The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

Armstrong DS, Nixon GM, Carzino R, Bigham A, Carlin JB, Robins-Browne RM, Grimwod K. Detection of a widespread clone of Pseudomonas aeruginosa in a pediatric cystic fibrosis clinic. Am J Resp Crit Care 2002; 166:983-987 [PubMed]
The authors comment that cross-infection by Pseudomonas aeruginosa between unrelated patients with CF is believed to be uncommon. After detecting a genotypically identical strain of P. aeruginosa in five unrelated children with CF dying from severe lung disease at their centre, the authors determined its prevalence within a large CF clinic using pulsed-field gel electrophoresis and random amplified polymorphic DNA assays. P. aeruginosa was detected in 118 (78%) children of mean age 13.5 years - 65 (55%) of infected patients carried an indistinguishable or closely related strain and were more likely  to have been hospitalized in the preceding 12 months for respiratory exacerbations.

This study demonstrates extensive spread of a single, clonal strain of P. aeruginosa in a large paediatric CF clinic. Whether such a strain is also more virulent than sporadic isolates remains to be determined however the fatal outcome for 5 of these children suggests this was almost certainly the case.  As transmissible strains could emerge elsewhere, the authors suggested that other CF clinics may also need to consider molecular methods of surveillance for cross-infection; such surveillance was already routine in many large CF centres.

This is a really tragic story and further evidence of the potential and at times very real dangers of spread of highly transmissible strains of P. aeruginosa. The fact the 5 children died attests to this strain's virulence and this type of highly transmissible infection also leads to a requirement for more treatment (Jones AM et al. 2002 below). This is yet another study recommending to others that molecular methods should be used when studying cross infection in CF centres. It is interesting and of some concern that around this time in some major CF centres, there were still clinicians who doubted the need for segregation even though the first major epidemic had been described in 1996 from Liverpool (Cheng et al, 1996 above).

 

 

Augarten A, Goldman R, Laufer J, Szeinberg A, Efrati O, Barak A, Miller MS, Yahav Y. Reversal of digital clubbing after lung transplantation in cystic fibrosis patients: a clue to the pathogenesis clubbing. Pediatr Pulmonol 2002; 34:378-380. [PubMed]
Digital clubbing is a common sign in cystic fibrosis and in a variety of other diseases. However, its pathogenesis remains obscure. In diseases other than CF, regression of clubbing has been noted after cure of the underlying disease. The aim of this study was to assess whether clubbing is reversible in CF patients after lung transplantation. Digital clubbing was investigated in 3 CF patients, prior to and after lung transplantation.

The authors conclude that digital clubbing is reversible in CF patients who undergo lung transplantation. Regression was usually noted during the first 3 months post transplantation. This could be explained either by adequate inactivation of a circulating "clubbing-inducing molecule"(!) by the normal transplanted lungs, or by removal of the diseased lungs in which this presumably causative substance was produced.

 

The reversal clubbing was noted by some of the people with CF who had the first transplants in the Eighties. This paper merely confirms that clubbing may regress after lung transplantation.

 

 

Ben-Chetrit A. Antenos M. Jurisicova A. Pasyk EA. Chitayat D. Foskett JK. Casper RF. Expression of cystic fibrosis transmembrane conductance regulator during early human embryo development. Mol Human Reprod 2002; 8:758-764. [PubMed]
Formation of the blastocyst is one of the first morphological changes in early embryonic development. Ion transport has been shown to be crucial for blastocoele cavity formation and expansion, although the mechanisms that underlie this process are presently unknown. As a transmembrane Cl(-) channel, the cystic fibrosis transmembrane conductance regulator (CFTR) may participate in ion transport and early blastocoele formation. CFTR mRNA was detected throughout preimplantation embryo development and in the unfertilized oocyte. Immunocytochemistry disclosed the presence of CFTR protein from the 8-cell stage, reaching maximum immunoreactivity at early blastocyst stage embryos. Patch clamp electrophysiology of morulae and blastocysts demonstrated typical CFTR Cl(-) channel activities in the apical membrane of trophectoderm cells.

 

Thus CFTR is expressed both at mRNA and protein levels in human morulae and blastocysts, and functions as a cAMP-regulated apical membrane Cl(-) channel. These data suggest that CFTR may contribute to blastocoele formation in the early human embryo.

 

There has been discussion as to the need for CFTR during the development of the human embryo and fetus.

 

 

Ballmann M, von der Hardt H. Hypertonic saline and recombinant human DNase: a randomised cross-over pilot study in patients with cystic fibrosis. J Cyst Fibros 2002; 1:35-37). [PubMed]

 The first evidence that there was a comparable increase in FEV1 with rhDNase and hypertonic saline. The authors commented that a larger study was required to confirm these findings.

This has not been the general experience - usually rhDNase appears to be the more effective.

 

 

Bobadilla JL, Macek M, Fine JP, Farrell PM. Cystic fibrosis: A worldwide analysis of CFTR mutations: correlation with incidence data and application to screening. Hum Mutat 2002; 19:575-606. [PubMed]
The results confirmed wide mutational heterogeneity throughout the world. The authors also examined CF incidence, DeltaF508 frequency, and regional mutational heterogeneity in a subset of populations and there is a significant positive correlation between DeltaF508 frequency and the CF incidence levels of regional populations. Regional analyses were also performed to search for trends in the distribution of CFTR mutations across migrant and related populations; this led to clarification of ancestry-genotype patterns that can be used to design CFTR multi-mutation panels for CF screening programs.

 

This is an immense study bringing together all the information from over 100 published papers to achieve a global understanding of the population molecular genetics associated with CF in an effort to increase understanding of ancestry-genotype relationships, to compare mutational arrays with incidence and to gain insight for decisions regarding screening program enhancement through CFTR mutational analysis.

Milan Macek (figure 1) is Professor of Genetics at Prague University and involved in a number of international genetics initiatives including Presidency of the Czech Society of Medical genetics and European Society of Human Genetics . His main interest is DNA diagnostics in paediatrics with a particular focus on cystic fibrosis. he is a major contributor to the work of the European Cystic Fibrosis Society.

Fig 1: Milan Macek.

Colombo C, Battezzati PM, Crosignani A, Morabito A, Costantini D, Padoan R, Giunta A. Liver disease in cystic fibrosis: A prospective study on incidence, risk factors, and outcome. Hepatology 202; 36:1374-1382. [PubMed]
Incidence of liver disease (LD) associated with cystic fibrosis and its clinical characterization still is unsettled. The authors assessed prospectively the incidence and risk factors of this complication, and its impact on the clinical course of CF. Between 1980 and 1990, they enrolled 177 CF patients without LD in a systematic clinical, laboratory, ultrasonography screening program of at least a 10-year duration. During a 14-year median follow-up (2,432 patient-years), 48 patients developed LD, with cirrhosis already present in 5. Incidence rate (number of cases per 100 patient-years) was 1.8% (95% confidence interval: 1.3-2.4), with sharp decline after the age of 10 years and higher risk in patients with a history of meconium ileus (incidence rate ratio, 5.5; 2.7-11), male sex (2.5; 1.3-4.9), or severe mutations (2.4; 1.2-4.8) at multivariate analysis.

Incidence of cirrhosis was 4.5% (2.3-7.8) during a median period of 5 years from diagnosis of liver disease. Among the 17 cirrhotic patients, 13 developed portal hypertension, 4 developed oesophageal varices, 1 developed liver decompensation requiring liver transplantation. Development of LD did not condition different mortality (death rate ratio, 0.4; 0.1-1.5) or higher incidence of other clinically relevant outcomes.

The authors concluded that liver disease is a relatively frequent and early complication of CF, whose detection should be focused at the first life decade in patients with history of meconium ileus, male sex, or severe genotype. Although liver involvement does not condition a different clinical course of CF, in some patients it may progress rapidly and require liver transplantation.

 

 

Cuthbert AW. Bicarbonate secretion in the murine gallbladder - lessons for the treatment of cystic fibrosis. J Pancreas 2002; 2(4 Suppl):257-262. [PubMed]
The epithelium lining the gallbladder of mammalian species has absorptive and secretory functions. An important function is the secretion of a bicarbonate rich fluid that helps neutralise stomach acid and provides an appropriate environment for intestinal enzymes. In cystic fibrosis (CF) this secretory function is lost.

This study concerns the bicarbonate secreting activity of murine gallbladders in vitro using wild type and CF mice and four main questions are considered as follows:

a) Does the murine gallbladder secrete bicarbonate electrogenically and is this prevented in CF?

b) Can the secretory activity in CF gallbladders be restored by gene therapy or pharmacologically?

c) How is the cystic fibrosis transmembrane conductance regulator (CFTR) involved in bicarbonate secretion?

d) Does the data offer prospects for the treatment of CF?. Work from both the author's laboratory and the literature is reviewed.


Consideration of the currently available data indicates that the wild type murine gallbladder does secrete bicarbonate electrogenically and that this is absent in CF mice. Further it has been demonstrated that bicarbonate secretory activity can be restored by both gene therapy and by the use of drugs. The role of CFTR in bicarbonate secretion remains equivocal. Much evidence suggests that CFTR can act as a channel for HCO(3)(-) ions as well as Cl(-) ions, while others propose a parallel arrangement of CFTR with a Cl(-)/HCO(3)(-) exchanger is necessary. The matter is further complicated by the regulatory role of CFTR on other transporting activities. Opportunities for possible application to man are discussed.

 

There is a steady flow of articles on bicarbonate in relation to CFTR. Here Alan Cuthbert reviews the current knowledge on the subject. Professor Paul Quinton has been a strong advocate of the importance of bicarbonate secretion.

 

 

Garske LA. Bell SC. Pamidronate results in symptom control of hypertrophic pulmonary osteoarthropathy in cystic fibrosis. Chest 2002; 121:1363-4. [PubMed]

Hypertrophic pulmonary osteoarthropathy (HPOA) may complicate the advanced lung disease that is associated with cystic fibrosis, resulting in severe joint pain and early-morning stiffness. Symptoms are usually controlled with the administration of nonsteroidal anti-inflammatory drugs, physiotherapy, and, on occasions, oral corticosteroids.

This report describes a case of refractory HPOA with complete remission following the administration of IV pamidronate, which is a potent inhibitor of osteoclastic bone resorption. Symptom relief resulted for up to 3 months, but repeated courses of pamidronate have been required to maintain symptom control.

This is a practically helpful report of a treatment for hypertrophic pulmonary osteoarthropathy where other measures have failed.

 

 

Goss CH, Mayer-Hamblett N, Kronmal RA, Ramsay BW. The cystic fibrosis therapeutics development network (CF TDN): a paradigm of a clinical trials network for genetic and orphan diseases. Adv Drug Deliv Rev 2002; 54:1505-1528. [PubMed]
The CF Foundation's Therapeutics Development Network conducted 18 clinical trials in 3.5 years and the concept is a major advance in accelerating the introduction of new treatments which can be painstakingly slow. The Network uses internet applications for study conduct and communication, the development of statistical methodology to enhance the efficiency of clinical trial design, the development of outcome measures specific to CF and an infrastructure necessary for expediting protocol development. This was a very successful initiative of the CF Foundation to speed the progress of potentially useful treatments into clinical use for patients. The CF Foundation funded the network of centres and specialist nurses to speed the clinical trials and thus the introduction of new treatments.

See also Rowe SM et al. Progress in cystic fibrosis and the CF Therapeutics Development Network. Thorax 2012; 67:882-890.[PubMed] below.

 

 

González-González MC, García-Hoyos M, Trujillo MJ, Rodríguez de Alba M, Lorda-Sánchez I, Díaz-Recasens J, Gallardo E, Ayuso C, Ramos C. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diag 2002; 22:946-948. [PubMed]
Detection of a single-gene disorder such as a fetal paternally inherited Cystic Fibrosis mutation (Q890X) in maternal plasma at 13 weeks.

 

 

Elkin SL, Vedi S, Bord S, Garrahan NJ, Hodson ME, Compston JE. Histomorphometric analysis of bone biopsies from the iliac crest of adults with cystic fibrosis. Am J Respir Crit Care 2002; 166:1470-4. [PubMed]
This study reports the results of quantitative analysis of iliac bone histology in adults with cystic fibrosis (CF) and low bone mineral density (BMD). Twenty patients with CF had bone biopsies taken after double tetracycline labeling. Histomorphometric measurements were made by image analysis, and data were compared with those of healthy control subjects. Cancellous bone area was lower in the patients with CF (p = 0.003), and there was a trend towards a decrease in cancellous bone connectivity. Bone formation rate at tissue level was significantly lower in patients with CF (p = 0.0002). Wall width, representing the amount of bone formed within individual remodeling units, was decreased (p < 0.0001), as was mineralizing perimeter and mineral apposition rate. Analysis of resorption cavities revealed lower cavity area, reconstructed surface lengths, and cavity depths (p < 0.003) in patients with CF, whereas eroded surface area was higher (p = 0.0004).

The authors commented that these results demonstrate low cancellous bone volume in adult patients with CF with low BMD, the main cause of which appears to be low bone formation at tissue and cellular level. Osteomalacia was diagnosed in one patient. This condition should be excluded as a cause of low bone mineral density in patients with CF and vitamin D insufficiency corrected.

 

 

Fig. 1a: Andy Bush.

From www1.imperial.ac.uk

Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002; 360:978-84.
A major UK trial of macrolides from the Royal Brompton Hospital, London following the report of Jaffe et al, 1998 (above). 41 children with CF received either azithromycin or placebo for 6 months in addition to their usual treatments. The median relative difference in FEV1 between azithromycin and placebo patients was 5.4%. However, this was made up as follows - FEV1 of 13 (31.7%) patients improved by more than 13% but five (12.2%) deteriorated by more than 13% (p=0.059). Seventeen (41.5%) of the azithromycin treated patients required fewer oral antibiotic courses but five had extra courses (p=0.005). Sputum bacterial densities, inflammatory markers, exercise tolerance, and subjective well-being did not change. There were no noticeable side-effects.

This was an important trial as it gave further support to one of the major new treatments of the Millennium which would become widely used not only in patients chronically infected with Pseudomonas but eventually also in younger uninfected patients. However, the clear importance of considering the effect of treatment on individual patients is apparent as the FEV1 of five children deteriorated by more than 13%.  It is interesting, and perhaps not without relevance in regard to the effects of macrolides, that Harry Shwachman used erythromycin on more severely affected patients and at times saw significant benefit. Also Margaret Mearns in London used erythromycin in the young patients - perhaps they appreciated that there was some additional effect from the macrolides? By 2011 no less than 70.6% of patients with CF in the USA who met the criteria were taking regular azithromycin.


Professor Andy Bush (figure 1a) is paediatrician at the Royal Brompton Hospital, London and has been a leading researcher and clinician involved in CF from the early Nineties. This is one of the many important studies to come from the paediatric department at the Brompton where one of the early observations on the favourable effect of macrolides was published and undoubtedly stimulated further investigations into their possible role in cystic fibrosis treatment (Jaffe et al, 1998 above).

 

 

Heinzl B, Eber E, Oberwaldner B, Haas G, Zach MS. Effects of inhaled gentamicin prophylaxis on acquisition of Pseudomonas aeruginosa in children with cystic fibrosis: a pilot study. Pediatr Pulmonol 2002; 33:32-37. [PubMed]
Inhaled antibiotics are an established treatment for chronic Pseudomonas aeruginosa (PA) infection in patients with cystic fibrosis (CF). However, inhaled antibiotics might also have prophylactic potential to delay acquisition of PA in early stages of the disease. From 1986-1989, all CF patients at this center who experienced defined risk situations for acquisition of PA (28 patients) received inhaled gentamicin (80 mg BID for those < 12 months; 120 mg BID for those > 12 months) for a minimum of 3 years. Twelve patients had repeated risk situations and continued this prophylaxis without interruption during the entire study period (group 1). In the remaining 16 patients, inhaled antibiotics were discontinued at various times for a variety of reasons (group 2). None of the patients in group 1, but 7 in group 2, became chronically infected with PA (P = 0.01). Lung function and chest X-ray scores were significantly worse in those 7 infected patients, when compared to the non infected ones in both groups. This suggests that long-term-prophylaxis with inhaled gentamicin can effectively delay acquisition of PA and decrease disease progression in children with CF.

 

This study from Austria appeared to start the year after the first report of eradication of early P. aeruginosa in 1985 (Littlewood JM et al. 1985. above). The treatment appeared to be very effective in avoiding chronic infection. However, a previous study of urinary NAG levels from the same group suggested some renal involvement so the gentamicin was stopped in some patients (Ring E, Eber E, Erwa W, Zach M. Urinary N-acetyl-beta-D-glucosaminidase activity in patients with cystic fibrosis on long term gentamicin inhalation. Arch Dis Child 1998; 78:540-543.[PubMed]).

 

Fig.2: Maximillian Zach

Professor Maximillian Zach (figure 2) is one of Europe's leading respiratory paediatricians actively engaged in CF care, research and teaching in Graz, Austria. He was appointed Professor in 1987 and in 1993 built up the "Division of Pediatric Pulmonology and Allergology" in Graz. In addition to a wide range of publications and lectures, many of those on CF relating to exercise, swimming and physiotherapy, and assisting in numerous national and international working and consensus groups, he is an editor, conference organiser, and president of various professional societies. He played an important part in building the "European Respiratory Society", first as head of the "Paediatric Assembly" (1990-1993), then (so far the only paediatrician) as President of the ERS (1994-1995).

 

 

Hoffmann IM, Rubin BK, Iskandar SS, Schechter MS, Nagaraj SK, Bitzan MM. Acute renal failure in cystic fibrosis: association with inhaled tobramycin therapy. Pediatr Pulmonol 2002; 34:375-377. [PubMed]
A report of a 20-year-old patient with cystic fibrosis who developed acute nonoliguric renal failure associated with inhaled tobramycin. Clinical evaluation and renal biopsy findings were consistent with aminoglycoside-induced changes. Renal failure due to inhaled aminoglycosides has not been previously reported. The incidence may rise, however, with the increased use of this treatment modality. Measurable tobramycin levels due to inhalational therapy with conventional dosing in the reported patient indicate that the drug can be systemically absorbed, and renal tubular toxicity may occur.

 

This report is worrying for inhaled tobramycin is now widely used and certainly in the doses used (for example 300mg twice daily) there is definite systemic absorption. Whether this will be harmful in the long term remains to be seen.

 

 

Jaffé A, Buchdahl R, Bush A, Balfour-Lynn IM. Are annual blood tests in preschool cystic fibrosis patients worthwhile? Arch Dis Child 2002; 87:518-520.[PubMed]
To investigate whether routine annual assessment blood tests in cystic fibrosis (CF) patients under 5 years influence management. A total of 169 patients (100 female), median age 2.2 years (range 0.3-4.9) were identified. Eleven per cent of patients underwent subsequent management changes, including liver ultrasound, fasting glucose, and a short course of iron. Of particular importance, vitamin A and E concentrations were low in 9% of patients, which prompted an increase in prescribed dose. These results support the recommendations for routine blood tests at annual review in preschool CF children.

 

This study on Annual Assessments fully justifies the time, expense (and for the patient at times distress!) of regular annual reviews of relevant laboratory tests in children with CF. In Leeds we have been performing such Annual Assessments since 1980 (influenced by Douglas Crozier 1974) and have found them very valuable in detecting subclinical abnormalities at an early stage - somewhat analagous to regular servicing of a car!! We were pleased that others have found the practise useful. Annual Reviews are now regarded as mandatory in the UK and the details described in the CF Trust's Standards of Care document. Dec 2011 (www.cftrust.org.uk).

 

 

Jones AM, Dodd ME, Doherty CJ, Govan JR, Webb AK. Increased treatment requirements of patients with cystic fibrosis who harbour a highly transmissible strain of Pseudomonas aeruginosa. Thorax 2002; 57:924-925.[PubMed]
A study was undertaken to see if there was a difference in treatment requirements between CF patients with chronic infection with their own unique P. aeruginosa strains (group 1) and those who harbour a highly transmissible strain (group 2). It was apparent that the patients who harbour the highly transmissible P. aeruginosa strain have a greater treatment burden than patients with CF who harbour their own unique strains.

The authors suggest that these findings support the need for microbiological surveillance for highly transmissible P. aeruginosa and the implementation of infection control measures to prevent cross infection.

 

 

Journal of Cystic Fibrosis is launched. Dr Harry Heijerman is the founder editor.
This new journal, the first devoted entirely to cystic fibrosis, was launched in January 2002 and is the official journal of the European Cystic Fibrosis Society. Dr Harry Heijerman was the Founding Editor and under his guidance the journal was increasingly successful; the editorship was taken over by Prof. Gerd Döring in 2006.

 

Fig. 3: Harry Heijerman

Dr Harry Heijerman (figure 3) is Physician at Haga Teaching Hospital, Deb Haag in the Netherlands. He is a leading figure in CF in Europe and Medical Advisor to CF Worldwide.

 

Main KM, Skov M, Sillesen IB, Dige-Petersen H, Muller J, Koch C, Lanng S. Cushing's syndrome due to pharmacological interaction in a cystic fibrosis patient. Acta Paediatr 2002; 91:1008-11. [PubMed]
Treatment of allergic bronchopulmonary aspergillosis with itraconazole is becoming more widespread in chronic lung diseases. A considerable number of patients are concomitantly treated with topical or systemic glucocorticoids for anti-inflammatory effect. As azole compounds inhibit cytochrome P450 enzymes such as CYP3A isoforms, they may compromise the metabolic clearance of glucocorticoids, thereby causing serious adverse effects.
A patient with cystic fibrosis is reported who developed iatrogenic Cushing's syndrome after long-term treatment with daily doses of 800 mg itraconazole and 1,600 microg budesonide. The patient experienced symptoms of striae, moon-face, increased facial hair growth, mood swings, headaches, weight gain, irregular menstruation despite oral contraceptives and increasing insulin requirement for diabetes mellitus. Endocrine investigations revealed total suppression of spontaneous and stimulated plasma cortisol and adrenocorticotropin. Discontinuation of both drugs led to an improvement in clinical symptoms and recovery of the pituitary-adrenal axis after 3 months.

 

This observation suggests that the metabolic clearance of budesonide was compromised by itraconazole's inhibition of cytochrome P450 enzymes, especially the CYP3A isoforms, causing an elevation in systemic budesonide concentration.

This provoked a complete suppression of the endogenous adrenal function, as well as iatrogenic Cushing's syndrome. Patients on combination therapy of itraconazole and budesonide inhalation should be monitored regularly for adrenal insufficiency. This may be the first indicator of increased systemic exogenous steroid concentration, before clinical signs of Cushing's syndrome emerge.

 

An important report as Aspergillus is increasingly common and the two drugs are used together not infrequently. The occurrence was later investigated further by the Copenhagen team. Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole-caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.[PubMed] There was also a further case report from the UK [PubMed].

 

 

Moore JE, McIlhatton B, Buchanan J, Gilpin D, Shaw A, Hall V, Murphy PG, Elborn JS. Occurrence of Burkholderia cepacia in the hospital environment. Irish J Med Sci 2002; 171:131-133. [PubMed].

To determine the prevalence of Burkholderia cepacia from the environment in a regional adult cystic fibrosis (CF) care centre. B. cepacia was not detected from commonly shared items of equipment, staff hands, staff uniforms or toilets. In addition, the organism was not detected in toilet bowls, even in the B. cepacia unit. With regard to positive environments for B. cepacia, 4/10 (40%) of the outside surfaces and inner rims of patients' plastic disposable sputum collection containers and 4/17 (23.5%) of air from patients' rooms, following physiotherapy, were positive. All positive samples originated in the B. cepacia segregation area of the inpatient wards and B. cepacia was not detected in the non-cepacia area of the CF centre. Consequently, these two positive sites should therefore be treated as high risk, where organisms may be potentially transmitted from environment to patient.

 

Fig. 4: John Moore.

From uklinkedin.com

Dr John Moore (figure 4) is Clinical Microbiologist at the Belfast City Hospital and very active in research and clinical work including many practically useful papers on cystic fibrosis relating to the environment and infection prevention and control. This present study confirming that B.cepacia only appeared to be a potential problem in areas inhabited by CF patients already infected by the organism and also confirms the potential for airbourne spread.

 

McCallum SJ, Gallagher MJ, Corkill JE, Hart CA, Ledson MJ, Walshaw MJ. Spread of an epidemic Pseudomonas aeruginosa strain from a patient with cystic fibrosis (CF) to non-CF relatives. Thorax 2002; 57:559-560.[PubMed]
Chronic infection with Pseudomonas aeruginosa is common in adults with cystic fibrosis (CF) and there is increasing evidence that transmissible strains may cross colonise patients. However, transmission of these strains by social contact to healthy non-CF individuals has not been described.


A case is reported where an adult CF patient colonised by an epidemic P. aeruginosa strain infected her non-CF parents with subsequent morbidity.

 

Fig.4a: Jonny McCormick. From whiskyadvocate.com

McCormick J, Green MW, Mehta G, Culross F, Mehta A. Demographics of the UK cystic fibrosis population: implications for neonatal screening. Eur J Hum Genet 2002; 10:583-590. [PubMed]
The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5,274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, deltaF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are deltaF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer deltaF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with deltaF508/deltaF508, deltaF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P<0.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired >80% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.

 

Dr Jonny McCormick is a Consultant Respiratory Paediatrician in Dundee, Scotland and following this paper published regularly on cystic fibrosis. He is also an acknowledged expert and writer on Whisky.

 

 

Proesmans M, De Boeck K. Evaluation of dietary fiber intake in Belgian children with cystic fibrosis: is there a link with gastrointestinal complaints? J Pediatr Gastr Nutr 2002; 35:610-614. [PubMed]
A low fibre intake is suspected to be an underlying factor in gastrointestinal complaints of people with CF. In this study the overall fibre intake was found to be adequate in the cystic fibrosis population.

 

There was no relation between low fiber intake and gastrointestinal problems in the patients with cystic fibrosis.

 

Ramalho AS, Beck S, Meyer M, Penque D, Cutting GR, Amaral MD. Five percent of normal cystic fibrosis transmembrane conductance regulator mRNA ameliorates the severity of pulmonary disease in cystic fibrosis. Am J Resp Cell Mol 2002; 27:619-627.
Estimates of the level of transcripts from the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene required to develop a CF phenotype range from 4-20% of normal. Due to the importance of obtaining reliable data on this issue for therapeutic strategies, the authors developed a novel polymerase chain reaction-based method to quantify CFTR transcripts and applied it to the analysis of nasal epithelium RNA of five patients with CF and the 3272-26A>G/F508del genotype. They calculated that 8.2 +/- 0.84% of the total CFTR RNA present in these five patients is normal full-length CFTR mRNA. They then demonstrated (in nasal samples from F508del carriers, n = 30) that the abundance of full-length F508del CFTR transcripts is reduced compared with wild-type transcripts, and estimated that the average ratio of F508del/wild-type transcripts is 0.87 +/- 0.06. To determine the amount of full-length transcripts relative to levels found in normal individuals, they corrected for the lower abundance of the F508del transcripts and calculated that the five patients with CF have, on average, 4.7 +/- 0.45% of the normal level of wild-type CFTR mRNA. Because these patients have mild CF compared with F508del homozygotes, this CFTR mRNA level appears to be sufficient to avoid the severe complications of the disease.

The question often raised is just how much CFTR activity is required to avoid serious lung involvement. Obviously 50% of normal, as is present in heterozygotes, is quite adequate. Certain patients with mild mutations seem to avoid serious lung involvement. So the present study is reassuring indicating that the 5 - 10%, which may be achieved with gene therapy, may be adequate to have a significant effect in reducing the tendency to chronic respiratory infections.

 

Fig. 5 : The 2001 Nutrition Consensus Group at Artimino. (Marrten Sinaasappel 2nd from R. on front row in brown jacket)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Sinaasappel M, Stern M, Littlewood J, Wolfe S, Steinkamp G, Heijerman H, Robberecht E, Döring G. Nutrition in patients with cystic fibrosis: a European Consensus. J Cyst Fibros 2002; 1:51-75. [PubMed]
The outcome of a European CF Society Consensus Group at Artimino, Italy in March 2001 involving 33 experts on nutrition in patients with cystic fibrosis (figure 5).
The contents give an idea of the current nutritional management of people with CF. The full text is available on the European CF Society website (www.ecfsoc.org).

 

Fig. 5a: Marrten Sinaasappel

Author's photo

Dr Martin Sinaasappel (Dr Martin Orange) (figure 5 in brown jacket and figure 5a) coordinated this consensus document on nutrition. 

A paediatrician in Rotterdam, who retired in 2007 to spend more time involved with yachts and yachting. As a clinician and researcher he was involved in various aspects of gastroenterology. In 2011 he was awarded the Rare Angel Award for which he was nominated by the Najjar Foundation, a patient and parent organisation, for his work into the genetic causes and treatment of this very rare and serious liver disease

 

 

Stutman HR, Lieberman JM, Nussbaum E, Marks MI. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomised controlled trial. J Pediatr 2002; 140:299-305.
A 7-year, multicenter, double-blind, placebo-controlled study of continuous anti staphylococcal therapy. Otherwise healthy children less than 2 years of age with CF were randomly assigned to be treated with daily cephalexin (80-100 mg/kg /day) or placebo. Only 119 of the 209 children enrolled completed a 5- to 7-year course of therapy. Respiratory cultures from children treated with cephalexin were significantly less likely to be positive for S. aureus (6.0% vs. 30.4%) They were, however, more likely to be positive for Pseudomonas aeruginosa (25.6% vs. 13.5%). These differences became apparent in the first year after enrolment and persisted over the duration of the study. In contrast to these microbiologic differences, there were no differences in clinical outcome measures. The authors concluded that although long-term prophylaxis with cephalexin successfully delayed the acquisition of S. aureus, it enhanced colonization with P. aeruginosa and did not lead to clinically significant improvement in major health outcomes. Hence they considered the findings did not support routine anti staphylococcal prophylaxis in otherwise healthy infants and young children with cystic fibrosis.

The plan of this study was reported some 10 years previously at the 1992 N American CF Conference by Dr Stutman but the results not published until 2002. This study with cephalexin,(a broader spectrum antibiotic than flucloxacillin which has a narrow spectrum) does not provide useful information about the use of long term flucloxacillin (currently recommended for the first 3 years for all CF infants by the UK CF Trust Antibiotic Working Group 2009). Also during the study early eradication treatment of P. aeruginosa was not practiced in the USA. In UK centres where both long term flucloxacillin AND early P. aeruginosa eradication is routine the prevalence of both chronic S. aureus and P. aeruginosa is very low (Lee et al, 2004. [PubMed]).


The plan of this study was reported at the 1992 N American CF Conference by Dr Stutman but the results not published until 2002. This study with cephalexin,(a broader spectrum antibiotic than flucloxacillin) does not provide useful information about the use of long term flucloxacillin (currently recommended for the first 3 years for all CF infants by the UK CF Trust Antibiotic Working group 2009). Also during the study early eradication treatment of P. aeruginosa was not practiced in the USA. In UK centres where both long term flucloxacillin AND early P. aeruginosa eradication is routine the prevalence of both chronic S. aureus and P. aeruginosa is low (Lee et al, 2004).
It seems that if an organism is eradicated from the airways of a person with CF another potential pathogen from the environment colonizes and, if not treated, infects the airway. For example when S. aureus is treated, P aeruginosa appears (a fact noted since the early days of CF treatment); when P. aeruginosa is eradicated and prevented other environmental organisms appear particularly Aspergillus fumigatus and Stenotrophomonas maltophilia (noted both in the Copenhagen and Leeds CF centres). But this is not a good reason to fail to eradicate potential pathogens as they appear which is the policy in many European and N. American CF centres, evidenced by the high prevalence of chronic S. aureus infection.
Finally, it should be noted that it is not essential to give long term flucloxacillin to achieve a very low prevalence of S aureus infection, an alternative is to culture regularly (every clinic attendance and also when unwell) as is the policy in some European centres and treat vigorously whenever S. aureus appears (Szaff and Hoiby,1981 above - see discussion after this entry for more on anti-Staphylococcal prophylaxis).

Fig. 6: Harris Stutman


Dr Harris Stutman (figure 6) is a specialist in Pediatric Infectious Disease at the Memorial Health Care System in California. His interests include Health Technology Informatics and Medical Informatics Clinical information systems. He has not published on CF since this present study.

 

It seems that if an organism is eradicated from the airways of a person with CF another potential pathogen from the environment colonizes and, if not treated, infects the airway. For example when S. aureus is treated, P aeruginosa appears (a fact noted since the early days of CF antibiotic treatment with penicillin and aureomycin); subsequently when P. aeruginosa is eradicated and prevented other environmental organisms appear particularly Aspergillus fumigatus and Stenotrophomonas maltophilia (noted both in the Copenhagen and Leeds CF centres). But this is not a good reason to fail to eradicate any potential pathogens, symptoms or not, as they appear.

Finally, it should be noted that it is not essential to give long term flucloxacillin to achieve a very low prevalence of S. aureus infection. An alternative is to culture regularly (every clinic attendance and also when unwell) as is the policy in Copenhagen and treat vigorously whenever S. aureus appears (Szaff and Hoiby,1981 above - see discussion after this entry for more on anti-Staphylococcal prophylaxis).

 

 

van Koolwijk LM, Uiterwaal CS, van der Laag J, Hoekstra JH, Gulmans VA, van der Ent CK. Treatment of children with cystic fibrosis: central, local or both? Acta Paediatr 2002; 91:972-977. [PubMed]
The progress of 41 totally CF Centre-treated patients, 23 who came to the CF centre annually for review and 41 treated in close cooperation between the CF Centre and local hospitals. After 3 years there were no significant differences in pulmonary function, nutritional status or microbiological status. The authors conclude the results - could signify that local paediatricians have a special role in the care of patients with CF in close cooperation with the specialist centre”.

 

So should every patient attend a CF Centre as recommended by virtually all experienced CF clinicians since the Sixties? Even on 2014 there is still considerable discussion on this question. This study is reassuring as it provides some support for the concept of "shared-care” which, like it or not, is still widely practised in the UK and elsewhere. There is an appropriate standard, condoned in the CF Trust's 2011 Standards of Care document, but shared care is not recommended for adults. It is possible that as regimens of treatment become more established and standardised, the care at smaller local clinics will approach that at CF centres.  However, there are still some children attending their local hospital with only sporadic visits to and advice from the staff at the Specialist CF Centre which is unsatisfactory. Also the numbers in this present study are small to the extent that the question is not finally answered. Obviously local conditions and facilities will determine the most appropriate arrangements.

 

 

Williams SM, Goodman R, Thomson A, McHugh K, Lindsell DR. Ultrasound evaluation of liver disease in cystic fibrosis as part of an annual assessment clinic: a 9-year review. Clin Radiol 2002;57:365-370. [PubMed]
To review 9 years of annual assessment data in cystic fibrosis (CF) and evaluate the frequency of hepatobiliary abnormalities and the correlation between ultrasound and biochemical findings. Over a 9-year period (1990-99), 168 children (age range 1-18 years) with CF have undergone an annual assessment which has included clinical, biochemical and ultrasonographic evaluation of the hepatobiliary system. We have retrospectively reviewed the sequential ultrasound reports and correlated them with the contemporaneous biochemical results. A total of 725 ultrasound examinations were performed over the review period. Sixty patients had at least one examination showing an abnormality of liver echo texture and in 39 patients this was a persisting finding. Seven patients (4.2%) developed frank cirrhotic change on ultrasound criteria, while 15 patients (8.9%) had evidence of persistent splenomegaly. Gall-bladder calculi were present in 4.8%. In 176 examinations (24%) there was disparity between the ultrasound findings and aspartate aminotransferase (AST) levels. In 3.0% of cases (five patients) there were persisting abnormalities of liver echo texture and persisting splenomegaly with a normal range AST value.

The authors concluded no perfect method of assessing hepatobiliary involvement in CF is currently available. Ultrasonographic and biochemical assessment may reflect different aspects of disease progression. Routine use of ultrasound in annual assessment allows identification of a minority of patients with liver changes but with normal biochemistry.