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Perspective on the papers by Cipolli et al and Hilliard et al (see pages 842 and 898)
Audit used appropriately can significantly alter our practice, and two such studies appear in this month's issue of Archives of Disease in Childhood. The first from Italy and Australia addresses the outcome of infants detected through newborn screening (NBS) who are pancreatic sufficient at birth, and informs us that outcome is dependent on genotype.1 The second from London assesses the value of flexible bronchoscopy to obtain a brochoalveolar lavage (BAL) following a clinical diagnosis of cystic fibrosis (CF), and highlights the fact that the preschool CF child often has ongoing infection despite the absence of symptoms or positive upper airway culture.2
CF is caused by mutations within the gene encoding the protein cystic fibrosis transmembrane conductance regulator (CFTR), and it is now clear that there is a hierarchy of disease severity associated with different genotypes. Mutations within the gene can be divided into five broad categories (I–V) dependant on how the gene defect affects CFTR protein production,3 and by and large CFTR function at the apical membrane decreases sequentially from milder class V to severe class I mutations. So subjects with two severe mutations (classes I, II and III) have a poorer prognosis and are less likely to be pancreatic sufficient compared to subjects with one or two milder mutations (classes IV and V).4 Different organ systems appear to show differential sensitivity to decreased CFTR function, and disease phenotype is a reflection of CFTR function within those organs. For example, the vas deferens is very sensitive and affected even when CFTR function is relatively well preserved, and thus male infertility is a feature even in mild cases. In contrast, severe early lung disease is generally not seen until CFTR function is very low, and so is present in more severe phenotypes. The pancreas lies between these two extremes, and those with milder CFTR mutations, and so a higher level of CFTR function, are often pancreatic sufficient.
Historically, pancreatic sufficiency was associated with greater life expectancy,5 and the temptation has been to be relatively more positive with parents of pancreatic sufficient infants. However, there was concern that although the majority of these infants have milder genotypes (with at least one class IV or V mutation), a small proportion of pancreatic sufficient infants carried two severe genes (class I–III). The report by Cipolli et al is helpful as they show that during the first decade of life 20 out of 34 infants with severe genotype became pancreatic insufficient, while none of those with a milder phenotype did. These findings are in accordance with previous smaller observational studies6 and with the US CFF national registry where 97% of subjects with severe CFTR genotype are pancreatic insufficient compared with 51% of those with a mild CFTR genotype.7
However, CF care in the UK is different from that in Italy or Australia – the NBS protocol in the UK is markedly different, and currently 80% of the UK CF population carry one or more ΔF508 mutation. Furthermore, Cipolli assessed pancreatic sufficiency by the classic measurement of 3‐day faecal fat; this test is unpopular both with the families collecting the samples and the laboratories who have to process them, and so is rarely performed in the UK. The majority of the laboratories in the UK now measure faecal elastase which has the advantage of simplicity of collection and excellent correlation with direct and indirect measures of pancreatic function.8 Nevertheless, Cipolli's findings are applicable to clinical practice in the UK.
All infants with CF, irrespective of their genotype, should have exocrine pancreatic function measured at diagnosis, and those who are pancreatic insufficient should be commenced on pancreatic enzyme replacement therapy (PERT). Measurement of faecal elastase is by far the easiest option. If in doubt it is better to start PERT as treatment does not interfere with subsequent faecal elastase measurements. In those infants who are pancreatic sufficient but carry a severe CF genotype, faecal elastase should be monitored as part of their annual assessment, or at any time if symptoms suggest maldigestion. For those subjects with milder phenotype, there seems little need to measure pancreatic function during the first decade of life. In my limited experience, teenagers with CF seem more reluctant to supply faecal samples than virtually any other bodily material. It may therefore be reasonable to propose that pancreatic sufficient children with a mild genotype should only have assessment of pancreatic function if there is onset of symptoms suggestive of maldigestion. Cipolli's findings add to the evidence that genotype is the strongest predictor of pancreatic exocrine function, irrespective of pancreatic function at birth.
The proportion of subjects with CF who are pancreatic sufficient differs depending on how the population was identified. It is likely that the relatively lower rate of approximately 15% of pancreatic sufficiency in historical studies reflects under‐diagnosis. Using the older immunoreactive trypsin (IRT)/IRT based screening protocol, the Australian authors reported a 37% rate of pancreatic sufficiency, but using IRT/DNA the proportion fell to 28%. The proportion of pancreatic sufficiency in the Italian population was lower still at 23%. However, the Australian investigators tested only for ΔF508, while the Italian investigators tested for 13 mutations. In contrast, the new UK NBS programme screens for either 31 or 33 mutations. It will be interesting to see if this results in a comparatively higher proportion of identified infants being pancreatic sufficient.
Although the CF airway appears normal at birth, there is compelling evidence that infection and an exuberant inflammatory response occur early in life. It is now over a decade since Grimwood9 reported that even in young infants with CF (mean age 2.6 months) detected almost entirely through NBS, a third had lower airway bacterial infection on BAL. A third of the infected infants were asymptomatic at the time of BAL, and upper airway cultures were poorly predictive of lower airway culture. This same group of children subsequently had elective BALs performed on an annual basis for their first 3 years of life. Lower airway bacterial infection was present in a quarter of BALs, and only half of these were symptomatic at the time of testing.10 In a similar study of infants with CF diagnosed clinically who had BALs performed for their first 3 years of life, a CF pathogen was isolated annually in two thirds of subjects.11
Hilliard and colleagues elected to obtain a BAL sample for microscopy and culture in all new CF patients, the vast majority of whom had been diagnosed on clinical presentation.2 Nearly half of the 25 patients had a positive culture on BAL, despite the fact that 80% of the infants were on prophylactic antibiotics at the time of BAL. Furthermore, nearly half of the 18 children who were asymptomatic at the time of BAL had a positive culture. Most importantly, five of the subjects had Pseudomonas aeruginosa identified on BAL while upper airway cultures were negative, confirming the often poor relationship between upper airway cultures such as cough swabs and lower airway culture. The BAL resulted in a change in management in nearly half of the cases, although it is difficult to prove that this changed outcome.
Although these infants may have been asymptomatic at the time of the BAL, the majority of them would have presented with respiratory symptoms sufficient for the diagnosis of CF to be considered, and so their lungs would in no way be considered pristine. In contrast, those of us fortunate enough to care for infants who are diagnosed through NBS recognise that many of these infants are completely asymptomatic at diagnosis, and with appropriate therapy can remain relatively asymptomatic throughout infancy. We thus hope that infants identified through NBS will still have perfect lungs at diagnosis, and that early intervention will preserve their pristine nature. The reality is that we underestimate the ongoing infection and inflammation within the infant CF lung, and that sensitive measures of pulmonary function,12 high resolution computed tomography13 and BAL2,9,10,11 all demonstrate significant ongoing damage.
How should Hilliard's observations change our practice? Current practice in infants with CF is to blindly treat with oral antibiotics at the onset of lower airway symptoms, yet in Hilliard's study, in the seven symptomatic infants BAL identified three pathogenic organisms (including one P aeruginosa) not identified by upper airway culture. Although numbers were small, it is arguable that we should perform BAL on all symptomatic infants with CF prior to treatment. Flexible bronchoscopy is quick, safe and informative; I would disagree that bronchoscopy always requires general anaesthesia as it can be performed simply (particularly in this age group) under sedation. Whether we should routinely collect BAL from asymptomatic CF infants is unclear. There is insufficient evidence at present, and we must await the findings of ongoing prospective trials from Australasia.
The strong message from this study is that infants with CF often have ongoing lower airway infections, and that these infections frequently will not be detected without bronchoscopy. We should have a much lower indication for culture by BAL, and it should become routine CF practice. And lastly, we need prospective trials to examine whether systematic collection of BAL will alter outcomes.
Competing interests: None.