangements and the database (Mayell SJ et al. J Cyst Fibros 2009; 8:71-78.[. PubMed])

2009 Castellani C, Southern KW, Brownlee K, Dankert Roelse J, Duff A, Farrell M, Mehta A, Munck A, Pollitt R, Sermet-Gaudelus I, Wilcken B, Ballmann M, Corbetta C, de Monestrol I, Farrell P, Feilcke M, Férec C, Gartner S, Gaskin K, Hammermann J, Kashirskaya N, Loeber G, Macek M Jr, Mehta G, Reiman A, Rizzotti P, Sammon A, Sands D, Smyth A, Sommerburg O, Torresani T, Travert G, Vernooij A, Elborn S. European best practice guidelines for cystic fibrosis neonatal screening. J Cyst Fibros 2009; 8:153-173). . [PubMed]

A European document full of good advice. When starting a newborn screening programme for CF it is important to take precautions in order to minimise avoidable risks and maximize benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes.

2009 Sly PD. Brennan S. Gangell C. de Klerk N. Murray C. Mott L. Stick SM. Robinson PJ. Robertson CF. Ranganathan SC. Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST-CF). Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. Am J Resp Crit Care 2009; 180:146-152. [PubMed]

Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol. MEASUREMENTS AND MAIN RESULTS: Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 x 10(3) cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectable free neutrophil elastase activity. Inflammation was increased in those with infection and respiratory symptoms; however, the majority of those infected were asymptomatic. Radiologic evidence of structural lung disease was common, with 46 (80.7%) having an abnormal CT; 11 (18.6%) had bronchial dilatation, 27 (45.0%) had bronchial wall thickening, and 40 (66.7%) had gas trapping. On multivariate analysis, free neutrophil elastase activity was associated with structural lung disease. Most children with structural lung disease had no clinically apparent lung disease. The authors suggested that these data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of NBS for CF is to be realized.

The evidence is strong that lung infection and damage occurs very early in many CF infants. The use of prophylactic anti-staphylococcal treatment (as recommended in the UK) and agressive eradication treatment of Pseudomonas would certainly improve the situation revealed in these Australian studies. Certainly the findings support the advice that all screened CF infants should be treated at a CF Centre.

2009 Thauvin-Robinet C. Munck A. Huet F. Génin E. Bellis G. Gautier E. et al. Collaborating Working Group on R117H. The very low penetrance of cystic fibrosis for the R117H mutation: a reappraisal for genetic counselling and newborn screening. J Med Genet 2009; 46:752-758. [PubMed]

Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p(R117H)), on either intron 8 T5 or T7 background, and F508del (p(F508del)) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults’ severe pulmonary symptoms. In 5245 healthy adults, p(F508del) was 1.06%, p(R117H;T7) 0.27% and p(R117H;T5)<0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%.

The authors suggest that these results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes.

2009 Mayell SJ, Munck A, Craig JV, Sermet I, Brownlee KG, Schwarz MJ, Castellani C, Southern KW. European Cystic Fibrosis Society Neonatal Screening Working Group. A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis. J Cyst Fibros 2009; 8:71-78. [PubMed].

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists with established.

As neonatal screening has now been widely adopted it is likely that not all infants who are detected as possibly having CF will be seen at CF centres. Therefore this document provides good evidence based on experience of the contributors for dealing with the infant where the diagnosis is in doubt. There is a helpful list of most of the eventualities that one is likely to encounter. In my experience of over 20 years neonatal CF screening in Leeds these cases are the exception.

2010

2010 Sermet-Gaudelus I, Mayell SJ, Southern KW. European Cystic Fibrosis Society (ECFS), Neonatal Screening Working Group. Guidelines on the early management of infants diagnosed with cystic fibrosis following newborn screening. J Cyst Fibros 2010; 9:323-329. [PubMed].

In response to current varied practice, the ECFS Neonatal Screening Working Group developed a consensus on the early management of these infants using the Delphi methodology. Following detailed literature review, statements were generated by a core group of experts and then assessed by a larger group using modified Delphi methodology. Forty-one statements were written by the core group. Eighty-six CF specialists contributed to the modified Delphi process. During three rounds, extra statements were added and consensus achieved on 44 (one statement did not achieve consensus). These statements will provide a framework for the management of screened infants in the first year of life. This process highlights the paucity of published and trialed evidence on which to base management of these infants. The authors suggest that to improve this situation, it is important that each infant with CF identified through NBS has opportunity to be included in a randomised controlled trial.

This is a practical guide to management of infants detected by neonatal screening. In view of the widely diverse approaches of some paediatricians regarding early treatment (or not!) the guidance was welcome and based on wide opinion of clinicians interested in the subject via the Delphi method. This a good method as both published evidence and clinical experience are combined with common sense. Paediatricians who have been screening for decades are increasingly impressed by the need to start treatment at an early stage as both infection and poor weight gain occur extremely early. In Leeds we would start pancreatic enzymes and vitamins, regular flucloxacillin and physiotherapy at the time of diagnosis.

2010 Hult G, Li Z. Scotet V, Dugueperoux I, Ferec C, Roussey M, Laxova A, Farrell PM. Participating CF centres of Brittany, France. Pulmonary outcome differences in US and French cystic fibrosis cohorts diagnosed through newborn screening. J Cyst Fibros 2010; 9:44-50. [PubMed]

A comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries is a “first”. The study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system. A single pediatric pulmonologist blinded to all identifiers scored the films. RESULTS: Generalized estimating equation analyses adjusted for age, genotype, sex, pancreatic insufficiency, and meconium ileus showed worse WCXR scores in Brittany patients compared to Wisconsin patients (average score difference=4. 48; p<0. 001). Percent predicted FEV1 was also worse among Brittany patients (p<0. 001). The finding of milder radiographically-quantified lung disease using the WCXR scoring system, as well as better FEV1 values, may be explained by variations in nutrition, environmental exposures, or health care delivery.

This is the first long term comparison of children diagnosed by neonatal screening in two different countries. The clearly worse condition of the Brittany children compared to those born in Wisconsin is not explained. Although the suggestion was made that the French children had less rigorous infection avoidance and more hospitalizations, the bacteriological data was said to be not suitable for comparison which is unfortunate for it is likely to be relevant.

2010 Massie J, Curnow L, Gaffney L, Carlin J, Francis I. Declining prevalence of cystic fibrosis since the introduction of newborn screening. Arch Dis Child 2010; 95:531-533. [PubMed]

Newborn screening for cystic fibrosis (CF) facilitates early diagnosis and genetic counselling for parents of affected infants. Many parents elect to use prenatal testing for subsequent pregnancies, and this may affect the prevalence of CF. The authors reviewed the records of the Victorian newborn screening programme and the clinical records of the three centres caring for patients with CF in Victoria, Australia, in order to determine the live-birth prevalence of patients with CF; before (1979-1988) and after (1989-2006) the introduction of newborn screening. Between 1979 and 1988, the live-birth prevalence of CF was 3. 96 (95% CI 3. 48 to 4. 49) per 10 000 live births. Following the introduction of newborn screening (1989-2006) the live-birth prevalence of CF was 3. 28 (95% CI 2. 97 to 3. 63) per 10 000 live births, representing a reduction of 17% (95% CI 2% to 29%, p=0. 025). In the pre screening period, there were 10 prenatal tests, which identified three affected pregnancies, all of which were terminated. In the later period, there were 304 prenatal tests (mean 17/year), of which 76 were affected, and 70 of these pregnancies were terminated.

The authors observed a modest reduction in the live-birth prevalence of CF since the introduction of newborn screening. This is principally due to at-risk couples detected by newborn screening electing to use prenatal testing on subsequent pregnancies.

The introduction of CF newborn screening has resulted in a reduction of the number of infants with CF being born. This was also the experience in East Anglia in the UK where neonatal screening was started in the early Eighties (Green MR, Weaver LT. J R Soc Med 1994; 87(Suppl 21):5-10) [PubMed] ; also it has been the experience in Leeds over the last thirty years and elsewhere that the incidence of CF has fallen following the introduction of neonatal CF screening which is not surprising and to be expected.

2011 Hall GL, Logie KM, Parsons F, Schulzke SM, Nolan G, Murray C, Ranganathan S, Robinson P, Sly PD, Stick SM, Berry L, Garratt L, Massie J, Mott L, Poreddy S, Simpson S. Air trapping on chest CT is associated with worse ventilation distribution in infants with cystic fibrosis diagnosed following newborn screening. PLoS ONE [Electronic Resource].2011; 6:e23932. [PubMed]

The primary objective of this analysis was to determine the relationships between ventilation distribution outcomes and the presence and extent of structural damage as assessed by chest CT in infants and young children with CF. The findings suggest that in early CF lung disease there are weak associations between ventilation distribution and lung damage from chest CT. These finding are in contrast to those reported in older children. These findings suggest that assessments of lung clearance index could not be used to replace a chest CT scan for the assessment of structural lung disease in the first two years of life. Further research is required to assess the role of ventilation distribution in tracking the progression of lung damage in infants with CF.

The detection of even minor abnormalities in infants is of importance and the presence and severity correlated with later progressive damage. This paper lends caution to the suggestion that lung clearance index would be a useful method to follow lung involvement in the early years.

2011 Stafler P, Davies JC, Balfour-Lynn IM, Rosenthal M, Bush A. Bronchoscopy in cystic fibrosis infants diagnosed by newborn screening. Pediatr Pulmonol 2011; 46:696-700. [PubMed]

There is evidence of early functional and structural changes in babies with cystic fibrosis (CF) diagnosed on newborn screening (NBS). The aim of the present study was to determine the yield of bronchoalveolar lavage (BAL) microbiology and cytology, and 24 hr pH monitoring in a group of CF infants diagnosed on NBS. Infants referred to the Brompton tertiary pediatric respiratory center between July 2007 and November 2009 underwent fiber-optic bronchoscopy (FOB), BAL, and insertion of a 24 hr dual pH probe under a single general anesthetic. The authors studied 33 infants, median age of 100 days (47-215 days) at the time of bronchoscopy. In 9 of 33 (27%) bacterial organisms were identified. Seven of the nine patients (78%) were asymptomatic and only one had had a positive cough swab prior to bronchoscopy. Neutrophilia was identified in 18/27 (67%) cases with a median of 11% (6-73%). 13/31 (42%) had an abnormal pH study with a pH index >12%. The authors concluded that the high yield of microbiology, cytology, and pH probe investigations in screened CF infants justifies invasive surveillance. Longitudinal studies to determine if early aggressive treatment results in improved outcome are awaited.

Another study by the experienced paediatric team at the Royal Brompton in London. These results are impressive and confirm the early changes even in screened CF infants. However, an Australian study failed to show a major advantage of periodic bronchopscopic surveillance when the infants are reviewed at 5 years (Wainwright CE et al. JAMA; 2011; 306:163-171.[PubMed] ). However, it is clear that lung infection occurs early and close follow up from diagnosis is mandatory for screened infants – it is noted that median age of these infants at the time of bronchoscopy was over 3 months.

2011 Jadin SA, Wu GS, Zhang Z, Shoff SM, Tippets BM, Farrell PM, Miller T, Rock MJ, Levy H, Lai HJ. Growth and pulmonary outcomes during the first 2yr of life of breast fed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program. Am J Clin Nutr 2011; 93:1038-47. [PubMed]

The optimal feeding (breast milk, formula, or a combination) for infants with cystic fibrosis (CF) is unknown. Recommendations from the CF Foundation are based on limited data. The authors compared growth and pulmonary outcomes between breast-fed and formula-fed infants through the age of 2 yrs. A total of 103 CF infants born in 1994-2006 and diagnosed through newborn screening in Wisconsin were studied. Breast fed infants were classified by the duration of exclusive breast feeding (ExBF). Exclusive formula-feeding (ExFM) was classified by the formula’s caloric density (i.e., standard [0.67 kcal/mL (20 kcal/oz) (ExFM20)] throughout infancy or high density [>=0.74 kcal/mL (22 kcal/oz) (ExFM22+)] for some duration of infancy). RESULTS: Fifty-three infants (51% of infants) were breast fed and 50 infants (49% of infants) were ExFM. In breast fed infants, the duration of ExBF was <1 mo (53% of infants), 1-1.9 mo (21% of infants), 2-3 mo (17% of infants), and 4-9 mo (9% of infants). In ExFM infants, 23 infants (46%) received a formula with a high caloric density; approximately half (n = 13) of the ExFM infants received the formula by 6 mo of age. Proportionately more infants with pancreatic sufficiency (n = 9) were ExBF >=1 mo (44% of infants), and none of the infants were ExFM22+, compared with infants with meconium ileus (n = 24; 13% of infants were ExBF >=1 mo, and 38% of infants were ExFM22+) or pancreatic insufficiency (n = 70; 25% of infants were ExBF >=1 mo, and 20% of infants were ExFM22+) (P = 0.02). In infants with pancreatic insufficiency, weight z scores declined from birth to 6 mo (P < 0.0001) in infants who were ExBF >=2 mo, and the number of Pseudomonas aeruginosa infections through the age of 2 y was fewer in breast fed than in ExFM infants (P = 0.003) but did not differ by the duration of ExBF.

The authors concluded that for infants with CF, ExBF <2 mo does not compromise growth and is associated with a respiratory benefit.

Early nutrition of CF infants is very important and this paper contains useful information. One striking feature of screened CF infants is the degree of weight loss in the first few weeks before treatment is started and the time required to regain a reasonable nutritional state. It had been suggested that exclusive breast feeding did not provide suffcient energy to support maximal growth. Our own experience of feeding screened CF infants in Leeds also suggested that exclusive breast feeding is adequate for some CF infants (Wolfe et al J Cyst Fibros 2005; 4(S1):S94).See entry of Reardon et al 1984 above for weights of Leeds infants (figure 4).

2012 Scotet V. Dugueperoux I. Saliou P. Rault G. Roussey M. Audrezet MP. Ferec C. Evidence for decline in the incidence of cystic fibrosis: a 35-year observational study in Brittany, France. Orphanet J Rare Dis 2012; 7:14. [PubMed]

This study assessed time trends in the birth incidence of CF over a long period (35 years: 1975-2009) in an area where CF is frequent (Brittany, France) and where NBS has been implemented for more than 20 years. The average number of patients born each year declined from 18.6 in the late 1970’s (period 1975-79) to 11.6 nowadays (period 2005-09). The corresponding incidence rates dropped significantly from 1/1983 to 1/3268, which represented a decline close to 40% between these two periods A clear breakpoint in incidence rate was observed at the end of the 1980’s (p < 0.0001). However, the incidence rate has remained quite stable since that time. The authors observed a 40% drop in incidence which seems consecutive to the availability of prenatal diagnosis.

In other areas where neonatal screening (UK and Australia) and indeed antenatal screening (Edinburgh) have been introduced there has been a significant reduction in the incidence of infants born with CF. Theoretically the means are now available to prevent all CF births (carrier detection, antenatal diagnosis, preimplantation genetic diagnosis) however neither the finances nor the will to do this appear to be in place at present.

2012 Martin B. Schechter MS. Jaffe A. Cooper P. Bell SC. Ranganathan S.. Comparison of the US and Australian cystic fibrosis registries: the impact of newborn screening.  Pediatrics 2012; 129:e348-55. [PubMed]

National data registries for cystic fibrosis (CF) enable comparison of health statistics between The authors compared the 2003 US and Australian registries. Differences in pulmonary and growth outcomes were assessed by creating models controlling for differences in age, gender, genotype, and diagnosis after newborn screening. RESULTS: Data on 12994 US and 1220 Australian patients aged <=18 years were analyzed. A significant difference was noted in the proportion who had been diagnosed after newborn screening (Australian 65.8% vs United States 7.2%; P < .001). Australian children had significantly greater mean height percentile (41.0 vs 32.6; P < .001) and weight percentile (43.5 vs 36.1; P = .028) than US children. Mean forced expiratory volume in 1 second (FEV(1)) percent predicted adjusted for age, gender, and genotype was similar in the 2 countries (P = .80). Patients diagnosed after newborn screening had higher mean FEV(1) (5.3 [95% confidence interval (CI): 3.6-7.0]) percent predicted and BMI (0.26 [95% CI: 0.09-0.43]). Mean FEV(1) of Australian patients diagnosed after newborn screening was lower by 5.2 (95% CI: 2.8-7.6) percent predicted compared with US children.

The authors concluded that children diagnosed with CF after newborn screening benefited from better lung function and BMI than those diagnosed clinically. The benefit of newborn screening on lung function was significantly less in Australian children compared with US children. Statistical comparisons between CF registries are feasible and can contribute to benchmarking and improvements in care

2012 Hoo AF, Thai LP, Nguyen TT, Bush A, Chudleigh J, Lum S, et al. London Cystic Fibrosis Collaboration. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax 2012; 67:874-881. [PubMed].(http://dx.doi.org/10.1136/thoraxjnl-2012-201747 for full text

Long-term benefits of newborn screening (NBS) for cystic fibrosis (CF) have been established with respect to nutritional status, but effects on pulmonary health remain unclear. Lung clearance index (LCI) and functional residual capacity (FRC) using multiple breath washout (MBW), plethysmographic (pleth) FRC and forced expirations from raised lung volumes were measured in 71 infants with CF (participants in the London CF Collaboration) and 54 contemporaneous healthy controls age ∼3 months.    Compared with controls, and after adjustment for body size and age, LCI, FRC(MBW) and FRC(pleth) were significantly higher in infants with CF (mean difference (95% CI): 0.5 (0.1 to 0.9), p=0.02; 0.4 (0.1 to 0.7), p=0.02 and 0.9 (0.4 to 1.3), p<0.001, z-scores, respectively), while forced expiratory volume (FEV(0.5)) and flows (FEF(25-75)) were significantly lower (-0.9 (-1.3 to -0.6), p<0.001 and -0.7 (-1.1 to -0.2), p=0.004, z-scores, respectively). 21% (15/70) of infants with CF had an elevated LCI (>1.96 z-scores) and 25% (17/68) an abnormally low FEV(0.5) (below -1.96 z-scores). While only eight infants with CF had abnormalities of LCI and FEV(0.5), using both techniques identified abnormalities in 35% (24/68). Hyperinflation (FRC(pleth) >1.96 z-scores) was identified in 18% (10/56) of infants with CF and was significantly correlated with diminished FEF(25-75) (r=-0.43, p<0.001) but not with LCI or FEV(0.5).

The authors concluded that despite early diagnosis of CF by NBS and protocol-driven treatment in specialist centres, abnormal lung function, with increased ventilation inhomogeneity and hyperinflation and diminished airway function, is evident in many infants with CF diagnosed through NBS by 3 months of age.

This is an important study from the UK’s leading paediatric respiratory group confirming that many screened CF infants already have abnormal lung function – 61% of the screened infants had had some respiratory symptoms (52% mild, 9% severe), 23% a positive cough swab and 73% had received antibiotics in addition to their routine prophylactic medication. With the exception of a significantly lower FEV0.5 in those who had received additional antibiotics for symptoms or positive cough swab, there was no significant association between LF outcomes and the infant’s genotype, clinical status, growth trajectory or treatment prior to the LFTs at 3 months of age.

It is perhaps encouraging that many infants who had been treated aggressively for respiratory exacerbations in the first few months had entirely normal LF by 3 months, whereas others with no prior symptoms or cause for concern had evidence of early lung disease. So damage from very early infection is not inevitable but does support the view that early specialised management is absolutely essential to achieve the maximum benefit from newborn CF screening.

2012 Belessis Y, Dixon B, Hawkins G, Pereira J, Peat J, Macdonald R, Field P, Numa A, Morton J, Lui K, Jaffe A. Early cystic fibrosis lung disease detected by bronchoalveolar lavage and lung clearance index. Am J Resp Crit Care 2012; 185:862-873. [PubMed]

A study to determine whether the lung clearance index (LCI) is a sensitive and repeatable noninvasive measure of airway infection and inflammation in newborn-screened children with CF. Methods: Forty-seven well children with CF (mean age, 1.55 yr) and 25 healthy children (mean age, 1.26 yr) underwent multiple-breath washout testing. LCI within and between-test variability was assessed. Children with CF also had surveillance bronchoalveolar lavage performed. Measurements and Main Results: The mean (SD) LCI in healthy children was 6.45 (0.49). The LCI was higher in children with CF (7.21 [0.81]; P < 0.001). The upper limit of normal for the LCI was 7.41. Fifteen (32%) children with CF had an elevated LCI. LCI measurements were repeatable and reproducible. Airway infection was present in 17 (36%) children with CF, including 7 (15%) with Pseudomonas aeruginosa. Polymicrobial growth was associated with worse inflammation. The LCI was higher in children with Pseudomonas (7.92 [1.16]) than in children without Pseudomonas (7.02 [0.56]) (P = 0.038). The LCI correlated with bronchoalveolar lavage IL-8 (R(2) = 0.20, P = 0.004) and neutrophil count (R(2) = 0.21, P = 0.001). An LCI below the upper limit of normality had a high negative predictive value (93%) in excluding Pseudomonas.

The authors of this study from Sydney concluded that the LCI is elevated (abnormal) early in children with CF, especially in the presence of Pseudomonas and airway inflammation. They suggest that LCI is a feasible, repeatable, and sensitive noninvasive marker of lung disease in young children with CF.

The lung clearance index seems to be emerging as practical and accurate measure of airway function particularly useful in very young patients.

2013 Byrnes CA. Vidmar S. Cheney JL. Carlin JB. Armstrong DS. Cooper PJ. Grimwood K. Moodie M. Robertson CF. Rosenfeld M. Tiddens HA. Wainwright CE. ACFBAL Study Investigators. Prospective evaluation of respiratory exacerbations in children with cystic fibrosis from newborn screening to 5 years of age. Thorax 2013; 68:643-651. [PubMed]

Newborn screening allows novel treatments for cystic fibrosis (CF) to be trialled in early childhood before irreversible lung injury occurs. As respiratory exacerbations are a potential trial outcome variable, we determined their rate, duration and clinical features in preschool children with CF; and whether they were associated with growth, lung structure and function at age 5 years.

Respiratory exacerbations were recorded prospectively in Australasian CF Bronchoalveolar Lavage trial subjects from enrolment after newborn screening to age 5 years, when all participants underwent clinical assessment, chest CT scans and spirometry.

168 children (88 boys) experienced 2080 exacerbations, at an average rate of 3.66 exacerbations per person-year; 80.1% were community managed and 19.9% required hospital admission. There was an average increase in exacerbation rate of 9% (95% CI 4% to 14%; p<0.001) per year of age. Exacerbation rate differed by site (p<0.001) and was 26% lower (95% CI 12% to 38%) in children receiving 12 months of prophylactic antibiotics. The rate of exacerbations in the first 2 years was associated with reduced forced expiratory volume in 1 s z scores. Ever having a hospital-managed exacerbation was associated with bronchiectasis (OR 2.67, 95% CI 1.13 to 6.31) in chest CT scans, and lower weight z scores at 5 years of age (coefficient -0.39, 95% CI -0.74 to -0.05).

The authors concluded respiratory exacerbations in young children are markers for progressive CF lung disease and are potential trial outcome measures for novel treatments in this age group.

It is interesting that the exacerbation rate was 26% lower in children receiving prophylactic antibiotics – lending some support to the UK recommendation of prophylactic flucloxacillin for the first 3 years.

2013 Dugueperoux I. Audrezet MP. Parent P. Audebert-Bellanger S. Roussey M. Ferec C. Scotet V. Cascade testing in families of carriers identified through newborn screening in Western Brittany (France). J Cyst Fibros 2013; 12:338-44. [PubMed]

An assessment of family testing following the identification of carriers by newborn screening for over 20 years, in an area where CF is frequent. The authors reviewed all of the carriers identified by NBS between 1991 and 2010 and registered the tests done in those families.

NBS identified 0.1% of the newborns as carriers, which correspond only to 2.6% of the expected carriers born within the period, and 1/3 of those with an increased IRT level. Of the 195 families, 75.9% requested testing (2.5 tests per family). We identified 183 carriers and five 1-in-4 risk couples. Reassurance about genetic status was provided to 96% of the couples.

The authors concluded that carriers detected by newborn screening appeared to be well managed in their area, and cascade testing that informs on genetic status seems relatively active.    The late Maurice Super successfully pioneered the use of cascade screening in the UK during the Nineties (Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G. Active cascade screening for carriers of cystic fibrosis gene. BMJ 1994; 308:1462-1467. [PubMed]). Identification of carriers is a major additional advantage of newborn CF screening; it difficult to understand those who initially  opposed the disclosure of an infant’s carrier status.

2014 Lim MT. Wallis C. Price JF. Carr SB. Chavasse RJ. Shankar A. Seddon P. Balfour-Lynn IM. Diagnosis of cystic fibrosis in London and South East England before and after the introduction of newborn screening. Arch Dis Child 2014; 99(3):197-202.[PubMed]

Newborn screening (NBS) for cystic fibrosis (CF) was introduced to London and South East England in 2007. 347 patients were diagnosed with CF. 126 patients were not screened (born before or abroad), and had a median age at diagnosis of 2.4 years, excluding those with meconium ileus (MI). Their median time to diagnosis from initial symptoms was 1 year, and in 10% it was >6 years.
After NBS started, 170 were diagnosed by NBS (48% were already symptomatic); 7 moved into the region after NBS elsewhere; 34 presented with MI (6 were negative on NBS); and 10 screened children were missed (false negative cases). Median age of diagnosis was 3 weeks. Prevalence was 1 in 3991 live births. By 2 years of age (with data on 104 patients), 49 children (47%) had their first isolation of Pseudomonas aeruginosa, while 37 (36%) had their first growth of Staphylococcus aureus from respiratory cultures.

The authors concluded NBS has significantly reduced the age of diagnosis, although many were symptomatic even at 3 weeks of age. A small number of patients with CF can still be missed by the screening programme, and the diagnosis should be considered even with a negative screen result.

2014 Nguyen TT. Thia LP. Hoo AF. Bush A. Aurora P. Wade A. Chudleigh J. Lum S. Stocks J. London Cystic Fibrosis Collaboration (LCFC). Evolution of lung function during the first year of life in newborn screened cystic fibrosis infants. Thorax 2014; 69:910-7. [PubMed]

A study to assess changes in pulmonary function during the first year of life in CF infants detected by newborn screening. CF NBS infants and healthy controls were recruited between 2009 and 2011. Lung Clearance Index (LCI), plethysmographic lung volume (plethysmographic functional residual capacity (FRCpleth)) and forced expired volume (FEV 0.5) were measured at 3 months and 1 year of age.
Paired measurements were obtained from 72 CF infants and 44 controls. At 3 months, CF infants had significantly worse lung function for all tests. FEV 0.5 improved significantly (0.59 (95% CI 0.18 to 0.99) z-scores; p<0.01) in CF infants between 3 months and 1 year, and by 1 year, FEV 0.5 was only 0.52 (0.89 to 0.15) z-scores less than in controls. LCI and FRCpleth remained stable throughout the first year of life, being on average 0.8 z-scores higher in infants with CF. Pulmonary function at 1 year was predicted by that at 3 months. Among the 45 CF infants with entirely normal LCI and FEV 0.5 at 3 months, 80% remained so at 1 year, while 74% of those with early abnormalities remained abnormal at 1 year.

This is the first study reporting improvements in FEV 0.5 over time in stable NBS CF infants treated with standard therapy. Milder changes in lung function occurred by 1 year than previously reported. Lung function at 3 months predicts a high-risk group, who should be considered for intensification of treatment and enrolment into RCTs. A very interesting study from the London CF Collaboration with implications for early management. The importance of early involvement and of identifying this early at risk group at 3 months, who may require more intensive treatment and supervision (at a specialist centre rather than care shared with a local hospital), is emphasised.

2014 Thia LP, Calder A, Stocks J, Bush A, Owens CM. Wallis C. Young C. Sullivan Y. Wade A. McEwan A. Brody AS. London Cystic Fibrosis Collaboration. Is chest CT useful in newborn screened infants with cystic fibrosis at 1year of age? Thorax 2014; 69(4):320-7.[PubMed]

The objectives of this study were to standardise CT data collection across multiple sites; ascertain the incidence of bronchial dilatation and air trapping in newborn screened (NBS) infants with CF at 1 year; and assess the reproducibility of Brody-II, the most widely used scoring system in children with CF, during infancy.
A multicentre observational study of early pulmonary lung disease in NBS infants with CF at age 1 year using volume-controlled chest CT performed under general anaesthetic.
65 infants with NBS-diagnosed CF had chest CT in three centres. Small insignificant variations in lung recruitment manoeuvres but significant centre differences in radiation exposures were found. Despite experienced scorers and prior training, with the exception of air trapping, inter- and intraobserver agreement on Brody-II score was poor to fair (e.g, inter observer total score mean (95% CI) coefficient: 0.34 (0.20 to 0.49)). Only 7 (11%) infants had a total CT score > 12 (i.e, > 5% maximum possible) by either scorer.

The authors concluded that in NBS infants with CF, CT changes were very mild at 1 year, and assessment of air trapping was the only reproducible outcome. CT is thus of questionable value in infants of this age, unless an improved scoring system for use in mild CF disease can be developed.
Another very useful study from the London Cystic Fibrosis Collaboration.

2014 Tluczek A. Laxova A. Grieve A. Heun A. Brown RL. Rock MJ. Gershan WM. Farrell PM. Long-term follow-up of cystic fibrosis newborn screening: psychosocial functioning of adolescents and young adults. J Cyst Fibros 2014; 13(2):227-34.[PubMed]

Long-term psychosocial outcomes of cystic fibrosis (CF) patients diagnosed through newborn screening remain unknown. This cross-sectional study compared three groups of youths (16 to 22 years): CF patients diagnosed through NBS (CF-NBS, n = 13), CF patients diagnosed through standard practice (CF-SP, n = 26) and healthy peers (H, n = 42), plus 72 of their parents.
Analysis showed significantly more depression among CF-NBS group parents (p = .006-.008). Parent-child cohesiveness was related to communication (p < .001). Cohesiveness and communication were associated with youth Internalising Problems (p = .037, p = .009), Emotional Symptoms (p = 0.018, p = 0.022), and Personal Adjustment (communication only, p = 0.009). Parent depression was related to youth Personal Adjustment (p = 0.022).

So CF patients report psychosocial function similar to healthy peers. However, parents of children diagnosed with CF through NBS may be at risk for depressive symptoms when their children reach adolescence.

2015  Audrézet MP, Munck A, Scotet V, Claustres M, Roussey M, Delmas D, Férec C, Desgeorges M. Comprehensive CFTR gene analysis of the French cystic fibrosis screened newborn cohort: implications for diagnosis, genetic counseling, and mutation-specific therapy.  Genet Med. 2015 Feb; 17(2):108-16. doi: 10.1038/gim.2014.113. Epub 2014 Aug 14. [PubMed]

Newborn screening (NBS) for cystic fibrosis (CF) was implemented throughout France in 2002.  During the 8-year period, 5,947,148 newborns were screened for cystic fibrosis. The data were collected by the Association Française pour le Dépistage et la Prévention des Handicaps de l’Enfant. The mutations identified were classified into four groups based on their potential for causing disease, and a diagnostic algorithm was proposed.
Combining the genetic and sweat test results, 1,160 neonates were diagnosed as having cystic fibrosis. The corresponding incidence, including both the meconium ileus (MI) and false-negative cases, was calculated at 1 in 4,726 live births. The CF30 kit, completed with a comprehensive CFTR gene analysis, provides an excellent detection rate of 99.77% for the mutated alleles, enabling the identification of a complete genotype in 99.55% of affected neonates. With more than 200 different mutations characterized, we confirmed the French allelic heterogeneity.

– The very good sensitivity, specificity, and positive predictive value obtained suggest that the four-tiered IRT/DNA/IRT/sweat test procedure provides an effective strategy for newborn screening for cystic fibrosis.

2014 Castellani C, Massie J. Newborn screening and carrier screening for cystic fibrosis: alternative or complementary? Eur Respir J. 2014 Jan;43(1):20-3. doi: 10.1183/09031936.00125613. Free full text        [PubMed]

After an interesting review of the two methods of screening the authors conclude CF newborn and carrier screening have complementary roles and neither can replace the other. In contrast to newborn screening, carrier screening allows informed reproductive choices before the birth of a child with CF. Carrier screening may get infants into medical care earlier than newborn screening, but would miss more affected babies.

– Both population carrier screening and newborn CF screening should be available in an ideal world. Unfortunately and understandably, the new very effective mutation specific drugs have overshadowed the fact that CF is a virtually totally preventable disease and has been for over 20 years.

2015

2015 Castellani C, Picci L, Tridello G, Casati E, Tamanini A, Bartoloni L, Scarpa M, Assael BM. Cystic fibrosis carrier screening effects on birth prevalence and newborn screening.  Genet Med. 2015 Jun 18. doi: 10.1038/gim.2015.68. [Epub ahead of print][PubMed]

The effects of cystic fibrosis (CF) carrier screening on birth prevalence trends and newborn screening (NBS) efficiency were compared in two Italian regions; carrier screening was performed in one region (eastern region (ER)) and not in the other (western region (WR)).
Annual births of infants with CF, NBS false-positive results, NBS uncertain diagnoses (borderline sweat chloride (BSC)), carrier tests performed, and carriers detected were monitored during the 1993-2013 period.
A total of 259 newborns with CF were detected. In the ER  (carrier screening), 150 carrier couples were found. Mean annual percentage of birth prevalence decrease was 9% per 10,000 (P = 0.002) and was greater in the ER (15%, P = 0.0008; WR 1%, P = ns). The WR (no carrier screening) estimated birth prevalence was 1/3,589 in 1993 and 1/3,870 in 2013; in the ER it was 1/2,730 in 1993 and 1/14,200 in 2013. The ER birth prevalence correlated inversely with the number of carrier couples (P = 0.0032). The ratio between CF cases and NBS-positive results significantly decreased in the ER (1.6%, P = 0.0001) but not in the WR. The ratio between prevalence of BSC and of CF cases increased in the ER (P = 0.008) but not in the WR (P = 0.1).

– Carrier screening was associated with a decrease in birth prevalence of CF. Poorer newborn screening performance was observed in the carrier screening area.

2014 Dell’Edera D, Benedetto M, Gadaleta G, Carone D, Salvatore D, Angione A, Gallo M, Milo M, Pisaturo ML, Di Pierro G, Mazzone E, Epifania AA.  Analysis of cystic fibrosis gene mutations in children with cystic fibrosis and in 964 infertile couples within the region of Basilicata, Italy: a research study.  J Med Case Rep. 2014 Oct 10;8:339. doi: 10.1186/1752-1947-8-339.  [PubMed] 

This study reports the results of a molecular screening of cystic fibrosis using DNA samples of patients enrolled from January 2009 to December 2013. Patients were referred for cystic fibrosis screening for infertile couples. In addition, gene mutations were identified in 76 patients affected by cystic fibrosis in the pediatric population of Basilicata.   In the 964 infertile couples examined, 132 subjects (13.7%) (69 women and 63 men) were heterozygous for one of the CFTR mutations, with an occurrence of carriers of 6.85%. The occurrence of carriers in infertile couples is significantly higher from the hypothetical value of the general population (4%).   In the Basilicata region of Italy the CFTR phenotype is caused by a small number of mutations. The authors aim to develop a kit able to detect not less than 96% of CTFR gene mutations.

–  Not sure if there is any general message here other than, in this particular region, the incidence of CF carriers in infertile couples is slightly higher than in the general population.

2014 Castellani C, Massie J. Newborn screening and carrier screening for cystic fibrosis: alternative or complementary? Eur Respir J. 2014 Jan;43(1):20-3. doi: 10.1183/09031936.00125613. Free full text    [PubMed]

After an interesting review of the two methods of screening the authors conclude CF newborn and carrier screening have complementary roles and neither can replace the other. In contrast to newborn screening, carrier screening allows informed reproductive choices before the birth of a child with CF. Carrier screening may get infants into medical care earlier than newborn screening, but would miss more affected babies.

– Both population carrier screening and newborn CF screening should be available in an ideal world. Unfortunately and understandably, the new very effective mutation specific drugs have overshadowed the fact that CF is a virtually totally preventable disease and has been for over 20 years.

2015 Munck A, Mayell SJ, Winters V, Shawcross A, Derichs N, Parad R, Barben J, Southern KW. Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID): A new designation and management recommendations for infants with an inconclusive diagnosis following newborn screening.  J Cyst Fibros. 2015 Nov;14(6):706-13. doi: 10.1016/j.jcf.2015.01.001. Epub 2015 Jan 24. [PubMed]

Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants.
A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists.  Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term “CF Screen Positive, Inconclusive Diagnosis (CFSPID)” was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition.
The authors note their exercise had generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.
– The detailed suggestions on the management of the two groups of infants are very helpful and supported by a large group of experienced professionals. The central recommendation common to both groups is that a paediatrician expert in cystic fibrosis should follow them all up for as long as necessary.

Newborn screening (NBS) for cystic fibrosis (CF) results in the recognition of a number of infants with a positive NBS result, but an inconclusive diagnosis. Varied practice exists with respect to the management of these infants.
A Delphi consensus approach was used to determine agreement on statements generated by a core group of specialists.  Infants were divided into group A (normal sweat chloride and two CFTR mutations, at least one of which has unclear phenotypic consequences) and group B (intermediate sweat chloride and one or no CFTR mutations). 32 statements were produced for Round 1 and 24 achieved consensus. After Round 1, a designation exercise was undertaken and the term “CF Screen Positive, Inconclusive Diagnosis (CFSPID)” was suggested for Round 2. Agreement was achieved for this statement and for all other statements aside from the need for routine respiratory culture, on which there was divided opinion. The core group advocated local practice for this issue. A sensitivity analysis demonstrated that consensus for Round 2 was achieved by change in opinion rather than attrition.
The authors note their exercise had generated a new designation and statements to guide the management of infants with CFSPID through a robust international Delphi process. These statements will be a valuable tool for CF teams and will improve the consistency of management of these infants.
– The detailed suggestions on the management of the two groups of infants are very helpful and supported by a large group of experienced professionals. The central recommendation common to both groups is that a paediatrician expert in cystic fibrosis should follow them all up for as long as necessary.

2015 Nishida K1, Smith Z, Rana D, Palmer J, Gallicano GI. Cystic fibrosis: A look into the future of prenatal screening and therapy. Birth Defects Res C Embryo Today. 2015 Mar;105(1):73-80. doi: 10.1002/bdrc.21091. [PubMed]

Despite recent guidelines suggesting prenatal screening for carriers of cystic fibrosis (CF) mutations, many physicians do not offer patients this service or even counseling. Some argue that the risks of miscarriage associated with prenatal diagnostic techniques outweigh the benefit of added insight, but with the advent of newer, noninvasive techniques, risks of miscarriage may be significantly lowered. Prenatal diagnosis provides parents the time to prepare for raising a child with CF, and soon, could provide treatment options in utero that could improve quality of life.
Here, the authors describe two of the most promising gene therapy approaches: lentivirus and adenoassociated virus (AAV)-mediated gene transduction. Thus, prenatal detection and treatment is in a most crucial stage for care of patients with CF.

– It is of some concern that intra uterine gene therapy treatment of a CF fetus is increasingly mentioned in the literature as a possibilty when the birth of such a fetus could be avoided by carrier indentification and preimplantation genetic diagnosis.    Although scientifically interesting, it is unlikely that anyone would be prepared to undertake intrauterine gene therapy for a human fetus affected by CF in the foreseeable future. However, there have been previous suggestions that fetal gene therapy would be necessary (Larson et al, 1997; Cohen & Larson, 2006 above) although the work on which these suggestions were based was not repeatable in a careful UK study (Buckley et al, 2008 below). Also it is very unlikely that fetal gene therapy would ever be advisable or indeed approved by the regulatory authorities.
– It is unfortunate that there seems to be lessening of interest in both antenatal screening and diagnosis and population screening for CF mutations – these aspects of prevention being overshadowed by the dramatic developments in specific mutational therapy. In this writer’s opinion this is unfortunate for the detection of a CF mutation in each of a couple proposing to have children can, by the use of preimplantation genetic diagnosis, allow them to have a healthy child unaffected by CF.

2015 Ooi CY, Castellani C, Keenan K, Avolio J, Volpi S, Boland M, Kovesi T, Bjornson C, Chilvers MA, Morgan L, van Wylick R, Kent S, Price A, Solomon M, Tam K, Taylor L, Malitt KA, Ratjen F, Durie PR, Gonska T. Inconclusive diagnosis of cystic fibrosis after newborn screening.  Share on Pediatrics. 2015 Jun;135(6):e1377-85. doi: 10.1542/peds.2014-2081. Epub 2015 May 11.   [PubMed]

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.
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.
– This report is rather confusing. The fact that 96% of subjects with “CF positive screen but inconclusive diagnosis (CFSPID)” had two CF mutations surely indicates they had cystic fibrosis and would eventually develop overt clinical signs if not already present in mild degree?  It is important to follow such infants carefully in the long term at a CF centre) (rather than at their local hospital to treat the very earliest signs of malabsorption or chest involvement.  The days of “not bad enough to refer to a CF centre” are over!  Many UK paediatricians would start long term flucloxacillin and vitamin supplements in the infants with two CF mutations and carefully assess their need for pancreatic enzymes as “normal weight” may also represent suboptimal weight gain for a particular infant.

2014 Williams SN, Nussbaum E, Chin TW, Do PC, Singh KE, Randhawa I.  Diagnosis of cystic fibrosis in the kindred of an infant with CFTR-related metabolic syndrome: importance of follow-up that includes monitoring sweat chloride concentrations over time.  Pediatr Pulmonol. 2014 Mar;49(3):E103-8. doi: 10.1002/ppul.22918. Epub 2013 Nov 4.[PubMed]

Newly implemented newborn screening (NBS) programs in California have resulted in a large subset of patients in whom at least two cystic fibrosis transmembrane conductance regulator (CFTR) mutations are identified, but subsequent sweat chloride analysis reveals normal or indeterminate values. These patients are diagnosed with CFTR-Related Metabolic Syndrome (CRMS). However, the natural progression and management of these patients are not clearly understood and frequently after the age of 1-year these patients are lost to follow-up with Cystic Fibrosis (CF) Centers. We present the first case of an infant who was referred to Miller Children’s Hospital for a NBS positive for CF and subsequent discovery of identical mutations in six of his seven older brothers. Several siblings had positive sweat chloride results on repeat testing after the age of 3 years.

– The authors wisely suggest the need for continued follow-up of CRMS in a CF center with diagnostic evaluation including repeat sweat chloride testing, beyond the currently recommended period. Such follow-up is absolutely essential and should be at a CF Center. It is very sad that many of the CRMS infants are being lost to follow-up.

2015 Ulph F, Cullinan T, Qureshi N, Kai J. Parents’ responses to receiving sickle cell or cystic fibrosis carrier results for their child following newborn screening.  Eur J Hum Genet. 2015 Apr;23(4):459-65. doi: 10.1038/ejhg.2014.126. Epub 2014 Jul 9.[PubMed] Free article 25005733

Universal newborn screening for sickle cell disorders and cystic fibrosis aims to enable the early identification and treatment of affected babies. Screening can also identify infants who are healthy carriers, with carrier results being the commonest outcome for parents and professionals to discuss in practice. However it is unclear what the effect will be on parents on being informed of their baby’s carrier result.
Semi-structured face-to-face interviews were conducted with a purposeful sample of 67 family members (49 mothers, 16 fathers, 2 grandparents) of 51 infants identified by universal newborn screening as carriers of cystic fibrosis (n=27) and sickle cell (n=24), across all health regions in England. Data were analysed by thematic analysis with subsequent respondent validation. Untoward anxiety or distress among parents appeared influenced by how results were conveyed, rather than the carrier result per se. Parents who had more prior awareness of carrier status or the possibility of a carrier result assimilated the information more readily. Being left in an information vacuum while awaiting results, or before seeing a professional, led some parents to fear that their child had a serious health condition. Parental distress and anxiety appeared mostly transient, subsiding with understanding of carrier status and
communication with a professional. Parents regarded carrier results as valuable information and sought to share this with their families and to inform their children in the future. However parents needed greater support after communication of results in considering and accessing cascade testing, and negotiating further communication within their families.

It is good that parents welcomed being informed of their infant’s carrier status as others have found, provided they receive adequate information, may regard as an opportunity for future prevention.

2015 Salinas DB, Sosnay PR, Azen C, Young S, Raraigh KS, Keens TG, Kharrazi M. Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants. J Cyst Fibros. 2015 Mar 28. pii: S1569-1993(15)00061-2. doi: 10.1016/j.jcf.2015.03.006. [Epub ahead of print][PubMed]

The authors analyzed CF disease-defining variables over 2-6 years in two groups of California CF screen- positive neonates born from 2007 to 2011: (1) children with two CF-causing variants and (2) children with one CF-causing and one non-CF-causing variant, as defined by CFTR2.
Children carrying non-CF-causing variants had significantly higher birth weight, lower immunoreactive trypsinogen and sweat chloride values, higher first year growth curves, and a lower rate of persistent Pseudomonas aeruginosa colonization compared to children with two CF-causing variants.
The outcomes in children 2-6 years of age with the L997F, G576A, R1162L, V754M, R668C, R31C, and S1235R variants are consistent with the CFTR2 non-CF-causing classification.

– These results would be expected. The informatioins regarding the specific mutations is valuable.

2015 Ren CL, Fink AK, Petren K, Borowitz DS, McColley SA, Sanders DB, Rosenfeld M, Marshall BC. Outcomes of infants with indeterminate diagnosis detected by cystic fibrosis newborn screening. Pediatrics. 2015 Jun;135(6):e1386-92. doi: 10.1542/peds.2014-3698. Epub 2015 May 11. [PubMed] 

Cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) describes asymptomatic infants with a positive cystic fibrosis (CF) newborn screen (NBS) but inconclusive diagnostic testing for CF. Little is known about the epidemiology and outcomes of CRMS. The goal of this study was to determine the prevalence, clinical features, and short-term outcomes of infants with CRMS.
The authors analyzed data from the US CF Foundation Patient Registry (CFFPR) from 2010 to 2012. They compared demographic, diagnostic, anthropometric, health care utilization, microbiology, and treatment characteristics between infants with CF and infants with CRMS.
There were 1983 infants diagnosed via NBS between 2010 and 2012 reported to the CFFPR. By using the CF Foundation guideline definitions, 1540 and 309 infants met the criteria for CF and CRMS, respectively (CF:CRMS ratio = 5.0:1.0). Of note, 40.8% of infants with CRMS were entered into the registry with a clinical diagnosis of CF. Infants with CRMS tended to have normal nutritional indices. However, 11% of infants with CRMS had a positive Pseudomonas aeruginosa respiratory tract culture in the first year of life.
CRMS is a common outcome of CF NBS, and some infants with CRMS may develop features concerning for CF disease. A substantial proportion of infants with CRMS were assigned a clinical diagnosis of CF, which may reflect misclassification or clinical features not collected in the CFFPR.

– It is no surprise that many of the “cystic fibrosis transmembrane conductance regulator related metabolic syndrome” (CRMS) were ventually classified as having cystic fibrosis.

2016 Castellani C, Massie J, Sontag M, Southern KW.  Newborn screening for cystic fibrosis information.  Lancet Respir Med. 2016; 4(8):653-661. [PubMed]

In the past decade, NBS has undergone rapid expansion and an unprecedented number of infants with cystic fibrosis have access to early diagnosis and care. Cystic fibrosis NBS has now moved on from the development phase and is entering an era of consolidation. The authors suggest that in the future, research should focus on the rationalization and optimization of existing programmes, with particular attention to bioethical implications such as unwanted detection of carriers and inconclusive diagnoses.

– The “unwanted carrier detection issue” was considered a problem and discussed at some length in years gone by. However, failing to reveal carrier status now would be regarded as bad practice by most clinicians and relatives who appreciate the full serious implications of having CF. Many welcome the opportunity that carrier detection in the infant offers in terms of subsequent cascade screening for the family and relatives.

2016 Castellani C, Tridello G, Tamanini A, Assael BM. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis.  Arch Dis Child. 2016 Jan 11. pii: archdischild-2015-309348. doi: 10.1136/archdischild-2015-309348. [Epub ahead of print. [PubMed]

Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007)

.- Interesting information but perhaps could have been predicted.  Presumably all will require careful follow up.

2016 Zhang Z; Lindstrom MJ; Farrell PM; Lai HJ; Wisconsin Cystic Fibrosis Neonatal Screening Group. Pubertal Height Growth and Adult Height in Cystic Fibrosis After Newborn Screening.  Pediatrics 2016; 137(5):May. [PubMed]

To examine long-term growth benefit of newborn screening (NBS), adolescent peak height velocity (PHV), and adult height were compared between the screened (diagnosed early via NBS) and the control (identified generally by symptoms) in the Wisconsin Randomized Clinical Trial. Data from 107 children born in 1985-1994 and followed through 2012 were analyzed. PHV was estimated by a semiparametric growth curve model and compared with Tanner reference. RESULTS: Meconium ileus (MI; n = 25) was associated with the worst pubertal growth and adult height, including 1 child who did not experience apparent PHV; children with pancreatic sufficiency (n = 18) achieved the best growth (normal PHV and adult height). In children with pancreatic insufficiency without meconium ileus (n = 64), the subgroup most likely to benefit from NBS, screened children had similar PHV but better adult height compared with controls. Specifically, in boys, the screened group (n = 22) achieved normal PHV (9.5 cm at 13.5 years); the control group (n = 19) had similar onset age (13.6 years) but 0.6-cm lower magnitude (P = .08). In girls, the screened group (n = 10) had somewhat later (12.5 years vs 11.7 years, P = .12) and lower PHV (7.3 cm vs 7.9 cm, P = .33) than the controls (n = 13), coinciding with later menarche (13.6 years vs 12.2 years, P = .10). Adult height was taller in the screened than the control (50th vs 29th percentile, P = .02), even after adjusted for genetic potential (32nd vs15th percentile, P = .006). Differences in adult height were primarily attributable to NBS and better prepubertal growth. CONCLUSIONS: Early linear growth benefits of NBS were sustained through puberty, leading to better adult height in cystic fibrosis.

– The better height achieved in later childhood by the screened CF infants compared to unscreened in an earlier Wisconsin study was one of the main reasons the UK government (Minister of Health –Yvette Cooper) wisely agreed with the UK CF Trust’s intensive campaign for the introduction of national neonatal CF screening in 2001 – against the advice of the National Screening Committee. (Farrell PM et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001; 107:1-13. [PubMed]). See 2001 entry for more details).

2016 Chudleigh J, Buckingham S, Dignan J, O’Driscoll S, Johnson K, Rees D, Wyatt H, Metcalfe A. Parents’ Experiences of Receiving the Initial Positive Newborn Screening (NBS) Result for Cystic Fibrosis and Sickle Cell Disease. J Genet Couns. 2016 Dec;25(6):1215-1226. Epub 2016 Apr 20.    [Pubmed]

This study followed the principles of grounded theory to explore parents’ experiences of receiving the initial positive newborn screening (NBS) result for their child with cystic fibrosis (CF) or sickle cell disease (SCD). Study conclusions indicate that most parents thought initial positive NBS results should be delivered by a health professional with “condition specific knowledge”, preferably with both parents present. Genetic counselling needs to include a focus on the impact of NBS results on parental relationships.

–    Ideally the news an infant has CF should be given to the parents by the paediatrician, expert in CF, who will be responsible for establishing the diagnosis and who will be looking after the child in the long term.   (“Grounded theory” is a systematic methodology in the social sciences involving the construction of theory through methodic gathering and analysis of data”).

Dr. Jane Chudleigh is Programme Director, School of Health Sciences, Division of Nursing, City University of London.

2017 Coffey MJ; Whitaker V; Gentin N; Junek R; Shalhoub C; Nightingale S; Hilton J; Wiley V; Wilcken B; Gaskin KJ; Ooi CY. Differences in Outcomes between Early and Late Diagnosis of Cystic Fibrosis in the Newborn Screening Era. J Pediatr 2017; 181:137-145.[Pubmed]

To evaluate children with cystic fibrosis (CF) who had a late diagnosis of CF (LD-CF) despite newborn screening (NBS) and compare their clinical outcomes with children diagnosed after a positive NBS (NBS-CF). A retrospective review of patients with LD-CF in New South Wales, Australia, from 1988 to 2010 was performed. LD-CF was defined as NBS-negative (negative immunoreactive trypsinogen or no F508del) or NBS-positive but discharged following sweat chloride < 60mmol/L. Cases of LD-CF were each matched 1:2 with patients with NBS-CF for age, sex, hospital, and exocrine pancreatic status.

A total of 45 LD-CF cases were identified (39 NBS-negative and 6 NBS-positive) with 90 NBS-CF matched controls. Median age (IQR) of  diagnosis for LD-CF and NBS-CF was 1.35 (0.4-2.8) and 0.12 (0.03-0.2) years, respectively (P<.0001). Estimated incidence of LD-CF was 1 in 45000 live births. Compared with NBS-CF, LD-CF had more respiratory manifestations at time of diagnosis (66% vs 4%; P<.0001), a higher rate of hospital admission per year for respiratory illness (0.49 vs 0.2;P=.0004), worse lung function (forced expiratory volume in 1 second percentage of predicted, 0.88 vs 0.97; P=.007), and higher rates of chronic colonization with Pseudomonas aeruginosa (47% vs 24%; P=.01). The LD-CF cohort also appeared to be shorter than NBS-CF controls (mean height z-score -0.65 vs -0.03; P=.02).

–    The authors’ conclusion that LD-CF, despite NBS, seems to be associated with worse health before diagnosis and worse later growth and respiratory outcomes, provides further support for NBS programs for CF and for very early intervention which is now receiving much attention.

Dr. Michel J Coffey (figure) of the School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, Australia with others involved in neonatal CF screening for many years.

2017 Gorrie A, Archibald AD, Ioannou L, Curnow L, McClaren B. Exploring approaches to facilitate family communication of genetic risk information after cystic fibrosis population carrier screening. J Community Genet. 2017 Oct 2. doi: 10.1007/s12687-017-0337-1. [Epub ahead of print] [Pubmed]

When an individual is identified as a carrier of CF they are encouraged to inform their relatives who are at increased risk of being a carrier. Research suggests that the uptake of CF carrier testing amongst relatives of carriers or people with CF is low.Suggested strategies to enhance current practice include mailing a fact sheet to carriers and a follow-up telephone call provided by a genetic counsellor to carriers to offer further support in communicating this information to their relatives.

2017 Leung DH; Heltshe SL; Borowitz D; Gelfond D; Kloster M; Heubi JE; Stalvey M; Ramsey BW; Baby Observational and Nutrition Study (BONUS) Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life. JAMA Pediatrics. 171(6):546-554, 2017 Jun 01. [Pubmed]

Since the implementation of universal newborn screening (NBS) for cystic fibrosis, the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described.

The objective was to examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS.

The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up.

Main Outcome and Measures: Attained weight and length for age and World Health Organisation normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori).  Of the 231 infants enrolled,110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. Infants had lower than mean birth weights (mean z score, -0.15; 95% CI,-0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI,0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulin like growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake.

The authors’ conclusions. Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalisation of weight in the first year of life. However, length stunting remains comm

Daniel H Leung (figure) is a Paediatric Gastroenterologist and Assistant Professor of Pediatrics, Baylor College of Medicine, Houston.

–   This study appears to support the suggestion that CF infants do have an intrinsic growth problem as has been suggested by others in previous studies.

2017 Seror V, Cao C, Roussey M, Giorgi R. PAP assays in newborn screening for cystic fibrosis: a population-based cost-effectiveness study. J Med Screen. 2016 Jun;23(2):62-9. doi: 10.1177/0969141315599421. Epub 2015 Aug 24.[Pubmed]

A study to compare the cost effectiveness of adding a pancreatitis-associated protein (PAP) assay to common immunoreactive trypsinogen (IRT) and DNA cystic fibrosis (CF) newborn screening strategies. Using data collected on 553,167 newborns, PAP cut-offs were calculated based on non-inferiority of the detection rates of classical forms of CF. Cost effectiveness was considered from the third-party payer’s perspective using only direct medical costs, and the unit costs of PAP assays were assessed based on a micro-costing study. Robustness of the cost-effectiveness estimates was assessed, taking the secondary outcomes of screening (ie. detecting mild forms and CF carriers) into account.

IRT/DNA, IRT/PAP, and IRT/PAP/DNA strategies had similar detection rates for classical forms of CF, but the strategies involving PAP assays detected smaller numbers of mild forms of CF. The IRT/PAP strategy was cost-effective in comparison with either IRT/DNA or IRT/PAP/DNA. IRT/PAP/DNA screening was cost-effective in comparison with IRT/DNA if relatively low value was assumed to be attached to the identification of CF carriers.

The authors concluded IRT/PAP strategies could be strictly cost-effective, but dropping DNA would mean the test could not detect CF carriers. IRT/PAP/DNA strategies could be a viable option as they are significantly less costly than IRT/DNA, but still allow CF carrier detection

– In the opinion of many, including this reviewer, the failure of a test to detect CF carriers would be definite disadvantage.

2017 Ren CL, Borowitz DS, Gonska T, Howenstine MS, Levy H, Massie J, Milla C, Munck A, Southern KW. Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis. J Pediatr. 2017 Feb;181S:S45-S51.e1. doi: 10.1016/j.jpeds.2016.09.066. [Pubmed]

An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries.

The authors concluded CRMS/CFSPID is a relatively common outcome of CF NBS, and clinicians need to be prepared to counsel families whose NBS test falls into this classification. The vast majority of infants with CRMS/CFSPID will remain free from disease manifestations early in life. However, a small proportion may develop clinical features concerning for CF or demonstrate progression to a clinical phenotype compatible with a CF diagnosis, and their long-term outcomes are not known. A consistent international definition of CRMS/CFSPID will allow for better data collection for study of outcomes and result in improved patient care.

Dr. Clement Ren (figure) is a pediatric pulmonologist in Indianapolis, Indiana and is affiliated with multiple hospitals in the area, including Indiana University Health North Hospital and Indiana University Health University Hospital.

– Experience in Leeds with continuous newborn CF screening from 1975 suggests these patients are not common and the essential is to follow them for as long as necessary ideally by the same paediatrician experienced in CF and known to the family.

2017 Castellani C, Tridello G, Tamanini A, Assael BM. Sweat chloride and immunoreactive trypsinogen in infants carrying two CFTR mutations and not affected by cystic fibrosis. Arch Dis Child. 2017 Jul;102(7):648-650. doi: 10.1136/archdischild-2015-309348. Epub 2016 Jan 11. [Pubmed]


Newborns with raised immunotrypsinogen levels who have non-pathological sweat chloride values and carry two cystic fibrosis transmembrane regulator (CFTR) mutations of which at least one is not acknowledged to be cystic fibrosis (CF)-causing, are at risk of developing clinical manifestations consistent with CFTR-related disorders or even CF. It is not known whether newborns with similar genotypes and normal immunoreactive trypsinogen (IRT) may share the same risk. This study found that newborns with these characteristics and normal IRT have lower sweat chloride values than those with raised IRT (p=0.007).

–   Negative sweat tests in children who later develop CF have been recognised for many years. It is important that that these infants have prolonged follow-up.

2016 Vears DF, Delany C, Massie J, Gillam L. Why Do Parents Want to Know their Child’s Carrier Status? A Qualitative Study. J Genet Couns. 2016 Dec; 25(6):1257-1266. Epub 2016 May 19. [27193897][Pubmed]

When a child is identified with a genetic condition, some parents want to know the carrier status of their other children. There has been little exploration of why parents want this information. To address this question, semi-structured interviews were conducted with parents of 32 children with cystic fibrosis, haemophilia, and Duchenne muscular dystrophy who wanted to know the carrier status of their other children. Data was analysed using inductive content analysis. Parents expressed a range of reasons for desiring their child’s carrier status, which fell into two broad categories: 1) benefit for the parents and 2) perceived benefit to the child. Parents discussed the desire for certainty and peace of mind derived from having knowledge of their child’s status. The most commonly expressed reason for wanting to know their child’s carrier status was in order to communicate the information to their child to provide them with the ability to make informed reproductive decisions.

These reasons suggest parents are seeking their children’s carrier information both as a coping strategy and to communicate carrier information as part of their role as a parent. This has important implications for genetic counselling practice, especially as international guidelines generally recommend against carrier testing in children. – as far as CF is concerned neonatal screening presents an opportunity to identify carrier infants.
It is to be hoped this information to identify other carriers in the family is used and the international guidelines regarded as not applicable to this particular situation.

2018  Schlüter DK, Griffiths R, Adam A, Akbari A, Heaven ML, Paranjothy S, Nybo Andersen AM, Carr SB, Pressler T, Diggle PJ, Taylor-Robinson D. Impact of cystic fibrosis on birthweight: a population based study of children in Denmark and Wales.Thorax. 2018 Jul 19. pii: thoraxjnl-2018-211706. doi: 10.1136/thoraxjnl-2018-211706. [Epub ahead of print] [Pubmed]

The authors studied the effect of CF on birth weight in Denmark and Wales, and assessed whether any associations are due to differences in gestational age at birth.  (Abstract for methods) Babies with CF were more likely to be born preterm and with low birth weight than babies with no CF (12.7% vs. 5% and 9.4% vs. 5.8% preterm; 11.9% vs. 4.2% and 11% vs. 5.4% low birth weight in Denmark and Wales, respectively). Using causal mediation methods, the total effect of CF on birth weight was estimated to be -178.8 g (95% CI -225.43 to -134.47 g) in the Danish population and -210.08 g (95% CI -281.97 to -141.5 g) in the Welsh population. About 40% of this effect of CF on birth weight was mediated through gestational age.

The authors confirmed that CF significantly impacts on intrauterine growth and leads to lower birth weight in babies with CF, which is only partially explained by shorter gestation. Also the suboptimal intrauterine growth is reflected in a slight reduction in head circumference.

Dr. Daniela Schuster is the Senior Research Associate in Biostatistics at Lancaster University.

2018 Hoch H, Sontag MK, Scarbro S, Juarez-Colunga E, McLean C, Kempe A, Sagel SD.   Clinical outcomes in U.S. infants with cystic fibrosis from 2001 to 2012. Pediatr Pulmonol. 2018 Sep 26. doi: 10.1002/ppul.24165. [Epub ahead of print]   [Pubmed]
                                                                                                            All 50 United States implemented newborn screening (NBS) for cystic fibrosis (CF) by 2010. The purpose of this study was to evaluate trends over the decade when NBS became universal to determine current rates of malnutrition, stunting, and infection rates in U.S. infants with CF.Data were obtained on 8178 infants diagnosed with CF. The percentage of infants diagnosed by NBS increased from 15% in 2001-83% in 2012 (P < 0.001).

The authors concluded nationwide implementation of CF NBS is temporally associated with significant improvements in growth outcomes and reductions in P. aeruginosa infections. However, current rates of malnutrition, stunting, and airway infection present a target for early intervention and quality improvement efforts.

(Full data in the PubMed abstract)

2018 Korten I, Kieninger E, Yammine S, Cangiano G, Nyilas S, Anagnostopoulou P, Singer F, Kuehni CE, Regamey N, Frey U, Casaulta C, Spycher BD, Latzin P; SCILD; BILD study group   Respiratory rate in infants with cystic fibrosis throughout the first year of life and association with lung clearance index measured shortly after birth.  J Cyst Fibros. 2018 Jul 27. pii: S1569-1993(18)30696-9. doi: 10.1016/j.jcf.2018.07.002. [Epub ahead of print]   30060960 [Pubmed]

Lung impairment in cystic fibrosis (CF) starts in infancy. However,tools to monitor early lung disease are limited. Respiratory rate (RR) as a key vital sign is easy to assess during sleep and is elevated during acute respiratory disease. Thus, elevated RR could indicate early lung impairment and potentially serve as a diagnostic tool in disease monitoring.                                                                   In a prospective cohort of infants with CF diagnosed by newborn screening and healthy controls RR was measured and respiratory symptoms reported weekly throughout infancy. Infants performed a lung function measurement within the first weeks of life.            The analyses included 5656 measurements from 153 infants (43 with CF). RR declined from 43.2 (40.5)/min at 6 weeks of age to 28.3 (24.6)/min at 50 weeks in infants with CF (healthy controls). Infants with CF had consistently higher RR than controls (mean difference: 4.15/min; (95% CI 2.86-5.44); p < .001). In both study groups, RR was increased throughout the study period in infants with higher lung clearance indices (LCI) and during episodes of respiratory infections.

The authors concluded infants with CF have a higher RR compared to healthy controls during the first year of life. The association with early LCI measurements, the current gold standard to assess physiology of peripheral airways, persisted throughout the study period. This may indicate tracking of lung function by RR. It might thus be an early subtle sign of functional respiratory deficit. Further studies will show if RR can be used as a sensitive and promising marker to monitor early CF lung disease.

The corresponding author, Philippe Latzin is Head of Paediatric Pulmonology at University of Berne Children’s Hospital.

2018 Munck A, Boulkedid R, Weiss L, Foucaud P, Wizla-Derambure N, Reix P, Bremont F, Derelle J, Schroedt J, Alberti C; Gastroenterology and Nutrition Société française de la Mucoviscidose (SFM) Working Group and the ALIMUDE Study Group.   Nutritional Status the First Two Years of Life in Cystic Fibrosis Diagnosed by Newborn Screening. J Pediatr Gastroenterol Nutr. 2018 Mar 14. doi: 10.1097/MPG.0000000000001956. [Epub ahead of print] [Pubmed]

A prospective longitudinal multi-centre study assessing nutritional status according to pancreatic status, feeding modalities, prescriptions, pulmonary outcome and biological nutritional parameters.

One-hundred-and-five infants were recruited and 99 completed the study. Nutritional care management prevented under nutrition and stunting in those with exocrine pancreatic sufficiency (EPS), but affected (13/87) 15% and (21/86) 24%, respectively, of infants with exocrine pancreatic insufficiency (EPI). The logistic regression model found a positive association between both weight and length z-scores “at risk” at month 24, and initial pulmonary symptoms (OR 0.06, p < 0.01 and OR 0.08, p < 0.01, respectively); these symptoms were less frequent when age at first visit was earlier than 1.2 months (33% versus 67%, p = 0.02); stunting was also associated with high-calorie density intake and Staphylococcus aureus (OR: 0.05, p = 0.01 and OR: 0.17, p < 0.01). Pulmonary outcome did not differ according to pancreatic status; breast-feeding for at least 3 months delayed first acquisition of Pseudomonas aeruginosa. Despite sodium and fat-soluble vitamin supplementation, half of both cohorts had low urinary sodium output and half of the EPI cohort had low vitamin D levels.

The authors’ data shed light on the fact that stunting was more frequent than undernutrition, while both parameters involved only patients with pancreatic insufficiency. Modalities of feeding were not associated with nutritional status; breast-feeding may provide some protection against acquisition of Pseudomonas aeruginosa.

– Presumably the significant proportion of infants who are stunted is a manifestation of the intrinsic growth problem reported in a number of previous publications.

2018 Sanders DB, Zhang Z, Farrell PM, Lai HJ; Wisconsin CF Neonatal Screening Group. Early life growth patterns persist for 12 years and impact pulmonary outcomes in cystic fibrosis.J Cyst Fibrosis  2018 Jan 30. pii: S1569-1993(18)30009-2. doi: 10.1016/j.jcf.2018.01.006. [Epub ahead of print]   [Pubmed]

In children with cystic fibrosis (CF), recovery from growth faltering within 2 years of diagnosis (Responders) is associated with better growth and less lung disease at age 6 years. This study examined whether theses benefits are sustained through to the age of 12 years.  Longitudinal growth from 76 children with CF enrolled in the Wisconsin CF Neonatal Screening Project was examined and categorised into 5 groups: R₁₂, R₆, and R₂, representing Responders who maintained growth improvement to age 12, 6, and 2 years, respectively, and I₆ and N_6, representing Non-responders whose growth did and did not improve during ages 2-6 years, respectively. Lung disease was evaluated by % predicted forced expiratory volume in one second (FEV₁) and chest radiograph (CXR) scores.   Sixty-two% were Responders. Within this group, 47% were R₁₂, 28% were R₆, and 25% were R₂. Among Non-responders, 76% were N₆. CF children with meconium ileus (MI) had worse lung function and CXR scores    compared to other CF children. Among 53 children with pancreatic insufficiency without MI, R₁₂ had significantly better FEV₁ (97-99% predicted) and CXR scores during ages 6-12 years than N₆ (89-93% predicted). Both R₆ and R₂ experienced a decline in FEV₁ by ages 10-12 years

The authors concluded early growth recovery in CF is critical, as malnutrition during infancy tends to persist and catch-up growth after age 2 years is difficult. The longer adequate growth was maintained after early growth recovery, the better the pulmonary outcomes at age 12 year

Dr. D B Sanders heads a research group in the Department of Pediatrics, University of Wisconsin

2018  Schmidt M, Werbrouck A, Verhaeghe N, De Wachter E, Simoens S, Annemans L, Putman K.  Strategies for newborn screening for cystic fibrosis: A systematic review of health economic evaluations.   J Cyst Fibros. 2018 Mar 20. pii: S1569-1993(18)30072-9. doi: 10.1016/j.jcf.2018.03.002. [Epub ahead of print]  [Pubmed]
                                                                                        

The objectives of this study are (1) to summarize study estimates of cost-effectiveness of cystic fibrosis newborn screening (CFNBS) strategies as compared to other strategies, (2) to assess the quality of the studies identified, and (3) to identify determinants of cost-effectiveness.  The evidence suggested that (i) all screening strategies are cost-effective as compared to the no-screening option and (ii) IRT-PAP seems to be the most cost-effective screening strategy towards CFNBS. Methodological and contextual differences of the individual studies make it difficult to derive strong conclusions from this evidence. Nevertheless, from a health-economic perspective, IRT-PAP should be included as an alternative when deciding on the screening.

2019 Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C.   Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.     J Cyst Fibros. 2019 Apr 17. pii: S1569-1993(18)30815-4. doi: 10.1016/j.jcf.2019.04.002. [Epub ahead of print] [Pubmed]


The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as “CF screen positive, inconclusive diagnosis” (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.

In 2011-2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) – meconium lactase – IRT2 – sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.

The authors identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).

The authors concluded that In 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.

Cystic Fibrosis Centre, Department of Paediatric Medicine, Anna Meyer Children’s University Hospital, Florence, Italy. Electronic address: terlizzivito@libero.it.

Dr V Terlizzi is a paediatrician at the Cystic Fibrosis Centre, Meyer Children’s Hospital Florence, Italy

2019 Southern KW, Barben J, Gartner S, Munck A, Castellani C, Mayell SJ, Davies JC, Winters V, Murphy J, Salinas D, McColley SA, Ren CL, Farrell PM.  Inconclusive diagnosis after a positive newborn bloodspot screening result for cystic fibrosis; clarification of the harmonised international definition.   J Cyst Fibros. 2019 Apr 24. pii: S1569-1993(19)30070-0. doi: 10.1016/j.jcf.2019.04.010. [Epub ahead of print] [Pubmed]


2019 Dankert-Roelse JE., Bouva MJ., Jakobs BS., Janssens HM., de Winter-de Groot KM., Schonbeck Y., Gille JJP., Gulmans VAM., Verschoof-Puite RK., Schielen PCJI., Verkerk PH.  Newborn blood spot screening for cystic fibrosis with a four-step screening strategy in the Netherlands J Cyst Fibros 2019; 18: 54 – 63. [Pubmed]


Newborn screening for cystic fibrosis (NBSCF) was introduced in the Dutch NBS program in 2011 with a novel strategy.   Dutch NBSCF consisted of four steps: immuno-reactive trypsin (IRT), Pancreatitis-associated Protein (PAP), DNA analysis by Inno-LiPa (35 mutations), extended gene analysis (EGA) as fourth step and as safety net. Only samples with two CFTR-variants were considered screen-positive, but samples with one disease-causing variant were considered also screen-positive from April 2013. The first 5 years of NBSCF were evaluated during a follow-up ranging from 2 to 6.8 years for sensitivity, specificity, positive predictive value (PPV), ratio of CF/Cystic Fibrosis Screen Positive infants with an Inconclusive Diagnosis (CFSPID) and median age at diagnosis, and were compared to other novel strategies for NBSCF and European Cystic Fibrosis Society (ECFS) Best Practice Standards of Care.    NBSCF achieved a sensitivity of 90% (95% CI 82%-94%), specificity of 99.991% (95% CI 99.989%-99.993%), PPV of 63% (95% CI 55%-69%), CF/CFSPID ratio of 4/1, and median age at diagnosis of 22 days, if samples with two variants as well as samples with one disease-causing variant were considered screen-positive.

The authors concluded the program achieved the goal to minimize the number of false positives and showed a favourable performance but sensitivity and CF/CFSPID ratio did not meet criteria of EFCS Best Standards of Care. Changed cut-off values for PAP and IRT and classification of R117H-7T/9T to non-pathogenic may improve sensitivity to ≥95% and CF/CFSPID ratio to 10/1. PPV is estimated to be around 60%.

Dr Jeanette-Dankert Roelse wrote her first paper on neonatal CF screening in 1987 reporting a meconium albumin study in the Netherlands of 1973-1979 (3591298) and has been actively involved in the area since then and a champion of neonatal CF screening.

School for Public Health and Primary Care, Dept Pediatrics, Maastricht University Medical Centre, Debyelaan 25, 6229 HX Maastricht, the Netherlands.

2019 DiBattista A, McIntosh N, Lamoureux M, Al-Dirbashi OY2, Chakraborty P, Britz-McKibbin P.   Metabolic Signatures of Cystic Fibrosis Identified in Dried Blood Spots For Newborn Screening Without Carrier Identification.  J Proteome Res. 2019 Mar 1;18(3):841-854. doi: 10.1021/acs.jproteome.8b00351. Epub 2019 Jan 7   [Pubmed]
 

The authors report the discovery of a panel of CF-specific metabolites from a single 3.2 mm diameter dried blood spot (DBS) punch when using multisegment injection-capillary electrophoresis-mass spectrometry (MS) as a high-throughput platform for non-targeted metabolite profiling from volume-restricted/biobanked specimens with quality control. This retrospective case-control study design identified 32 metabolites, including a series of N-glycated amino acids, oxidized glutathione disulfide, and nicotinamide that were differentially expressed in normal birth weight CF neonates without meconium ileus ( n = 36) as compared to gestational age/sex-matched screen-negative controls ( n = 44) after a false discovery rate adjustment ( q < 0.05). Also, 16 metabolites from DBS extracts allowed for discrimination of true CF cases from presumptive screen-positive carriers with one identified CFTR mutation and transient neonatal hypertrypsinogenemic neonates ( n = 72), who were later confirmed as unaffected due to a low sweat chloride (<29 mM) test result. Importantly, six CF-specific biomarker candidates satisfying a Bonferroni adjustment ( p < 7.25 × 10-5) from three independent batches of DBS specimens included several amino acids depleted in circulation (Tyr, Ser, Thr, Pro, Gly) likely reflecting protein maldigestion/malabsorption. Additionally, CF neonates had lower ophthalmic acid as an indicator of oxidative stress due to impaired glutathione efflux from exocrine/epithelial tissue and elevation of an unknown trivalent peptide that was directly correlated with IRT (ρ = 0.332, p = 4.55 × 10-4). Structural elucidation of unknown metabolites was performed by high-resolution MS/MS, whereas biomarker validation was realized when comparing a subset of metabolites from matching neonatal DBS specimens independently analyzed by direct infusion-MS/MS at an accredited NBS facility. This work sheds new light into the metabolic phenotype of CF early in life, which is required for better functional understanding of CFTR mutations of unknown clinical consequence and the development of more accurate yet cost-effective strategies for CF screening.

Pedersen MG, Højte C, Olesen HV, Pressler T, Skov M.    Late diagnosis and poor nutrition in cystic fibrosis diagnosed before implementation of newborn screening.  Acta Paediatr. 2019 Jun 19. doi: 10.1111/apa.14908. [Epub ahead of print].. 3121874   [Pubmed]


Denmark has a high standard cystic fibrosis care. However, newborn screening was not implemented until 2016. This article describes the clinical  status of cystic fibrosis patients at time of diagnosis prior to newborn screening.   Patients diagnosed with cystic fibrosis in Denmark in 2010-2014 were reviewed using the Danish Cystic Fibrosis Registry as well as patient files. Parameters collected were age at diagnosis, gender, weight, height, forced expiratory volume at 1 second, cystic fibrosis transmembrane regulator-genotype, lung bacteriology at diagnosis and previous diagnoses.                             A total of 63 patients were diagnosed in the study period. The most typical pre-cystic fibrosis diagnoses were asthma and pneumonia. The median age at diagnosis was 1.4 years for the pancreatic insufficient and 27.3 years for the pancreatic sufficient patients. Of the pancreatic insufficient patients, 21% had moderate to severe malnutrition with BMI below minus 2 SD and 40% had moderate to severe stunting with height below minus 2 SD.           Diagnosis was delayed considerably compared to diagnosis by newborn screening in other countries. Many cystic fibrosis patients diagnosed due to clinical symptoms were moderately to severely underweight or stunted at diagnosis

Skov M, Baekvad-Hansen M, Hougaard DM, Skogstrand K, Lund AM, Pressler T, Olesen HV, Duno M.  Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years.  Pediatr Pulmonol. 2019 Nov 4. doi: 10.1002/ppul.24564. [Epub ahead of print][Pubmed]
In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented.  The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed.

Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF.

The authors concluded that during the first 2 years of NBS CF screening in Denmark, they identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.

Dr Marianne Skov is in the Department of Pediatrics, CF Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

– It difficult to understand the very late introduction of neonatal CF screening (NBS) for undoubtedly, prior to NBS, a number of infants would not be diagnosed before irreparable damage occurred to the airways and chronic infection became established.

Corresponding author – Dr Hanne Vebert Olesen, Dept of Paedaitrics, Aarthus University Hospital

Course CW, Hanks R. Newborn screening for cystic fibrosis: Is there benefit for everyone? Paediatr Respir Rev. 2019 Aug;31:3-5. doi: 10.1016/j.prrv.2019.02.003. Epub 2019 Feb 28. [Pubmed]
Newborn screening for cystic fibrosis (CF) has become a widely accepted and endorsed public health strategy in economically developed countries, although there is little consensus on optimal screening methods and gene panels. Increasing understanding of CFTR genetics and consequent unpredictability of phenotypic and clinical outcomes lead to diagnostic uncertainty, and emergence of Cystic Fibrosis Screen Positive Inconclusive Diagnosis (CF-SPID). Many of these children are clinically well or have a mild phenotype yet may still experience the psychosocial impact of a CF diagnosis. This questions the role of newborn screening and how best to manage those it identifies with CF-SPID.

From Department of Paediatric Respiratory Medicine and Cystic Fibrosis, Children’s Hospital for Wales, Cardiff, United Kingdom. 

–  It is difficult to see how the occurrence of CF-SPID “questions the role of newborn screening” the introduction of which has been one of the major advances in CF care over the past 40 years.

David J, Chrastina P, Pešková K, Kožich V, Friedecký D, Adam T, Hlídková E, Vinohradská H, Novotná D, Hedelová M, Al Taji E, Holubová A, Skalická V, Macek M, Gaillyová R, Votava 1. Epidemiology of rare diseases detected by newborn screening in the Czech Republic. Cent Eur J Public Health. 2019 Jun;27(2):153-159. doi: 10.21101/cejph.a5441. [Pubmed] Presymptomatic detection of patients with rare diseases (RD), defined by a population frequency less than 1 : 2,000, is the task of newborn screening (NBS). In the Czech Republic (CZ), currently eighteen RD are screened: phenylketonuria/hyperphenylalaninemia (PKU/HPA), congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), cystic fibrosis (CF), medium chain acyl-CoA dehydrogenase deficiency (MCADD), long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), very long chain acyl-CoA dehydrogenase deficiency (VLCADD), carnitine palmitoyl transferase I and II deficiency (CPTID, CPTIID), carnitine-acylcarnitine translocase deficiency (CACTD), maple syrup urine disease (MSUD), glutaric aciduria type I (GA I), isovaleryl-CoA dehydrogenase deficiency (IVA), argininemia (ARG), citrullinemia (CIT), biotinidase deficiency (BTD), cystathionine beta-synthase-deficient homocystinuria (CBSD HCU), and methylenetetrahydrofolate reductase deficiency homocystinuria (MTHFRD HCU). The aim was to analyze the prevalence of RD screened by NBS in CZ.

The authors examined the NBS programme in CZ from 1 January 2010 to 31 December 2017, which covered 888,891 neonates. Dried blood spots were primarily analysed using fluorescence immunoassay, tandem mass spectrometry and fluorimetry. The overall prevalence of RD among the neonate cohort was 1 : 1,043. Individually, 1 : 2,877 for CH, 1 : 5,521 for PKU/HPA, 1 : 6,536 for CF (1 : 5,887 including false negative patients), 1 : 12,520 for CAH, 1 : 22,222 for MCADD, 1 : 80,808 for LCHADD, 1 : 177,778 for GA I, 1 : 177,778 for IVA, 1 : 222,223 for VLCADD, 1 : 296,297 for MSUD, 1 : 8,638 for BTD, and 1 : 181,396 for CBSD HCU.

They observed prevalence of rare diseases, based on NBS, corresponds to that expected, more precisely it was higher for BTD and lower for MSUD, IVA, CBSD HCU, MCADD and VLCADD. Early detection of rare diseases by means of NBS is an effective secondary prevention tool.

From the Department of Children and Adolescents, Third Faculty of Medicine, Charles University and University Hospital Kralovske Vinohrady, Prague, Czech Republic. Department of Paediatrics, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic

Terlizzi V, Mergni G, Buzzetti R, Centrone C, Zavataro L, Braggion C.   Cystic fibrosis screen positive inconclusive diagnosis (CFSPID): Experience in Tuscany, Italy.J Cyst Fibros.2019 Apr 17. pii: S1569-1993(18)30815-4. doi: 10.1016/j.jcf.2019.04.002. [Epub ahead of print]  [Pubmed]
The implementation of cystic fibrosis (CF) newborn screening (NBS) has led to identification of infants with a positive NBS test but inconclusive diagnosis classified as “CF screen positive, inconclusive diagnosis” (CFSPID). We retrospectively evaluated the prevalence and clinical outcome of CFSPID infants diagnosed by 2 NBS algorithms in the period from 2011 to 2016 in the Tuscany region of Italy.   In 2011-2016, we assessed the diagnostic impact of DNA analysis on the NBS 4-tier algorithm [immunoreactive trypsin (IRT) – meconium lactase – IRT2 – sweat chloride (SC)]. All CFSPID patients repeated SC testing every 6 months, and CFTR gene analysis was performed (detection rate 98%). We reclassified children as: CF diagnosis in presence of at least 2 pathological SC results; healthy carrier or healthy in presence of at least 2 normal SC results for age and either 1 or 0 CF-causing mutations, respectively.

The authors identified 32 CF and 50 CFSPID cases: 20/50 (40%) were diagnosed only by the IRT-DNA-SC algorithm and 16/50 (32%) only by IRT-meconium lactase-IRT2-SC. Both protocols identified the remaining 14 cases (28%). Thirty-seven of 50 (74%) CFSPID patients had a conclusive diagnosis on December 31, 2017:5 (10%) CF, 17 (34%) healthy and 15 (30%) healthy carriers; 13/50 (26%) cases were asymptomatic with persistent intermediate SC and followed as CFSPID (CF:CFSPID ratio 2.85:1).

The authors concluded that in 6 years, the CF:CFSPID ratio modified from 0.64:1 to 2.85:1, and 10% of CFSPID cases progressed to CF. Genetic analysis improved positive predictive value and identified a higher number of CFSPID infants progressing to CF.

Cystic Fibrosis Centre, Department of Paediatric Medicine, Anna Meyer Children’s University Hospital, Florence, Italy. Electronic address: terlizzivito@libero.it.

Dr V Terlizzi is a paediatrician at the Cystic Fibrosis Centre, Meyer Children’s Hospital Florence, Ital

 Dr Abigail L Schauble is in the Department of Pharmacy Services Michigan Medicine Ann Arbor.MI

– A useful review of the literature going back to the Sixties suggesting that NAC could be recommended as a first- or second-line therapy in older individuals. The free article is a useful review of DIOS.  The literature on meconium ileus is extensive and reviewed in the Topics section of this website (cystic fibrosis.online/history/topics/gastroenterology/ meconium ileus). Both N-acetylcysteine and oral gastrografin are recommended in the 4th edition of Hodson and Geddes Cystic Fibrosis (2016).

Schlüter DK, Southern KW, Dryden C, Diggle P, Taylor-Robinson D. Impact of newborn screening on outcomes and social inequalities in cystic fibrosis: a UK CF registry-based study.  Thorax. 2019 Nov 26. pii: thoraxjnl-2019-213179. doi: 10.1136/thoraxjnl-2019-213179. [Epub ahead of print] Free full text [Pubmed]

Newborn bloodspot screening (NBS) for cystic fibrosis (CF) was introduced across the UK in 2007 but the impact on clinical outcomes and health inequalities for children with CF is unclear.   We undertook longitudinal analyses of UK CF registry data on over 3000 children with CF born between 2000 and 2015. Clinical outcomes were the trajectories of percent predicted forced expiratory volume in one second (%FEV1) from age 5, weight for age and body mass index (BMI) SD-scores from age one, and time to chronic Pseudomonas aeruginosa (cPA) infection. Using mixed effects and time-to-event models we assessed the association of NBS with outcomes and potential interactions with childhood socioeconomic conditions, while adjusting for confounders.
Results : NBS was associated with higher average lung function trajectory (+1.56 FEV1 percentage points 95% CI 0.1 to 3.02, n=2216), delayed onset of cPA, and higher average weight trajectory intercept at age one (+0.16 SD; 95% CI 0.07 to 0.26, n=3267) but negative rate of weight change thereafter (-0.02 SD per year; 95% CI -0.03 to -0.00). We found no significant association of NBS with BMI or rate of change of lung function. There was no clear evidence of an impact of NBS on health inequalities early in life.

The authors concluded children diagnosed with CF by NBS in the UK have better lung function and increased early weight but NBS does not appear to have narrowed early health inequalities.

– These findings are not surprising as it is unlikely that NBS will significantly affect the overall standard of care subsequently offered to CF infants by their families or affect the environmental  inequalities. It has been accepted for decades that the outlook for CF infants is closely related to the overall standard of care most of which is provided by the families  with advice from the staff at their CF centres/hospitals.

Dr Daniela Schluter is Lecturer in Health Data Science at the Centre for Health Informatics, Computing and Statistics, Lancaster Medical School, Lancaster University, Lancaster, UK 

David Taylor-Robinson is Professor of Public Health and Policy, MRC Clinical Scientist and Hon. Consultant at Alder Hey Children’s Hospital Liverpool with expertise in public health, health inequalities, paediatrics and child health, epidemiology and statistics, and evidence synthesis.

2020

Farrell PM, Rock MJ, Baker MW.  The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy.  Genes 2020 Apr 8;11(4). pii: E401. doi: 10.3390/genes11040401.    Free full text [Pubmed]

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene  was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis(CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1-2 weeks of birth  when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

Dr Philip M Farrell is Emeritus Dean & Professor Departments of Pedaitrics and population Health Sciences, University of Wisconsin

Dr Michael J Rock is division Head of Pediatric Pulmonology, Director of the Cystic Fibrosis Center, director of the pediatric pulmonology fellowship and he chairs the CF Newborn Screening Advisory group University of Wisconsin School of Medicine

Dr Mei W Baker is a professor in the Dept of Pediatrics and co-director in the Newborn Screening Laboratory at the University of Wisconsin School of Medicine and Public Health

– The authors state that the era of genetic/genomic medicine has brightened the outlook for all patients with CF and especially children. There is a detailed account of the development of the Wisconsin neonatal CF screening programme. The Full Free Text can be strongly recommended.

Barreda CB, Farrell PM, Laxova A, Eickhoff JC, Braun AT, Coller RJ, Rock MJ.  Newborn screening alone insufficient to improve pulmonary outcomes for cystic fibrosis. J Cyst Fibros. 2020 Jun 13:S1569-1993(20)30731-1. doi: 10.1016/j.jcf.2020.06.002. Online ahead of print.[Pubmed]

The Wisconsin Cystic Fibrosis Neonatal Screening Project was a randomized clinical trial (RCT) revealing that children receiving an early diagnosis of CF via newborn screening (NBS) had improved nutritional outcomes but similar lung disease severity compared to those who presented clinically. Because the evaluations of these subjects by protocol ended in 2012, our objective was to assess long-term pulmonary and mortality outcomes.
Retrospective analysis of the RCT cohort utilized longitudinal outcome measures obtained from the Cystic Fibrosis Foundation Patient Registry (CFFPR). Data included screening assignment, clinical characteristics, percent predicted forced expiratory volume in 1 s (ppFEV₁) and mortality. A random intercept model was used to compare the ppFEV₁ decline of subjects between the two groups up to age 26 years. Mortality was analyzed using the Kaplan-Meier method.
Of the 145 subjects who consented to the original study, 104 subjects met inclusion criteria and had adequate data in the CFFPR. Of 57 subjects in the screened group and 47 in the control group, the rates of ppFEV₁ decline were 1.76%/year (95% CI 1.62 to 1.91%) and 1.43%/year (95% CI 1.26 to 1.60%), respectively (p<0.0002). Pseudomonas aeruginosa acquired before 2 years was partially responsible. There was no difference in mortality between the two groups
Conclusions: NBS alone does not improve pulmonary outcomes in CF, particularly when other risk factors supervene. In an era prior to strict infection control and current therapies, NBS for CF may be associated with worse pulmonary outcomes.

Dr Christina B Barreda is a paediatrician in the Department of Pediatrics, University of Wisconsin-Madison School of Medicine and Public Health.

Corinne A Muirhead is in the Department of Pharmacy, Oregon Health and Science University.
Kelvin D MacDonald  is paediatric pulmonologist, Oregon Health and Science University.

Munck A, Bourmaud A, Bellon G, Picq P, Farrell PM; DPAM Study Group.  Phenotype of children with inconclusive cystic fibrosis diagnosis after newborn screening.  Pediatr Pulmonol. 2020 Jan 9. doi: 10.1002/ppul.24634. [Epub ahead of print]  [Pubmed

To characterize the phenotypic expression of children with conductance regulator-related metabolic syndrome (CRMS)/cystic fibrosis screen positive inconclusive diagnosis (CFSPID) designation after positive newborn screening, reassign labelling if applicable and better define these children’s prognosis.
A multicentre cohort with CRMS/CFSPID designation was matched with cystic fibrosis (CF)-diagnosed cohort. Cohorts were prospectively compared on baseline characteristics, cumulative data and when they reached 6 to 7 years at endpoint assessment.
Results – Compared to infants with CF (n = 63), the CRMS/CFSPID cohort (n = 63) had initially lower   immunoreactive trypsinogen (IRT) and sweat chloride (SC) values, delayed visits, less symptoms, and better nutritional status; during follow-up, they had fewer hospitalizations, Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus identification, CF comorbidities, and treatment burden. At endpoint assessment, they presented a milder pulmonary phenotype on Brody computed tomography scores (0.0[0.0; 2.0] vs 13[2.0; 31.0]; P < .0001, respectively), Wisconsin and Brasfield chest radiograph scores, pulmonary function tests, and improved nutritional status. Among the inconclusive CF diagnosis cohort, 28 cases (44%) converted to CF diagnosis based on genotype (44%), SC (28%) or both (28%); yet, comparing those with or without final CF diagnosis, we found no differences, possibly related to their young age and mild degree of lung disease. In the total cohort, we found significant associations between Brody scores and IRT, SC values, genotype, Wisconsin and Brasfield score and spirometry.

The authors concluded the matched CRMS/CFSPID and CF cohorts showed differences in outcomes. By a mean age of 7.6 years, a high proportion of the CRMS/CFSPID cohort converted to CF. Our results highlight that monitoring at CF clinics until at least 6 years is needed as well as further studies.

 Dr Anne Munck is at the Service des maladies digestives et respiratoires de l’enfant, CRCM, Hôpital Robert Debré, Paris, France.

-The final practical message of this useful paper is important – these infants should be followed up by experts in CF for a long time.

Anne Munck^. Inconclusive Diagnosis after Newborn Screening for Cystic Fibrosis.  Int J Neonatal Screen  2020 Mar 12;6(1):19.doi: 10.3390/ijns6010019.eCollection 2020 Mar.Free PMC article [Pubmed]
An unintended consequence of newborn screening for cystic fibrosis (CF) is the identification of infants with a positive screening test but an inconclusive diagnostic testing. These infants are designated as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen-positive, inconclusive diagnosis (CFSPID) in Europe. Recently, experts agreed on a unified international definition of CRMS/CFSPID which will improve our knowledge on the epidemiology and outcomes of these infants and optimize comparisons between cohorts. Many of these children will remain free of symptoms, but a number may develop clinical features suggestive of CFTR-related disorder (CFTR-RD) or CF later in life. Clinicians should to be prepared to identify these infants and communicate with parents about this challenging and stressful situation for both healthcare professionals and families. In this review, we present the recent publications on infants designated as CRMS/CFSPID, including the definition, the incidence across Europe, the assessment of the CFTR protein function, the outcomes with the rates of conversion to a final diagnosis of CF and their management.

Dr Anne Munck is at the Hopital Necker Enfants-Malades, AP-HP, CF centre, Université Paris Descartes, 75015 Paris, France;

 Georges Travert , Mary Heeley, Anthony Heeley^.  History of Newborn Screening for Cystic Fibrosis-The Early Years. Int J Neonatal Screen   2020 Jan 31;6(1):8. doi: 10.3390/ijns6010008.eCollection 2020 Mar.   Free PMC article [Pubmed]

This review summarises the trajectory of neonatal screening strategies for the detection of cystic fibrosis (CF) using the measurement of Immunoreactive Trypsin (IRT) in dried blood spots (DBS) from 1979 until the beginning of the 21st century when newborn screening (NBS) programmes started to spread throughout many countries, using IRT measurement combined with a CF genotype analysis of DBS.

Dr Georges Travert of the University of Caen Normandy (UNICAEN), 14032 Caen, France.
Dr Anthony and Mrs Mary Heeley were from the East Anglian Biochemical Genetic Unit, Peterborough, UK.

Photo from 2020 meeting to celebrate the neonatal CF screening

– A very interesting account of the history by three pioneers of neonatal CF screening.

Jürg Barben, Carlo Castellani, Anne Munck, Jane C Davies, Karin deWinter, Silvia Gartner, Nataliya Kashirskaya, Barry Linnane, Sarah J Mayell, Susanna McColley, Chee Y Ooi, Marijke Proesmans, Clement L Ren. Danieli Salinas, Dorota Sands, Isabelle Sermet-Gaudelus, Olaf Sommerburg, Kevin W Southern, European CF Society Neonatal Screening Working Group (ECFS NSWG). Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID). J Cyst Fibros 2020 Nov 27;S1569-1993(20)30909-7.doi: 10.1016/j.jcf.2020.11.006.Online ahead of print. [Pubmed]

Over the past two decades there has been considerable progress with the evaluation and management of infants with an inconclusive diagnosis following Newborn Screening (NBS) for cystic Fibrosis (CF). In addition, we have an increasing amount of evidence on which to base guidance on the management of these infants and, importantly, we have a consistent designation being used across the globe of CRMS/CFSPID. There is still work to be undertaken and research questions to answer, but these infants now receive more consistent and appropriate care pathways than previously.
It is clear that the majority of these infants remain healthy, do not convert to a diagnosis of CF in childhood, and advice on management should reflect this. However, it is also clear that some will convert to a CF diagnosis and monitoring of these infants should facilitate their early recognition. Those infants that do not convert to a CF diagnosis have some potential of developing a CFTR-RD later in life. At present, it is not possible to quantify this risk, but families need to be provided with clear information of what to look out for.
This paper contains a number of changes from previous guidance in light of developing evidence, but the major change is the recommendation of a detailed assessment of the child with CRMS/CFSPID in the sixth year of age, including respiratory function assessment and imaging. With these data, the CF team can discuss future care arrangements with the family and come to a shared decision on the best way forward, which may include discharge to primary care with appropriate information. Information is key for these families, and we recommend consideration of a further appointment when the individual is a young adult to directly communicate the implications of the CRMS/CFSPID designation.

Prof Jurg Barben  at the Paediatric Pulmonology & CF Centre, Children’s Hospital of Eastern Switzerland, St. Gallen, Switzerland

Elizabeth Owen, Jane E Williams, Gwyneth Davies, Colin Wallis, Robert L Grant , Mary S Fewtrell^.   Growth, Body Composition, and Lung Function in Prepubertal Children with Cystic Fibrosis Diagnosed by Newborn Screening. Nutr Clin Pract. 2020 Dec 10.doi: 10.1002/ncp.10604. Online ahead of print. [Pubmed]

Background: Children with cystic fibrosis (CF) are at risk of altered body composition (BC). Newborn screening (NBS) may lead to improved BC outcomes. We investigated BC and its relationship with lung function in prepubertal children diagnosed with CF by NBS. Secondary aims explored predictors of fat-free mass (FFM) and lung function.
Methods: Thirty-seven screened (non-meconium ileus) children with CF (20 boys) born 2007-2012 had a dual-energy x-ray absorptiometry scan at 5-8 years to determine whole-body (WB) and appendicular BC. Anthropometry was performed and routine spirometry recorded. Results were converted to z-scores, height-adjusted (fat mass index [FMI] and FFM index [FFMI]) and compared with population mean values. Predictors of forced expiratory volume in 1 second (FEV₁ ) were assessed using linear regression.
Results: Height, body mass index (BMI), and FEV₁ were within normal limits, however, weight and BC were significantly low compared with reference data (weight, P = .03; WB FMI, P = .001; WB FFMI, P = .009). Gender differences were detected, with lower appendicular BC in boys and lower weight, BMI, and BC in girls. The association between FEV₁ and WB FFMI (r = 0.38; P = .02) was stronger than with BMI (r = 0.29; P = .08). WB FFMI was the only significant predictor of FEV₁ in a multivariable model (95% CI, 0.11-0.99; P = .016).
Conclusion: In this NBS CF population, gender differences in growth and BC were apparent despite preserved lung function. These results support BC assessment in prepubertal children, particularly girls, with an opportunity to direct interventions to optimize FFM

Elizabeth Owen is a  Specialist Dietitian at Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Lutz Naehrlich. The Changing Face of Cystic Fibrosis and Its Implications for Screening.   Int J Neonatal Screen. 2020 Jul 3;6(3):54.doi: 10.3390/ijns6030054.eCollection 2020 Sep.  Free PMC article [Pubmed]

Early diagnosis, multidisciplinary care, and optimized and preventive treatments have changed the face of cystic fibrosis. Life expectancy has been expanded in the last decades. Formerly a pediatric disease, cystic fibrosis has reached adulthood. Mutation-specific treatments will expand treatment options and give hope for further improvement of quality of life and life expectancy. Newborn screening for CF fits perfectly into these care structures and offers the possibility of preventive treatment even before symptoms occur. Especially in countries without screening, newborn screening will fulfil that promise only with increased awareness and new care structures.

Dr Lutz Naehrlich is at the Department of Pediatrics, Justus-Liebig-University Giessen, Germany.

– This is a clear concise history of CF leading to the point that if neonatal CF screening is to be a “game changer” its integration into well-establish CF care structures, interaction with other professionals and health authorities will be required.

Vito Terlizzi, Laura Claut, Antonella Tosco, Carla Colombo, Valeria Raia , Benedetta Fabrizzi , et al. A survey of the prevalence, management and outcome of infants with an inconclusive diagnosis following newborn bloodspot screening for cystic fibrosis (CRMS/CFSPID) in six Italian centres. J Cyst Fibros 2021 Apr 18;S1569-1993(21)00097-7. doi: 10.1016/j.jcf.2021.03.015.Online ahead of print. [Pubmed]

Objective: We evaluated the prevalence, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene profile, clinical data, management and outcome for infants with a CFTR-related metabolic syndrome/CF Screen Positive, Inconclusive Diagnosis (CRMS/CFSPID) designation from six Italian centres.
Methods: All newborn bloodspot screening (NBS) positive infants born from January 2011 to August 2018 with a CF diagnosis or a CRMS/CFSPID designation were enrolled. Data on sweat testing, genetics, clinical course and management were collected.
Results: We enrolled 257 CF patientsand 336 infants with a CRMS/CFSPID designation (CF: CRMS/CFSPID ratio of 1:1.30).Blood immuno-reactive trypsinogen (IRT) was significantly lower in CRMS/CFSPID infants and the F508del variant accounted for only 20% of alleles. Children with CRMS/CFSPID showed a milder clinical course, pancreatic sufficiency compared to CF infants. Varied practice across centres was identified regarding sweat testing, chest radiograph (8-100%) and salt supplementation (11-90%). Eighteen (5.3%) CRMS/CFSPID infants converted or were reclassified to diagnosis of CF. Four infants (1.3%) developed a clinical feature consistent with a CFTR-related disorder (1.2%). Twenty-seven were re-classified as healthy carriers (8.0%) and 16 as healthy infants (4.8%).
Conclusions: We have identified considerable variability in the evaluation and management of infants with an inconclusive diagnosis following NBS across six Italian centres. CRMS/CFSPID is more regularly seen in this population compared to countries with higher prevalence of F508del.Conversion to a CF diagnosis was recorded in 18 (5.3%) of CRMS/CFSPID infants and in 16 was as a result of increasing sweat chloride concentration.

(See also Daniela Dolce 2022)

June C Carroll, Robin Z Hayeems, Fiona A Miller, Carolyn J Barg^. Yvonne Bombard, Pranesh Chakraborty, Beth K Potter, Jessica Peace Bytautas, Karen Tam, Louise Taylor, Elizabeth Kerr, Christine Davies, Jennifer Milburn, Felix Ratjen, Astrid Guttmann.  Newborn screening for cystic fibrosis: Role of primary care providers in caring for infants with positive screening results.  Can Fam Physician 2021 Jun;67(6):e144-e152.doi: 10.46747/cfp.6706e144.  Free article   [Pubmed]

A mailed questionnaire in Ontario to explore primary care providers’ (PCPs’) preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results.
Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers’ health. Only 25% knew how to order parents’ CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16).

Conclusion: Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

Dr June C Carroll is a family physician and clinician scientist, Professor, and Sydney G. Frankfort Chair in Family Medicine in the Department of Family and Community Medicine with the Sinai Health System and the University of Toronto in Ontario.

Dr Vito Terlizzi is at the Cystic Fibrosis Regional Reference Center, Department of Paediatric Medicine, Anna Meyer Children’s University, Florence, Italy.

Stacey L Martiniano, Alexander Elbert, Phillip M Farrell, Clement L Ren , Marci K Sontag, Runyu Wu, Susanna A McColley. Outcomes of infants born during the first 9 years of CF newborn screening in the United States: a retrospective Cystic Fibrosis Foundation Patient Registry cohort study.  Pediatr Pulmonol 2021 Sep 1. doi:10.1002/ppul.25658. Online ahead of print.[Pubmed]

Introduction: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS.
Methods: We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit or hospitalization), demographics, and outcomes between 3 cohorts born between 2010-2012, 2013-2015, and 2016-2018.
Results: In 6354 infants, the median age at first CF event decreased from the 1^st to the 3^rd cohort. Weight-for-age (WFA) was < 10^th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was > 0 but height-for-age (HFA) z-score was < 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection was less common in later cohorts. About 1/3 of infants were hospitalized in the first year of life with no changes over time.
Conclusion: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts, but early life nutritional deficits and a high rate of infant hospitalizations persist.

Dr Stacey L Martiniano is pediatric pulmonologist at the University of Colorado Anschutz Medical Center, United States and the Children’s Hospital Colorado, United States

Tanja Gonska, Katherine Keenan, Jacky Au, Annie Dupuis, Mark A Chilvers, Caroline Burgess et al. Outcomes of Cystic Fibrosis Screening-Positive Infants With Inconclusive Diagnosis at School Age. Pediatrics 2021 Nov 16;e2021051740.doi: 10.1542/peds.2021-051740. Online ahead of print.   [Pubmed]

Background and objectives: Cystic fibrosis (CF) screen-positive infants with an inconclusive diagnosis (CFSPID) are infants in whom sweat testing and genetic analysis does not resolve a CF diagnosis. Lack of knowledge about the health outcome of these children who require clinical follow-up challenges effective consultation. Early predictive biomarkers to delineate the CF risk would allow a more targeted approach to these children.
Methods: Prospective, longitudinal, multicenter, Canada-wide cohort study of CF positive-screened newborns with 1 to 2 cystic fibrosis transmembrane conductance regulator gene variants, of which at least 1 is not known to be CF-causing and/or a sweat chloride between 30 and 59 mmol/L. These were monitored for conversion to a CF diagnosis, pulmonary, and nutritional outcomes.
Results: The mean observation period was 7.7 (95% confidence interval 7.1 to 8.4) years. A CF diagnosis was established for 24 of the 115 children with CFSPID (21%) either because of reinterpretation of the cystic fibrosis transmembrane conductance regulator genotype or because of increase in sweat chloride concentration ≥60 mmol/L. An initial sweat chloride of ≥40 mmol/l predicted conversion to CF on the basis of sweat testing. The 91 remaining children with CFSPID were pancreatic sufficient and showed normal growth until school age. Pulmonary function as well as lung clearance index in a subgroup of children with CFSPID were similar to that of healthy controls.
Conclusions: Children with CFSPID have good nutritional and pulmonary outcomes at school age, but rates of reclassifying the diagnosis are high. The initial sweat chloride test can be used as a biomarker to predict the risk for CF in CFSPID.

Tanja Gonska is Associate Professor Endocrine, Gastroenterology in the Divisions of Gastroenterology, Hepatology and Translational Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

Daniella Ginsburg, Choo Phei Wee, Maria Carmen Reyes, John J Brewington, Danieli B Salinas. When CFSPID becomes CF.  J Cyst Fibros 2021 Oct 28;S1569-1993(21)01296-0.doi: 10.1016/j.jcf.2021.06.012.Online ahead of print.  [Pubmed]

There has been a growing number of infants identified as CRMS/CFSPID in countries applying genetic testing as part of cystic fibrosis (CF) newborn screening. Currently there are neither standardized protocols for follow up beyond infancy, nor established predictors to stratify this population as high or low risk of reclassification to CF or CFTR-related disorder.
We report a series of 10 children who reclassified, including eight carrying CFTR variants of varying clinical consequence and seven with initial sweat chloride measurements <30 mmol/L. The overall increase in sweat chloride concentration was 5.8 mmol/L/year. Pseudomonas aeruginosa was isolated from respiratory cultures in five subjects, and reclassification was aided by human nasal epithelial cultures in two cases.
In this centre’s experience, 6% of all CRMS/CFSPID referrals reclassified to CF over a 12-year period. The rate of sweat chloride increase, genotype, and CFTR functional assay can potentially be used as prognostic tools in the CRMS/CFSPID population.

Dr Daniella K Ginsburg is paediatric Pulmonogist at the Department of Pediatrics, Division of Pediatric Pulmonology, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern

Elinor Langfelder-Schwind, Karen S Raraigh, Richard B Parad, CF newborn screening genetic counseling workgroup.  Genetic counseling access for parents of newborns who screen positive for cystic fibrosis: consensus guidelines.  Pediatr Pulmonol 2021 Dec 29.doi: 10.1002/ppul.25806. Online ahead of print. [Pubmed

Introduction: A risk associated with cystic fibrosis newborn screening (CFNBS) is parental misunderstanding of genetic information generated by the over 6,600 positive screens reported annually in the US. CFNBS algorithms incorporating DNA analysis can generate genetic information that requires clinical interpretation and has significance for the newborn, parents, and other relatives. Engagement between CF care centers and trained genetic counseling providers, such as licensed and/or certified genetic counselors (GCs), is variable and limited in providing information to CFNBS positive (CFNBS+) families.
Methods: Using a modified Delphi process, a workgroup of CFNBS experts developed recommendations for engagement of genetic counseling services in CF care centers where CFNBS+ diagnostic evaluations are performed. Statements were assessed over three rounds of surveys, one face-to-face meeting, and through public feedback.
Results: Seventeen statements achieved >80% consensus (range: 82-100%). The workgroup affirmed prior CFF policy statements recommending genetic counseling for parents of infants with CFNBS+. The remaining statements addressed infrastructure and logistics of genetic counseling services, including defining appropriate training for genetic counseling providers and counseling content, establishing a path to equal access to genetic counseling providers across CF care centers, and setting a standard for client-centered CFNBS genetic counseling that is respectful of diverse patient needs and autonomy.

Conclusions: Implementation of client-centered genetic counseling for CFNBS+ families in CF care centers by providers with expertise in both CF and genetic counseling will require efforts to further define core concepts, enhance education of providers, and develop opportunities for access via telemedicine.

Elinor Langfelder-Schwind is a genetic counselor at the Cystic Fibrosis Center, Mount Sinai Beth Israel, Department of Pulmonary, Critical Care, and Sleep Medicine, Icahn School of Medicine at Mount Sinai, 1st Ave at 16th Street, S403, New York, NY, 10003, USA

Aurelie Hatton, Anne Bergougnoux, Katarzyna Zybert, Benoit Chevalier, Myriam Mesbahi, Jean Pierre Altéri , Katarzyna Walicka-Serzysko , Magdalena Postek , Magali Taulan-Cadars , Aleksander Edelman , Alexandre Hinzpeter , Mireille Claustres , Emmanuelle Girodon , Caroline Raynal , Isabelle Sermet-Gaudelus , Dorota Sands  Reclassifying innclusive diagnosis after newborn screening for cystic fibrosis. Moving forward.  J Cyst Fibros 2021 Dec 20;S1569-1993(21)02169-X.doi:10.1016/j.jcf.2021.12.010.Online ahead of print   [Pubmed]

Background: Newborn screening for Cystic Fibrosis (CF) is associated with situations where the diagnosis of CF or CFTR related disorders (CFTR-RD) cannot be clearly ruled out.
Materials/patients and methods: We report a case series of 23 children with unconclusive diagnosis after newborn screening for CF and a mean follow-up of 7.7 years (4-13). Comprehensive investigations including whole CFTR gene sequencing, in vivo intestinal current measurement (ICM), nasal potential difference (NPD), and in vitro functional studies of variants of unknown significance, helped to reclassify the patients.
Results: Extensive genetic testing identified, in trans with a CF causing mutation, variants with varying clinical consequences and 3 variants of unknown significance (VUS). Eighteen deep intronic variants were identified by deep resequencing of the whole CFTR gene in 13 patients and were finally considered as non-pathogenic. All patients had normal CFTR dependent chloride transport in ICM. NPD differentiated 3 different profiles: CF-like tracings qualifying the patients as CF, such as F508del/D1152H patients; normal responses, suggesting an extremely low likelihood of developing a CFTR-RD such as F508del/TG11T5 patients; partial CFTR dysfunction above 20% of the normal, highlighting a remaining risk of developing CFTR-RD such as F508del/F1052V patients. The 3 VUS were reclassified as variant with defective maturation (D537N), defective expression (T582I) or with no clinical consequence (M952T).

Conclusion: This study demonstrates the usefulness of combining genetic and functional investigations to assess the possibility of evolving to CF or CFTR-RD in babies with inconclusive diagnosis at neonatal screening.

Aurelie Hatton  is at INSERM U1151, Institut Necker Enfants Malades, Université de Paris, 149 rue de Sévres, Paris 75015, France; Université de Paris, Paris, France.

Daniela Dolce, Laura Claut, Carla Colombo, Antonella Tosco, Alice Castaldo, Rita Padoan, Silviana Timpano, Benedetta Fabrizzi, Paolo Bonomi, Giovanni Taccetti, Vito Terlizzi.  Different management approaches and outcome for infants with an inconclusive diagnosis following newborn screening for cystic fibrosis (CRMS/CFSPID) and Pseudomonas aeruginosa isolation. J Cyst Fibros 2022 Jul 19;S1569-1993(22)00626-9.doi: 10.1016/j.jcf.2022.07.007.Online ahead of print.   [Pubmed]

Introduction: Evidence is currently lacking to guide the management of cystic fibrosis (CF) transmembrane conductance regulator-related metabolic syndrome CF screen-positive inconclusive diagnosis (CRMS/CFSPID) with Pseudomonas aeruginosa (Pa)-positive respiratory culture. This study assessed the clinical data, management, and outcomes of an Italian cohort of CRMS/CFSPID infants with Pa isolated from their airways.

Methods: Data of Pa-positive CRMS/CFSPID infants born between January 2011 and August 2018 and followed at five CF Italian centres were retrospectively extracted. Further data were collected until June 2021 to assess outcomes, prevalence of subjects treated with antimicrobials, and treatment type and duration.
Results: Forty-three asymptomatic CRMS/CFSPID patients (median age on 30 June 2021, 82 months; interquartile range [IQR], 63-98 months) with at least one positive airway culture for non-mucoid Pa (median age at first isolation, 18.7 months; IQR, 7-25 months) were enrolled. Of them, 24 (55.8%) underwent anti-Pa therapy. Pa clearance occurred in 22 (91.6%) of 24 patients versus spontaneous clearance in 16 of 19 (84.2%) untreated patients (chi-square, 0.5737; p = 0.44878). After a median follow-up of 6.2 years (IQR, 3.0-9.9), 7 (16.3%) were diagnosed with CF after a pathological sweat test (median age, 43 months; IQR, 28-77 months), 3 (7%) developed recurrent pancreatitis or isolated bronchiectasis consistent with CFTR-related disorder, and the CRMS/CFSPID classification remained in 33 (76.7%).

Conclusions: Pa detection frequently occurs in asymptomatic infants with CRMS/CFSPID but tends to clear spontaneously. More studies are needed to determine if Pa isolation can predict evolution.

Daniela Dolce is at the Meyer Children’s Hospital, Cystic Fibrosis Regional Reference Center, Department of Paediatric Medicine, Florence, Italy.

Ralph Fingerhut, Corina Silvia Rueegg , Orell Imahorn , Eva Sophie Lunde Pedersen , Claudia Elisabeth Kuehni , Sabina Gallati  , Nicolas Regamey  , Jürg Barben. Immunoreactive trypsinogen in healthy newborns and infants with cystic fibrosis. Arch Dis Child Fetal Neonatal Ed
. 2022 Sep 8;fetalneonatal-2021-323549. doi: 10.1136/archdischild-2021-323549. Online ahead of print.  pubmed.ncbi.nlm.nih.gov/36351789/

Objective: Newborn screening (NBS) for cystic fibrosis (CF) was introduced in Switzerland in 2011 based on an immunoreactive trypsinogen (IRT)-DNA-IRT protocol. CF diagnosis was confirmed by sweat test and/or genetics but remained inconclusive for some newborns (cystic fibrosis transmembrane conductance regulator related metabolic syndrome (CRMS)/CF screen positive, inconclusive diagnosis (CFSPID)). We aimed to (1) Describe IRT levels in healthy newborns in the first year of life and by gestational age (GA), and (2) Compare IRT at two time points between healthy newborns and newborns with CF and CRMS/CFSPID. Design: Retrospective study. Setting: National NBS database.
Patients: All children with an IRT measurement by heel prick test from 2011 to 2019
Main outcome measures: IRT values were extracted from the National NBS Laboratory, and clinical characteristics of positively screened children from the CF-NBS database. Second IRT assessment in positively screened children was usually performed after 18-24 days. We calculated internal IRT Z-Scores and multiples of the median to compare our results across different laboratory tools.
Results: Among 815 899 children; 232 were diagnosed with CF, of whom 36 had meconium ileus (MI); 27 had CRMS/CFSPID. Among all samples analysed, mean IRT Z-Scores were higher for newborns with GA <33 weeks and ≥43 weeks (all Z-Scores >0.11) compared with term babies (all Z-Scores ≤0.06). Repeated IRT Z-Scores after a median (IQR) of 19 (17-22) days remained high for infants with CF with or without MI but decreased for infants with CRMS/CFSPID.
Conclusions: Measurement of a second IRT value can help distinguish between children with CRMS/CFSPID and CF, early in life

Ralph Fingerhut is at the Swiss Newborn Screening Laboratory, University Children’s Hospital Zürich, Zurich, Zürich, Switzerland

Corina Silvia Rueegg is at the Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway.