The History of Cystic Fibrosis by Dr James Littlewood OBE

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 1).

Fig. 1: Electrophoresis of meconium in this study.

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 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.


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!)”.

Fig. 2: Jeanette Crossley

In 2009 Dr Jeanette Crossley (figure 2) kindly commented 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 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)

 

Fig. 3: Gianni Mastella. From European Cystic Fibrosis Society website

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 3) 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 to1981, 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 18 main text) the biochemist in Peterborough and his wife Mary (figure 19 main text) 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 22 in main text) 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)(figure 4)

 

Fig. 4: Early weight loss even in screened CF infants - median age of diagnosis 30 days.
(Wolfe et al. J Cyst Fibros 2005; 4(S1):S94).

 

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 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 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 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 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.
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.


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, 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 5) 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.

 

Fig. 5: Pillip Farrell. From website research.med.wisc.edu /farrell/.

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.
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 cystic fibrosis. 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 both 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). Similar findings re. antenatal diagnosis and termination were reported from Brittany (Scotet et al, 2000 above).

 

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 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])

 

 

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.

 

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. United Kingdom 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]
In a cross-sectional analysis of cohorts retrospectively ascertained, patients who were homozygous deltaF508 with cystic fibrosis, attending specialist cystic fibrosis centres, and 1 to 10 years of age between 2000 and 2002 were identified from the United Kingdom Cystic Fibrosis Database and stratified into newborn-screened, early-clinically diagnosed, or late-clinically diagnosed cohorts. Newborn screening was associated with higher height Z score, higher Shwachman-Kulczycki score, lower likelihood of height <10th percentile, and fewer long-term therapies compared with late-clinically diagnosed patients.

Further hard evidence in support of neonatal CF screening using data from the UK database.

 

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 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.

 

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.

 

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.
 
 

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.


 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.
24381320 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.
 
 

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.

 

 

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.


 

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.

 

 


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
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.

 

 

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.IN TOPIC [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.