The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

1954 West JR, Levin MS, di Sant’Agnese PA. Studies of pulmonary function in cystic fibrosis of the pancreas. Pediatrics 1954; 13:155-164. [PubMed]
These were the first pulmonary function tests reported in children with cystic fibrosis. Most children find pulmonary function tests using a spirometer difficult to perform before the age of six years or so. But as more patients survived through early childhood to an age when they could perform lung function, of a number of studies were reported. The findings in six patients aged 12 to 14 years clearly identified most of the important features of impaired lung function found in cystic fibrosis i.e. essentially there was difficulty moving air in and out of the lungs.

These abnormalities in respiratory function were confirmed in later studies e.g. the increase in residual volume in relation to total lung capacity as early changes and reduced total lung capacity and CO2 retention as late features; also noted were abnormal pulmonary gas mixing and other features of non-uniform distribution of alveolar ventilation as a result of bronchial obstruction (also West JR, di Sant'Agnese PA. Am J Dis Child 1953; 86:496-498).

 

1957 White R Jr, Dent JH, Derbes VJ. Asthmatic states caused by mucoviscidosis. J Louisiana St Med S 1957; 109:299-302. [PubMed]
Thirty eight of 66 children with CF from New Orleans had some degree of wheezing. The authors comment “It has been the common experience of mature pediatricians that administration of epinephrine in such circumstances has led to prompt, albeit transient, alleviation. The mechanical factors that cause impairment of pulmonary function in asthma – bronchospastic contraction, edema of the mucous membrane and excessive secretion and retention of mucus, are present both in CF and asthma".

The authors' wise message from their paper being - “it is the responsibility of all physicians who treat wheezing children to exclude this disorder (i.e. cystic fibrosis)”.

 

1959 Gandevia B, Anderson CM. The effect of bronchodilator aerosol on ventilatory capacity in fibrocystic disease of the pancreas. Arch Dis Child 1959; 34:511-515. [PubMed]
An early report, from the Royal Children’s Hospital Melbourne, of the favourable effect of bronchodilators in some people with cystic fibrosis. A 1/1000 solution of isoprenaline was used for its potency and rapidity of action. One third of 16 children with CF showed impressive improvement in their respiratory function tests after the bronchodilator, most marked in the moderately affected group rather than the severely or mildly affected patients. The authors note that there are only two previous references to bronchodilator therapy in CF - West et al, 1954 (above) who found no improvement in six patients during their early respiratory function studies and Royce 1956 (above) who noted improvement in one child. White et al, 1957 (above) reported some degree of wheezing in 38 of 66 children with CF which was relieved by epinephrine. Subsequently Landau & Phelan measured the maximum expiratory flow volumes and cautioned on the use of bronchodilators as they may impair respiratory function (Landau & Phelan. Pediatr 1973; 82:863, below).

Note this present paper is by Charlotte Anderson – a paediatrician from Melbourne, Australia where she started the CF clinic. She eventually was appointed Professor of Paediatrics in Birmingham, UK (not Dorothy Andersen the pathologist from New York who described the disease in 1938 - above).

 

1959 Cook CD, Helliesen PJ, Kulczycki L, Barrie H, Freidlander L, Agathon S, Harris GB, Shwachman H. Studies of respiratory physiology in children. II. Lung volumes and mechanics of respiration in 64 patients with cystic fibrosis of the pancreas. Pediatrics 1959; 24:181-193. [PubMed]
Detailed respiratory function on 64 patients aged 6 to 25 years. (Previous reports of West et al, 1954 above and Royce et al, 1958 are mentioned). Tidal volume and respiratory rate were abnormal in only the worst affected patients. The most frequent finding was an increased residual volume (46%) and functional residual capacity (21%). Vital capacity was reduced in 34%. The RV/TLC ratio was increased in 70%.

There was a definite correlation between respiratory function tests and clinical condition of the patients.

 

1959 Wright BM, McKerrow CB. Maximum expiratory flow rate as a measure of ventilatory capacity - with a description of a new portable instrument for measuring it. Brit Med J 1959; 2:1041-1947. [PubMed]
Writing about this original paper later in 1981 Dr Martin Wright (figure 26 in main text) says "I think the paper has been cited so much because it describes a test and an instrument which are practical and useful. In those days there was also room to put in a decent historical review and quite a bit of useful discussion and useful detail. Some years ago I noticed that although the peak flow meter (PFM) was mentioned and as often the key to the whole work, there was no longer any reference to our paper. It was evidently assumed that the PFM had been created by God. I have never got any award or honour but the Minimeter, a sort of paperback version (BMJ 1978; 2:1627-8), got a design award and is selling hundreds of thousands because it can be used by patients at home. My reward is knowing that I have made a substantial contribution to clinical medicine"

Undoubtedly the Wright Peak Flow Meter was a major advance in that useful repeated measurements of the patient's respiratory function were possible at any time and anywhere without the use of a large spirometer. Standard values of peak flow rates were available for adults and children. Subsequently the advent of the Minimeter allowed patients to use it in the home and chart their own respiratory function. This was a major step forward in the management of both asthma, cystic fibrosis and other respiratory conditions. Dr Wright says that "physiologists were a bit sniffy about the PFM holding that the proper way to measure flow is by volume and time but Colin McKerrow and Margery McDermott kindly did a very thorough calibration study".

 

1962 Polgar G, Denton R. Cystic fibrosis in adults. Studies in pulmonary function and some physical properties of bronchial mucus. Am Rev Respir Dis 1962; 85:319-327. [PubMed]
At this time only 2% of people with CF were over 20 years of age. Two of the 4 adults studied died and were autopsied. In all the recognition of CF had been only after years of illness. Interestingly the use of hypertonic saline was mentioned as causing “symptomatic improvement” – eventually, some 40 years later, this was confirmed in a large trial (Elkins et al, 2006 below). Functional abnormalities were: airway obstruction, stiffening of the lungs, increased arterial carbon dioxide and reduced arterial oxygen saturation.
The authors concluded the primary cause of the respiratory disease was obstruction of the airways secondary to impaired flow of abnormal bronchial mucus. They suggested that the practical conclusion would be to search for methods that could be used for mobilisation of the mucus from the airways.
Subsequently such treatments as hypertonic saline or rhDNase (Pulmozyme) proved to be an effective means of improving and preserving lung function.

 

1968 Mearns MB. Simple tests of ventilatory capacity in children with cystic fibrosis. Arch Dis Child 1968; 4:528-539. [PubMed]
The first reports of respiratory function tests in children with CF had been performed by West et al, 1954 (above). In Margaret Mearns's study from London the results of respiratory function tests were correlated with clinical and radiological findings. Thirty three of 85 patients had normal FEV1 and FVC but the day to day variability were considered to limit the value of the respiratory function tests. Reversibility in response to bronchodilators was described. Twenty eight had minimal X-ray change, stable and normal; 16 with localised damage had greater reduction in FEV1 than FVC; extensive damage was associated with significant reductions in both. The tests were a valuable aid to clinical assessment especially in those patients with no or little radiological changes.

Margaret Mearns observed that “the present study shows that without the mist tent (given such prominence by Leroy Matthews and others in the USA during the Sixties), but using intensive treatment for acute respiratory illness and very close follow up from the time of diagnosis, children presenting without permanent lung damage can remain well and maintain good respiratory function over a period of years”.

These were early days for respiratory function tests in many paediatric clinics in the UK. The Vitalograph was the first widely available bellows spirometer for non-specialist use. But most general paediatricians in the UK did not have a Vitalograph although most eventually used the Wright peak flow meter. Few children treated in general paediatric clinics lived to an age when the results would have been reliable – say over six years.

 

1969 Phelan PD, Gracey M, Williams HE, Anderson CM. Ventilatory function in infants with cystic fibrosis. Physiological assessment of inhalation therapy. Arch Dis Child 1969; 44: 393-400. [PubMed]
An early (possibly the first?) study of respiratory function in CF infants (figure 33 main text). Total gas volume, dynamic compliance and mean pulmonary resistance were measured in 18 infants less than 9 months old. Nine infants with no infection and others with infections all returned to normal when treated with intermittent inhalations of propylene glycol 10%, glycerine 2%, in 0.9% saline 2ml + 0.25 ml of 2% orciprenaline 1-4 x daily.

More recent studies of infant respiratory function show a mild but consistent degree of airways obstruction and hyperinflation even in uninfected young infants with cystic fibrosis (Ranganathan SC et al, Lancet 2001; 358:1964-1965.[PubMed]).

 

1971 Godfrey S, Mearns M. Pulmonary function and response to exercise in cystic fibrosis. Arch Dis Child 1971; 46:144-151. [PubMed]
In 41 patients with CF, aged between five and 21 years, there was a linear relationship between FEV1 and maximum voluntary ventilation and the general clinical grading. The authors suggested that “the pattern of physiological disturbance is so characteristic that it could well serve as an aid to diagnosis in doubtful cases and can be revealed by steady state exercise without the use of cardiac or arterial catheterisation”.

This may have been so in the authors’ experience but these physiological studies have never been made generally available to most people with CF in the UK nor have they made a significant contribution to clinical management or the understanding of the basic CF defect. Simon Godfrey, an academic respiratory paediatrician working at the Hammersmith Hospital, London, and Margaret Mearns at the Queen Elizabeth Hospital, Hackney combined on a number of interesting studies.

 

1973 Day G, Mearns MB. Bronchial lability in cystic fibrosis. Arch Dis Child 1973; 48:355-359. [PubMed]
The authors comment that Heimlich EM et al, in an abstract (J Allerg 1966; 37:103) surprisingly had failed to show a difference in bronchial lability between normal children and those with cystic fibrosis. However, the exercise had been more gentle. In the present study only 14 (27%) of the 52 children with CF had normal results; 50% had abnormal bronchodilatation on exercise and 46% had abnormal bronchoconstriction after exercise.

Bronchial lability is commonly present in people with CF and can be seen to gradually lessen as the bronchial infection is treated with intravenous antibiotics during an exacerbation.

 

1973 Landau LI, Phelan PD. The variable effect of a bronchodilating agent on pulmonary function in cystic fibrosis. J Pediatr 1973; 82:863-868. [PubMed]
An important paper from the Royal Children’s Hospital, Melbourne. Nine (18%) of 50 patients with CF had measurable response to bronchodilators as judged by the maximum expiratory flow-volume curve which demonstrates the maximum expiratory flow rate throughout the forced vital capacity manoeuvre (figure 1). The changes were complex. In 5 (10%) the changes were typical of asthma. Four had a fall in Vmax thought to be due to airway compression during forced expiration as had been reported previously. The authors note that previous reports indicate no effect or minimal improvement with bronchodilators (Cook CD et al. Pediatrics 1959; 24;181; Gandevia B & Anderson C. Arch Dis Child 1959; 34:511; Polgar G & Barbero GJ. Am J Dis Child 1960; 100:733; Zaptetal A et al. Pediatrics 1971; 48:64). Most people with CF have no changes, a few will show typical asthmatic response and will benefit from bronchodilators, BUT some develop reduced maximum expiratory flow rates possibly from compression of the larger airways (figure 2) – this could impair coughing and sputum clearance.


This is a paper from two experts with a clear message that bronchodilators can sometimes make the situation worse. The authors suggest that MEFV curve should be performed before bronchodilators are prescribed. Despite this and other studies, bronchodilators are prescribed for many people with CF and usually their effect on the MEFV is not checked – usually just the effect on FEV1 and FVC by simple spirometry – and also how the patient feels after the bronchodilator should be noted!! This approach seems to work well for most people with cystic fibrosis.

Maximum expiratory flow curves. From paper with permission.

 

Maximum expiratory flow curve from patient before and after bronchodilator. From paper with permission.

 

1979 Price JF, Weller PH, Harper SA, Matthews DJ. Response to bronchial provocation and exercise in children with cystic fibrosis. Clin Allerg 1979; 9:563-570. [PubMed]
Ten of 15 children with CF who had positive skin prick tests to allergens had an immediate reaction to the allergen inhaled; five had late reactions also but only one had a history of asthma. The most common positive skin reaction was to Aspergillus fumigatus - inhalation of the allergen was negative in two, immediate in one and dual in three. None showed the typical reaction to exercise of asthmatic children. Although the bronchial allergy did not totally explain the tendency for children with CF to have asthma and anti-allergy treatment may have a place.

 

1994 Beardsmore CS, Thompson JR, Williams A, McCardle EK, Gregory GA, Weaver LT, Simpson H. Pulmonary function in infants with cystic fibrosis: effect of antibiotic treatment. Arch Dis Child 1994; 71:133-137. [PubMed]
Children from the East Anglian neonatal screening programme (1985-1992) who were included in the flucloxacillin trial (Weaver et al, 1994 above) underwent infant respiratory function tests at three to four months and one year of age (measurements of thoracic gas volume and airway conductance using an infant whole body plethysmograph and maximum expiratory flow by the “squeeze” technique). There was no difference in lung function between the flucloxacillin treated infants and the control CF infants at any age.

Dr Carolyn Beardsmore (figure 34 main text) was one of the few experts in infant lung testing at the time in the UK and since has published widely on a variety of paediatric respiratory topics.
Periodically studies are published on infant respiratory function testing but the techniques are so complicated and time-consuming that they are usually only performed by the authors of the papers. Although valuable for research they have never been of great practical value in the clinic for most patients. In the present study it is not surprising that there was no difference between the treated and control infants as some hyperinflation is present in all CF infants from early infancy whether they are infected or not. Hyperinflation in most CF infants was confirmed in subsequent studies (Ranganathan et al, 2001 below).

 

2001 Ranganathan SC, Dezateux C, Bush A, Carr SB, Castle RA, Madge S, Price J, Stroobant J, Wade A, Wallis C, Stocks J. Airway function in infants newly diagnosed with cystic fibrosis. Lancet 2001; 358:1964-5. [PubMed]
The airway function of 33 infants with CF was significantly reduced compared with 87 healthy controls, even in those without clinically recognised previous lower respiratory illness.

Some degree of airway obstruction, increased residual volume and hyperinflation from an early age has been recognised for many years (Keats TE. Generalized pulmonary emphysema as an isolated manifestation of early cystic fibrosis of the pancreas. Radiology 1955; 65:223-226. [PubMed] above and subsequent studies). This present study confirms this fact. A follow up study was performed by Ranganathan et al. (Am J Resp Crit Care Med 2004; 169:928-933. [PubMed]) FEV 0.5 was measured soon after diagnosis (median age of 28 weeks) and 6 months later in subjects with CF and in healthy infants on two occasions 6 months apart using the raised-volume technique. The mean FEV 0.5 was significantly lower in infants with CF both shortly after diagnosis and at the second test with 72% of infants having a value less than the fifth percentile. So the airway function is already diminished soon after diagnosis in infants with CF and does not catch up during infancy and early childhood. These findings have important implications for early interventions in CF.

 

2005 Fischer R, Lang SM, Brückner K, Hoyer HX, Meyer S, Griese M, Huber RM. Lung function in adults with cystic fibrosis at altitude: impact on air travel. Eur Respir J 2005; 25:718-724. [PubMed]
Current guidelines for air travel state that patients with chronic respiratory diseases are required to use oxygen if their in-flight arterial oxygen tensions (Pa,O2) drop below 6.6 kPa. This recommendation may not be strictly applicable to cystic fibrosis patients, who may tolerate lower Pa,O2 for several hours without clinical symptoms. Lung function, symptoms, blood gas levels and signs of pulmonary hypertension were studied in 36 cystic fibrosis patients at altitudes of 530 m and, after 7 h, 2,650 m. A hypoxia inhalation test (inspiratory oxygen fraction 0.15) was performed at low altitude in order to predict high-altitude hypoxaemia. Median Pa,O2 dropped from 9.8 kPa at low altitude to 7.0 kPa at high altitude. Mild exercise at a workload of 30 W further decreased Pa,O2. Two-thirds of all patients exhibited Pa,O2 of <6.6 kPa during exercise and, except for one patient, were asymptomatic. Patients were significantly less obstructed at an altitude of 2,650 m. Low forced expiratory volume in one second at baseline was associated with a low Pa,O2 at altitude.

The authors concluded that cystic fibrosis patients with baseline arterial oxygen tensions of >8.0 kPa safely tolerate an altitude of 2,650 m for several hours under resting conditions. The risk assessment of low in-flight oxygenation should encompass the whole clinical situation of cystic fibrosis patients, with special attention being paid to the presence of severe airway obstruction.

 

2005 Aurora P, Bush A, Gustafsson P, Oliver C, Wallis C, Price J, Stroobant J, Carr S, Stocks J. London Cystic Fibrosis Collaboration. Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am J Resp Crit Care 2005; 171:249-256.[PubMed]
Sensitive measures of lung function applicable to young subjects are needed to detect early cystic fibrosis (CF) lung disease. Forty children with CF aged 2 to 5 years and 37 age-matched healthy control subjects performed multiple-breath inert gas washout, plethysmography, and spirometry. Thirty children in each group successfully completed all measures, with success on first visit being between 68 and 86% for all three measures. Children with CF had significantly higher lung clearance index (mean [95% CI] difference for CF control 2.7 [1.9, 3.6], p < 0.001) and specific airway resistance (1.65 z-scores [0.96, 2.33], p < 0.001), and significantly lower forced expired volume in 0.5 seconds (-0.49 z-scores [-0.95, -0.03], p < 0.05). Abnormal lung function results were identified in 22 (73%) of 30 children with CF by multiple-breath washout, compared with 14 (47%) of 30 by plethysmography, and 4 (13%) of 30 by spirometry. Children with CF who were infected with Pseudomonas aeruginosa had significantly higher lung clearance index, but no significant difference in other lung function measures, when compared with non infected children. Most preschool children can perform multiple-breath washout, plethysmography, and spirometry at first attempt. Multiple-breath washout detects abnormal lung function in children with CF more readily than plethysmography or spirometry

Dr Paul Aurora is Consultant Paediatrician at Great Ormond Street Hospital for Children, London. He subsequently further developed this test for use in children with early lung disease (Aurora P. Thorax 2010; 65:373-374.[PubMed]). He also has a major involvement in the paediatric transplantation programme at Great Ormond Street.

 

2008 Linnane BM, Hall GL, Nolan G, Brennan S, Stick SM, Sly PD, Robertson CF, Robinson PJ, Franklin PJ, Turner SW, Ranganathan SC. AREST-CF. Lung function in infants with cystic fibrosis diagnosed by newborn screening. Am J Resp Critical Care 2008; 178:1238-1244. [PubMed]
A study to measure lung function in infants with CF diagnosed by newborn screening and describe its association with pulmonary infection and inflammation. Lung function, measured by forced expiration, is normal in infants with CF at the time of diagnosis by newborn screening but is diminished in older infants. These findings suggest that in CF the optimal timing of therapeutic interventions aimed at preserving lung function may be within the first 6 months of life.

 

2008 Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008; 63:129-134. [PubMed].
The lung clearance index (LCI) from multiple-breath washout (MBW) is known to detect abnormal lung function more readily than spirometry in children and teenagers with CF, but its relationship to structural lung abnormalities is unknown. The authors concluded that LCI is a more sensitive indicator than FEV1 or FEF75 for detecting structural lung disease in CF, and a normal LCI almost excludes HRCT abnormalities. The finding of an abnormal LCI in some patients with normal HRCT scans suggests that LCI may be even more sensitive than HRCT scanning for detecting lung involvement in CF.

The lung clearance index is gaining increasing support as a measure of early non-invasive lung function also useful in young children.

 

2009 Fuchs SI, Eder J, Ellemunter H. Gappa M. Lung clearance index: normal values, repeatability, and reproducibility in healthy children and adolescents. Pediatr Pulmonol 2009; 44:1180-1185. [PubMed]
The aim of this prospective study was to assess within-test repeatability, short term reproducibility and long term reproducibility, and to establish normal values for the LCI in healthy children and adolescents using the sidestream ultrasonic flow sensor (EasyOne Pro, MBW Module, ndd Medical Technologies, Switzerland).This study confirms the reliability and robustness of equipment, protocol and analysis and the reliability of the MBW technique in general. The present data will help to interpret the effect of therapeutic interventions and interpretation of longitudinal data in patients with pulmonary diseases.

Further evidence that this test does seem to be an extremely useful.

 

2009 Horsley A. Lung clearance index in the assessment of airways disease. Respir Med 2009; 103:793-799. [PubMed]
In the last few years there has been a growing interest in lung clearance index (LCI), a measure of lung physiology derived from multiple breath washout tests. This resurgence of interest was initially driven by the recognition that such assessments were capable of detecting early airways disease in children, and are more sensitive and easier to perform in this population than conventional lung function tests [Aurora P, Kozlowska W, Stocks J. Gas mixing efficiency from birth to adulthood measured by multiple-breath washout. Respir Physiol Neurobiol, 2005;148(1-2):125-39]. With an appreciation of the importance of earlier identification of airways dysfunction, and prevention of irreversible structural airway changes, methods of following airways disease in these "silent years" are especially important. LCI has now been reported in studies involving all age groups, from infants to adults [Lum S, Gustafsson P, Ljungberg H, Hulskamp G, Bush A, Carr SB, et al. Early detection of cystic fibrosis lung disease: multiple-breath washout versus raised volume tests. Thorax, 2007;62(4):341-7; Horsley AR, Gustafsson PM, Macleod K, Saunders CJ, Greening AP, Porteous D, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax, 2008;63:135-40], and has a narrow range of normal over this wide age range, making it especially suitable for long-term follow-up studies. In cystic fibrosis (CF) particularly, there is a pressing need for sensitive and repeatable clinical endpoints for therapeutic interventions [Rosenfeld M. An overview of endpoints for cystic fibrosis clinical trials: one size does not fit all. Proc Am Thorac Soc, 2007;4(4):299-301], and LCI has been proposed as an outcome measure in future CF gene therapy studies [Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index in CF: a sensitive marker of lung disease severity. Thorax, 2008;63(2):96-7]. This review will consider how LCI is derived, how it differs from conventional lung function testing, and its applications and limitations.

This is an detailed review of lung clearance index with many useful references so the abstract has been included in full. Does seem to be an important applicable advance in respiratory function testing.

 

2010 Ellemunter H, Fuchs SI, Unsinn KM, Freund MC, Waltner-Romen M, Steinkamp G, Gappa M. Sensitivity of Lung Clearance Index and chest computed tomography in early CF lung disease. Resp Med 2010; 104:1834-1842. [PubMed].
The aim of this study was to prospectively investigate the diagnostic accuracy of the lung clearance index (LCI) measured by multiple Breath Washout (MBW) in comparison to chest computed tomography (CT) in CF patients with early lung disease and normal FEV(1) (>80% pred. ). The diagnostic accuracy of the LCI for detecting CF lung disease in patients with normal FEV(1) was good when compared to CT. Results indicate that structural changes are unlikely if a normal LCI is measured. The authors suggest that serial measurements of the LCI for assessing ventilation inhomogeneity may help to identify early structural lung disease and help to reduce the individual cumulative radiation dose.

Further evidence that LCI is a sensitive measure of even mild lung involvement in CF. It has the advantage of reducing the radiation to which people with CF are exposed over a lifetime. The technique appears to be a significant advance particularly as chest involvement is less gross in children but even so the early detection of abnormalities is crucial to avoid permanent progressive damage. LCI does seem to represent a significant advance. Paul Aurora from Great Ormond Street, London has published extensively in support of the technique.

 

2010 Amin R, Subbarao P, Jabar A, Balkovec S, Jensen R, Kerrigan S, Gustafsson P, Ratjen F. Hypertonic saline improves the LCI (lung clearance index) in paediatric patients with CF with normal lung function. Thorax 2010; 65:379-383. [PubMed]
The authors objective was to study the ability of the lung clearance index (LCI), a measure of ventilation inhomogeneity, to detect a treatment response to hypertonic saline inhalation in paediatric patients with CF with normal spirometry. In a crossover trial, 20 patients with CF received 4 weeks of hypertonic saline (HS) and isotonic saline (IS) in a randomised sequence separated by a 4 week washout period. The primary end point was the change in the LCI due to HS versus IS. Four weeks of twice-daily HS inhalation significantly improved the LCI compared with IS (1. 16, 95% CI 0. 26 to 2. 05; p=0. 016), whereas other outcome measures such as spirometry and quality of life failed to reach statistical significance. Randomisation order had no significant impact on the treatment effect. The LCI, but not spirometry was able to detect a treatment effect from HS inhalation in patients with CF with mild disease and may be a suitable tool to assess early intervention strategies in this patient population.

The early administration of hypertonic saline has a definite effect on improving lung function as measured by the lung clearance index - a sensitive test that is steadily gaining in popularity particularly as more children with CF have normal spirometry.

 

2011 Kieninger E, Singer F, Fuchs O, Abbas C, Frey U, Regamey N, Casaulta C, Latzin P. Long-term course of lung clearance index between infancy and school-age in cystic fibrosis subjects. J Cyst Fibros 2011; 10:487-490. [PubMed]
Multiple breath washout (MBW) measurements have recently been shown to be sensitive for detection of early cystic fibrosis (CF) lung disease, with the lung clearance index (LCI) being the most common measure for ventilation inhomogeneity. The aim of this observational study was to describe the longitudinal course of LCI from time of clinical diagnosis during infancy to school-age in eleven children with CF. Elevated LCI during infancy was present in seven subjects, especially in those with later clinical diagnosis. Tracking of LCI at follow-up was evident only in the four most severe cases. These are the first longitudinal data describing the long-term course of LCI in a small group of infants with CF. Our findings support the clinical usefulness of MBW measurements to detect and monitor early lung disease in children with CF already present shortly after clinical diagnosis.

See later study from Australia, mentioned below, which seems to cast doubt on the value of this tests in the first 2 years (Hall GL, et al. 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]).

 

2011 Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, Bush A, Price J, Carr SB, Shankar A, Stocks J. London Cystic Fibrosis Collaboration. Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care 2011; 183:752-758. [PubMed]
There is an urgent need for alternative surrogates that detect early lung disease and track through early childhood. This study aimed to determine whether multiple-breath washout (MBW) results at preschool age can predict subsequent abnormal lung function. Preschool children (3-5 yr) with CF and healthy control subjects underwent spirometry and MBW with testing repeated during early school age (6-10 yr). Primary outcomes were FEV1 from spirometry and lung clearance index (LCI) from MBW. Forty-eight children with CF and 45 healthy children completed testing. Thirty-five (73%) children with CF had abnormal LCI at preschool age, whereas only five had abnormal FEV1. The positive predictive value of preschool LCI for predicting any abnormal school-age result was 94%, with a negative predictive value of 62%. Only one child with abnormal FEV1 at school age had had a normal preschool LCI. In contrast, for preschool FEV1 the positive predictive value was 100%, but negative predictive value was only 25%. The authors concluded that their study demonstrates that an abnormal preschool LCI predicts subsequent lung function abnormalities, whereas a normal preschool LCI usually remains normal. MBW has potential as a clinical and research outcome in young children with CF.

The fact that 35/48 (73%) of preschool CF children had an abnormal lung clearance index but only 5/45 (11%) had an abnormal FEV1 attests to the sensitivity of the LCI. An abnormal LCI in preschool children with CF predicts later abnormalities.

 

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.

 

 

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 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.

 

2012 Pittman JE, Johnson RC, Davis SD. Improvement in pulmonary function following antibiotics in infants with cystic fibrosis. Pediatr Pulmonol 2012; 47:441-446. [PubMed]
While pulmonary function testing (PFT) is often used to follow progression of lung disease and guide treatment in older children with CF, little data is available on change in infant PFTs in young children with CF. Pre- and post-antibiotics PFT data was available on 11 infants with CF, with a mean age of 102 weeks at time of first PFT. The majority of infants were symptomatic prior to antibiotics, and showed statistically significant improvement in clinical parameters following treatment. Prior to antibiotics, PFTs showed evidence of substantial obstructive disease. Following antibiotics, all of the parameters showed statistically significant improvement. The authors have shown a statistically significant improvement in infant PFT measures following antibiotic therapy in a cohort of 11 infants with CF, which paralleled improvement in clinical parameters. Though infant PFTs showed improvement, they remained abnormal in the majority of subjects, with persistent air-trapping and hyperinflation after antibiotic therapy. So these findings suggest that infant PFTs are sensitive to acute clinical changes in children with CF, and may be a useful tool in managing infants with CF.

These findings are to be expected but the increasing use of more accurate objective measurement in young CF infants is an important advance particularly as the emphasis is increasingly on very early intervention with treatment such as antibiotics, rhDNase and hypertonic saline. Once again the significant proportion of CF infants who already have changes in their respiratory function, even after antibiotic therapy, is apparent.

 

2012 Haidopoulou K, Lum S, Turcu S, Guinard C, Aurora P, Stocks J, Sonnappa S. Alveolar LCI vs. standard LCI in detecting early CF lung disease. Respir Physiol Neurobiol 2012; 180:247-251. [PubMed]
Multiple breath washout (MBW) is a sensitive technique that detects early airways disease. However in very young children, large equipment and physiological dead space relative to lung volumes may result in a higher Lung Clearance Index (LCI). The authors investigated whether alveolar LCI (aLCI) is a more sensitive index than standard LCI in children. MBW data-sets from children aged 0.1-10.7 years [97 healthy controls and 93 with cystic fibrosis (CF)] were analysed. LCI is traditionally calculated by dividing the cumulative expired volume (CEV) by functional residual capacity (FRC) after correcting for equipment dead space. aLCI was calculated similarly, but after correcting the CEV and FRC for Langley's physiological dead space. There was a significant correlation between LCI and aLCI in health (r(2): 0.993; p<0.0001) and disease (r(2): 0.984; p<0.0001). Sensitivity of both LCI and aLCI in detecting abnormal lung function in CF was 39% during infancy, which increased to 77% and 83% respectively in older children. However, the difference in sensitivity (aLCI vs. LCI) was not significant (p=0.36).

The authors conclude that LCI is minimally affected by airway deadspace, or relative equipment deadspace, and is an appropriate measure of lung function in infancy.

Further evidence supporting the use of lung clearance index in young children

 

*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 essential to achieve the maximum benefit from newborn CF screening.

 

2012 Vandenbranden SL, McMullen A, Schechter MS, Pasta DJ, Michaelis RL, Konstan MW, Wagener JS, Morgan WJ, McColley SA. Investigators and Coordinators of the Epidemiologic Study of Cystic Fibrosis. Lung function decline from adolescence to young adulthood in cystic fibrosis. Pediatr Pulmonol 2012; 47:135-143. [PubMed].
The authors identified 4,680 patients in the Epidemiologic Study of Cystic Fibrosis 1994-2005 with data in both adolescence (age 14.0-17.4 years) and young adulthood (age 18.5-22.0 years) and analyzed 2,267 who had >=5 encounters and >=5 measurements of forced expiratory volume in 1 second (FEV(1) ) spanning >=1 year during both adolescence and young adulthood, and >=1 encounter with weight and height and >=1 FEV(1) measurement age 17.5-18.5 years. They compared the annualized rates of decline in FEV(1) during adolescence and young adulthood stratified by best FEV(1) around age 18. Logistic regression was used to identify risk factors associated with substantial decline (>20 points) in FEV(1) % predicted in young adulthood.

The annual rate of decline was greater in young adulthood than in adolescence. Risk factors for substantial decline included slower rate of FEV(1) decline, greater FEV(1) variability, faster body mass index (BMI) decline, male sex, chronic inhaled antibiotics, Hemophilus influenzae detection, and absence of multidrug-resistant Pseudomonas aeruginosa in adolescence, and lower than expected FEV(1) and BMI around age 18.

The authors concluded that decline in lung function accelerates in young adults with CF, especially in those with early stage lung disease. Adolescents at risk for substantial decline in lung function in young adulthood have higher FEV(1) and worse nutritional status, among other identifiable risk factors.

 

2013 Horsley AR. Davies JC. Gray RD. Macleod KA. Donovan J. Aziz ZA. Bell NJ. Rainer M. Mt-Isa S. Voase N. Dewar MH. Saunders C. Gibson JS. Parra-Leiton J. Larsen MD. Jeswiet S. Soussi S. Bakar Y. Meister MG. Tyler P. Doherty A. Hansell DM. Ashby D. Hyde SC. Gill DR. Greening AP. Porteous DJ. Innes JA. Boyd AC. Griesenbach U. Cunningham S. Alton EW. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013; 68:532-9. [PubMed]

A study by members of the UK Gene Therapy Consortium to evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for their 2013-2014 clinical trial of CFTR gene therapy. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers.

Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31).

The authors identified the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with their study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

The UK Gene Therapy Consortium commenced their multi-dose major gene therapy trial in June 2012 (Alton EW et al. Pediatr Pulmonol 2013; Suppl 36: Poster 245). This study helped to determine the parameters which would be used in the trial. The primary outcome chosen was the FEV1 and secondary outcomes the lung clearance index, CT changes and CFQ questionnaire. The trial will be completed around June 2014.

The Cystic Fibrosis Trust provided substantial funding for these studies and many other studies during the decade leading up to the gene therapy trial but was unable to fund the trial itself for which the GTC, due to the excellence of their work, were successful in achieving funding from the Medical Research Council Efficacy and Mechanism Evaluation (EME) funding.

 

2013 Adam RJ. Michalski AS. Bauer C. Abou Alaiwa MH. Gross TJ. Awadalla MS. Bouzek DC. Gansemer ND. Taft PJ. Hoegger MJ. Diwakar A. Ochs M. Reinhardt JM. Hoffman EA. Beichel RR. Meyerholz DK. Stoltz DA. Air trapping and airflow obstruction in newborn cystic fibrosis piglets. Am J Resp Crit Care 2013; 188:1434-41.[PubMed]

Air trapping and airflow obstruction are being increasingly identified in infants with cystic fibrosis. These findings are commonly attributed to airway infection, inflammation, and mucus build up. This study was to determine if air trapping and airflow obstruction are present before the onset of airway infection and inflammation in cystic fibrosis. On the day they are born, piglets with CF lack airway infection and inflammation so the authors used newborn wild-type piglets and piglets with CF to assess air trapping, airway size, and lung volume with inspiratory and expiratory X-ray computed tomography scans. Micro-computed tomography scanning was used to assess more distal airway sizes. Airway resistance was determined with a mechanical ventilator. Mean linear intercept and alveolar surface area were determined using stereologic methods.

On the day they were born, piglets with cystic fibrosis exhibited air trapping more frequently than wild-type piglets (75% vs. 12.5%, respectively). Moreover, newborn piglets with CF had increased airway resistance that was accompanied by luminal size reduction in the trachea, mainstem bronchi, and proximal airways. In contrast, mean linear intercept length, alveolar surface area, and lung volume were similar between both genotypes. The authors conclude that the presence of air trapping, airflow obstruction, and airway size reduction in newborn piglets with cystic fibrosis before the onset of airway infection, inflammation, and mucus accumulation indicates that cystic fibrosis impacts airway development. They suggest their findings suggest that early airflow obstruction and air trapping in infants with cystic fibrosis might, in part, be caused by congenital airway abnormalities.

This is a fascinating study showing what has been suspected previously – that the airways of the newborn with CF are anatomically abnormal. Anatomical abnormalities have already been described in airways of CF piglets (Meyerholz DK et al, 2010. [PubMed] 20622026). The trachea and mainstem bronchi had a uniformly small calibre and cross-sections of trachea were less circular than in controls, the trachealis smooth muscle had an altered bundle orientation and increased transcripts in a smooth muscle gene set, the submucosal glands were hypoplastic and had global reductions in tissue-specific transcripts. To learn whether any of these changes occurred in young patients with CF, they examined CT scans from children 2 years of age and younger, and found that CF tracheas were less circular in cross-section, but lacked differences in lumen area. However, analysis of previously published morphometric data showed reduced tracheal lumen area in neonates with CF.

Occasionally the lower airway abnormalities are such that a young infant presents a clinical picture resembling tracheomalacia with intractable expiratory wheezing which gradually improves through infancy.

 

2013 Rosenfeld Mj, Arets BH, Aurora P, Beydon N, Calogero C, Castile RG, Davis SD, Fuchs S, Gappa M, Gustaffson PM, Hall GL, Jones MH, Kirkby JC, Kraemer R, Lombardi E, Lum S, Mayer OH, Merkus P, Nielsen KG, Oliver C, Oostveen E, Ranganathan S, Ren CL,, Robinson PD, Seddon PC, Sly PD, Sockrider MM, Sonnappa S, Stocks J, Subbarao P, Tepper RS, Vilozni D. American Thoracic Society Assembly on Pediatrics Working Group on Infant and Preschool Lung Function Testing. An official American Thoracic Society workshop report: optimal lung function tests for monitoring cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheezing in children less than 6 years of age. Annals of the American Thoracic Society 2013; 10:S1-S11. [PubMed]

Official American Thoracic Society workshops were convened in 2009 and 2010 to review six lung function tests based on a comprehensive review of the literature (infant raised-volume rapid thoracic compression and plethysmography, preschool spirometry, specific airway resistance, forced oscillation, the interrupter technique, and multiple-breath washout). In these proceedings, the current state of the art for each of these tests is reviewed as it applies to the clinical management of infants and children under 6 years of age with cystic fibrosis, bronchopulmonary dysplasia, and recurrent wheeze, using a standardized format that allows easy comparison between the measures. Although insufficient evidence exists to recommend incorporation of these tests into the routine diagnostic evaluation and clinical monitoring of infants and young children with cystic fibrosis, bronchopulmonary dysplasia, or recurrent wheeze, they may be valuable tools with which to address specific concerns, such as ongoing symptoms or monitoring response to treatment, and as outcome measures in clinical research studies

As it is realised that very early treatment and monitoring are of crucial importaance to identify infection and reduce early lung damage this review is timely. Previously unavailable to many infants it appears feasible to use the newer techniques such as multiple breath washouts even infants.

 

2013 Singer F. Kieninger E. Abbas C. Yammine S. Fuchs O. Proietti E. Regamey N. Casaulta C. Frey U. Latzin P. Practicability of nitrogen multiple-breath washout measurements in a pediatric cystic fibrosis outpatient setting. Pediat Pulmonol 2013; 48:739-46. [PubMed]

Although lung clearance index (LCI) is a sensitive indicator of mild cystic fibrosis (CF) lung disease, it is rarely measured due to lengthy protocols and the commercial unavailability of multiple-breath washout (MBW) setups and tracer gases. We used a newly validated, commercially available nitrogen (N2 ) MBW setup to assess success rate, duration, and variability of LCI within a 20min timeframe, during clinical routine. We also evaluated the relationship between LCI and other clinical markers of CF lung disease. METHODS: One hundred thirty six children (83 with CF) between 4 and 16 years were studied in a pediatric CF outpatient setting. One hundred eighteen out of 136 children were naive to MBW. Within 20min, each child was trained, N2 MBW was performed, and LCI was analyzed. We assessed intra- and between-test reproducibility in a subgroup of children. RESULTS: At least one LCI was feasible in 123 (90%) children, with a mean (range) of 3.3 (1.2-6.4) min per test. Two or more measurements were feasible in 56 (41%) children. Comparing LCI in CF versus controls, LCI mean (SD) was 12.0 (3.9) versus 6.1 (0.9), and the intra- and inter-test coefficient of repeatability was 1.00 versus 0.81 and 0.96 versus 0.62, respectively. LCI was correlated with spirometry, blood gases, and Pseudomonas aeruginosa infection.

The authors concluded that using available N2 MBW equipment, LCI measurements are practical and fast in children. LCI is correlated with markers of CF lung disease.

 

 

2013 Subbarao P. Stanojevic S. Brown M. Jensen R. Rosenfeld M. Davis S. Brumback L. Gustafsson P. Ratjen F. Lung clearance index as an outcome measure for clinical trials in young children with cystic fibrosis. A pilot study using inhaled hypertonic saline. Am J Respir Crit Care 2013; 188:456-60. [PubMed]

To study the feasibility of using LCI to assess treatment effect outcomes in CF trials of infants and preschoolers. The Infant Study of Inhaled Saline trial was a multicenter, randomized, controlled trial of hypertonic (7%) versus isotonic (0.9%) saline inhaled twice daily for 48 weeks in children with CF under 6 years of age.

LCI measurements were performed in a single-center pilot substudy at baseline and 48 weeks using a respiratory mass spectrometer and sulfur hexafluoride as the tracer gas. LCI measurements were standardized using published normative data (zLCI) to account for height-related changes in LCI during early childhood. A generalized estimating equation model with an interaction between treatment group and test occasion was used to estimate a treatment effect.

A total of 27 participants were randomized; 25 participants, aged (median [range]) 2.6 (0.34-4.95) years, had acceptable baseline and follow-up LCI measures. On average, LCI decreased in the hypertonic saline group (n = 12) by 1.19 z-scores units (95% confidence interval [CI] = -2.46 to 0.06), and remained stable in the isotonic saline group (n = 13) at 0.81 (95% CI = -0.40 to 2.02).

A significant treatment effect was observed for zLCI (2.01; 95% CI = 0.26 to 3.76; P = 0.025)

The authors concluded that multiple breath washout (MBW) testing is feasible in an interventional study in infants and preschool children with CF. These pilot findings support the development of MBW and LCI as an objective outcome measure in interventional trials in young children with CF, and provide estimates for sample size calculations for future studies.

The lung clearance index appears to be deservedly gaining general acceptance as a measure of respiratory function in prescchool children - such an important age group as the need for early intervention and its effects become increasingly apparent.

 

 

2014 Kent L. Reix P. Innes JA. Zielen S. Le Bourgeois M. Braggion C. Lever S. Arets HG. Brownlee K. Bradley JM. Bayfield K. O'Neill K. Savi D. Bilton D. Lindblad A. Davies JC. Sermet I. De Boeck K. European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) Standardisation Committee. Lung clearance index: evidence for use in clinical trials in cystic fibrosis. J Cyst Fibros 2014;13(2):123-38. [PubMed]
The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease.
 
This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF. Thisi method of respiratory function testing, applicable to all age groups, has undoubtedly been one of the major advaces in recent years.

 

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 Rodriguez Hortal MC. Hjelte L. Time point to perform lung function tests evaluating the effects of an airway clearance therapy session in cystic fibrosis. Respir Care 2014; 59:1537-41.2014.[PubMed]
The authors found that performing spirometry 30 min after a session in adults and immediately after in children appeared to be optimal if individual peak time values cannot be used.

 

 

2014 Welsh L, Robertson C F, Ranganathan SC. Increased rate of lung function decline in Australian adolescents with cystic fibrosis. Pediatr Pulmonol 2014; 49:873-7. [PubMed]
Although baseline lung function as measured by spirometry in children with cystic fibrosis has improved, the annual rate of decline has not changed significantly during the critical period of adolescence. The aim of this study was to describe factors associated with longitudinal decline in lung function in a contemporary cohort of children with CF.
The authors confirmed that FEV(1) declines at its sharpest rate during adolescence even in the presence of newborn screening. Genotype, increasing age, CFRD, PsA infection, pancreatic insufficiency and a greater number of respiratory hospitalizations are all associated with an increased rate of lung function decline in Australian children and adolescents with cystic fibrosis.


This data from Melbourne confirms the tendency for decline in respiratory function to be a frequent occurrence during adolescence.
Liam Welsh (figure) is Senior Scientist in the Respiratory Unit at the Royal Children's Hospital Melborne.

 


2015 Banton GL, Hall GL, Tan M, Skoric B, Ranganathan SC, Franklin PJ, Pillow JJ, Schulzke SM, Simpson SJ. Multiple breath washout cannot be used for tidal breath parameter analysis in infants. Pediatr Pulmonol. 2015 Oct 5. doi: 10.1002/ppul.23326. [Epub ahead of print]
 [PubMed]

Multiple breath washout (MBW) testing with SF6 gas mixture is routinely used to assess ventilation distribution in infants. It is currently unknown whether SF6 changes tidal breathing parameters during MBW in infants. We investigated if SF6 does change tidal breathing parameters in infants and whether a separate tidal breathing trace prior to MBW testing is necessary.
The authors found differences in tidal breathing parameters during MBW testing with SF6 in infants. It is, therefore, important to measure a separate tidal breathing trace in room air, prior to MBW testing to ensure rigour of tidal breath indices derived from analysis.

 

2015Davis SD, Ratjen F, Brumback LC, Johnson RC, Filbrun AG, Kerby GS, Panitch HB, Donaldson SH, Rosenfeld M; ISIS Study Group. Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis. J Cyst Fibros. 2015 Nov 4. pii: S1569-1993(15)00249-0. doi: 10.1016/j.jcf.2015.10.007. [Epub ahead of print]        [PubMed]
The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilise infant pulmonary function tests (iPFTs) as an endpoint. However, the authors concluded iPFTs are, as yet, not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. However, they suggest raised volume measures have potential to serve as secondary endpoints in future clinical CF trials.
 

Davies J, Sheridan H, Bell N, Cunningham S, Davis SD5, Elborn JS, Milla CE, Starner TD, Weiner DJ, Lee PS, Ratjen F.  Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry: a randomised controlled trial.  Lancet Respir Med. 2013 Oct;1(8):630-8. doi: 10.1016/S2213-2600(13)70182-6. Epub 2013 Sep 10. [PubMed]
Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV1) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV1 >90% predicted.
This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV1 >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI.
Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group).
Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor.
The authors concluded that in patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in Lung Clearance Index. They suggest that LCI might be a more sensitive alternative to FEV1 in detecting response to intervention in these patients with mild lung disease.
 
2015 Ellemunter H, Eder J, Fuchs S, Gappa M, Steinkamp G.  Long-term improvement of lung clearance index in patients with mild cystic fibrosis lung disease: Does hypertonic saline play a role?  J Cyst Fibros. 2015 Jul 16. pii: S1569-1993(15)00162-9. doi: 10.1016/j.jcf.2015.06.009. [Epub ahead of print]  [PubMed]
A study to assess effect of long-term inhalation of hypertonic saline (HS). 34 patients with mild lung disease (FEV1≥70% of predicted) had at least one LCI result before and ≥2 LCI measurements after start of hypertonic saline (HS) therapy. After a mean follow-up of 39.7 (SD 7.4) months after starting HS, LCI improved significantly from 7.89 (SD 1.35) at baseline to 6.96 (SD 1.03), and 19/34 patients had a normal LCI value at the last measurement. No decrease in mean FEV1 was observed. Thus, ventilation inhomogeneity can improve in patients with mild lung disease.
 

- The authors, whilst admitting the drawbacks of the study, in particular the retrospective file evaluation of longitudinal MBW and spirometry measurements, observed a statistically significant and clinically relevant improvement in LCI over three years of hypertonic saline inhalation, in parallel with stable FEV1 results. This was in sharp contrast to the one percent yearly decline in FEV1 observed before starting HS. They suggest that the deterioration of lung disease can be halted in mildly affected patients, provided that early lung disease is detected with sensitive methods and treatment is adjusted accordingly.
 
- A number of previous publications have reported normal LCI values for children (Fuchs SI et al 2009 [PubMed]). Mean LCI (SD) on three occasions was 6.2 (0.4), 6.3 (0.4), and 6.0 (0.4) at the 1st, 2nd, and 3rd test. The upper limit of normal was 7.0 for all subjects. Within-test repeatability was 5.1%. Short-term reproducibility (1st test vs. 2nd test) was 4.2% with a mean difference of -0.13 (95% CI -0.350; 0.087). Long-term reproducibility (1st test vs. 3rd test) was 5.1%, with a mean difference of 0.017 (95% CI -0.016; 0.348).
 

 

2015 Matecki S, Kent L, de Boeck K, Le Bourgeois M, Zielen S, Braggion C, Arets HG, Bradley J, Davis S, Sermet I, Reix P; respiratory function group of the European Cystic Fibrosis Society Clinical Trial Network.  Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis?  J Cyst Fibros. 2015 Apr 15. pii: S1569-1993(15)00070-3. doi: 10.1016/j.jcf.2015.03.015. [Epub ahead of print][PubMed]
The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status.
The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. They advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies and emphasise the need for (1) more short-term variability and longitudinal 'natural history' studies, and (2) robust reference values for commercially available devices.

 


Ramsey KA, Ranganathan S, Park J, Skoric B, Adams AM, Simpson SJ, Robins-Browne RM, Franklin PJ, de Klerk NH, Sly PD, Stick SM, Hall GL; AREST CF.  Early respiratory infection is associated with reduced spirometry in children with cystic fibrosis.  Am J Respir Crit Care Med 2014; 190(10):1111-6.     doi: 10.1164/rccm.201407-1277OC. [PubMed]
Lung function (forced expiratory volume in the first three-quarters of a second [FEV0.75], FVC) was assessed in individuals with cystic fibrosis diagnosed after newborn screening and healthy subjects during infancy (0-2 yr) and again at early school age (4-8 yr). Individuals with cystic fibrosis underwent annual bronchoalveolar lavage fluid examination, and chest computed tomography. They determined which clinical outcomes (pulmonary inflammation, infection, structural lung disease, respiratory hospitalisations, antibiotic prophylaxis) measured in the first 2 years of life were associated with reduced lung function in infants and young children with cystic fibrosis, using a mixed effects model.
Children with cystic fibrosis (n = 56) had 8.3% (95% confidence interval [CI], -15.9 to -6.6; P = 0.04) lower FEV0.75 compared with healthy subjects (n = 18). Detection of pro-inflammatory bacterial pathogens in bronchoalveolar lavage fluid was associated with clinically significant reductions in FEV0.75 (ranging between 11.3 and 15.6%).
The onset of lung disease in infancy, specifically the occurrence of lower respiratory tract infection, is associated with low lung function in young children with cystic fibrosis. Deficits in lung function measured in infancy persist into childhood, emphasising the need for targeted therapeutic interventions in infancy to maximise functional outcomes later in life.
 

- More evidence that intervention against infection must be very early in CF infants if the decline in respiratory function is to be minimised or hopefully even avoided.  The UK CF Trust Antibiotic Working Group’s recommendation of longterm flucloxacillin for CF infants from birth for at least the first 3 years seems to be supported by recent studies of this type.

 

 

2015 Subbarao P; Milla C; Aurora P; Davies JC; Davis SD; Hall GL; Heltshe S; Latzin P; Lindblad A; Pittman JE; Robinson PD; Rosenfeld M; Singer F; Starner TD; Ratjen F; Morgan W.  Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report.  Ann Amer Thorac Soc 2015; 12(6):932-9.  [PubMed]
This workshop, of distinguished attendees, concluded that the Multiple Brehttp://www.sickkids.ca/images/Staff%20profiles/9748-011549.jpgath Washout (MBW) test is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients
with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardisation across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, they concluded there are insufficient data to support the use of Lung Clearance Index or MBW parameters in the routine clinical management of patients with CF.
 

- This attractive, non-invasive, test has received considerable attention and evaluation in recent years, particularly as a measure of respiratory function in young children. It is likely to gain general acceptance as a measure of respiratory function in young patients and represents a major advance

 

2015 Sonneveld N, Stanojevic S, Amin R, Aurora P, Davies J, Elborn JS, Horsley A, Latzin P, O'Neill K, Robinson P, Scrase E, Selvadurai H, Subbarao P, Welsh L, Yammine S, Ratjen F. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations.  Eur Respir J. 2015 Oct; 46(4):1055-64. doi: 10.1183/09031936.00211914. Epub 2015 Jul 9. [PubMed]
A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.
Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI −0.60– −0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: −0.9%, 95% CI −1.0– −0.4%).
LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.
A retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations in CF and to understand factors explaining the heterogeneous response.
The study confirms that LCI does decrease significantly in patients with CF treated for a pulmonary exacerbation. However the overall effect size was smaller for LCI than for FEV1, and there was discordance between FEV1 and LCI.
The authors suggest future studies should assess how treatment response assessed by LCI is linked to the subsequent course of lung disease as well as long-term outcomes.
 
 2015 Sanders B, Emerson J, Ren CL, Schechter MS, Gibson RL, Morgan W, Rosenfeld M; EPIC Study Group.  Early Childhood Risk Factors for Decreased FEV1 at Age Six to Seven Years in Young Children with Cystic Fibrosis.  Ann Am Thorac Soc. 2015; 12(8):1170-6.    doi: 10.1513/AnnalsATS.201504-198OC. [PubMed]
To evaluate early childhood predictors of lung function at age 6-7 in a large U.S. CF cohort in the current era of widespread early eradication therapy for P. aeruginosa.   Participants were children with CF enrolled before age 4 in the Early Pseudomonas Infection Control (EPIC) Observational Study, a multicenter, longitudinal study that enrolled P. aeruginosa-negative children not exceeding 12 years of age. Linear regression was used to estimate the association between potential early childhood risk factors and the best FEV1% predicted at age 6-7 years.
Four hundred and eighty-four children (of 1,797 enrolled in the EPIC Observational Study) met the eligibility criteria for this analysis. Mean (SD) age at enrolment was 2.0 (1.3) years.
In a multivariable model adjusted for age at enrolment, the following risk factors were significantly associated with lower mean (95% confidence interval) FEV1% predicted at age 6-7: weight percentile less than 10% during the year of enrolment (-5.3 [-9.1, -1.5]), P. aeruginosa positive during the year of enrolment (-2.8 [-5.7, 0.0]), crackles or wheeze during the year of enrolment (-5.7 [-9.4, -1.9]), mother's education of high school or less (-4.2 [-7.3, -1.2]), and mother smoked during pregnancy (-4.4 [-8.8, 0.1]).
In this large U.S. cohort, the authors identified several early childhood risk factors for lower FEV1 at age 6-7 years, most of which are modifiable.
 

- Most of the factors identified are predictable and have been suggested in previous studies but it is good to have them clearly documented in a alrge population.

 


2015 Schultz A, Stick S. Early pulmonary inflammation and lung damage in children with cystic fibrosis. Respirology 2015 Mar 30. doi: 10.1111/resp.12521. [Epub ahead of print]
[PubMed]

Individuals with cystic fibrosis (CF) suffer progressive airway inflammation, infection and lung damage. Airway inflammation and infection are present from early in life, often before children are symptomatic. CF gene mutations cause changes in the CF transmembrane regulator protein that result in an aberrant airway microenvironment including airway surface liquid (ASL) dehydration, reduced ASL acidity, altered airway mucin and a dysregulated inflammatory response. This review discusses how an altered microenvironment drives CF lung disease before overt airway infection, the response of the CF airway to early infection, and methods to prevent inflammation and early lung disease.

- Already there are a number of significant structural changes in the CF infant by the time of birth as evidenced by the often severe pancreatic changes (figure: neonatal CF pancreas). These changes permitted Dorothy Andersen to recognise CF as a distinct entity among the many marasmic infants that came to postmortem in New York during the Thirties. These changes are likely to be irreversible as may also be the case with the prenatal changes in the lung where early structural and inflammatory changes, even in the fetus, have been described and reviewed (Verhaeghe C et al. J Cyst Fibros 2007; 6:304-308. [PubMed] Full text of an interesting review), the possibility of inflammatory changes being related to ion channel abnormalities was suggested.

 


Sanders B, Emerson J, Ren CL, Schechter MS, Gibson RL, Morgan W, Rosenfeld M; EPIC Study Group.  Early Childhood Risk Factors for Decreased FEV1 at Age Six to Seven Years in Young Children with Cystic Fibrosis.  Ann Am Thorac Soc. 2015; 12(8):1170-6.    doi: 10.1513/AnnalsATS.201504-198OC. [PubMed]

To evaluate early childhood predictors of lung function at age 6-7 in a large U.S. CF cohort in the current era of widespread early eradication therapy for P. aeruginosa.   Participants were children with CF enrolled before age 4 in the Early Pseudomonas Infection Control (EPIC) Observational Study, a multicenter, longitudinal study that enrolled P. aeruginosa-negative children not exceeding 12 years of age. Linear regression was used to estimate the association between potential early childhood risk factors and the best FEV1% predicted at age 6-7 years.
Four hundred and eighty-four children (of 1,797 enrolled in the EPIC Observational Study) met the eligibility criteria for this analysis. Mean (SD) age at enrolment was 2.0 (1.3) years.
In a multivariable model adjusted for age at enrolment, the following risk factors were significantly associated with lower mean (95% confidence interval) FEV1% predicted at age 6-7: weight percentile less than 10% during the year of enrolment (-5.3 [-9.1, -1.5]), P. aeruginosa positive during the year of enrolment (-2.8 [-5.7, 0.0]), crackles or wheeze during the year of enrolment (-5.7 [-9.4, -1.9]), mother's education of high school or less (-4.2 [-7.3, -1.2]), and mother smoked during pregnancy (-4.4 [-8.8, 0.1]).
In this large U.S. cohort, the authors identified several early childhood risk factors for lower FEV1 at age 6-7 years, most of which are modifiable.
 

- Most of the factors identified are predictable and have been suggested in previous studies but it is good to have them clearly documented in such a large population.

 


2015 Hall H; Gadhok R; Alshafi K; Bilton D; Simmonds NJ. Eradication of respiratory tract MRSA at a large adult cystic fibrosis centre. Respir Med 2015; 109(3):357-63.  [PubMed]

This is an observational cohort study from the Royal Brompton Hospital of all patients with MRSA positive sputum, 2007-2012. All eradication attempts with subsequent culture results were reviewed. Single vs. dual antibiotic regimens were compared for both new and chronic infections.
37 patients (median FEV1 58.7 (27.6-111.5)% predicted) were identified, of which 67.6% (n = 25) had newly acquired MRSA. Compared with single regimens, a high proportion of dual regimens achieved MRSA eradication (84.6% vs. 50%; p = 0.1) for new infections. Rifampicin/Fusidic acid was associated with high success rates (100% vs. 60% for other dual regimens (p = 0.13)). Compared with new infections, chronic MRSA was much less likely to be eradicated (18.2%, p = 0.01).
The authors concluded combined antibiotic therapy, particularly Rifampicin/Fusidic acid, is a well-tolerated and effective means of eradicating MRSA in patients with cystic fibrosis.