RESPIRATORY FUNCTION

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 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' 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 (figure 25).

Figure 25: A young man with CF showing the typical appearance associated with pulmonary involvement - an over inflated chest, severe kyphosis and very poor nutritional state typical of CF at the time.

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) 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). 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).

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 et al, (J Allerg 1966; 37:103) surprisingly had failed to show a difference in bronchial lability between normal children and those with cystic fibrosis. 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 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 8). 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 9) – 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.

Figure 8: Maximum expiratory flow curves. From paper with permission.

Figure 9: 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.

Figure 28. Professor John Price.

Professor John Price founded the Paediatric Respiratory Unit at Kings College Hospital, London. He developed the CF service there and also a shared care programme for children with CF at other general hospitals in the South East of England. More recently he was closely involved in the supervision and organisation of the successful introduction of neonatal screening into the UK in 2007.

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) 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.

Fig. 21.1: Dr Sarath Ranganathan.

Dr Sarath Ranganathan (figure 21.1) from Royal Melbourne Children's Hospital carried out this work at Great Ormond Street Hospital in London in Professor Stocks department. He subsequently moved to Royal Melbourne Children's Hospital as Respiratory Paediatrician and has now returned to Brighton University in the UK.

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 excellent review of lung clearance index with many useful references - abstract has been included in full. Does seem to be an important applicable advance in respiratory function testing.

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