Al-Aloul M, Crawley J, Winstanley C, Hart CA, Ledson MJ, Walshaw MJ. Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients. Thorax 2004; 59:334-336. [PubMed]

Fig. 1 Mo Al-Aloul LinkedIn

Chronic infection with the Liverpool epidemic P. aeruginosa strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods.

The long term effects of the epidemic strain originally described by Cheng et al in 1996 in the Liverpool paediatric CF unit (Cheng K, et al. Spread of ß-lactam resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet 1996; 348:639-642. [PubMed]).

Dr Mo Al-Aloulis (Fig. 1) at the Regional Adult Cystic Fibrosis Unit, The Cardiothoracic Centre, Liverpool, UK. More recently consultant Respiratory and Transplant Physician at Manchester University NHS Foundation Trust  Manchester, England,

Balfour-Lynn IM, Mohan U, Bush A, Rosenthal M. Intravenous immunoglobulin for cystic fibrosis lung disease: a case series of 16 children. Arch Dis Child 2004; 89:315-319.[PubMed]
Some children with severe cystic fibrosis (CF) lung disease develop chest tightness, recurrent dry cough, and intractable wheeze, often accompanied by deteriorating lung function and failure to expectorate sputum. In an attempt to reduce the use of regular oral corticosteroids, we treated a group of 16 such children with monthly courses of intravenous immunoglobulin (IVIG). The authors suggest that an n = 1 trial of IVIG in carefully selected patients with severe obstructive CF lung disease is worth considering, as for some it may lead to significant benefit.

Bruzzese E, Raia V, Gaudiello G, Polito G, Buccigrossi V, Formicola V, Guarino A. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Therapeut 2004; 20:813-819. pubmed.ncbi.nlm.nih.gov/15379842/
To assess the incidence of intestinal inflammation in children with cystic fibrosis and to investigate whether probiotics decrease it. Mean faecal calprotectin was significantly higher in the two groups of patients than in controls. Abnormal values were detected in 27 of 30 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Also mean nitric oxide production was increased in both group of patients, and abnormal values were detected in 19 of 20 cystic fibrosis and in 15 of 15 inflammatory bowel disease children. Calprotectin and nitric oxide concentrations were reduced after probiotics administration. Intestinal inflammation is a major feature of cystic fibrosis and is reduced by probiotics.

The latter finding suggests that intestinal microflora play a major role in intestinal inflammation in cystic fibrosis children. Fortunately the gastrointestinal aspects of CF are receiving more attention. There is increasing evidence that the bowel is inflamed in CF as shown by inflammatory markers in the faeces as in the present paper, by breath tests and endoscopic camera studies. Although, as the authors suggest, the intestinal microflora play a part in the inflammation it is almost certainly not the whole story.

Eugenia Bruzzese is in the  Department of Paediatrics University of Naples Frederico II.

Bech B, Pressler T, Iversen M, Carlsen J, Milman N, Eliasen K, Perko M, Arendrup H. Long-term outcome of lung transplantation for cystic fibrosis – Danish results. Eur J Cardio-Thor Surg 2004; 26:1180-1186. [PubMed]

 Fig. 2 Bo Bech

In a 10-year period, 47 patients with CF were listed for lung transplantation; 29 patients underwent transplantation and 18 patients died while waiting for donor organs. Eleven patients received en block double lung transplantation with direct bronchial artery revascularization and 18 patients received bilateral sequential lung transplantation. Median age at transplantation was 29 years (range 11-50). The perioperative mortality (< or =30 days) was 3.5% (1/29 patients). Actuarial survival of transplanted patients at 1, 3, 5 and 8 years was 89, 80, 80 and 70%, respectively. Actuarial survival of non-transplanted patients on the waiting list at 1 and 2 years was 28 and 11% (P<0.0001). Impressive results from the Danish CF centre with 5-year survival of 80%.

Bo Bech (fig.2)  is a specialist Vascular Surgeon in the Rigshospitalet, Copenhagen.

Berger AL, Randak CO, Ostedgaard LS, Karp PH, Vermeer DW, Welsh MJ. Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl- channel activity. J Biol Chem 2005; 280:5221-6. [PubMed]
Previous studies suggested that the herbal extract curcumin might affect the processing of a common CF mutant, CFTR-DeltaF508. Here, the authors tested the hypothesis that curcumin influences channel function. Curcumin increased CFTR channel activity in excised, inside-out membrane patches by reducing channel closed time and prolonging the time channels remained open. Stimulation was dose-dependent, reversible, and greater than that observed with genistein, another compound that stimulates CFTR. Curcumin-dependent stimulation required phosphorylated channels and the presence of ATP. They found that curcumin increased the activity of both wild-type and DeltaF508 channels. Adding curcumin also increased Cl(-) transport in differentiated non-CF airway epithelia but not in CF epithelia.

These results suggest that curcumin may directly stimulate CFTR Cl(-) channels.

– There is continuing interest in the role of curcumin in the treatment of cystic fibrosis (Colas J et al. Disruption of cyto-keratin-8 interaction with F508-CFTR corrects its functional defect. Hum Mol Genet 2012; 21:623-634. [PubMed]).

Allen L Berger is in the Department of Internal Medicine, Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City

Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Chest physiotherapy, gastro-oesophageal reflux and arousal in infants with cystic fibrosis. Arch Dis Child 2004; 89:435-439. [PubMed]
This is similar to Brenda Button’s 1997 study (above) comparing standard physiotherapy (SPT) and modified physiotherapy without the head down position (MPT). The Melbourne team monitored the cardio-respiratory state during the procedures. They confirmed that more episodes of gastro-oesophageal reflux occurred when the head down position was used; the left lateral position was associated with fewer episodes than the others. There were more episodes in supine and prone in the SPT head down and the infants were more likely to cry. Oxygen saturation was lower in SPT but improved with non-nutritive sucking (i.e. a dummy).

The authors concluded that the SPT is associated with gastroesophageal reflux, distressed behaviour and lower oxygen saturation. These studies certainly influenced the physiotherapy recommendations for CF infants particularly as screened infants often have very little in the way of respiratory secretions to remove, although their respiratory function tests are usually significantly below normal (Ranganathan et al, 2001 above).

Not all physiotherapists and paediatricians initially accepted that reflux was increased in the head down position. For example the Brompton CF team in London refuted the need to change physiotherapy routines in infants with CF (Phillips GE et al. Holding the baby: head downwards positioning for physiotherapy does not cause gastro-oesophageal reflux. Eur Resp J 1998; 12:954-957. [PubMed]). Perhaps this is area where one rule does not suite all?

Blackburn L, Brownlee K, Conway S, Denton M. ‘Cepacia syndrome’ with Burkholderia multivorans, 9 years after initial colonization. J Cyst Fibros 2004; 3:133-134. [PubMed]
A 16-year-old boy with cystic fibrosis developed ‘cepacia syndrome’ 9 years after the first isolation of Burkholderia multivorans. It is important to recognise that ‘cepacia syndrome’ is not restricted to those infected with genomovar type III strains and that rapid, irreversible clinical decline can occur many years after the 1st isolation of Burkholderia cepacia complex (Bcc).

– A word of warning after the reassuring report that B. multivorans may occasionally cause the cepacia syndrome.

Louise Blackburn is at the Regional Paediatric Cystic Fibrosis Unit, St. James’s University Hospital, Beckett Street, LS9 7TF, Leeds, UK

Borowitz D, Baker SS, Duffy L, Baker RD, Fitzpatrick L, Gyamfi J, Jarembek K. Use of fecal elastase-1 to classify pancreatic status in patients with cystic fibrosis. J Pediatr 2004; 145:322-326. [PubMed]

Fig. 3 Drucy Borowitz

Intestinal fat absorption and faecal elastase-1 (FE-1) were compared in subjects with CF at 33 CF centers. The authors concluded that FE-1 is an accurate, easily obtained screening test to classify pancreatic status in patients with CF. This information is important for prognostication, treatment, and to avoid misclassification in clinical research. They suggested that measurement of FE-1 should become a standard of care for patients with CF.
So there is general agreement that this test is an accurate and very convenient method to determine the presence of pancreatic insufficiency in people with CF.

Dr Drucy Borowitz (fig. 3) is a paedaitric pulmonologist in the School of Medicine and Biomedical Sciences, University of Buffalo. She has extensive involvement in many aspects of CF research and care including a leading role in the nutritional and gastrointestinal aspects of care.

Campbell WB, Elworthy S, Peerlinck I, Vanslembroek K, Bangur R, Stableforth D, Sheldon CD. Sites of implantation for central venous access devices (ports): a study of the experiences and preferences of patients. Euro J Vasc Endovasc 2004; 28:642-644. [PubMed]
To obtain information which might guide vascular specialists and their patients in the choice of site for implantation of central venous access devices (CVADs). Questionnaires were sent to 69 patients with cystic fibrosis and 54 (78%) responded (39 females: age 5-63, median 24 years). They had received a total of 79 CVADs placed in the upper chest (60), lower chest (13), thigh (3) and arm (3). Only 46% patients had been offered a choice of site. Questions about 14 specific areas of disability or concern found problems most frequently with discomfort (54%), wearing a seatbelt (51%), cosmetic appearance (44%), scarring (44%), choice of clothing (42%) and lying in bed or sleeping (42%). There were no significant differences between upper and lower chest CVADs. Patients with upper chest CVADs seldom had any problems with use of their arm (12%). 81% CVADs could not be accessed by the patients, and in 39% of these cases patients would have liked to do so.

– Many patients complain of few problems with their CVADs, regardless of site, but half have some persistent discomfort. Cosmetic considerations frequently cause concern and patients should be given choice in the site of their CVADs Totally implantable venous access devices have been used in CF since the mid-Eighties. Although a wide variety of complications have been reported, overall they have been a major advance facilitating repeated courses of intravenous antibiotics over many years. These practical points discussed in this article are of great importance for the patient; also problems are less if the surgeon has experience in inserting the devices.

Bruce Campbell is at the Royal Devon and Exeter Hospital, Wonford, Exeter EX2 5DW, UK.

O’Carroll MR, Syrmis MW, Wainwright CE, Greer RM, Mitchell P, Coulter C, Sloots TP, Nissen MD, Bell SC. Clonal strains of Pseudomonas aeruginosa in paediatric and adult cystic fibrosis units. Eur Respir J 2004; 24:101-106. [PubMed]
Despite recent reports of clonal strains of Pseudomonas aeruginosa in cystic fibrosis units, the need for routine microbiological surveillance remains contentious. Sputum was collected prospectively from productive patients attending the regional paediatric and adult CF units in Brisbane, Australia. All P. aeruginosa isolates were typed using pulsed-field gel electrophoresis. Spirometry, anthropometrics, hospitalisations and antibiotic sensitivity data were recorded.

The first 100 sputum samples (first 50 patients at each clinic) harboured 163 isolates of P. aeruginosa. A total of 39 patients shared a common strain (pulsotype 2), 20 patients shared a strain with at least one other patient and 41 patients harboured unique strains. Eight patients shared a strain identical to a previously reported Australian transmissible strain (pulsotype 1). Compared with the unique strain group, patients harbouring pulsotype 2 were younger and had poorer lung function. Treatment requirements were similar in these two groups, as were the rates of multi resistance.

In conclusion, 59% of patients harboured a clonal strain, supporting the need for routine microbiological surveillance. In contrast to previously described clonal strains, the dominant pulsotype was indistinguishable from non clonal strains with respect to both colonial morphology and multi resistance. The clinical significance of clonal strains remains uncertain and requires longitudinal study.

– Yet another major clinic where a significant number of patients shared a particular strain with others. In the case of those harbouring pulsotype2 strain, they were in worse condition. Most centres now regard the need for microbiological surveillance as mandatory.

Dr M R O;Carroll is at the Adult Cystic Fibrosis Unit, The Prince Charles Hospital, Chermside, Australia.

Courtney JM, Dunbar KE, McDowell A, Moore JE, Warke TJ, Stevenson M, Elborn JS. Clinical outcome of Burkholderia cepacia complex infection in cystic fibrosis adults. J Cyst Fibros 2004; 3:93-98. [PubMed]
Nineteen CF adults infected with BCC and 19 controls infected with Pseudomonas aeruginosa were studied over a 4-year period at the Adult CF Centre in Belfast. The BCC infected group displayed a significantly greater reduction of FEV(1) and BMI compared to the P. aeruginosa infected group. Sixteen patients infected with a single Burkholderia cenocepacia strain had a significantly greater rate of FEV(1) decline compared to those infected with Burkholderia multivorans (n=3) or P. aeruginosa (p=0.01 and p<0.0001, respectively). The rate of BMI decline was significantly greater in patients infected with B. cenocepacia compared to those with P. aeruginosa (p=0.007), but not significantly different in those with B. multivorans (p=0.29). BCC infection is associated with an accelerated decline in pulmonary function and BMI. Infection with a single B. cenocepacia strain was associated with a more rapid decline in lung function than those infected with either B. multivorans or P. aeruginosa.

– Confirmation the B. cepacia should be avoided at all costs by people with CF, the infection with B. cenocepacia being more serious than with B. multivorans.

Dr J M Courtney is at the Adult Cystic Fibrosis Centre, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, North Ireland, UK.

Conway SP, Oldroyd B, Morton A, Truscott JG, Peckham DG. Effect of oral bisphosphonates on bone mineral density and body composition in adult patients with cystic fibrosis: a pilot study. Thorax 2004; 59:699-703. [PubMed

Fig. 5 Daniel Peckham 

Fig. 4  Steve Conway

Approximately two thirds of adult patients with CF have reduced bone mineral density and up to a quarter have osteoporosis at one or more sites. Patients attending the Leeds Regional Adult Cystic Fibrosis Unit with either osteopenia or osteoporosis on dual energy X-ray absorptiometry (DXA) scanning were offered treatment with oral bisphosphonates after exclusion of abnormal vitamin D, calcium, or phosphate levels, abnormal thyroid function, or hypogonadism. The medians of the differences in annual changes in bone parameters between treatment and control groups showed significant differences in bone mineralisation in favour of the treatment group.  The authors concluded that treatment with oral bisphosphonates may improve bone mineralisation in adult patients with CF and suggested a randomised controlled trial.

Drs Steven Conway (fig 4) and Daniel Peckham (Fig. 5)  – present and future directors of  the Adult CF Centre, St James’s University Hospital, Leeds

Egan ME, Pearson M, Weiner SA, Rajendran V, Rubin D, Glockner-Pagel J, Canny S, Du K, Lukacs GL, Caplan MJ. Curcumin, a major constituent of turmeric, corrects cystic fibrosis defects. Science 2004; 304:600-602. [PubMed]

Fig. 6. Mary Egan medicine.yale.edu

Curcumin is a non-toxic Ca-adenosine triphosphatase pump inhibitor that can be administered safely to humans. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans, corrected their abnormal nasal potential difference. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene (i.e. they had not even any abnormal CFTR). Curcumin also induced functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, it was suggested that curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR.

– It was no surprise that this publication led to a great deal of interest and was widely reported in the media , for example “Daily curcumin slashed the death rate of CF-stricken mice”! Unfortunately these results could not be repeated (Song Y et al. J Biol Chem 2004; 279:40629-40633; Dragomir A et al. 2004. [PubMed]; Loo TW et al. 2004.[PubMed])

Dr Mary Egan (Fig.6) is Professor of Pediatrics (Respiratory) and of Cellular and Molecular Physiology at Yale School of Medicine.

The subject of curcumin has been reviewed in detail elsewhere. It is a natural polyphenol used in ancient Asian medicine. Since the first article referring to the use of curcumin to treat human disease was published in The Lancet in 1937, more than 2,600 research studies using curcumin or turmeric have been published in English language journals (Strimpakos AS. Sharma RA. Curcumin: preventive and therapeutic properties in laboratory studies and clinical trials. Antioxid Redox Sign 2008; 10:511-545. [PubMed]). Although others could not reproduce these results of Egan et al in CF patients and a Phase 1 trial in CF patients did not show correction of CFTR there is continuing interest in the role of curcumin in the treatment of cystic fibrosis (Colas J et al. Disruption of cyto-keratin-8 interaction with F508-CFTR corrects its functional defect. Hum Mol Genet 2012; 21:623-634. [PubMed]).

Eisen S, Painter H, Hyde SC, Davies J, Jaffe A. Clinical improvement in cystic fibrosis following anti-tumourous chemotherapy. Arch Dis Child 2004; 89:1179-80[PubMed] 

Fig. 7 Sarah Eisen

A 7 year old boy with CF, homozygous for DF508, underwent chemotherapy for acute myeloid leukaemia and remained remarkably well during 6 months of chemotherapy and during the following 6 months.

– The authors mention previous examples of improvement with chemotherapy (Lallemand JY et al. Lancet 1997; 350:711-712.[PubMed]; Sermet-Goudelus I et al. Pediatr Pulmonol 1997; 17(suppl): 219-220. An abstract describing 3 patients with CF with fibrosarcoma , lymphoma and leukaemia respectively who had an impressive improvement in their CF following a variety of anti-tumour drugs.

Dr Sarah Eisen  (Fig.7) eventually became a Consultant Paediatrician with a special interest in Infectious Diseases, Tropical Medicine and Migrant/Refugee Health at UCLH/Hospital for Tropical Diseases.

Festini F, Ballarin S, Codamo T, Doro R, Loganes C. Prevalence of pain in adults with cystic fibrosis. J Cyst Fibros 2004; 3:51-57.[PubMed]

Fig 8 Filippo Festini                   ResearchGate

This study was aimed at evaluating the prevalence of pain symptoms in adult CF patients, if they are noticed and treated, and the influence of pain symptoms on patients’ life. Using a questionnaire, 239 adults with CF there was a high prevalence of painful episodes among CF adult patients, as for both intensity and frequency. In a 2 months period 32.6% of patients experienced episodes of pain described as intense to severe, and 29.7% had more than 10 occurrences of pain in the same location. Headache, gastric pain and backache were the most frequently reported kind of pain. 59.8% of subjects perceived pain episodes as the cause of unfavorable effects on their life. Only 42.6% of those with pain asked a CF center physician for help and another 3.5% a general practitioner.

– Painful symptoms are surprisingly common in adults with CF a fact that this study from Italy confirms. They are a definite cause of a worsening of the quality of life for adults with CF and have received relatively little attention.

Dr Filippo Festini (fig 8) is at the Cystic Fibrosis Center of Tuscany, Meyer Pediatric Hospital, University of Florence, via L. Giordano 13, 50132 Florence, Italy.

Fig. 9 Tim Lee           author’s photo

Lee TW, Brownlee KG, Denton M, Littlewood JM, Conway SP. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center. Pediatr Pulmonol 2004; 37:104-110. [PubMed]
Over the years various management strategies were introduced at the Leeds CF centre in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early nebulised antibiotic treatment of first isolations of P. aeruginosa (1984), intensive Fig. 1cintravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991).

Fig 10. Miles Denton author’s photo

The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups as follows : never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with < 50% of months with samples positive for P. aeruginosa over the previous 12 months; and chronic P. aeruginosa infection with >50% of months with samples positive for P. aeruginosa over the previous 12 months.

The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. However, it is of interest that the annual incidence and mean age of first positive culture of P. aeruginosadid not alter significantly suggesting that the acquisition of new infection from the environment was unchanged.

In conclusion, anti-Pseudomonal management strategies in Leeds were associated with both reduced prevalence of chronic infection and an increase in the mean age of onset of chronic P. aeruginosa infection. The actual incidence of new isolations was not significantly altered suggesting that now most new infections are acquired from the environment.

Dr Tim Lee (fig 9) is a Consultant Paediatrician and Head of Studies for the Postgraduate Programmes in Child Health, one of the largest Postgraduate Programmes within the School of Medicine. He is  Lead Clinician and Consultant at the Leeds Regional Paediatric Cystic Fibrosis Centre. He has been involved in the clinical care of children and young people with cystic fibrosis since 1995.

Dr Miles Denton (fig.10) is a Consultant Microbiologist at Leeds Teaching Hospitals and the Leeds Regional CF Centre. He is also one of the main advisors on microbiological issues to the UK CF Trust and has published on many aspects of CF in particular a number of papers on Stenotrophomonas maltophilia (Denton M et al. J Clin Microbiol 1998; 36:1953-1958.[PubMed]; Denton M et al. J Antimicrob Chemother. 1999; 43:555-558.[PubMed]) and others on various aspects of S. maltophilia infection in CF including contamination of nebulisers (J Hosp Inf 2008;68:371-2.[PubMed]), presence in salads (Emerg Inf Dis 2005;11:1157-8.[PubMed]), nebulisers (J Hosp Inf 2003;55:180.[PubMed]), implantable venous access devices (J Infect 2002;44:53. [PubMed]).

The Burkholderia cepacia complex. Suggestions for Prevention and Infection Control. Cystic Fibrosis Trust Infection Control Group. Second edition. London. Cystic Fibrosis Trust, September 2004. 
Full text available on (www.cysticfibrosis.org.uk)

Pseudomonas aeruginosa infection in people with cystic fibrosis. 2nd edition. Cystic Fibrosis infection Control Group. London. Cystic Fibrosis Trust, November 2004. Full text available on (www.cysticfibrosis.org.uk)

Döring G, Hoiby N, Consensus Study Group. Early intervention and prevention of lung disease in cystic fibrosis: a European consensus. J Cystic Fibrosis 2004; 3:67-91.[PubMed]

Fig. 11 Gerd Döring

One of a number of valuable Artimino conference consensus reports organised by Gerd  Döring, the then President of the ECFS. Delegates representing most countries in Europe were invited to a meeting in Artimino in northern Italy to consider a particular area of interest and produce a consensus report. This one, on early intervention, was particularly relevant in view of the increasing introduction of neonatal CF screening which presented the opportunity for early intervention.
The full text is available on the European CF Society website (www.ecfsoc.org).

Freedman SD, Blanco PG, Zaman MM, Shea JC, Ollero M, Hopper IK, Weed DA, Gelrud A, Regan MM, Laposata M, Alvarez JG, O’Sullivan BP. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Eng J Med 2004; 350:560-569. [PubMed]

Fig. 12 Steven David Freedman

The ratio of arachidonic to docosahexaenoic acid was increased in mucosal and submucosal nasal-biopsy specimens (P<0.001) and rectal-biopsy specimens (P=0.009) from subjects with cystic fibrosis and pancreatic sufficiency and subjects with cystic fibrosis and pancreatic insufficiency, as compared with values in healthy control subjects.

So alterations in fatty acids similar to those in cystic fibrosis-knockout mice are present in CFTR-expressing tissue from subjects with cystic fibrosis.

Steven Freedman (fig.12) is in the Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.

Gawande A. The Bell Curve. What happens when patients find out how good their doctors really are? New Yorker, December 6th, 2004.  (The full text of this article is available on the New Yorker website)

Fig. 13 Atul Gawande

Although not technically a scientific paper, this is a very interesting article examining the increasingly popular question of differences in performance of various CF Centres and how this should be handled; perhaps the article should be mandatory reading for all concerned with CF care!!

The subject is now a major source of interest to CF organisations such as the CF Foundation, the UK CF Trust and the European CF Society. Such differences have been documented for many years and are now receiving the attention they deserve (Woods & Piazza, 1988 above; Padman R et al. Pediatr 2007; 119:531-537).

Dr Gawande (fig.13) considers the methods of Dr. Warren Warwick, a successful veteran USA CF clinician and clinic director, and produces a thought-provoking article along the lines of analysing the differences between the best and the rest. The differences between Centres and how to achieve optimal care is one of the current areas of interest. The US CF Foundation has estimated that if all CF Centres achieved the same results as the best CF Centres the life expectancy of their patients would increase by 7 years.

For more information on Dr Warren Warwick see his entry below under “w” in this 2004 section.

Griffiths AL. Armstrong D, Carzino R, Robinson P. Cystic fibrosis patients and families support cross-infection measures. Eur Respir J 2004; 24:449-452. [PubMed]
A clonal strain of Pseudomonas aeruginosa (PA) was isolated in 1999 at the Royal Children’s Hospital, Melbourne, Australia, after five unrelated children with cystic fibrosis (CF) died from severe lung disease aged <5 yrs. Subsequently, more than half of the patients in the clinic with PA were found to harbour this strain, and segregation measures were instituted at the hospital to prevent further spread. The aim of the present study was to assess CF parent and patient responses to the segregation measures to determine overall support. A questionnaire was sent out to the families of 291 CF children treated at the centre. A 65% response rate was obtained. The majority of parents (85%) and patients > or=12 yrs old (63%) were positive about the segregation measures instituted. A total of 11% of parents and 25% of patients were unsure, and 4% of parents and 12% of children gave negative responses. Those who were not happy listed reasons such as concerns about the emotional impact of not socializing with other CF children, inconclusive evidence about person-person spread of infection and feelings of alienation created in the clinic by the separation. In conclusion, the majority of responding cystic fibrosis patients and their families understand and are supportive of infection control measures instituted at the Royal Children’s Hospital, Melbourne, Australia.

– This is a sad story of the ravages a highly transmissible strain of Pseudomonas can cause in a CF clinic. It is not surprising that the vast majority of parents supported the segregation policy as five children had died from the particular Pseudomonas strain. It is difficult to understand how anyone cannot support strict segregation policies in the circumstances.

Dr A L Griffiths is in the Dept of Respiratory and Sleep Medicine, Princess Margaret Hospital for Children, Roberts Rd, Subiaco, 6008, Perth WA, Australia.

Hudson VM. New insights into the pathogenesis of cystic fibrosis: pivotal role of glutathione system dysfunction and implications for therapy. [Review] [204 refs] Treat Respir Med 2004; 3:353-363. [PubMed]

Fig. 14 Valerie Hudson               LinkedIn

The cystic fibrosis transmembrane regulator (CFTR) should no longer be viewed primarily as a ‘chloride channel’ but recognized as a channel that also controls the efflux of other physiologically important anions, such as glutathione (GSH) and bicarbonate. More effective approaches to cystic fibrosis treatment may result from this reconceptualization of the CFTR by researchers and clinicians.

– This is a very detailed review with a long summary of the role of glutathione.

Valerie M Hudson (fig.14) is at the Brigham Young University, 760 SWKT, Provo, UT 84602, USA. Valerie Hudson is a prolific researcher, teacher and writer on a wide variety of subjects which include glutathione and cystic fibrosis  Link to her  full biography .https://congress.gov/115/meeting/house/106900/witnesses/HHRG-115-FA18-Bio-HudsonV-20180227.pdf

Johansen HK, Nørregaard L, Gøtzsche PC, Pressler T, Koch C, Høiby N. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success?–A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection. Pediatr Pulmonol 2004; 37:427-432. [PubMed]

Fig. 15 Helle Krogh Johansen
DTU Orbit

The authors studied the effects of increasingly intensive treatment regimens on anti-pseudomonal antibody response and survival in five successive cohorts of a total of 157 Danish cystic fibrosis patients after they had acquired chronic P. aeruginosa lung infection.

The time periods were 1971-1975 (N = 21), 1976-1980 (N = 64), 1981-1986 (N = 27), 1987-1993 (N = 26), and 1994-2000 (N = 19). This study shows that CF patients who are treated intensively have lower antibody responses and longer survival after acquisition of chronic P. aeruginosa lung infection.

The details are given in the full abstract but essentially the steady improvement in survival in Copenhagen over the years associated with an aggressive treatment policy is mirrored by a declining level of Pseudomonas precipitins in the patients over the years. Pseudomonas antibodies were originally investigated by Niels Hoiby to determine the significance of Pseudomonas infection in people with CF (the first of many his publications on the subject  –  Hoiby N, Axelson NH. Acta Pathol Microbiol Scand B Microbiol Immunol 1973; 81:298-308.[PubMed]).

Prof. Helle Krogh Johansen (Fig 15)  is a senior member of the Clinical Microbiology Department, Rigshospitalet, Copenhagen.

Jones AM, Dodd ME, Govan JR, Barcus V, Doherty CJ, Morris J, Webb AK. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis. Thorax 2004; 59:948-951. [PubMed]

Fig. 16 Andy Jones Research& Innovation

Forty nine patients had an initial infection with either B multivorans (n = 16) or B cenocepacia (n = 33); 8/16 and 31/33, respectively, developed chronic infection (p<0.001). Deaths from “cepacia syndrome” occurred in both BCC groups. Patients with B cenocepacia infection had a shorter survival than patients with P. aeruginosa infection (p = 0.01). There was no difference in survival between CF patients infected with B multivorans and P aeruginosa. There were no observed differences in changes in spirometry and BMI or treatment requirements between the BCC groups and respective controls. In CF, the genomovar status of BCC may influence both the likelihood of progression from initial to chronic infection and the overall survival of the patients.

Dr Andy Jones (Fig. 16) is consultant and clinic director.   This study from a large CF centre in Manchester confirms the more serious prognosis for patients infected with B. cenocepacia than for those infected with B. multivorans.

Konstan MW, Stern RC, Trout JR, Sherman JM, Eigen H, Wagener JS, Duggan C, Wohl ME, Colin P. Ultrase MT12 and Ultrase MT20 in the treatment of exocrine pancreatic insufficiency in cystic fibrosis: safety and efficacy. Aliment Pharm Ther 2004; 20:1365-1371. [PubMed]

Fig 17. Michael Konstan WebMD

Patients receiving the Ultrase MT12 and Ultrase MT20 experienced a mean fat and protein absorption 79.4% and 83.8%, and 87.3% and 88.6%, respectively. No adverse events related to study drug were reported. This study further supports the use of enzymes to treat pancreatic insufficiency in cystic fibrosis (if this needed support!). The authors consider that excellent fat and protein absorption was achieved with minimal adverse events and safe doses.

This was one of the studies demanded by the FDA on pancreatic enzymes following the appearance of fibrosing colonopathy in 1994. The relative importance of the polymer coating of the enzymes and the high doses of lipase and other components has never been agreed. Both these enzymes contain the copolymer covering but this does not seem to be a major problem unless very large doses are used. It is also reassuring that there does not seem to be a group of patients with subclinical colonic damage.

Konstan MW, Davis PB, Wagener JS, Hilliard KA, Stern RC, Milgram LJ, Kowalczyk TH, Hyatt SL, Fink TL, Gedeon CR, Oette SM, Payne JM, Muhammad O, Ziady AG, Moen RC, Cooper MJ. Compacted DNA nanoparticles administered to the nasal mucosa of cystic fibrosis subjects are safe and demonstrate partial to complete cystic fibrosis transmembrane regulator reconstitution. Hum Gene Ther 2004; 15:1255-1269[PubMed]
The authors showed that compacted DNA nanoparticles can be safely administered to the nares of CF subjects, with evidence of vector gene transfer and partial NPD correction.

Kumar N, Balachandran S, Millner PA, Littlewood JM, Conway SP, Dickson RA. Scoliosis in cystic fibrosis: is it idiopathic? Spine 2004; 29:1990-1995. [PubMed]

Fig. 18 Naresh Kumar

This is a retrospective study of all the patients registered with the Leeds Regional Adult and Paediatric Cystic Fibrosis units from 1982 to 1997 carried out by an orthopaedic surgeon, Mr Naresh Kumar,  who, at the time, was working with Professor Bob Dickson (an authority on scoliosis) at St James’s University Hospital in Leeds. Of the 316 patients, there were 184 adults (age 17 years and above) and 132 children (age 0-6 years). In the 4- to 16-year age group, the prevalence of scoliosis was 15.6%, which is 20 times the prevalence in 15,793 school children with a similar age and sex distribution from the same geographic area. The majority of curves were single-thoracic, apical around T6-T8 with no side predilection. In the adult population (above 16 years), the prevalence was 9.8%, which is higher than that of the general population. These curves were thoracic, apical around T7-T8, and approximately two thirds of them were right-sided.

The study shows a high prevalence of scoliosis in people with cystic fibrosis. These are benign short midthoracic curves, apical between T6-T8 with no side predilection. It should be noted that some of these patients from the Eighties were more severely affected with chest and nutritional problems that would be the case in more recent years.

Mr Naresh Kumar (fig.18) eventually became Consultant Orthopaedic Surgeon in Wolverhampton UK and Senior Lecturer in Orthopaedics in the University of Birmingham and then Associate Professor at the University of Hong Kong.

Koscik RL, Farrell PM, Kosorok MR, Zaremba KM, Laxova A, Lai HC, Douglas JA, Rock MJ, Splaingard ML. Cognitive function of children with cystic fibrosis: deleterious effect of early malnutrition. Pediatrics 2004; 113:1549-1558. [PubMed]

Fig. 19 Rebecca Koscik arc.wisc.edu

The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

– This was an important study from the Wisconsin screening group adding further evidence of the need for neonatal screening and of great importance of adequate nutritional management once diagnosed by neonatal screening. The relationship between early malnutrition and mental development had previously been suggested by John Lloyd-Still (Lloyd-Still JD et al. Pediatrics 1974; 54:306-311.[PubMed]).

Dr Rebecca Koscik (Fig. 19) is a Senior Scientist with the Wisconsin Alzheimer’s Institute of the University of Wisconsin School of Medicine and Public Health; she is also affiliated with the Wisconsin Alzheimer’s Disease Research Center

Koscik RL, Lai HJ, Laxova A, Zaremba KM, Kosorok MR, Douglas JA, Rock MJ, Splaingard ML, Farrell PM. Preventing early, prolonged vitamin E deficiency: an opportunity for better cognitive outcomes via early diagnosis through neonatal screening. J Pediatr 2005; 147:S51-6.[PubMed]
The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Significantly lower cognitive scores correlated with indicators of malnutrition and un favourable family factors such as single parents, lower socioeconomic status, and less parental education. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, following neonatal screening, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

– More important evidence that diagnosis via newborn screening may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy which is the majority. Another important positive in favour of newborn screening for CF from the Wisconsin study.

Lang AB, Rudeberg A, Schoni MH, Que JU, Furer E, Schaad UB. Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces the proportion of patients infected and delays time to infection. Pediatr Infect Dis J 2004; 23:504-510. [PubMed]

   Fig. 20 Alois B Lang

A 10-year retrospective analysis of outcomes in a group of vaccinated patients. In 1989-1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients >/=18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study.

The authors concluded that regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

– On the basis of this study a major Phase III multicentre trial of the vaccine (Aerugen) was undertaken. Unfortunately, the vaccinated group showed no advantage over those receiving placebo. The failure was attributed to the change in clinical practice with a more widespread practice of early Pseudomonas eradication. In view of these disappointing results further development of the vaccine was halted.

Dr Alois B Lang (fig.20).  At the time of this work Dr Lang was head of the Department of  Immunology, Berna Biotech, Ltd., Bern, Switzerland.  He subsequently became Professor of Immunology at the University of Bern and an independent pharma and biotech consultant.

Li Z, Lai HJ, Kosorok MR, Laxova A, Rock MJ, Splaingard ML, Farrell PM. Longitudinal pulmonary status of cystic fibrosis children with meconium ileus. Pediatr Pulmonol 2004; 38:277-284. [PubMed]

Fig. 21 Zhanhai Li

The authors prospectively compared from diagnosis to the age of 12 years 32 CF children with meconium (MI) to 50 CF children without MI who were diagnosed during early infancy through neonatal screening.

MI children showed significantly worse forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC), forced expiratory flow between 25-75% of FVC (FEF(25-75)), % predicted FEV(1), % predicted FEF(25-75), and total lung capacity (TLC). These differences were particularly apparent beginning at age 8-10 years.

In conclusion, this study shows that MI children have worse lung function and more obstructive lung disease than those without MI. Such abnormalities are accompanied by reduced lung volume. MI is a distinct CF phenotype with more severe pulmonary dysfunction.

Dr Zhanhai Li (fig. 21) is a biostatistian in the University of Wisconsin School of Medicine and Public Health working on this study with the Department of Pediatrics.

Mack EH, Brett AS, Brown D. Fibrosing colonopathy in an adult cystic fibrosis patient after discontinuing pancreatic enzyme therapy. Southern Med J 2004; 97:901-904. [PubMed]

Fig. 22 Elizabeth Mack Medical News Today

Fibrosing colonopathy, a complication of cystic fibrosis, has generally been reported in young children with exposure to high doses of pancreatic enzymes. The authors report the case of a 25-year-old male with cystic fibrosis who presented with gradually progressive symptoms of bowel obstruction. Pathologic examination of the right colon revealed findings consistent with fibrosing colonopathy. This case is distinctive because of the adult presentation, and because the patient’s symptoms developed long after he had discontinued taking a high-strength enzyme preparation.

– This case suggests that multiple etiologic factors, and not simply exposure to pancreatic enzymes, may result in fibrosing colonopathy in adults with cystic fibrosis. There is no need to postulate other factors as the obstruction may have developed on an existing partial obstruction from previous high strength enzymes as we have seen in one patient.

Dr Elizabeth Hayes Mack (fig. 22) is in the Department of Pediatrics, University of South Carolina.

McKeon D, Day A, Parmar J, Alexander G, Bilton D. Hepatocellular carcinoma in association with cirrhosis in a patient with cystic fibrosis. J Cyst Fibros 2004; 3:193-195.[PubMed]

Fig. 23 Diana Bilton LinkedIin

Cystic fibrosis liver disease (CFLD) occurs in 37% of patients with CF. There has not been a documented case of hepatocellular carcinoma in association with cirrhosis and CF. A 32-year-old lady with cystic fibrosis (CF) had ultrasound lesions consistent with hepatocellular carcinoma, confirmed on histology. She was also pregnant at the time of diagnosis. Her tumour was considered too large for resection and liver transplantation and she was referred to a national centre for laser ablative therapy.

– The authors are concerned that with the increased life expectancy of patients with CF and the chronic nature of CFLD that this may be an increasingly recognised complication amongst the CF adult population. Therefore, they have changed their practice to more intense surveillance of patients with established CFLD to incorporate biannual ultrasound imaging of the hepatic system and yearly serum concentration measurements of alpha-fetoprotein.

From the CF Unit, Papworth Hospital, Cambridge where Dr Di Bilton (fig.23) in 1994 was founder and Director before she moved to the Royal Brompton in London in 2007 as Director of the Adult CF Centre. Di retired due to ill health in 2018.

Munck A, Malbezin S, Bloch J, Gerardin M, Lebourgeois M, Derelle J, Bremont F, Sermet I, Munck MR, Navarro J. Follow-up of 452 totally implantable vascular devices in cystic fibrosis patients. Eur Respir J 2004; 23:430-434. [PubMed]

Fig. 24 Anne Munck

This retrospective study involved 36 CF centres. TIVADs (n = 452) were implanted in 315 patients. The mean functional time per device was 32 +/- 25 months. Long-term complications occurred with 188 devices (42%); they consisted mainly of occlusion (21%, requiring removal in 77%), infection (9.3%); septicaemia in 7.3%; rate 0.3 per 1,000 days, Candida in 66%), and vascular thrombosis (4.7%, removal in 58%). Multivariate survival analysis showed that removal, whatever the reason, was associated with polyurethane (versus silicone) and routine use of the device for blood sampling (versus never). No risk factors, including heparin lock, were identified for septicaemia or for removal for obstruction.
The authors concluded that totally implantable venous access devices appear to be safe and reliable for long-term intermittent venous access. Although retrospective, this study suggests that the characteristics of the material and blood sampling are risk factors for removal.

Dr Anne Muck (fig. 24) from the Dept of Paediatric Gastroenterology and Nutrition, Hospital Robert Debré, Paris, France.

Parker EM, O’Sullivan BP, Shea JC, Regan MM, Freedman SD. Survey of breast-feeding practices and outcomes in the cystic fibrosis population. Pediatr Pulmonol 2004; 37:362-367.  pubmed.ncbi.nlm.nih.gov/15022134/

Fig. 25 Eiza M Parker LinkedIn

Three thousand, two hundred questionnaires were sent to 30 accredited CF centers for anonymous completion. Eight hundred and sixty-three questionnaires were returned. Fifty-three percent of those who breast-fed exclusively > or = 6 months had FEV1% values > 90%, compared to 47% of those not breast-fed. This is a suggestive but not statistically significant difference. In conclusion, breast-feeding for > or = 6 months is associated with decreased use of intravenous antibiotics in the 2 years prior to administering the questionnaire.

The authors conclude that this survey indicates that breast-feeding is not harmful to children with CF, and may be beneficial.

Dr Eliza M Parker (fig.25) is in the Department of Pediatrics, University of Massachusetts Medical School and UMass Memorial Health Care, Worcester, Massachusetts 01655, USA.

Phillips GE, Pike SE, Jaffé A, Bush A. Comparison of active cycle of breathing and high-frequency oscillation jacket in children with cystic fibrosis. Pediatr Pulmonol 2004; 37:71-75.[PubMed]
Comparison of the active cycle of breathing techniques (ACBT) with the Hayek Oscillator Cuirass, performing HFCC on secretion clearance in children with CF during an exacerbation. Ten children (7 males; median age, 14 years; range, 9-16) received either two supervised sessions using HFCC or two self-treatment ACBT sessions in random order on successive days. Baseline pulmonary function was similar prior to treatments. Sputum weight increased significantly with ACBT compared with HFCC during treatment (5.2 g vs. 1.1 g, P < 0.005, morning; 4.1 g vs. 0.7 g, P < 0.01, afternoon). Pulmonary function improved significantly after morning ACBT (forced vital capacity (FVC): 2.67 l to 2.76 l, P < 0.03; forced expiratory volume in 1 sec (FEV1): 1.59 l to 1.62 l, P < 0.03). Following afternoon ACBT, there was a significant increase in FVC (2.64 to 2.79, P < 0.02), but no significant change in FEV1. Pulmonary function did not change at any time following HFCC. Compared with ACBT, HFCC by Hayek Cuirass is not an effective airway clearance treatment modality for children with CF during an infective exacerbation.

– These are small numbers and small volumes of sputum. The findings reinforce the lack of enthusiasm from UK physiotherapists for the “vest” which is used by many people with CF in the USA,  apparently with satisfactory results! As mentioned elswhere, the use of the HFFC devices in the USA is encouraged by the insurance companies.

Gillian E Phillips is a physiotherapist in the Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK.

Regnath T, Kreutzberger M, Illing S, Oehme R, Liesenfeld O. Prevalence of Pseudomonas aeruginosa in households of patients with cystic fibrosis. Internat J Hyg Envir Health 2004; 207:585-588. [PubMed]
Using a standardized sampling protocol, the authors prospectively examined the presence of Pseudomonas aeruginosa (PA) in 102 households of people with CF in Germany. PA was detected in 73 (71.6%) of 102 households. PA was detected most frequently in drains of showers (39.6%), drainpipes of hand-basins in kitchens (35.0%) and bathrooms (34.7%), and drainpipes of toilets (26.5%). Toilet seats and dish-clothes did not show PA in any household. The frequency and intensity of cleaning measures did not impact the detection rate of PA.

Results of the present study for the first time determine the rate of contamination with PA in households of patients with CF. Future studies will determine the risk of transmission of PA from households locations to patients with CF.

As staff in CF centres became aware of patient to patient spread of infection in hospitals it became apparent that many new Pseudomonas infections were acquired from the environment outside the hospitals. Here the home is shown to be a rich source of these organisms.

Dr Thomas Regnath is in the Laboratory of Prof. G. Enders & Partners, Stuttgart, Germany.

Robert R, Thoreau V, Norez C, Cantereau A, Kitzis A, Mettey Y, Rogier C, Becq F. Regulation of the cystic fibrosis transmembrane conductance regulator channel by beta-adrenergic agonists and vasoactive intestinal peptide in rat smooth muscle cells and its role in vasorelaxation. J Biol Chem 2004; 279:21160-8. [PubMed]
These results identify, for the first time, the expression and function of CFTR in smooth muscle where it plays an unexpected but fundamental role in the autonomic and hormonal regulation of the vascular tone.

This finding is likely to be relevant in many of the gastrointestinal problems which occur in people with CF e.g. distal intestinal obstruction; also in the abnormalities of the autonomic nervous system that have been noted by a number of authors over the years e.g. altered pupillary reactions and abnormal skin wrinkling (Rubin LS et al. 1966. [PubMed]; Davis PB, 1983[PubMed] ; Mirakhur A, Walshaw MJ. Autonomic dysfunction in cystic fibrosis. J R Soc Med 2003; 96 Suppl 43:11-17. [PubMed]).

Renaud Robert of the Laboratoire des Biomembranes et Signalisation Cellulaire CNRS Unité Mixte de Recherche 6558, Université de Poitiers, 86022 Poitiers, France.

Rosenberg MF, Kamis AB, Aleksandrov LA, Ford RC, Riordan JR. Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR). J Biol Chem 2004; 279:39051-7.[PubMed]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein that is mutated in patients suffering from cystic fibrosis. Here the authors report the purification and first crystallization of wild-type human CFTR. Functional characterization of the material showed it to be highly active. Electron crystallography of negatively stained two-dimensional crystals of CFTR has revealed the overall architecture of this channel for two different conformational states. These show a strong structural homology to two conformational states of another eukaryotic ATP-binding cassette transporter, P-glycoprotein. In contrast to P-glycoprotein, however, both conformational states can be observed in the presence of a nucleotide, which may be related to the role of CFTR as an ion channel rather than a transporter. The hypothesis that the two conformations could represent the “open” and “closed” states of the channel is considered.

Mark F Rosenberg of the Department of Biomolecular Sciences, University of Manchester Institute of Science and Technology, Manchester M60 1QD, United Kingdom.

Scott FW, Pitt TL. Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales. J Med Microbiol 2004; 53:609-615. [PubMed]

Fig 26  Ty Pitt

Most previous studies of cross-infection with P. aeruginosa (PA) among patients with CF in the UK suggested that it is a rare occurrence. However, two recent UK reports of highly transmissible strains of PA in patients in regional centres in Liverpool (Cheng et al, 1996 above) and Manchester (Jones et al, 2001 above) raised questions as to the extent of the problem.

These reports prompted the UK CF Trust to fund this nationwide survey to establish the distribution of PA genotypes among these patients. The study was carried out by Fiona Scott and Dr Ty Pitt (fig 26) of the Laboratory of HealthCare Associated Infection, Specialist and Reference Microbiology Division, Health Protection Agency, 61 Colindale Avenue, London.  Isolates of PA were requested from over 120 hospitals in England and Wales and a sample size of approximately 20% of the CF patient population in each centre was recommended. In total, 1225 isolates were received from 31 centres (range 1 to 330). Single patient isolates were typed by SpeI macrorestriction and PFGE. A panel of strains of the common genotypes including representatives of reported transmissible strains was assembled and further characterized by fluorescent amplified fragment length polymorphism (FAFLP) genotyping.

The important findings were as follows:-

–  At least 72% of all patients harboured strains with unique genotypes.
–  Small clusters of related strains were evident in some CF centres, presumably indicating limited transmission of local strains.
– The most prevalent strain was indistinguishable from that previously described as the ‘Liverpool’ genotype, and accounted for approximately 11% of patient isolates from 15 centres in England and Wales.
– The second most common genotype (termed Midlands 1) was recovered from 86 patients in nine centres
– The third genotype, which matched closely the PFGE profile of Clone C, a genotype originally described in Germany, was found in eight centres and was isolated from 15 patients.
– A fourth genotype, identical to the published Manchester strain, was found in three centres. FAFLP analysis revealed some microheterogeneity among strains of the Liverpool genotype but all isolates of this genotype were positive by PCR for a strain-specific marker. These data are mentioned in detail in view of their great importance for clinic routines and suggest that cross-infection with PA has occurred both within and widely between CF centres in England and Wales.

The two most common genotypes accounted for more than one-fifth of patients’ isolates examined and transmissible genotypes were found in all but three of the 31 CF centres studied. These results emphasize the need for continued surveillance of P. aeruginosa genotypes in CF patients to provide informed infection control policy in treatment centres.

Starnes VA, Bowdish ME, Woo MS, Barbers RG, Schenkel FA, Horn MV, Pessotto R, Sievers EM, Baker CJ, Cohen RG, Bremner RM, Wells WJ, Barr ML. A decade of living lobar lung transplantation: recipient outcomes. J Thorac Cardiov Surg 2004; 27:114-122[PubMed]

Fig 27. Vaughn Starnes

One hundred twenty-eight living lobar lung transplantations were performed in 123 patients between 1993 and 2003. Eighty-four patients were adults (age, 27 +/- 7.7 years), and 39 were pediatric patients (age, 13.9 +/- 2.9 years). The primary indication for transplantation was cystic fibrosis (84%). At the time of transplantation, 67.5% of patients were hospitalized, and 17.9% were intubated. One-, 3-, and 5-year actuarial survival among living lobar recipients was 70%, 54%, and 45%, respectively. There was no difference in actuarial survival between adult and pediatric living lobar recipients (P =.65). There were 63 deaths among living lobar recipients, with infection being the predominant cause (53.4%), followed by obliterative bronchiolitis (12.7%) and primary graft dysfunction (7.9%). The overall incidence of acute rejection was 0.8 episodes per patient. Seventy-eight percent of rejection episodes were unilateral. Age, sex, indication, donor relationship, preoperative hospitalization status, use of preoperative steroids, and HLA-A, HLA-B, and HLA-DR typing did not influence survival. However, patients on ventilators preoperatively had significantly worse outcomes and those undergoing retransplantation had an increased risk of death. These results support the continued use of living lobar lung transplantation in patients deemed unable to await a cadaveric transplantation. The authors consider that patients undergoing re transplantations and intubated patients to be at significantly high risk because of the poor outcomes in these populations.

Dr Vaughn Starnes (fig. 27)) and his team in Los Angeles who pioneered this technique have impressive results. The operation has not been developed to any extent in the UK transplant centres.

Thornton J, Elliott R, Tully MP, Dodd M, Webb AK. Long term clinical outcome of home and hospital intravenous antibiotic treatment in adults with cystic fibrosis. Thorax 2004; 59:242-246.[PubMed]
A total of 116 patients received 454 courses of intravenous antibiotics. At the end of 1 year there had been a mean percentage decline in FEV(1) compared with the baseline “average” for patients treated mostly at home but an improvement in patients treated mostly in hospital. For all patients there was a mean percentage decline in FEV(1) from the baseline “best” value. For each course of treatment the mean percentage improvements in FEV(1) at the end of the course from the start of the course were significantly higher for patients treated in hospital than for those treated at home. Clinical outcome, as defined by spirometric parameters and body weight, was better after a course of treatment in hospital than after home treatment, and this benefit was maintained over 1 year of treatment. The results suggest that patients treated at home need closer supervision.

– This study from a large UK adult CF centre in Manchester addresses the home IV or hospital IV question. It is likely that clinicians will consider each patient’s individual case and capabilities in making these decisions. However, the authors do correctly stress the importance of adequate supervision at home if this treatment is to be undertaken.

Judith Thornton is in the School of Pharmacy and Pharmaceutical Sciences, University of Manchester M13 9PL, UK.

Warwick WJ, Wielinski CL, Hansen LG. Comparison of expectorated sputum after manual chest physical therapy and high-frequency chest compression. Biomed Instru Tech 2004; 38:470-475[PubMed]

Fig. 28. Warren Warwick. Author’s photo

These results show that sputum production by subjects with CF who receive chest physiotherapy (CPT) by certified respiratory therapists can be as great as the sputum produced by the same subjects who receive high frequency chest compression (HFCC). The results also suggest that unknown factors attributed to the therapists may produce different levels of effort from time to time that may decrease the respiratory therapists’ effectiveness, whereas the HFCC therapy may be more consistently effective because it is entirely machine based.

A helpful practical paper from Warren Warwick on the use of the vest compared with manual physiotherapy.

Warren J. Warwick (1928 – 2016)  (Fig.14) was an American pediatrician, notable for co-inventing a chest wall oscillationdevice called the Vest Airway Clearance System, or “The Vest”, a mechanical vest for clearing the lungs of children with cystic fibrosis. He was Professor of Pediatric Pulmonology at the University of Minnesota and director from 1962 to 1999 of the Cystic Fibrosis Center at the University of Minnesota. He was an outstanding leader in the field of CF .

 Dr Gawande (fig. 13) (reference above) considers the methods of Dr. Warren Warwick, a successful veteran USA CF clinician and clinic director, and produces a thought-provoking article along the lines of analysing the differences between the best and the rest. An article highly recommended.

Dr Warwick was keen on collection of data relating to CF and I had many discussions with him over the years when we met at conferences.  Warren was directly responsible for starting the US Patient Registry in 1964 which was not accepted without misgivings by some centres. Warren writes of those times “One of the factors that led to the establishment of this ten year annual grant from the CFF was the desire of some of the early leaders in CF to prove that LeRoy Matthews was a fraud in claiming have reduced the annual mortality of CF by some ten-fold in his patients. When the Patient Registry data showed that the annual mortality win Cleveland CF Center was indeed less than 2% per year they engineered a conference Philadelphia to show that the statistical studies done in Minnesota were incorrect. A leading life insurance actuary from the University of Michigan was asked to evaluate the questions the technique of handling the data and the statistical approach.  The conclusions of the conference wee that the the Minnesota reports were accurate!! …..   I believe that the confidential reports of the CF Center Directors about the survival of their patients was the force that led the Center Directors, however reluctantly, accept some form of Matthews Comprehensive Therapy Program for CF” (From Warren Warwicks entry in “Cystic Fibrosis in the 20th Century” Ed. Doershuk. 2002)

Westall GP, Binder J, Kotsimbos T, Topliss D, Thomson N, Dowling J, Wilson JW. Nodular glomerulosclerosis in cystic fibrosis mimics diabetic nephropathy. Nephron 2004; 96:c70-75.[PubMed]
The authors describe 3 adult CF patients, who on renal biopsy had histological evidence of nodular glomerulosclerosis in the absence of abnormal glucose metabolism. They speculate that the pro-inflammatory cytokine profile, typical of cystic fibrosis, predisposes to the lesions described.

Zeitlin PL, Boyle MP, Guggino WB, Molina L. A phase I trial of intranasal Moli1901 for cystic fibrosis. Chest 2004; 125:143-149. [PubMed]

Fig 29. Pam Zeitlin

Moli1901 (Duramycin) a drug which activates alternative Cl channels, stimulates chloride transport in normal and CF nasal epithelia in vivo, but may have a shorter duration of action in CF participants. The investigation into the use of Moli 1901 (Duramycin) for CF continued (Oliynyk I et al. APMIS 2010; 118:982-990. [PubMed]).

Dr Pamela Zeitlin (fig. 29) is Director of the Eudowood Division of Pediatric Respiratory Sciences and Deputy Director of the Institute for Clinical and Translation Research at Johns Hopkins University. Her research focuses on the role of chloride channels in inherited diseases of the respiratory tract, e.g. cystic fibrosis. She co-directs the Johns Hopkins Cystic Fibrosis Therapeutics Development Network site.