strict the segregation of patients infected with Burkholderia
cepacia. This was the start of the era of cross-infection control,
which was to radically alter the whole attitude to infection, cross-infection
and social contact in CF Centres and in the community.
Also there was
increasing evidence of cross-infection with Pseudomonas aeruginosa. The concept of cross-infection between people with CF with organisms
other than B. cepacia had not been regarded as a major
consideration by the staff in most CF centres; the exception was
the Danish CF Centre in Copenhagen where Neils Hoiby and his colleagues
realised segregation of patients according to their microbiological
status was important. Cross-infection with so-called ‘highly
transmissible’ strains of Pseudomonas aeruginosa has been increasingly reported (Cheng et al, 1996 below; Jones et
al, 2001 below) and there followed many reports of cross-infection
with P. aeruginosa in cystic fibrosis.
As a result
of these developments it is was recommended that people with CF
should be segregated according to their microbiological status and
those with B. cepacia should also be segregated even from
each other as those with less virulent genomovars (strains) may
be infected by those with the more severe ones.
Other
advances in treatment in the Nineties
Support for the routine use of prophylactic anti-staphylococcal
antibiotics (flucloxacillin) in young children came from a controlled
trial in screened CF infants in East Anglia in 1994 (Weaver et al,
1994 below), although some clinicians still considered the treatment
predisposed to Pseudomonas aeruginosa infection. Intravenous
antibiotics were increasingly used in less severely affected patients
at a much earlier stage rather than as a last resort – a principle
central to modern treatment (“a matter of degree rather than
kind”). Early eradication treatment for early Pseudomonas
infection became increasingly used in many European CF Centres.
Recombinant
human DNase (Pulmozyme) was the first really effective mucolytic,
which was very effective in reducing the viscosity of the sputum
and improving respiratory function in a significant proportion of
people with cystic fibrosis (Shak et al, 1990 below; Fuchs et al,
1994 below). It became an important and effective part of the daily
treatment for many patients with chronic infection and there is
also evidence that even mildly affected patients may benefit (Harms
et al, 1998).
A special preparation
of tobramycin for inhalation (TOBI) became available in the Nineties.
Although inhaled aminoglycosides (the IV preparations of gentamicin
and tobramycin) have been widely used in the UK since Margaret Hodson’s
1981 paper (above), an important, well-conducted controlled trial
to confirm the beneficial effect of this special preparation of
tobramycin for inhalation (TOBI) was welcome (Ramsey et al, 1999
below). This preparation is now increasingly used but unfortunately
its use limited by cost in some parts of the UK.
From the early
Nineties the new high strength pancreatic enzymes (Pancrease HL,
Creon 25,000) were available and welcomed by people with CF many
of whom, when taking a normal fat intake, did require a large number
of standard enzyme capsules. So it was not surprising that patients,
and their professional advisers, welcomed the introduction of the
new "high lipase enzymes" in 1992, However, in 1993 a
new unexpected and serious complication, fibrosing colonopathy with
colonic strictures, was observed in Liverpool and eventually related
to the very high doses of enzymes some patients were taking (Smyth
et al, 1994 below); subsequently further patients with colonic strictures
were reported from UK and the United States. Studies in the UK (Smyth
et al, 1995 below) and the US (FitzSimmons et al, 1997 below) showed
a relationship with the very high doses of lipase achieved with
the new enzymes but the studies differed on showing an association
with the copolymer covering of some preparations – the UK
study suggested this was a factor. The problem has since receded
in the UK following advice from the Committee on the Safety of Medicines
to restrict the daily dose to an equivalent of lipase to not more
than 10,000 IU /kg/day (Littlewood, 1999 below).
With increasing
survival, problems related to CF including diabetes mellitus, liver
disease, osteoporosis, pregnancy and fertility became increasingly
common and presented further major management problems. New challenges,
beyond imagination of the early CF clinicians, include the management
of pregnancy in women with CF and successful treatment of infertility
in men with cystic fibrosis. Also it is encouraging that even the
problems of old age and CF are now being addressed (Warwick, 2003).
|
Figure
15: Mrs Rosie Barnes. Chief Executive Officer of the UK Cystic
Fibrosis Trust. |
In 1996 Mrs
Rosie Barnes (figure 15) was appointed as Chief Executive Officer
of the UK Cystic Fibrosis Trust. Rosie, as she is affectionately
known, was a Member of Parliament (SDP) for Greenwich between 1987
and 1992. Prior to that she was involved in market research and
marketing. Her interests in Parliament included health, education
and the problems of children in care. She joined the Cystic Fibrosis
Trust in 1996, after four years as Director of WellBeing, formerly
Birthright. She takes a keen interest in the NHS, particularly in
relation to the clinical care of those with cystic fibrosis. Rosie
has had a major impact on the work, development and influence of
the CF Trust. In addition to the annual income increasing year by
year from £3 million to £11 million over the next decade,
it was under her initiative that the three leading gene therapy
research groups in the UK came together to form the collaborative
Gene Therapy Consortium to speed the translation of the gene discovery
into the treatment of patients. This is now regarded as an important
major decision focusing the major part of the CF Trust’s research
funds on treatment of the basic defect by gene therapy. Also the
CF Trust, with the advice of a specially appointed Scientific Advisory
Committee, guaranteed ongoing financial support for the Gene Therapy
Consortium.
1990
Pasque MK, Cooper JD, Kaiser LR, Haydock DA, Triantafillou A, Trulock
EP. Improved technique for bilateral lung transplantation: rationale
and initial clinical experience. Ann Thorac Surg 1990; 49:785-791. [PubMed]
The first bilateral lung transplantation in CF was performed in
Toronto in 1988 and 17 were carried out between 1988 and 1991 (Ramirez
JC et al. J Thorac Cardiovac Surg 1992; 103:287-293). [PubMed]. This improved operation was done through a transverse
thoracosternotomy and involves sequential replacement of the two
lungs. Positive features included separate bronchial anastomoses
to reduce ischemic airway complications and elimination of the need
for total cardiopulmonary bypass. Three patients were reported,
one had CF, all recovered without complications and post operative
function was excellent.
The double lung
transplant operation gradually replaced heart-lung transplants for
people with cystic fibrosis.
1990
Knowles MR, Church NL, Waltner WE, Yankaskas JR, Gilligan P, King
M, Helms RW, Boucher RC. A pilot study of aerosolized amiloride
for the treatment of lung disease in cystic fibrosis. N Eng J Med
1990; 322:1189-1194. [PubMed]
Michael Knowles first discovered the increased bioelectrical potential
difference across respiratory epithelium in CF (Knowles M et al.
N Eng J Med 1981; 305:1489-1495 above). In this present study Knowles
and Boucher investigate whether the inhibition of excessive absorption
of sodium by inhaled amiloride might favourably affect the course
of CF lung disease. Fourteen of 18 patients completed a one year
double-blind, crossover trial comparing aerosolized amiloride (5
mmol per litre; 3.5 ml four times daily) with control solution.
The mean (+/- SEM) loss of forced vital capacity (FVC) was reduced
from 3.39 (+/- 1.13 ml) per day during treatment with vehicle alone
to 1.44 (+/- 0.67) ml per day with amiloride (P <0.04). Sputum
viscosity and elasticity, mucociliary and cough clearance improved
during treatment with amiloride suggesting some beneficial effect.
This trial created
considerable interest but the effect of amiloride was modest and
short-lived; also the loss of FVC in the control group seemed excessive.
Apparently the action of inhaled amiloride is very transient and
subsequently longer acting analogues were explored. However, this
report did encourage us in Leeds to look at the effect of giving
nebulised amiloride during the intravenous antibiotic treatment
of exacerbations of respiratory infection in CF. We observed a definite
but insignificant improvement in the early response to intravenous
antibiotics in the amiloride group (Bowler et al, 1995 below). No
benefit was seen from amiloride by Graham A et al (No added benefit
from nebulised amiloride in patients with cystic fibrosis. Eur Respir
J 1993; 6:1243-1248). [PubMed] nor in a French multi-centre randomized double blind placebo
controlled trial in patients more than 5 years old (Pons G, et al,
Pediatr Pulmonol 2000; 30:25-31). [PubMed] However, earlier Kohler et al showed inhaled amiloride
improved mucociliary clearance in patients with CF (Kohler et al,
Eur J Respir Dis 1986; 69 (Suppl 146:319-326); also the same group
confirmed this with a larger study (App AM et al. Am Rev Respir
Dis 1990; 141:605-612. [PubMed] Also Lindemann et al from Giessen had reported 50.4% more
sputum was produced by autogenic drainage after inhalation of amiloride
than after isotonic saline also visible liquefaction of secretions
was noted by the physiotherapist and patients (Lindemann H et al.
Elimination of secretions in CF patients under amiloride inhalation.
Pneumologie 1990; 44:1148-1150 [PubMed] [German]).
Later more active and longer acting drugs (P- 680 & P- 522-O2-Parion
Sciences/Gilead) that Inhibit excess Na absorption showed more promise
and their development continues.
1990
Yacoub M, Banner NR, Khaghani A, Fitzgerald M, Madden B, Tsang V,
Smyth R, Hodson ME. Heart lung transplantation for CF and subsequent
domino cardiac transplantation. J Heart Transplantation 1990; 9:459-67. [PubMed]
Between September 1984 and October 1988, 27 patients underwent combined
heart-lung transplantation for treatment of end-stage respiratory
disease caused by CF: survival was 78% at 1 year and 72% at 2 years.
Lung function was greatly improved after transplantation, and long-term
survivors achieved an excellent quality of life. Lymphoproliferative
disorders developed in two patients; these disorders regressed after
a reduction in immunosuppression. Two patients required retransplantation:
one because of obliterative bronchiolitis and the other because
of recurrent respiratory infections associated with a moderate tracheal
stenosis and severe deterioration in lung function. A modification
of the technique used for heart-lung transplantation allowed 20
hearts from cystic fibrosis patients to be used for subsequent heart
transplantation.
This report
by Mr Yacoub and his team, who performed the first heart lung transplantations
in people with CF at Harefields Hospital, London in 1984. There
were also reports from Mr Wallwork’s unit at Papworth, Cambridge
(Penketh et al, 1987 above; Jones et al, 1988 above and later from
Professors Dark and Paul Corrie from Newcastle)>
1990
Devlin J, Beckett NS, David TJ. Elevated sweat potassium, aldosteronism
and pseudo-Bartter's syndrome: a spectrum of disorders associated
with cystic fibrosis. J Roy Soc Med 1989; 82 (Suppl 16): 38-43.
The term “Pseudo-Bartter syndrome” is used to describe
metabolic alkalosis in association with low serum electrolyte concentrations
(hyponatraemia, hypokalaemia and hypochloraemia). This complication
is an Important cause of failure to thrive in CF and in this study
was detected by estimation of the serum electrolytes in five non-thriving
infants with cystic fibrosis (also Rendle-Short J Arch Dis Child
1956; 31:28-30; Beckerman RC, Taussig LM. Pediatrics 1979; 63:930-936;
79:930-936; Kennedy JD et al. Arch Dis Child 1990; 65:786-787).
Pseudo-Bartter
Syndrome in infants with CF is identified by estimation of the plasma
electrolytes - a mandatory investigation in any infant, CF or non-CF,
who is failing to thrive or chronically unwell. Rarely, in non-CF
infants who are not thriving, genuine Bartter’s syndrome may
be discovered by estimating plasma electrolytes in a non-thriving
infant (Littlewood et al, Arch Dis Child 1978; 53:43-48).
|
Figure
16: Professor Carla Colombo. |
1990
Colombo C, Battezzati PM, Crosignani A, Assaisso M, Ronchi M, Giunta
A. Effects of taurine and ursodeoxycholic acid on liver function
tests in patients with cystic fibrosis. Acta Universitatis Carolinae
– Medica 1990; 36:148-151. [PubMed]
The report of a memorable presentation by Prof. Carla Colombo (figure
16) of Milan at the European CF Society meeting in Prague in 1989
which I was fortunate to hear. This was the first report of the
beneficial effect of oral ursodeoxycholic acid (URSO) in people
with CF associated liver disease – before this there was no
treatment for the liver disease. In nine CF patients with clinical
and biochemical evidence of liver disease, taurine (30 mg/kg/day)
was administered one month before and during the successive treatment
with ursodeoxycholic acid (10-15 mg/kg/day). Standard liver function
tests were determined before and after each period of treatment.
Taurine administration produced only inconsistent changes of liver
function tests from baseline, whereas after the addition of ursodeoxycholic
acid there was a substantial improvement in all abnormal liver function
tests (details reported in J Pediatr 1990; 117:482-489 below).
1990
Colombo C, Setchell KD, Podda M, Crosignani A, Roda A, Curcio L,
Ronchi M, Giunta A. Effects of ursodeoxycholic acid therapy for
liver disease associated with cystic fibrosis. J Pediatr 1990; 117:482-
489. [PubMed]
The published report from Milan of data presented in 1989 at the
European CF Society Meeting in Prague (1990 above) reporting the
favourable effect of ursodeoxycholic acid (URSO) treatment 10-15
mg /kg day in 9 patients with CF who had chronic liver disease (presumably
the same patients as reported in Prague in 1989). Liver function
tests improved significantly (AST- by 34%, alanine aminotransferase
– by 41%, gamma gutamyl transpeptidase – by 41% and
alkaline phosphatase– by 19%).
Subsequently
URSO was widely used in people with CF associated liver disease
and represented one of the major advances in CF management. A further
trail was published in 1996 (Colombo et al, 1996). Much information
was published supporting URSO treatment at an early stage of liver
involvement and eventually most people with evidence of liver involvement
were treated with URSO.
However, a Cochrane Review updated in 2008 concluded "There
is insufficient evidence to justify its (URSO) routine use in cystic
fibrosis". In the writer's opinion this conclusion was unfortunate
as it could influence clinicians to withhold treatment from people
with liver involvement. The following statement would have been
more appropriate - "There is a considerable amount of evidence
that URSO improves liver function in people with CF particularly
if used at an early stage; but, as yet, there is no clinical trial
that conforms to Cochrane standards to show this".
1990
Simmonds EJ, Conway SP, Ghoneim ATM, Ross H, Littlewood JM. Pseudomonas
cepacia: a new pathogen in patients with cystic fibrosis referred
to a large centre in the United Kingdom. Arch Dis Child 1990; 65:874-877. [PubMed]
Although the first reports from N. America of this organism appeared
in the late Seventies (Lararya-Cuassay et al, 1977 above), this
was the first to report Burkholderia cepacia in the UK
– previously known as Pseudomonas cepacia. We were
impressed by the very serious consequences of this infection in
some patients. Some clinicians in the UK still doubted the serious
nature of this infection although three of our 11 patients died
– two after an alarming and rapid deterioration now described
as the “cepacia syndrome”. We could not identify any
source of cross infection in the Leeds CF centre at that stage nor
was there an inappropriate use of antibiotics. However, in retrospect,
we suspected that at least two of our patients had acquired the
infection at CF holiday camps in N. America some months before the
organism appeared in their respiratory cultures.
A further report
of 13 infected patients (three of whom died) from Manchester in
the UK also failed to show evidence of cross infection and the authors
suggested that further studies were required before segregation
of patients should be recommended (Gladman G et al, Arch Dis Child
1992; 67:192-195). It was not until 1993, following Professor Govan’s
publication from Edinburgh (Govan et al, 1993 below), that the UK
CF Trust’s advisory group recommended strict segregation of
all B. cepacia infected patients.
1990
Strandvik B, Hollsing A, Mollby R, Granstrom M. Antistaphyloccocal
antibiotics in cystic fibrosis. Infection 1990; 18:48-50. [PubMed]
Chronic Staphylococcus aureus infection was present in
40-50% of the Stockholm patients. The presence of IgG ELISA serum
anti-Staphylococcal antibodies reflected the presence and severity
of the infection. The authors suggested the raised antibodies may
indicate significant tissue damage and more severe disease and would
be an indication for treatment.
This paper
supported the use of an aggressive anti-Staphylococcal policy originally
advocated by David Lawson, both involving the long term use of an
antistaphyloccocal antibiotics with additional antibiotics
when required. In our clinic this resulted in a low overall chronic S. aureus infection rate - in the whole clinic of only
14.5% with no children chronically infected below the age of 5 years
and of only 8.3% of those less than 10 years old infected (Southern
KW et al.1993 ECFS Madrid). Later the clinical trial of Weaver et
al, (1994 below) supported the use of long term flucloxacillin therapy
up to the age of two years of age. Brigitte Strandvik later noted
that despite long term flucloxacillin treatment it was rare to isolate
methicillin resistant strains (Strandvik B. Ann Nestlé (Engl)
2006; 64:131-140); this was our experience in Leeds - MRSA appeared
to be acquired from others with the infection rather than developing
when receiving longterm flucloxacillin. It was interesting that
we noticed the few children who did grew S. aureus despite
apparently taking flucloxacillin, also had low vitamin E levels
and when their routine clinic urine specimen was checked for antibiotic
activity there was none!! Adherence, or lack of it, seemed to be
a definite possibility!!
|
Figure
17: Dr Steve Shak. From New Insights into Cystic fibrosis. September
1993. |
1990 Shak S, Capon DJ, Hellmiss R, Marsters SA, Baker CL. Recombinant
human DNase 1 reduces the viscosity of cystic fibrosis sputum. Proc
Natl Acad Sci 1990; 87:9188-9192. [PubMed]
An early report of the significant effect
of recombinant human DNase1 (Pulmozyme) on sputum viscosity
in people with CF by Steve Shak (Figure 17). To evaluate the potential
clinical utility of recombinant human DNase I (rhDNase) in the treatment
of CF, the authors cloned, sequenced, and expressed rhDNase. Catalytic
amounts of rhDNase greatly reduced the viscosity of purulent CF
sputum, transforming it within minutes from a non-flowing viscous
gel to a flowing liquid. The reduction in viscosity is associated
with a decrease in size of the DNA in the sputum. The authors suggested
that inhalation of an rhDNase aerosol may be a simple direct approach
that would help individuals with CF, and other patients with pneumonia
or bronchitis, to clear their airways of purulent secretions.
In 1950 Armstrong
JB & White JC (Lancet 1950; 2:739-742. [PubMed])
had shown that bovine pancreatic DNase1, added to viscid purulent
sputum, destroyed the extra cellular fibres of DNA and reduced the
viscosity. Later Elmes PC & Armstrong JB (Thorax 1953; 8:295-300. [PubMed]) reported its use in chronic bronchitis, but the side effects of
the bovine preparation eventually precluded its use and further
development at that time (Raskin P. Am Rev Respir Dis 1968; 98:697-698). [PubMed] Subsequently the rhDNase (Pulmozyme) reported here proved to
be one of, if not the, major therapeutic advance of the Nineties.
By 2005 Pulmozyme was taken by almost 70% of people on the US CF
Foundation patient registry; eventually it would be used earlier
and by milder affected and younger patients.
1990
Regelmann WE, Elliot GR, Warwick WI, Clawson CC. Reduction of sputum Pseudomonas aeruginosa density by antibiotics improves
lung function in cystic fibrosis more than do bronchodilators and
physiotherapy alone. Am Rev Respir Dis 1990; 141:914-921. [PubMed]
This widely quoted paper provided definite objective evidence of
the beneficial effect of antibiotics over and above the other measures
used when patients with chronic Pseudomonas aeruginosa infection
were treated for a pulmonary exacerbation. The study has a rather
complex design but is generally accepted as providing evidence of
the beneficial effect of intravenous antibiotics and so it is described
here in some detail.
For the first 4 days of study, all patients received bronchodilating
aerosols and chest physiotherapy but no antibiotics. During this
time, the patients showed significant improvement in mean FVC, FEV1,
and maximal midexpiratory flow rate (FEF25-75). In 12 of 13 trials,
the patients showed no significant increases in the density of Pseudomonas
aeruginosa during these first four days. In these 12 trials,
the patients were stratified by their initial FVC and randomized
to receive either parenteral tobramycin and ticarcillin (n = 7)
or placebo (n = 5), and in addition to continuing aerosol and chest
physiotherapy. In the remaining trial, the patient had a significant
rise in the density of P. aeruginosa during the run in
and therefore was assigned to the antibiotic group.
During the next 14 days of therapy, the antibiotic group showed
significantly (p < 0.01) greater reductions in log10 colony-forming
units (cfu) of P. aeruginosa per gram of sputum and greater
increases in FVC, FEV1, and FEF25-75 than did the placebo group.
The degree of decrease in log10 cfu P. aeruginosa/g sputum
correlated significantly (p < 0.001) with the degree of improvement
in FVC, FEV1, and FEF25-75.
The favourable
effect of antibiotics had been questioned in a previous trial from
Toronto where it was stated “there was no difference in the
course during the 6 to 24 months after the study period. Intravenous
antibiotics are not essential in the management of all acute respiratory
exacerbations of mild to moderate severity in patients with cystic
fibrosis” (Gold R et al. J Pediatr 1987; 111:907-913). [PubMed] This was a finding quite out of keeping with the experience
of most experienced CF clinicians who, fortunately, did not heed
the Toronto advice!
1990
Waters DL, Dorney SF, Gaskin KJ, Gruca MA, O'Halloran M, Wilcken
B. Pancreatic function in infants identified as having cystic fibrosis
in a neonatal screening program. N Eng J Med 1990; 322:303-308. [PubMed]
Assessment of pancreatic function in 78 children identified in the
New South Wales neonatal screening program as having cystic fibrosis.
Measurements of faecal fat excretion, pancreatic-stimulation tests,
and estimations of the serum level of pancreatic isoamylase indicated
that 29 of the 78 children (37 percent) had substantial preservation
of pancreatic function. These 29 children (median age, four years)
had growth that was close to normal and comparable to growth in
children with severe pancreatic insufficiency who received oral
enzyme therapy. Pancreatic insufficiency subsequently developed
in 6 of the 29 patients, at 3 to 36 months of age. The authors concluded
that the serum immunoreactive-trypsin assay used in neonatal screening
programs identifies patients with CF who have sufficient pancreatic
function to achieve normal fat absorption and that a substantial
proportion of infants identified as having cystic fibrosis are in
this category (also Gaskin et al, 1991 below)
Thirty four of these 76 children had their pancreatic function assessed
an average of 2.3 years after diagnosis – so subsequently
a further 20 infants were studied at the time of diagnosis (Gaskin
et al, 1991 below).
The number of children who were pancreatic sufficient in this series
is higher than expected but would depend on the proportion carrying
a mild mutation.
|
|
Figure
18: Faecal neutral fat - microscopy vs. chemical analysis. With
permission of BMJ Publishing Group. |
Figure
18.1 Fat droplets in faecal sample under microscope |
1990
Walters MP, Kelleher J, Gilbert J, Littlewood JM. Clinical monitoring
of steatorrhoea in cystic fibrosis. Arch Dis Child 1990; 65:99-102. [PubMed]
When compared with chemical faecal fat assays and steatocrit the
simple microsopy method was highly sensitive (97%) and only three
of 80 patients with steatorrhoea would have been missed using this
technique. All patient with severe steatorrhoea (> 60 mmol fat/day)
were clearly identified (figure 18). This method is still used in
the Leeds CF Centre and gives some indication as to the success
of the enzyme replacement therapy as chemical estimations of faecal
fat are rarely done unless as part of a research project. This is
unfortunate as severe fat malabsorption may be present without significant
abdominal symptoms and conversely severe symptoms may be present
without there being steatorrhoea - a situation which would not respond
to increasing the enzyme dose as, unfortunately, does occur on occasion.
1990
Kennedy JD, Dinwiddie R, Daman-Willems C, Dillon MJ, Matthews DJ.
Pseudo-Bartter's synrome in cystic fibrosis. Arch Dis Child `1990;
65:786-787. [PubMed]
A further seven cases of Pseudo-bartter's syndrome are
described from Great Ormond Street, London. Chronic salt depletion
was associated with severe failure to thrive which was soon reversed
when the salt deficit was corrected.
|
Figure
18.2. Dr Robert (Bob) Dinwiddie. |
Dr Bob Dinwiddie
(Figure 18.2), the senior author, was consultant Respiratory Paediatrician
at the Hospital for Sick Children, Great Ormond Street in London
where he succeeded Dr Archie Norman as Director of the CF Unit.
He was heavily involved in CF care and respiratory paediatrics both
nationally and internationally until his retirement in the 2000s.
1991
Gaskin K, Waters D, Dorney S, Gruca M, O'Halloran M, Wilcken B.
Assessment of pancreatic function in screened infants with cystic
fibrosis. Pediatr Pulmonol 1991; Suppl 7:69-71. [PubMed]
Previously these authors reported that 37% of infants with CF diagnosed
by neonatal screening with the dried blood spot immunoreactive trypsin
assay were pancreatic sufficient (Waters et al, 1990 above). However,
34 of the 78 infants had pancreatic function tests an average 2.3
years after diagnosis, thus it was possible that the percentage
with neonatal pancreatic sufficiency was even underestimated, due
to the loss of pancreatic function with time in some infants. To
assess this hypothesis the authors assessed pancreatic function
at the time of diagnosis in a further 20 infants since the completion
of the previous study. Results of fecal fat determinations and/or
pancreatic stimulation tests indicated that no less than 10 (50%)
of these infants have pancreatic sufficiency. Combining these results
with those of the previous study, 31 of 64 patients (48%) have pancreatic
sufficiency at this early age. The authors monitored the progression
of pancreatic disease in the 39 children with pancreatic sufficiency
recognized to date. Eleven have developed pancreatic insufficiency
and require enzyme replacement therapy. Five others have shown further
improvement of colipase secretion with age.
So the authors
confirmed their previous conclusion that the dried blood immunoreactive
trypsin screening program for cystic fibrosis does recognize patients
with pancreatic sufficiency and at diagnosis nearly half their patients
were in this category. To date, 28% of patients with pancreatic
sufficiency have demonstrated a variable decline in pancreatic function
with age.
|
Figure
18.2: Some of the Sydney CF doctors in 1998. Peter Cooper (paediatrician),
Kevin Gaskin (paediatrician), visitor (Jim Littlewood) and Peter
Bye (respiratory physician). |
In this study
there were a surprisingly large number of infants who were pancreatic
sufficient (48%) and this is quite different from our experience
of screened infants with CF over the last 30 years in Leeds, although,
of course, the frequency will depend on the mutations which the
infants have. For example of the last 15 screened infants with CF
in Leeds only 2 were pancreatic sufficient (Wolfe et al. J Cyst
Fibros 2005; 4(S1):S94).
The faecal pancreatic elastase is now a convenient and reliable
way of determining pancreatic function and following the progress
of pancreatic function in these infants.The lesson here is that
not all newborns with CF require enzyme replacement therapy so it
is important to make sure there is evidence of pancreatic insufficiency
before commencing enzymes - in practice easily done with a faecal
elastase measurement and a small specimen of stool for fat microscopy
(Walters et al, 1990 above). The test is also reliable indicator
of pancreatic function even when the infant is taking enzyme replacement
therapy - in this respect it differs from faecal trypsin and chymotrypsin.
|
Prof
Gerrard McElvaney |
1991
McElvaney NG, Hubbard RC, Birrer P, Chernick MS, Caplan DB, Frank
MM, Crystal RG. Aerosol alpha-1-antitrypsin treatment for cystic
fibrosis. Lancet 1991; 337:392-394. [PubMed]
A1-antitrypsin, the main inhibitor of neutrophil elastase, was given
in aerosol form to 12 CF patients and found to suppress neutrophil
elastase in respiratory lining fluid and restore its anti-neutrophil
elastase capacity. Also, the treatment reduced the reversed inhibitory
effect of CF epithelial lining fluid on Pseudomonas killing.
Apparently the material used in this trial (purified human plasma
a1-antitrypsin - Prolastin, Cutter Biological) was very difficult
to obtain in sufficient quantities. A subsequent trial, with a genetically
engineered product which eventually became available, disappointingly
failed to show significant benefit to patients and was not further
developed as a treatment for cystic fibrosis (Martin SL, et al,
2006 below). However, some interest continues in Germany and there
may be further developments.
1991
Laroche D, Travert G. Abnormal frequency of delta F508 mutation
in neonatal transitory hypertrypsinaemia Lancet 1991; 337:55. [PubMed]
Neonatal CF screening programmes that involve DNA testing for CF
mutations identify some infants who are CF carriers. There was much
discussion as to whether parents should be told their infant is
a carrier of one CF mutation – most clinicians were quite
firmly in favour of informing the parents. Most generally agreed
that it was acceptable to detect CF carriers provided adequate genetic
advice was provided to the parents and child bearing relatives for
planning future pregnancies now it was known that one of them may
be a CF carrier.
1991
Malfroot A, Dab I. New insights on gastro-oesophageal reflux in
cystic fibrosis by longitudinal follow up. Arch Dis Child 1991;
66:1339-1345. [PubMed]
Gastro oesophageal (GO) reflux was first described as a problem
in CF by Jean Feigelson (Feigelson et al, 1975 above) and subsequently
the problem was thought to be related to progressive CF in older
children. In this Belgian study 21 of 26 (81%) young children with
CF aged less than 60 months were studied and 20 confirmed to have
reflux by oesophageal pH tracings. Sixteen improved with anti-reflux
treatment with improved weight gain, less cough and wheeze but half
still had the reflux one year later. The authors concluded the reflux
was not caused by the CF chest problems as it improved with time
– at the same time as the CF gets worse – hence their
title “new insights into GO reflux”.
There was to
be continuing interest in GO reflux both in respect to physiotherapy
practices in CF infants (Button et al, 1997 below) and in adults
where GO reflux was shown to be frequent and important in exacerbating
respiratory symptoms (Scott RB et al, 1985; Ledson MJ et al, 1998)
particularly in relation to patients after lung transplantation
(Button BM et al. J Heart Lung Transplant 2005; 24:1522-1529). Newer
techniques of oesophageal pH monitoring and also fibreoptic endoscopy
allowed more frequent recognition and more accurate diagnosis.1991
Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas
aeruginosa infection in cystic fibrosis by early treatment. Lancet
1991; 338:725-726. [PubMed]
A randomised controlled trial from Copenhagen confirming that early P. aeruginosa infection could be eradicated in 80% of patients
with CF by three weeks treatment with oral ciprofloxacin and nebulised
colistin. The infection became chronic in only 2 of 14 (14%) of
treated patients but in 7 of 12 (58%) of the controls. The authors
comment - "Our results thus confirm and extend the preliminary
report by Littlewood et al, colleagues (1995 above) who used colistin
inhalations Since chronic colonisation with Ps aeruginosa is
associated with increased morbidity and mortality we recommend the
use of anti-Pseudomonas treatment whenever Ps aeruginosa is
isolated from the sputum of cystic fibrosis patients"
Even though the numbers were small and the patients not formally
randomised, this was certainly one of the most important papers
of the decade and confirmed that early Pseudomonas infection could
be eradicated with nebulised colomycin and oral ciprofloxacin. It
is difficult to understand why this satisfactory trial from Copenhagen,
which clearly contradicted the previous widely held belief that
it was impossible to eradicate Pseudomonas once cultured, was not
followed by the widespread introduction of early eradication treatment
for P. aeruginosa. Fortunately a few centres did introduce
early eradication treatment but they were a minority. The fact that
early treatment of Pseudomonas was so slow to be introduced in the
UK and much of Europe (with notable exceptions) and was still not
recommended in the USA over a decade after this report, was surprising
and still difficult to explain.
It was predictable that these varied approaches to early treatment
of Pseudomonas were reflected gradually in the markedly different
prevalence of chronic Pseudomonas infection in different CF centres-
this difference in the prevalence of chronic infection became increasingly
obvious first in paediatric patients as time progressed (Frederiksen
et al, 1996; Lee et al, 2003; Lebecque et al, 2006 all below).
|
Figure
19: Dr. Christian Koch in the clinic. |
In 1997 I had
the good fortune to interview the late Dr Christian Koch (figure
19), then the Medical Director of the Copenhagen CF centre, for
a video. When I asked him at the end of the day what aspect of CF
treatment he regarded as the most important, he thought for some
time and then replied -
“When
I look back on what we’ve done all through the years that
I’ve been involved with cystic fibrosis, I would say that
the early treatment of Pseudomonas is probably the best thing that
we have done for the patients. It becomes more and more clear that
really what determines the long term course is whether you get Pseudomonas
or not” .
It is of interest
that even in 1998, reviewing the history of Pseudomonas infection
in people with CF, a highly regarded US CF centre director wrote
- “early administration with aerosol colistin may delay colonisation
with P. aeruginosa. This intriguing observation has not
been verified by prospective controlled studies” (Ramsey BW.
Pediatrics 1998; Supplement: 210-213) - even though by this time
early eradication of P. aeruginosa was widespread practice
in Europe and already supported by many publications in addition
to that of Valerius et al, 1991 from Copenhagen (Brett MM et al.
Arch Dis Child 1992; 67:1066-1068; Frederiksen B et al, Pediatr
Pulmonol 1997; 23:330-335; Weismann HG, et al. Pediatr Pulmonol
1998; 25:88-92; Ratjen F, et al. Lancet 2000; 358:983-984; Munck
A et al. Pediatr Pulmonol 2001; 32:288-292).
1991
Hodson ME, Madden BP, Steven MH, Tsang VT, Yacoub MH. Non-invasive
mechanical ventilation of CF patients – the bridge to transplantation.
Eur Resp J 1991; 4:524-7.[PubMed]
This technique of non-invasive ventilation was developed as a direct
result of attempting to prolong the survival of people with CF awaiting
a heart-lung transplant at the Brompton Hospital – prior to
the possibility of heart-lung transplantation assisted ventilation
was usually regarded as inappropriate for people with CF in respiratory
failure as their prognosis was uniformly bad. The case histories
of six patients with CF using nasal ventilation while awaiting heart-lung
transplantation are reviewed; four patients did well.
This method
of ventilation proved to be a useful bridge to transplantation when
a patient suddenly deteriorates. This is also a very cost effective
method of ventilation and does not encroach on conventional Intensive
Care Unit facilities.
1991
Morrison G, Morrison JM, Redmond AOR, Byers CA, McCormack KJ, Dodge
JA, Guilford SA, Bowden MW. Comparison between a standard pancreatic
supplement and a high enzyme preparation. Aliment Pharmacol Ther
1992; 6:549-555. [PubMed]
First of a number of reports showing new “high strength”
enzymes were effective. This study compared the relative effectiveness
of a standard pancreatic enzyme supplement ('Creon', Dumpcart) and
a new high strength preparation ('Pancrease HL', Cilag) containing
about 3 times the lipase and more than 5 times the protease activity.
Capsule dosage was adjusted to a ratio of approximately 3 Creon
to 1 Pancrease HL to provide similar intakes of lipase. Fat balances
showed that absorption of fat did not change significantly on conversion
to the new high-lipase product, and the coefficient of absorption
of total energy was similarly maintained. The coefficient of protein
absorption was significantly enhanced with the high enzyme preparation
(P < 0.01), which may explain the reported subjective improvement
in stool odor. No adverse effects were recorded. Patient acceptability
of the new compound was high; the great reduction in the number
of capsules required at each meal was cited by all patients as the
reason for their preference.
Later reports
associated fibrosing colonopathy with the use of Pancrease HL but
not with the new high strength Creon 25,000.(Smyth et al, 1994)
which some considered due to the presence of the copolymer, eudragit,
in the covering of all the new high strength enzymes other than
Creon 25,000.
1991
Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide
neonatal screening for cystic fibrosis by assay of trypsinogen concentrations.
N Eng J Med 1991; 325:769-774. [PubMed]
Keith Hammond was one of the early enthusiasts for neonatal CF screening
and was the biochemist involved with these screening studies from
Denver, Colorado on 278,399 infants from 1982 to 1987, using immunoreactive
trypsin. They confirmed that the method was feasible and could be
implemented with acceptable rates of repeat testing and false positives
and false negatives. 95% of infants with CF who did not have meconium
ileus could be identified by the screening method.
Many subsequent
valuable reports have resulted from this Denver screening programme
including the early bacteriologic and clinical course (Abman SH
et al. J Pediatr 1991; 119:211-217), early respiratory course (Accurso
FJ et al. Pediatr Pulmonol Suppl 1991; 7:42-45), fat soluble vitamin
status (Sokol RJ et al. Pediatr Pulmonol Suppl 1991; 7:52-55) and
pancreatic and nutritional state (Bronstein MN et al. J Pediatr
1992; 120:533-540).
1991
Scott-Jupp R, Lama M, Tanner MS. Prevalence of liver disease in
cystic fibrosis. Arch Dis Child 1991; 66:698-701. [PubMed]
A search for the presence of liver disease among 524 patients with
CF in the UK by Dr Robert Scott-Jupp working with Prof. Stuart Tanner
in Leicester; details of a further 576 patients were obtained from
databases. The overall prevalence of overt liver disease as indicated
by the presence of an enlarged liver or spleen (or both) was 4.2%.
The age related prevalence rose to a peak in adolescence, and then
fell in patients over 20 years old. The implied increase in mortality
among those with liver disease was not explained by deaths from
liver disease, which were rare. Male patients were significantly
more affected than female, the ratio being 3:1 among adolescents.
Increasing prevalence of liver disease in patients with cystic fibrosis
was not just a result of longevity.
|
Figure
20: Patient wearing the vest. |
|
Figure
21: Professor Warren Warwick. Author's photo in 2005. |
1991
Warwick WJ, Hansen LG. The long-term effect of high frequency chest
compression therapy on pulmonary complications of cystic fibrosis.
Pediatr Pulmonol 1991; 11:265-271.[PubMed]
A high-frequency chest compression
(HFCC) device for clearance of mucous secretions from airways was
tested in 16 patients with CF with significant improvement in pulmonary
function for the HFCC period, which averaged 22 months per patient.
The device consists of a variable air pulse delivery system and
a non-stretch inflatable vest worn by the patient to cover the entire
torso. Ninety-four percent of patients' regression line slopes for
percent predicted forced vital capacity (FVC) and forced expiratory
volume in 1 second (FEV1) became more positive during self-administered
HFCC therapy as compared to slopes before HFCC therapy, when manual
chest physical therapy was used.
Although this
device (figure 20) has never found favour amongst physical therapist
in the UK, over the next 15 years “the vest” became
popular and widely used in North America by some 60% of people with
CF and by many others with chronic respiratory disorders. The device
has been pioneered by veteran CF centre director Warren Warwick
(figure 21) from Minnesota and has been the subject of many subsequent
publications showing comparative efficiency with other forms of
physiotherapy and improvements with alterations in the wave form
created. The first reports on high frequency chest wall compression
were from King M et al.(Am Rev Respir Dis 1983; 128:511-515.[PubMed];
Am Rev Respir Dis 1984; 130:703-706. [PubMed]).
1991
Chatfield S, Owen G, Ryley HC, Williams
J, Alfaham M, Goodchild MC, Weller P. Neonatal screening for cystic
fibrosis in Wales and the West Midlands: clinical assessment after
five years of screening. Arch Dis Child 1991; 66:29-33. [PubMed]
A UK neonatal CF screening study, funded by the Cystic Fibrosis
Trust, using measurement of immunoreactive trypsin, was undertaken
in Wales (Mary Goodchild) and the West Midlands (Peter Weller) on
alternate weeks for five years from 1985. Fifty eight infants, not
considered to be at risk of CF (i.e. they did not present with meconium
ileus and did not have a sibling with cystic fibrosis) were detected
by screening and were compared with 44 children born on the non-screening
weeks whose CF was diagnosed clinically. The false negative rate
in the screened group was a disappointing 13.4%. Predictably, the
screened group were diagnosed earlier and spent less time in hospital.
In other respects the groups were similar to the age of 4 years.
Treatment of CF in 1985 in the UK was often undertaken at the local
hospitals (Littlewood et al, 1984 above, 1988 above and 1993 below)
and half these children were only seen at their local hospitals
by general paediatricians who had no particular expertise in CF
– this was the major flaw of this Wales & West Midlands
study. However, the study did show that if clinical care was not
of a high standard there was no advantage in neonatal diagnosis.
Subsequently
this study was not considered to provide support for the introduction
of national neonatal CF screening by the UK National Screening Committee.
There was a
final report of this data from Cardiff by Iolo Doull (Doull IJ et
al. Pediatr Pulmonol 2001; 31:363-366). Eligible children with CF
who died in the first five years of life were identified from the
local paediatricians and from the National UK CF Survey. In all,
230,076 infants had been screened and 234,510 unscreened. 176 children
with CF were identified, of whom seven died in the first five years
of life, three having presented with meconium ileus. Median age
of diagnosis in the screened group was eight weeks (this would not
be regarded as acceptable now but DNA testing was not available
in addition to IRT until after 1990). On an intention to treat analysis,
all four non-meconium ileus-related deaths occurred in the unscreened
group; however, the clinical presentation of two of these infants
led to their being diagnosed prior to eight weeks, i.e., earlier
than would have been likely by screening as practiced in the study.
The authors concluded that newborn screening has the potential to
decrease infant CF deaths, but if it is to be successful, identification
and treatment must occur as soon as possible after birth.
Eventually
neonatal CF screening was agreed by the UK government in 2001 after
the Cystic Fibrosis Trust made personal representation to Ms Yvette
Cooper the then Health Minister. As a result of the overwhelming
pressure from the CF Trust and the whole CF professional and lay
community rather than on the advice of the National Screening Committee
that, even then, still considered the evidence for screening inadequate
even after the Government recommendation! The 2001 Farrell paper,
which showed a long term nutritional advantage in the screened infants
(Farrell et al, 2001; 107:1-13 below), was important in finally
convincing the government to introduce national neonatal CF screening.
The major lessons from all this being that, of course neonatal
diagnosis is essential but must be followed by good CF care from
the start to prevent irreversible malnutrition and chronic respiratory
infection.
Dr Peter Weller
(figure 22) was Director of the CF Centre at the Birmingham Children’s
Hospital from 1980 to 2007 and closely involved with this screening
study. Dr Henry Riley, (figure 23) was the microbiologist from Cardiff,
who was closely involved with this and many other studies on CF
and also with the European CF Society.
|
Figure
22 Dr Peter Weller. |
| |
|
Figure
23: Dr Henry Riley |
|
Figure
24: Sonny Laing aged 15 years. Photograph kindly provided by
the family. |
|
Figure
25: Ann Littlewood with this poster in Denmark at 1991 European
Working Group for Cystic Fibrosis. |
1991
Warner JO. Heart-lung transplantation: all the facts. Arch Dis Child
1991; 66:1013-1017.[PubMed]
John Warner, then paediatrician at the Brompton Hospital, London,
wrote this cautionary article on heart lung transplantation as it
applied to children in the UK and called for open discussion on
the subject. His article was published alongside two papers on heart-lung
transplantation in children from Great Ormond Street (Whitehead
B et al. Arch Dis Child 1991;66;1018-1021 [PubMed] &
Whitehead B et al, Arch Dis Child 1991; 66:1022-1026.[PubMed] Of 27 children referred to GOS for assessment of suitability for
heart-lung transplant, 10 (37%) were actually transplanted. Six
were still alive from three months to three years after the operation
but two thirds of the cohort had died at various stages during referral,
assessment, and transplant.
Warner maintained that while the transplant has offered miraculous
new life to a few children, many more have experienced increased
and unnecessary suffering. Planning of transplant programmes must
take all facts into account. Also he emphasised that the possibility
of heart-lung transplant must not deter further efforts to control
chronic lung diseases medically and must not influence appropriate
terminal care.
These were early days for transplantation (the first adults had
only received transplants in 1984), and although there were some
similar views, the latest being in 2008, the outlook for children
having transplants continued to improve although as for older patients
shortage of donor organs remained a problem.
Figure 24: Sonny Laing’s CF was not diagnosed until she was
18 months old when she was referred to Leeds by which time her lungs
were irreparably severely damaged. She was the youngest child with
CF to receive a heart-lung transplant at Great Ormond Street, London
when she was 5 years old. In the figure she is 15 years old, very
well, active and a keen gymnast.
1991
Littlewood AE, Bowler IM, Littlewood JM. A method of data collection
and computerisation in use at a regional CF unit. 17th European
Cystic Fibrosis Conference Denmark. June 1991. Poster 94.
Much of the clinical research data and the smooth running of the
Leeds CF clinic were dependent on the Administrator Mrs Christine
Silburn, and the clerks and secretaries.
The computer data management had been in operation since the early
Eighties using first a computer funded by the Variety Club of Great
Britain. Ann Littlewood (figure 25) a state registered nurse (and
my wife!), was responsible for the running of our data service from
the early Eighties until we both retired from clinical work in 1997.
The introduction of a Comprehensive CF Assessment service in Leeds
from 1981 generated such vast amounts of data on every patient that
computerisation became essential and was introduced in 1982. The
system, initially using an Epson PC AX with 80Mb hard disk and 640K
using Symantec Q&A software, provided a database and word processing
facilities. By 1991 four databases were in use – a patient
register, clinic visit database, an inpatient database and an assessment
database for the results of Comprehensive Assessments. The system
had been repeatedly modified and adapted over the next eight years
by interested colleagues and professional computer programmers.
The Leeds CF units are now totally computerised for both clinical
and research purposes - a system developed by Dr Daniel Peckham,
Respiratory Physician on the Adult CF Unit.
1992
Madden BP, Hodson ME, Tsang V, Radley-Smith R, Khaghani A, Yacoub
MY. Intermediate term results of heart-lung transplantation for
cystic fibrosis. Lancet 1992; 339:1583-1587. [PubMed]
Between 1984 and 1991 79 patients with CF had heart-lung transplantations
in London by Mr Yacoub’s team with a 69% survival to 1 year,
52% to 2 yrs and 49% to 3 years. Cumulative probability of development
of obliterative bronchitis was 17%, 23% and 48% at 1, 2, and 3 years.
These were encouraging results but the authors noted serious shortage
of donor organs – which in 2008 was still a major problem
in the UK (Penketh et al, 1987 above; Yacoub et al, 1990 above;
Scott et al, 1988 above for first reports from Brompton and Harefields
and Cambridge)
1992 Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes
MR. Birth of a normal girl after in vitro fertilization
and preimplantation diagnostic testing for cystic fibrosis. N Engl
J Med 1992; 327:905-909. [PubMed]
Preimplantation genetic diagnosis of cystic fibrosis was attempted
in three couples, both members of which carried the delta F508 deletion. In vitro fertilization techniques were used to recover
oocytes from each woman and fertilize them with her husband's sperm.
Three days after insemination, embryos in the cleavage stage underwent
biopsy and removal of one or two cells for DNA amplification and
analysis. Only two oocytes from one woman were fertilized normally;
DNA analysis of one of the embryos failed and cystic fibrosis was
diagnosed in the other (i.e. it was homozygous for delta F508),
so neither was transferred. The oocytes of each of the other two
women produced non-carrier, carrier, and affected embryos. Both
couples chose to have one non-carrier embryo and one carrier embryo
transferred. One woman became pregnant and gave birth to a girl
free of the deletion in both chromosomes.
This is the
first report of preimplantation genetic diagnosis to identify the
delta F508 deletion causing cystic fibrosis using in vitro fertilization,
biopsy of a cleavage-stage embryo, and amplification of DNA from
single embryonic cells (also Handyside et al, 1988 above). Subsequent
reports indicated an approximately 30% chance of a successful pregnancy
after such an embryo had been implanted.p
1992
Anguiano A, Oates RD, Amos JA, Dean M, Gerrard B, Stewart C, Maher
TA, White MB, Milunsky A. Congenital bilateral absence of the vas
deferens. A primarily genital form of cystic fibrosis. JAMA 1992;
267:1794-1797. [PubMed]
It had been suggested that otherwise healthy men with congenital
bilateral absence of the vas deferens (CBAVD), previously considered
a distinct genetic entity, have an increased frequency of CF gene
mutations (Dumur V et al. Abnormal distribution of CF delta F508
allele in azospermic men with congenital aplasia of epididymis and
vas deferens. Lancet 1990; 336:512; Rigot JJM et al. Cystic fibrosis
and congenital absence of the vas deferens. N Eng J Med 1991; 325:64-65).
The association was first suggested by Douglas Holsclaw (Holsclaw
DS, et al. Congenital abnormalites in male patients with cystic
fibrosis. J Urol 1871; 106:568-574). The present report of 25 unselected
men with CBAVD found 16 (64%) had at least one detectable CF mutation,
16 times the expected frequency; 3 men were compound heterozygotes.
Some, if not
all, otherwise healthy men with CBAVD reflect a newly recognized,
primarily genital, phenotype of CF. A very important practical suggestion
was that prior to sperm aspiration to remedy infertility, CF mutation
analysis should be recommended for them and their partners, as well
as for their relatives.
In a later study (Chillon M et al. NEJM 1995; 332:1475-1480) 19
of 102 (18.6%) CBAVD patients had 2 CF mutations and none had the
5T allele. 54 had one copy and 34 had the 5T allele in the other
CFTR gene. 29 had no CF mutations but 7 of them had the 5T allele.
So most men with CBAVD have mutations in the CFTR gene. The combination
of the 5T allele in one copy of the CFTR gene with a cystic fibrosis
mutation in the other copy is the most common cause of CBAVD. The
5T allele mutation has a wide range of clinical presentations, occurring
in patients with CBAVD or moderate forms of cystic fibrosis and
also in fertile men.
1992
Mennie ME, Gilfillan A, Compton M, Curtis L, Liston WA, Pullen I,
Whyte DA, Brock DJH. Prenatal screening for cystic fibrosis. Lancet
1992; 340:214-216. [PubMed]
This is the first report of antenatal couple screening
for CF in the Edinburgh maternity hospitals. Of 4348 women, 14%
declined prenatal screening and 13% were not sreened
for other reasons. Amongst 3165 women there were 111 carriers detected
of whom four had carrier partners and all 4 couples opted for prenatal
diagnosis. One pregnancy with an affected fetus was terminated.
The importance of adequate counselling was stressed.
Antenatal screening
for CF became routine in Edinburgh but was eventually discontinued
in 2005 for various reasons including the improving prognosis for
CF and also the introduction of neonatal screening in Scotland (also
Brock 1985 above; Livingstone et al, 1994 below). National antenatal
CF carrier screening had not been introduced in the UK by 2009 although
accepted in principle by the UK National Screening Committee.
1992
Lanng S, Thorsteisson B, Nerup J, Koch C. Influence of the development
of diabetes mellitus on the clinical status in patients with cystic
fibrosis. Eur J Paediatr 1992; 151:684-687. [PubMed]
The first of a series of papers about CF related diabetes (CFRD)
from Copenhagen and other centres. The new and important message
from this paper being that diabetes mellitus adversely affects progress
for some time before it becomes clinically obvious. When diabetes
develops in CF patients, an insidious decline in overall clinical
status is observed for some years prior to its clinical diagnosis.
Whether clinical deterioration in CF leads to DM, or pre-diabetes
results in declining CF clinical status is unclear. Accumulating
evidence suggests that the latter may be the case since insulin
therapy seems to improve lung function in cystic fibrosis.
The subject is reviewed in detail in the CF Trust’s consensus
document “Management of Cystic Fibrosis related Diabetes Mellitus.
June 2004 - the full text of which is on the CF Trust website www.cftrust.org.uk.
This Danish study encouraged the introduction of the policy of searching
for glucose intolerance when patients of 12 years and older were
seen for their Annual Review - a policy agreed by most, but not
all, CF physicians.
1992
Conway SP, Simmonds EJ, Littlewood JM. Acute severe deterioration
in cystic fibrosis associated with influenza A virus infection.
Thorax 1992; 47:112-114. [PubMed]
The role of non-bacterial infection in respiratory exacerbations
of cystic fibrosis has been studied less than that of bacterial
infection. Some non-bacterial infections, such as influenza A, may
be associated with acute respiratory deterioration and may be preventable.
Three patients reported here had severe deterioration in their lung
function and general wellbeing during the influenza A virus epidemic
in the winter of 1989-90.
Although a Cochrane Systematic Review found no evidence that annual
influenza vaccination for people with CF was effective, with experience
such as the present report patients with cystic fibrosis are offered
immunisation at the beginning of each influenza season. Rapid diagnostic
tests and the use of antiviral drugs may have a prophylactic role
in minimising lung damage.
1992
Kristidis P, Bozon D, Corey M, Markiewicz D, Rommens J, Tsui LC.
Genetic determination of exocrine pancreatic function in cystic
fibrosis. Am J Hum Genet 1992; 50:1178-1184. [PubMed]
A review of the association of so-called "mild" mutations
with pancreatic sufficiency. Although the majority of CF mutations
- including the most common, delta F508 - are strongly correlated
with pancreatic insufficiency (PI), approximately 10% of the mutant
alleles may confer pancreatic sufficiency (PS). To extend this observation,
genomic DNA of 538 CF patients with well-documented pancreatic function
status were analyzed for a series of known mutations in their CFTR
genes. A total of 30 different, complete genotypes could be determined
in 394 (73%) of the patients. The data showed that each genotype
was associated only with PI or only with PS, but not with both.
This result is thus consistent with the hypothesis that PI and PS
in CF are predisposed by the genotype at the CFTR locus; the PS
phenotype occurs in patients who have one or two so-called mild
CFTR mutations, such as R117H, R334W, R347P, A455E, and P574H, whereas
the PI phenotype occurs in patients with two severe alleles, such
as delta F508, delta I507, Q493X, G542X, R553X, W1282X, 621 + 1G----
T, 1717-1G----A, 556delA, 3659delC, I148T, G480C, V520F, G551D,
and R560T.
This large study from Toronto strengthens the view that pancreatic
function status in CF is genetically determined by specific mutations
at the CF locus. Subsequent studies established this beyond any
doubt.
1992
Heeley AF, Bangert SK. The neonatal detection of cystic fibrosis
by measurement of immunoreactive trypsin in blood. Ann Clin Biochem
1992; 29:361-376. [PubMed]
Anthony Heeley has been a pioneer of neonatal CF screening in the
UK. This is a detailed review of the situation at this time (also
Green et al, 1993 below for Heeley’s East Anglian results;
also Crossley et al, 1979 above).(Also comments after Crossley &
Elliott 1979 above; Heeley et al, 1982 above).
1993
Green MR, Weaver LT, Heeley AF, Nicholson K, Kuzemko JA, Barton
DE, McMahon R, Payne SJ, Austin S, Yates JR, et al. Cystic fibrosis
identified by neonatal screening: incidence, genotype, and early
natural history. Arch Dis Child 1993; 68:464-467. [PubMed]
This is the main report of the East Anglian neonatal CF screening
programme. The incidence of cystic fibrosis over the 10 years in
East Anglia (a region of the United Kingdom with a population of
2.1 million) had halved. Neonatal screening allowed early diagnosis,
genetic counselling of parents and relatives, and more recently
the option of prenatal diagnosis in subsequent pregnancies. One
hundred and seven children were born with cystic fibrosis between
1981 and 1990, eight of whom were siblings. The Guthrie blood spots
of the 82 infants detected by neonatal immunoreactive trypsin screening
between 1981 and 1990 were examined for the presence of the most
common cystic fibrosis gene mutation (delta F508). It was present
in 135 (82%) of the 164 cystic fibrosis genes analysed with 54 (66%)
cases being homozygous and 27 (33%) heterozygous. Sixty nine per
cent of infants were symptomatic at the time of diagnosis regardless
of genotype. No association was found between the early clinical
or biochemical features of the disease and homozygosity or heterozygosity
for this mutation.
Screening for
CF using the blood immunoreactive trypsin assay alone remains an
effective method of identifying infants with the CF within the first
weeks, thereby allowing early therapeutic intervention. Genetic
counselling and prenatal diagnosis have contributed to a reduction
in the number of children born with CF, but may not entirely explain
the decreasing incidence of the disease (also Heeley AF et al, 1982
above).
|
Figure
26: Dr Sarah Walters. |
|
Figure
27: Professor John Govan. |
|
Figure
28: Dr Ian Bowler (then the Leeds CF Research Fellow) undergoing
indirect calorimetry measurements. |
|
Figure
27.1 Dr Ty Pitt |
1993
Walters S, Britton J, Hodson ME. Demographic and social characteristics
of adults with cystic fibrosis in the United Kingdom. BMJ 1993;
306:549-552. [PubMed]
A survey of adults with CF in the UK by Dr Sarah Walters, (figure
26) a Birmingham doctor who herself has CF, which gave a picture
of the relatively new and expanding population of adults with cystic
fibrosis in the UK. 1052 adults were members of the Association
of Cystic Fibrosis Adults UK, accounting for the majority of adults.
Most were living fulfilling lives. 26% of men and 44% of women were
married or cohabiting. 55% were working, fewer than 56% had less
than two weeks' sick leave a year. Half of those not employed gave
ill health as the reason. Unfortunately, revealing that they had
CF at job interviews reduced the likelihood of being employed for
those with mild to moderate disease. People with CF had been less
successful than the general population in achieving O level or equivalent
qualifications, but more successful in achieving A level or higher
qualifications.
So contrary to an image of chronic ill health and disability, a
high proportion of adults with CF were living full and productive
lives - marked contrast to some of the earlier reports of adults
with CF.
A further survey by Sarah Walters in 2000 showed considerable further
improvement in many aspects of the condition and also the hospital
care of the adults with CF in the UK.
1993
Govan JR, Brown PH, Maddison J, Doherty CJ, Nelson JW, Dodd M, et
al. Evidence for transmission of Pseudomonas cepacia by
social contact in cystic fibrosis Lancet 1993; 342:15-19.[PubMed]
Prof. John Govan of Edinburgh (Figure 27) has for many years been
a leading UK and international authority on CF microbiology. In
this important paper he reported the definite transfer of B. cepacia infection between people with CF which finally
convinced most CF clinicians. An analysis of isolates from 210 patients
attending regional CF clinics in Edinburgh and Manchester between
1986 and 1992 showed that the main cause of increased isolations
of P. cepacia from 1989 was the emergence of an epidemic
strain that had spread between patients in both clinics. Epidemiological
evidence indicated that social contact was important in spread of
the epidemic strain within and between clinics. Guidelines to limit
the acquisition of B. cepacia should not be restricted
to patients in hospital, and that intimate or frequent social contact
is associated with a high risk of cross-infection.
Following this important paper the UK CF Trust advisory group of
clinicians and microbiologists advised that strict segregation of B. cepacia-infected patients was essential as some clinics,
even in 1993, were not yet segregating B. cepacia infected
patients from others in the clinic. The widespread introduction
of segregation from this time led to a steady reduction in the incidence
of new B. cepacia infections and a reduction in the prevalence
of chronic B. cepacia infections.
1993
Phillips RJ, Crock CM, Dillon MJ, Clayton PT, Curran A, Harper JI.
Cystic fibrosis presenting as kwashiorkor with florid skin rash.
Arch Dis Child 1993; 69:446-448. [PubMed]
Two infants with a florid erythematous rash and generalised oedema,
hypoalbuminaemia, and anaemia were found to have cystic fibrosis.
This rare presentation is associated with false negative sweat tests,
delays in diagnosis, and a considerable mortality. The authors suggested
that this presentation represents a manifestation of kwashiorkor
secondary to intestinal malabsorption.
1993
Ranasinha C, Assoufi B, Shak S, Christiansen D, Fuchs H, Empey D,
Geddes D, Hodson M. Efficacy and safety of short-term administration
of aerosolised recombinant human DNase I in adults with stable stage
cystic fibrosis. Lancet 1993; 342:199-202. [PubMed]
A phase II trial of DNase (Pulmozyme) from the Brompton Hospital,
London, in which the mean percentage change in FEV1 from baseline
was a 13.3% rise on rhDNase and only a 0.2% fall on placebo (p <
0.001). There was an insignificant rise of FVC of 7.2% in the rhDNase
group and 2.3% in the placebo group. This study provided further
confirmation that short-term administration of rhDNase in stable
patients with cystic fibrosis was safe and resulted in an impressive
improvement in lung function (also Shak et al, 1990 above; Fuchs
et al. 1994 below).
1993
Smith DL, Gumery LB, Smith EG, Stableforth DE, Kaufmann ME, Pitt
TL. Epidemic of Pseudomonas cepacia in an adult cystic
fibrosis Unit: Evidence of person-to-person transmission. J Clin
Microbiol 1993; 31:3017-3022. [PubMed]
Report of transmission between patients in the Birmingham Adult
CF Centre investigated in collaboration with Dr Ty Pitt of the Central
Public Health Laboratory, London. Prevalence rose from 1.4% in 1988
to 8.3% in 1992. At the time of writing five (30%) of the 17 affected
patients had died. In only two of the six patients referred to the
CF centre had P. cepacia been identified before referral.
Dr Ty Pitt (fig 27.1) has been a central figure in understanding
the microbiological aspects of cystic fibrosis collaborating closely
with clinicians both at the Brompton Hospital in London and also
with national studies. Of particular importance was the national
survey of CF centres revealing widespread evidence of cross infection
both within and between CF Centres in the UK (Scott and Pitt, 2003.
below).
1993
Bowler IM, Green JH, Wolfe SP, Littlewood JM. Resting energy expenditure
and substrate oxidation rates in cystic fibrosis. Arch Dis Child
1993; 68:754-759. [PubMed]
Ian Bowler (figure 28) coordinated this study on the resting energy
expenditure (REE) and substrate oxidation rates in 16 patients with
CF who had mild chest disease and 11 healthy controls were measured
using indirect calorimetry. The mean REE (% predicted) in the patients
with CF was 11% greater than in the controls. Five patients with
CF were hypermetabolic but only one of these had a clinically significant
reduction of respiratory function. A greater proportion of REE was
derived from carbohydrate oxidation in the CF patients (43.5% v
29.9%). However, the 24 hour dietary intake of carbohydrate was
greater in the cystic fibrosis group (49.6 v 45.8% of energy intake).
These data suggest that a high dietary intake of carbohydrate may
contribute to the increased oxidation of carbohydrate in these CF
patients.
<1>1993
Littlewood JM. The value of comprehensive assessment and investigation
in the management of cystic fibrosis. In Clinical Ecology of Cystic
Fibrosis. H Escobar, CF Baquero Suarez (Eds). Elsevier Science Publishers.
1993:181-187.[Conference publication]
This was a report of the 427 new patients seen at the Leeds CF centre
for a Comprehensive CF Assessment between 1980 and 1992, 364 of
whom had at least one follow-up assessment. They were referred from
10 hospitals in Yorkshire and a further 26 hospitals in the UK.
The details of their management and condition are recorded and a
comparison made between a previous 100 referral between 1985 and
1987 and 100 new referral between 1988 and 1992 showing improvement
in their condition in a number of areas reflecting the general improvement
in CF care in the UK (figure 29). The details give an idea of the
condition of the patients at the time.See also
Littlewood et al, 1984 above; Littlewood et al, 1988 above)
|
Figure
29: One hundred new referrals 1988 -1992. Previous 100 new referrals
1985-1987 bracketed. |
1994
Fuchs HJ, Borowitz DS, Christiansen DH, Morris EM, Nash ML, Ramsey
BW, Rosenstein BJ, Smith AL, Wohl ME. Effect of aerosolized recombinant
human DNase on exacerbations of respiratory symptoms and on pulmonary
function in patients with cystic fibrosis. The Pulmozyme Study Group.
N Engl J Med 1994; 331:637-642. [PubMed]
|
Figure
29.1 Dr Henry J Fuchs. From www.bmm.com |
Dr Henry J Fuchs,
while working at Genentech from 1987 to 1996, led the clinical programme
that resulted in the approval of Pulmozyme - one of the major clinical
advances introduced during the Nineties. Dr Fuchs is now Senior Vice
President and Chief Medical Officer of Biomarin.This
report, the main publication on rhDNase (Pulmozyme) describes a randomized,
double-blind, placebo- controlled study to determine the effects of
once-daily and twice- daily administration of rhDNase on frequency
of exacerbations of respiratory symptoms requiring parenteral antibiotics
and on pulmonary function. A total of 968 adults and children with
cystic fibrosis were treated for 24 weeks as outpatients. As compared
with placebo, the administration of rhDNase once daily and twice daily
reduced the age-adjusted risk of respiratory exacerbations by 28 percent
(P = 0.04) and 37 percent (P < 0.01), respectively. The administration
of rhDNase once daily and twice daily improved forced expiratory volume
in one second during the study by a mean (+/- SD) of 5.8 +/- 0.7 and
5.6 +/- 0.7 percent, respectively. Transient voice alteration and
laryngitis were more frequent in the rhDNase-treated patients.
This was the definitive Phase III trial showing the significant effect
of inhaled rhDNase – one of the most important large multicentre
studies of the 1990s. Pulmozyme was undoubtedly one of the major clinical
advances of the decade and was licensed by the FDA in 1994 following
this study. Regular treatment with DNase would become widely used
(by almost 70% of people with CF on the CFF registry by 2005) first
amongst those with significant chest involvement and then later for
those with milder chest problems (Quann et al, 2001 below) and eventually,
in some CF units for infants. The cost (approximately £7000
per year) proved a problem in certain parts of the UK. (Also Shak
et al, 1990 above; Ranasinha et al, 1993 above)
1994
Sawyer S, Bowes G, Phelan PD. Vulvovaginal candidiasis in young
women with cystic fibrosis. BMJ 1994; 308:1609. [PubMed]
Vulvovaginal candidiasis was more common in 55 women with CF than
in controls (13 vs.4) and more difficult to treat. Many women with
CF had recognized the association of the Candida infection with
their use of antibiotics. The authors suggested women with CF should
be given routine advice about the possibility of candidiasis.
This was an
important paper as it is unlikely that women would be asked about
such problems in a busy CF clinic for adults which are often “chest
orientated” – yet adequate treatment of the candidiasis
would significantly improve the patient’s quality of life.
Somewhat analogous to this problem was the later recognition of
the increased incidence of urinary incontinence in women with CF
(see Cornacchia et al, 2001).
1994
Super M, Schwarz MJ, Malone G, Roberts T, Haworth A, Dermody G.
Active cascade screening for carriers of cystic fibrosis gene. BMJ
1994; 308:1462-1467. [PubMed]
Dr Maurice Super (1936-2006) (figure 30) first
encountered CF in Windhoek in South West Africa (Namibia) in 1967
where he started a CF clinic. He subsequently became a leading geneticist
and paediatrician in the UK working in Manchester. He was a major
protagonist of carrier screening in the extended families of people
with cystic fibrosis – so-called “cascade screening”.
The present paper describes 15 carrier couples detected out of 1563
relatives of people with CF who were tested; eight had prenatal
tests and three pregnancies were terminated. An average of 16 people
per family had been tested. Cascade screening was acceptable to
relatives, particularly on the mother’s side of the family
and 10 times more successful in detecting carrier couples than unfocused
screening. <
The genetic
testing of all child-bearing relatives of a person with CF is now
provided by the UK NHS if the individuals wish to be tested.
|
Figure
30: Dr Maurice Super. |
1994
Arens R, Gozal D, Omlin KJ, Vega J, Boyd KP, Keens TG, Woo MS. Comparison
of high frequency chest compression and conventional physiotherapy
in hospitalized patients with cystic fibrosis. Am J Res Crit Care
1994; 150:1154-1157. [PubMed]
A study of 50 people with CF admitted for acute pulmonary exacerbations
that were randomly allocated to receive either high frequency chest
compression (HFCC) or conventional physiotherapy (CPT) three times
a day. After seven and 14 days of treatment, improvements were similar
in the two study groups, leading to patient discharge after similar
periods of hospitalization. The authors concluded that HFCC and
CPT are equally safe and effective when used during acute pulmonary
exacerbations in CF patients. They suggested that HFCC may provide
an adequate alternative in management of CF patients in a hospital
setting. (Also Warwick WJ, Hansen LG, 1991 above)
1994
Livingstone J, Axton RA, Gilfillan A, Mennie M, Compton M, Liston
WA, Liston WA, Calder AA, Gordon AJ, Brock DJ. Antenatal screening
for cystic fibrosis: a trial of the couple model. BMJ 1994; 308:1459-1462. [PubMed]
The second report of antenatal screening of 8536 couples in Edinburgh.
8.4% were “ineligible”, 1900 declined screening for
various reasons and 5922 (69.4%) were screened. There were four
positives (i.e. both partners were CF carrier heterozygotes) and
all four couples opted for prenatal diagnosis. There were three
terminations where the fetus was affected and one couple elected
to have the CF infant. There was 99% satisfaction by those screened.
Antenatal CF screening was pioneered in Edinburgh by David Brock
and his colleagues and this is one of the first reports (also Mennie
et al, 1992 first report above). Screening was introduced into the
two Edinburgh trial hospitals following this report. However, the
service was eventually discontinued in 2005 soon after neonatal
CF screening was introduced into Scotland. As the outlook for CF
improved parental attitudes changed to antenatal diagnosis and termination,
also the mutations tested differed from the neonatal ones, and finally
funding for both antenatal and neonatal screening was inadequate.
It has been estimated from various studies that for every CF fetus
detected by antenatal screening the cost is between £50K and
£100K.
1994
Walters S, Britton J, Hodson ME. Hospital care for adults with cystic
fibrosis: an overview and comparison between special cystic fibrosis
clinics and general clinics using a patient questionnaire. Thorax
1994; 49:300-306. [PubMed]
Another study from Sarah Walters on this occasion to assess the
current pattern of medical service received by adults with CF in
the UK and to compare the type of care between special CF centres
and general clinics. Two thirds of the patients were attending special
CF centres for either adults or adults and children. Significant
differences between cystic fibrosis and general clinics were noted.
Patients attending special cystic fibrosis clinics were more likely
to have had simple clinical investigations (blood tests, sputum
culture, oxygen saturation, chest radiography, weight and lung function
measurement) in the previous year. They were also more likely to
have received intravenous antibiotics at home, and to have access
to paramedical personnel. Patients attending cystic fibrosis clinics
were taking higher doses of pancreatic enzyme supplements with respect
to quantity and potency of preparation. Such patients also had less
severe symptoms irrespective of social class, and were more likely
to be satisfied with professional aspects of their care. Regardless
of type of clinic, potential deficiencies were identified in overall
medical care with omission of clinical investigations in severely
affected patients and evidence of under treated respiratory and
digestive symptoms in patients with moderate and severe disease.
This survey provides evidence that adults with cystic fibrosis attending
special cystic fibrosis clinics at that time received more intensive
care, had better symptom control, and are more satisfied with the
service provided than those attending general chest clinics. The
introduction of CF centre care was slow in the UK and was opposed
by some consultants working in general hospitals with a few CF patients.
Even in 2008 there was still considerable discussion about the best
care arrangements for people with CF. It is recommended by all CF
organisations including the UK CF Trust that all adults with CF
should receive all their medical care at a specialist CF Centre
for adults.
1994
Weaver LT, Green MG, Nicholson K, Mills J, Heeley ME, Kuzemko JA,
et al. Prognosis in cystic fibrosis treated with continuous flucloxacillin
for the neonatal period. Arch Dis Child 1994; 70:84-89. [PubMed]
This study from East Anglia provided satisfactory evidence for most
people that regular prophylactic flucloxacillin during the first
two years in 38 screened CF infants was associated with less cough,
fewer Staphylococcus aureus isolates, a lower hospital
admission rates (19 versus 5) and for shorter periods (6.4 versus
2.2 days) and the need for only half the number of additional antibiotics.
The study was possible as neonatal screening had been introduced
into East Anglia by Anthony Heeley and his colleagues in 1981 –
the first IRT screening in the UK ( Heeley et al, 1982 above).
Prophylactic anti-Staphylococcal therapy had been recommended many
years ago by David Lawson, paediatrician at Carshalton, London and
was routine practice in some large CF centres in the UK, from the
mid-Seventies. Evidence from this trial provided a basis for the
CF Trust Antibiotic Group's recommendations in 2002 (and later in
2009) for all infants with CF to receive continuous flucloxacillin
for the first 2 years; in fact the first 3 years was recommended
in 2009.
Arguments continued for the next decade as to whether this treatment
increased the likelihood of Pseudomonas infection – this was
not the case in centres where early eradication of Pseudomonas had
been practiced since the early Eighties but probably was the case
in the USA where early eradication of Pseudomonas was not routine
practice. As an alternative to long term flucloxacillin, the levels
of chronic S. aureus infection can also be reduced by early
active treatment whenever the organism was cultured as shown in
Copenhagen by Szaff and Hoiby (Szaff & Hoiby, 1981 above). It
is important to note that in Copenhagen respiratory cultures are
performed every month so S. aureus is detected at an early
stage when it can be eradicated; as with P. aeruginosa,
once allowed to become chronic eradication is difficult if not impossible.
The very high prevalence of chronic S. aureus infection
reported in recent CF Registry figures (in up to 50% of patients)
and from a number of countries, including the UK, is surprising
considering that S. aureus was the main cause of death
in the early years and is still associated with a definite inflammatory
response as shown in bronchoscopic studies of young CF infants (Armstrong
et al, 1995 below).
|
Figure
30.1: Professor Lawrence Weaver. |
Professor Lawrence
Weaver (figure 30.1) is Professor of Child Health in Glasgow and
paediatrician at the Royal Hospital for Sick Children Glasgow. The
present research, on the neonatal screened infants from East Anglia,
was carried out when he was working at the MRC Dunn Nutrition Unit
1994
Green MR, Weaver LT. Early and late outcome of cystic fibrosis screening.
J R Soc Med 1994; 87 (Suppl 21): 5-10. [PubMed]
More data from the East Anglian screened CF infants. During the
decade although the birth rate in the region had increased, the
incidence of CF had halved. Early detection of CF by neonatal screening
allows genotyping of infant and family. It also offers parents of
an affected child the opportunity of counselling before further
pregnancies and if desired subsequent antenatal testing. So both
neonatal and antenatal CF screening (Cunningham et al, 1998 below)
appear to reduce the incidence of CF. This has been the experience
in a number of regions but not all – for example Colorado.
1994
Smyth RL, van Velzen D, Smyth AR, Lloyd DA, Heaf DP. Strictures
of the ascending colon in cystic fibrosis and high strength pancreatic
enzymes. Lancet 1994; 343:85-86. [PubMed]
The first report of fibrosing colonopathy –
a new, unexpected and serious complication subsequently shown to
be related to the use of the new high strength pancreatic enzyme
preparations that had been introduced during the previous 2 years
(Pancrease HL, Creon 25,000, Nutrizym 22). The authors observed
five children with CF, who presented over a period of two months,
with meconium ileus equivalent that failed to respond to medical
management. At surgery, four had a stricture in the ascending colon
(figure 31 similar), and all had histopathological changes of post-ischemic
ulceration repair, with mucosal and submucosal fibrosis (figure
31). The only common change in the management of these children
had been a switch from conventional enteric-coated pancreatic enzymes
to a high-strength product between 12 and 15 months before presentation
A subsequent case controlled study from these authors (Smyth et
al, 1995 below) showed a significant correlation with both a high
enzyme dose and the make of preparation – only those enzymes
containing a covering of the copolymer eudragit being implicated.
A similar study from the USA confirmed the association with high
enzyme dosage but not with the copolymer covering (Freiman JP, FitzSimmons
SC. Colonic strictures in patients with cystic fibrosis: results
of a survey of 114 cystic fibrosis care centers in the United States.
J Pediatr Gastroenterol Nutr 1996; 22:153-156). [PubMed] However, no further cases were reported or have been since reported,
in patients taking the high strength Creon 25,000 preparation (which
does not contain eudragit) even when given for 3 years in high doses
to children (Connett et al, 1999 below).
In the UK the recommendations of the Committee on Safety of Medicines
to avoid doses of enzymes in excess of 10,000 IU lipase per kg day
and preparations containing the copolymer eudragit in children,
abolished the condition in the UK although a few cases continued
to occur in the USA. The enzyme content of the various preparations
are described in detail elsewhere (Littlewood JM, Wolfe SP, Conway
SP. Diagnosis and treatment of malabsorption in cystic fibrosis.
[PubMed]
|
|
Figure
32: Partial fibrosing colonopathy showing narrowing of the ascending
colon which did not progress after the high strength enzyme
preparation (Pancrease HL), containing the copolymer eudragit,
was stopped |
Figure
31: Fibrosing colonopathy. Barium enema and histology of the
colon. |
1994
Wilfond BS, Farrell PM, Laxova A, Mischler E. Severe hemolytic anemia
associated with vitamin E deficiency in infants with cystic fibrosis.
Implications for neonatal screening. Clin Pediatr 1994; 33:2-7. [PubMed]
Three infants with CF and malnutrition leading to severe anemia
beginning as early as six weeks of age. They had high reticulocyte
counts, negative Coombs' tests, abnormal peroxide haemolysis test
results, and biochemical evidence of vitamin E deficiency. Oral
administration of alpha-tocopherol resulted in rapid correction
of the laboratory abnormalities.
Phillip Farrell has published extensively on vitamin E deficiency
both in premature infants and those with CF (see Farrell et al,
J Clin Invest 1977; 60:233-241 above). This report emphasises the
early onset of fat soluble vitamin deficiencies in infants with
CF as also found in the Colorado screened infants (Sokol et al,
1991 above)
1994
Conway SP, Pond MN, Bowler I, Smith DL, Simmonds EJ, Joannes DN,
Hambleton G, Hiller EJ, Stableforth DE, Weller P, Littlewood JM.
The chest radiograph in cystic fibrosis: a new scoring system compared
with the Chrispin-Norman and Brasfield scores. Thorax 1994; 49:860-862.[PubMed]
A chest X-ray score devised and evaluated by members of the Northern
CF Club (NCFC) (figure 33) – an informal group of senior paediatricians
and respiratory physicians treating increasing numbers of children
with CF in the North of England. The group was formed in the mid-Eighties
by Jim Littlewood to discuss difficult clinical problems encountered
with increasing frequency by those of us responsible for treating
people with cystic fibrosis. The initial format of the meeting was
to meet at the Cottons Hotel in Cheshire to discuss specific patients
during the late afternoon and evening. It was essentially a mutual
support group fro clinicians to help each other to decide the best
treatment for some of these problems which many of us were encountering
|
Figure
33: Some of the original members of the NCFC in 1985 outside
the Cottons Hotel in Knutsford, Cheshire. Left to right; Pharmaceutical
firm representative (PFR), PFR, Tim David (Manchester), PFR,
Kevin Webb (Manchester), John Gilbert (Leeds), David Heaf (Liverpool),
Richard Page (Leeds), Jerry Kelleher (Leeds), Bob Nelson (Newcastle),
Gary Hambleton (Manchester), Jim Littlewood (Leeds).
|
“Northern
X-ray Score” is now used routinely in many CF centres
in the UK and the authors suggested it - “fulfils the requirements
of a chest radiograph score more successfully than the Chrispin-Norman
or Brasfield systems and does not require a lateral film”
– hence reducing considerably the irradiation to the patient.
So the published research output of our Northern CF Club was quality
not quantity; but countless patients benefited from the advice their
|
Figure:34:
Dr Carolyn Beardsmore. www.academicmedicne.ac.uk |
1994
Beardsmore CS, Thompson JR, Williams A, McCardle EK, Gregory GA,
Weaver LT, Simpson H. Pulmonary function in infants with cystic
fibrosis: effect of antibiotic treatment. Arch Dis Child 1994; 71:133-137. [PubMed]
Children from the East Anglian neonatal screening programme (1985-1992)
who were included in the flucloxacillin trial (Weaver et al, 1994
above) underwent infant respiratory function tests at three to four
months and one year of age (measurements of thoracic gas volume
and airway conductance using an infant whole body plethysmograph
and maximum expiratory flow by the “squeeze” technique).
There was no difference in lung function between the flucloxacillin
treated infants and the control CF infants at any age.
Dr Carolyn Beardsmore (figure 34) was one of the few experts in
infant lung testing at the time in the UK and since has published
Periodically
studies are published on infant respiratory function testing but
the techniques are so complicated and time-consuming that they are
usually only performed by the authors of the papers. Although valuable
for research they have never been of great practical value in the
clinic for most patients. In the present study it is not surprising
that there was no difference between the treated and control infants
as some hyperinflation is present in all CF infants from early infancy
whether they are infected or not. Hyperinflation in most CF infants
was confirmed in subsequent studies (Ranganathan et al, 2001 below).
1994
Konstan MW, Hilliard KA, Norvell TM, Berger M. Bronchoalveolar lavage
findings in cystic fibrosis patients with stable clinically mild
lung disease suggest ongoing infection and inflammation. Am J Respir
Crit Care med 1994; 150:448-454. [PubMed]
A rather surprising study on 18 patients which appears to demonstrate
the obvious i.e. that bronchiolar alveolar lavage in adolescents,
who were all chronically infected with P. aeruginosa, S. aureus and/or H. influenzae reveals evidence of ongoing inflammation.
It would have been surprising if it had not revealed evidence of
inflammation. The authors conclude “there is significant ongoing
infection and inflammation in the airways of CF patients with clinically
mild lung disease (FEV1 79%+/- 4%) and suggest a more aggressive
intervention might preserve their lung function for few of these
patient had received recent IV antibiotics (nine never and five
not in the past three years) and there is no mention of their taking
The unfortunate
use of the term “colonised” is evident from this study
– repeated positive cultures indicates that there is certainly
“chronic infection” of tissue, which also would have
been evident from serum antibody studies and by the presence of
inflammatory markers in the airways. The authors’ conclusions
that “intervention aimed at reducing ongoing infection and
destructive inflammatory response might be beneficial even when
patients do not have signs and symptoms of acute exacerbations”
– is a policy already adopted by the Danish CF centre since
the early Eighties and by many CF centres in the UK and Europe for
many years. This does highlight the marked differences in approach
between different CF centres and countries.
1995
Gan K-H, Geus WP, Bakker W, Lamers CBHW, Heijerman HGM. Genetic
and clinical features of patients with cystic fibrosis diagnosis
after the age of 16 years. Thorax 1995; 50:1301-1304. [PubMed]
Predictably, adult patients with late diagnosis have a better prognosis.
The differences between the early diagnosis of 4.6 years (ED) and
late diagnosis 27.7 years (LD) were FEV1 52% vs 72.5%; Pseudomonas
infection in 70% vs 24%; pancreatic insufficiency 81% vs 12%; homozygous
for DF508 58% vs none.
In other series
of adults with CF many have been diagnosed late and had other features
suggesting many had milder mutations – supported by the high
frequency of pancreatic sufficiency. However, it has been emphasised
that these patients require just as careful follow up and treatment
as those with the more usual clinical picture - rather than waiting
until they develop more obvious chest symptoms (Lording A, et al.
Pulmonary infection in mild variant cystic fibrosis: implications
[PubMed]
1995
Gan, K H. Veeze, H J. van den Ouweland, A M. Halley, D J. Scheffer,
H. van der Hout, A. Overbeek, S E. de Jongste, J C. Bakker, W. Heijerman,
H G. A cystic fibrosis mutation associated with mild lung disease.
New Eng J Med 1995; 333:95-99. [PubMed]
Among Dutch patients A455E the second most common mutation and associated
with preserved pancreatic function and some residual secretion of
chloride across membranes. Thirty three patients with compound heterozygosity
for the A455E mutation were compared with matched controls homozygous
for the delta F508 mutation. In those with the A455E mutation diagnosis
was later (mean age at diagnosis, 15.0 vs. 3.1 years; P < 0.001);
fewer had pancreatic insufficiency (21.2 percent vs. 93.9 percent,
P < 0.001), and none had diabetes mellitus (0 percent vs. 27.3
percent, P = 0.004). FEV1 and FVC were significantly higher (FEV1,
73.9 vs. 54.3 % predicted P = 0.002) and FVC, 88.7 vs. 76.3 % predicted
P = 0.04). Fewer had chronic pseudomonas infection (33.3 vs. 60.6
% P = 0.02).
Although several mutations were known to be associated with less
severe pancreatic disease, these findings showed a correlation between
the A455E mutation and mild pulmonary disease resulting in a better
|
Fig:
34.1 Dr Harry Heijerman |
Dr Harry Heijerman
(figure 34.1) was the Founding Editor of the Journal of Cystic Fibrosis.
Under his guidance the journal was increasingly successful; the
editorship was taken over by Prof. Gerd Döring in 2006 (see
2002 Journal of Cystic Fibrosis below).
Harry Heijerman is Physician at Haga Teaching Hospital, Deb Haag
in the Netherlands and a leading figure in CF care and research
in Europe.
1995
The Cystic Fibrosis and Genetic Disorders Group is a Collaborative
Review Group (CRG) of The Cochrane Collaboration and was formed
in 1995.
This Cochrane group for CF was formed in 1995 and was expanded to
cover other genetic disorders in 1997. It consists of a team led
by Prof. Ros Smyth of Liverpool (figure 35) who are interested in
producing high quality Systematic Reviews of controlled clinical
trials in CF and, since 1997, other genetic disorders. Initially
supported by the UK CF Trust, the group is now supported by the
NHS R&D (UK). Reviewers undertake the work on a voluntary basis
and by 2008 there were over 70 Systematic Reviews on various aspects
of treatment. Almost all the reviews highlight the lack of controlled
trials on many aspects of treatment; however, the information from
systematic reviews published on the website has proved an increasingly
valuable source of information for those dealing with CF –
even though the stringent standards of the Reviewers on occasion
have proved irritating to some elderly clinicians! Undoubtedly Ros
Smyth and the Group have had a major and favourable influence on
the number and standards of clinical trials which have favourably
influenced the management of people with CF.
|
Figure
35: Professor. Ros Smyth. From University of Liverpool website. |
| |
|
Figure
36: Professor Archie Cochrane. From the Cochrane website. |
Professor Archie
Cochrane (1908-1988) (figure 36) was born in Kirklands, Galashiels,
Scotland. He qualified in 1938 at University College Hospital, London,
and joined the Medical Research Council's Pneumoconiosis Unit at
Llandough Hospital, a part of Cardiff University School of Medicine
in 1948. Here he began a series of studies on the health of the
population of Rhondda Fach — studies which pioneered the use
of randomised controlled trials. His 1971 Rock Carling monograph
Effectiveness and Efficiency: Random Reflections of Health Services
was very influential. These ideas and his advocacy of randomized
controlled trials eventually led to the development of the Cochrane
Library database of systematic reviews, the establishment of the
UK Cochrane Centre in Oxford and the international Cochrane Collaboration
(from Cochrane website).
1995
Armstrong DS, Grimwood K, Carzino R, Carlin JB, Olinsky, Phelan
PD. Lower respiratory infection and inflammation in infants with
newly diagnosed cystic fibrosis. BMJ 1995; 310:1571-1572.[PubMed]
An important study from Melbourne documenting the early onset of
infection in screened infants with CF who, incidentally, were not
treated with long term anti-Staphylococcal antibiotics. Forty five
infants (32 screened and 12 with meconium ileus) had bronchoalveolar
lavage at a mean age of 2.6 months. Sixteen (36%) already had respiratory
symptoms and seven were receiving antibiotics at the time, although
long term flucloxacillin was not routine policy. Already lower respiratory
infection, usually with S. aureus, was present in almost
40% (17/45) of these young CF infants of whom a third were symptom
free. Follow up showed P. aeruginosa to be present in some
infants as early as 4 months.
I believe this study lends strong support to the use of long term
anti-Staphylococcal flucloxacillin, at least for the first 2 or
3 years as recommend by the UK CF Trust’s Antibiotic Group
in both 2002 and 2009 (full text on CF Trust website); also this
policy is supported by the trial of Weaver et al.1994 (above).
1995
Bowler IM, Kelman B, Worthington D, Littlewood JM, Watson A, Conway
SP, Smye SW, James SL, Sheldon TA. Nebulised amiloride in respiratory
exacerbations of cystic fibrosis: a randomised controlled trial.
Arch Dis Child 1995; 73:427-430. [PubMed]
As a result of Michael Knowles’s amiloride trial (Knowles
et al, 1990 above), we assessed the benefit of nebulised amiloride
added to the standard treatment of a respiratory exacerbation in
people with cystic fibrosis. We performed a prospective, randomised,
double blind, placebo controlled trial with 27 patients (mean age
12.8 years) in two hospitals in Leeds, UK. Both forced expiratory
volume in one second (FEV1) and forced vital capacity (FVC) showed
improvements over the course of treatment as would be expected but
there was no difference in respiratory function between the two
groups at any of three time periods during the study. However, the
time to reach peak FVC was significantly reduced in the amiloride
group (4.2 v 7.6 days; 95% CI 0.4 to 6.4 days), but not in the time
to reach peak FEV1 (5.7 v 7.9 days; 95% CI -1.2 to 5.6 days). Amiloride
did not result in a greater overall improvement in respiratory function.
On the modest
results of this trial we did not introduce amiloride into the treatment
regimen for exacerbations. Apparently the duration of action of
amiloride is so very short to the extent that it would be unlikely
to have a significant beneficial effect. (Also negative trials by
Graham et al Eur Respir J 1993; 6:1243-1248; Pons G et al, Pediatr
Pulmonol 2000; 30:25-31). Eventually more potent and more durable
ENaC blockers were synthesised e.g. compound 552-02 which was up
to 100 fold more potent and had a 170 fold slower fall off of effect
(Hirsch AJ, et al. J Pharmacol Exp Ther 2008; 325:77-88).
1995
Smyth RL, Ashby D, O'Hea U, Burrows E. Lewis P. van Velzen D. Dodge
JA. Fibrosing colonopathy in cystic fibrosis. Results of a case
controlled study. Lancet 1995; 346:1247-1251. [PubMed]
Fibrosing colonopathy was first described in children with CF in
1994 (Smyth et al, 1994 above). This study confirmed the relationship
between fibrosing colonopathy and high doses of lipase and the relation
of fibrosing colonopathy with certain brands of high strength enzymes,
which contained a copolymer – Eudragit. This is a report of
a nested case-control study to identify possible associations with
this condition. A case ascertainment within the UK CF population
to identify any cases that had occurred between January, 1984, and
April, 1994, revealed 14 cases, all less than 14 years and all confirmed
by independent histopathological review. All had presented since
April, 1993; 12 were boys and six had received some or all of their
care in Liverpool. Each child was matched, by date of birth, with
four controls from the UK CF Registry. Information was obtained
about the cases and the controls from their case records and by
a structured interview with the families. In the 12 months before
surgery, there was a dose related association between the occurrence
of fibrosing colonopathy and use of high-strength pancreatic enzyme
preparations. Odds ratio per extra 1000 high-strength capsules was
1.45 (95% CI 1.14-1.84). For use of protease, the odds ratio per
million extra units per kg was 1.55 (1.19-2.03). For usage of individual
high-strength products at any time during the 12 months before surgery
some differences were observed; for Creon 25000 the odds ratio was
0.38 (0.10-1.42), for Nutrizym 22 it was 43.4 (2.51-751), and for
Pancrease HL 8.4 (1.95-36.1). These last two confidence intervals
are extremely wide and compatible with these two products having
the same odds ratios. Laxative use was independently predictive
(odds ratio 2.42 [1.20-4.94]). The authors concluded that there
was a definite dose-related association between high-strength pancreatic
enzyme preparations and fibrosing colonopathy. (Also Fibrosing colonopathy
in children with cystic fibrosis. Proceedings of a conference in
Manchester organised by the Cystic Fibrosis Trust, 5th Nov. 1995.
Littlewood JM, Hind CRK (eds). Postgrad Med J 1996; 72 (Suppl 2):S1-S64).
1995
Pamucku A, Bush A, Buchdahl R. Effects of Pseudomonas aeruginosa colonisation on lung function and anthropomorphic variables
in children with cystic fibrosis. Pediatr Pulmonol 1995; 19:10-15. [PubMed]
Sixty two children with CF had three or more Annual Assessments
of their lung function at the Brompton Hospital, London. Despite
optimal pulmonary management children who were chronically infected
with P. aeruginosa deteriorated significantly faster than
those not so infected.
The term “chronically infected” would have been preferable
to the term “colonised” used in this paper.
This is one
of a number of valuable studies confirming an increasing rate of
pulmonary deterioration following the onset of chronic Pseudomonas
infection – an event which has been aptly described as “The
point of no return” (Drittanti et al,1997 below). There are
other studies confirming the importance of avoiding chronic Pseudomonas
infection (Kerem E et al, J Pediatr 1990; 116::714-719; Henry RL
et al. Pediatr Pulmonol 1992;12:158-161; Hudson VL et al. J Pediatr
1993; 122:854-860; CF Foundation Registry, 1996; Frederiksen B et
al. Pediatr Pulmonol 1997;21:153-158; Kosorok MR et al, Pediatr
Pulmonol 2001; 32:277-287).
1995
Konstan MW, Byard PJ, Hoppel CL, Davis PB. Effect of high dose ibuprofen
in patients with cystic fibrosis. N Engl J Med 1995; 332:848-854. [PubMed]
This was a major study funded by the CF Foundation to determine
the benefits of treating inflammation in the CF airways with long
term oral ibuprofen. A double-blind trial involving 85 patients,
five to 39 years of age, with mild lung disease who received oral
ibuprofen or placebo twice daily for four years in doses to achieve
peak plasma concentrations of 50 to 100 micrograms per ml. The patients
on ibuprofen had a slower annual rate of change in FEV1 than the
patients assigned to placebo (mean [+/- SE] slope, -2.17 +/- 0.57
percent vs. -3.60 +/- 0.55 percent in the placebo group; P = 0.02),
and weight (as a percentage of ideal body weight) was better maintained
in the former group (P = 0.02). Among the patients who took ibuprofen
for four years and had at least a 70 percent rate of compliance,
the annual rate of change in FEV1 was even slower (-1.48 +/- 0.69
percent vs. -3.57 +/- 0.65 percent in the placebo group, P = 0.03),
and this group of patients also had a significantly slower rate
of decline in forced vital capacity, the percentage of ideal body
weight, and the chest-radiograph score. There was no significant
difference between the ibuprofen and placebo groups in the frequency
of hospitalization. One patient was withdrawn from the study because
of conjunctivitis, and one because of epistaxis related to ibuprofen.
The authors concluded that in patients with CF and “mild”
lung disease, high-dose ibuprofen, taken consistently for four years,
significantly slows the progression of the lung disease without
serious adverse effects.
Despite these
results, the benefits of ibuprofen in this trial were not convincing
to most clinicians. Subsequently the modest effect and frequent
side effects prevented the widespread use of ibuprofen and the treatment
never became popular even in the United States – only some
5% of patients on the CF Foundation’s registry reported taking
the drug. For example Fennell PB et al (J Cyst Fibros 2007; 6:153-158)
reported half their patients stopped ibuprofen because of side effects
(mainly gastrointestinal pain and bleeding) and the treatment had
no effect on either the rate of pulmonary decline or hospitalisation
rates in those who tolerated the drug.
Yet subsequent reports from Michael Konstan remained supportive
(Konstan MW et al, Am J Resp Crit Care Med 2007; 176:1084-1089)
and Larry Land’s separate Canadian study showed slower FVC
but not FEV1 decline (Lands LC et al. J Pediatr 2007; 151:249-254).
An interesting and unrelated observational report suggested the
recurrence of nasal polyps was reduced while patients were receiving
ibuprofen (Lindstrom DR et al J Otolaryngol 2007; 36:309-314). So
few clinicians in the UK now advise using ibuprofen.
Professor Michael Konstan (figure 37) is Director of the Leroy Matthews
Cystic fibrosis Centre, Cleveland and particularly identified as
being associated with this study. He is a leading figure involved
in CF in the USA and heavily involved in both research and patient
|
Figure
37: Professor Michael Konstan |
| |
|
Figure
38: Dr Jeff Wagener. |
1995
Khan TZ, Wagener JS, Boast T, Martinez J, Accurso FJ, Riches DWH.
Early pulmonary inflammation in infants with cystic fibrosis. Am
J Respir Crit Care Med 1995; 151:1075-1082. [PubMed]
This paper from Denver is frequently quoted as providing evidence
of the presence of inflammation in the airways in the absence of
infection. Bronchoalveolar lavage fluid (BALF) from 16 infants with
CF and 11 disease control infants was examined for a variety of
inflammatory parameters. Each index of airway inflammation was increased
in the BALF of infants with CF as compared with control infants
– including those with negative microbiological cultures for
common CF-related pathogens, common respiratory viruses and fungi
at the time of bronchoalveolar lavage (BAL). The authors concluded
that these findings suggested that airway inflammation was already
present in infants with CF as young as four weeks.
However the authors did not know if the seven infants with evidence
of inflammation but negative cultures had received treatment previously
for infections from their own paediatricians prior to being referred
for bronchoscopy i.e. was there residual inflammation from a previous
bacterial infection? The number with positive lower respiratory
tract cultures was high (9/17) although the care of some infants
was with the local referring paediatrician not the authors.
Although, from
other publications, it seems very likely that there is a tendency
to an excessive inflammatory response in the CF airways, it is doubtful
if this study established that non-bacterial inflammation is common
in young screened CF infants. For example the study of Armstrong
et al 1996 (below) shows cells and inflammatory markers only where
there was also bacterial infection. It is therefore likely that
inflammation does not occur without infection but when it does occur
the degree of inflammation may be excessive.
Dr Jeff Wagner
(figure 38) of the University of Colorado Children's Hospital is
heavily involved in both CF care and research in the USA
1995
Littlewood JM. Abdominal pain in cystic fibrosis. J R Soc Med 1995;
88 (Suppl): 9-17.[PubMed]
A detailed review of the causes, investigation and treatment of
abdominal pain in CF summarising experience with over 600 patients
with CF seen at the Leeds Regional Paediatric CF Centre. As sub-specialisation
increased in paediatrics in the UK, the majority of paediatricians
working in CF centres were primarily interested in the treatment
of the chest – understandably as most people with CF died
from this cause. So the gastrointestinal aspects were relatively
under-investigated although a significant number of patients had,
and still do have, abdominal symptoms.
In this study recurrent abdominal pain occurred in 11% of children
receiving their care at the Leeds centre (where there was considerable
interest in and investigation of gastrointestinal problems) and
in 31% of those referred for Comprehensive CF Assessment from other
hospitals - admittedly a selected group.
It was interesting that the prevalence of recurrent abdominal pain
differed greatly with the mode of presentation e.g. meconium ileus
38%, respiratory 39%, malabsorption 47%, presence of a CF sibling
30% but only in 4% in those diagnosed by neonatal screening and
treated from the age of a few weeks (Littlewood JM J R Soc Med 1992;
85 (Suppl 18):13-19).
1995
Ghosal S, Taylor CJ, Pickering M, McGraw J, Beckles-Wilson, Wales
JKH. Disproportionate head growth retardation in cystic fibrosis.
Arch Dis Child 1995; 72:150-152. [PubMed]
Fifty children with CF (18 diagnosed with meconium ileus, four by
post natal screening, 30 by clinical diagnosis) were followed over
four years. The length SD scores improved from -1.24 at birth to
-0.15 at four years and the weight SD scores from -1.37 at 6 months
to -0.53 at four years. In contrast the head circumference SD score
reached a plateau of -1.0 from the age of 1.5 to four years and
remained significantly low throughout the four years of measurement
being -1.05 at four years. (also Lloyd-Still JD et al, Pediatrics
1974; 54:306-311 - "malnutrition in infancy can affect intellectual
development in the first five years").
This was the
first report that the head circumference of children with CF may
be slightly smaller than expected. The high proportion of infants
with meconium ileus (34%) in the series probably was due to Sheffield
Children’s Hospital being a regional centre for neonatal surgery.
The authors suggested that the data may support the expression of
CFTR in the choroid plexus and ependyma. There is very little in
the literature on head circumference in CF although in the Wisconsin
screening data on cognitive score index (CSI) – “the
highest proportion of CSI scores >84 occurred in the control
<300E group (41%). Patients in this group also had the lowest
mean head circumference z-scores at diagnosis” (Koscik RL
et al. J Pediatr 2005; 147(3 Suppl):S51-6). A further study of screened
CF infants from Sheffield confirmed that head growth appeared to
lag behind somatic growth supporting the functional expression of
CFTR in the brain (Ghosal S et al. Arch Dis Child 1996; 75:191-193. [PubMed]
1995
Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF.
Ocular findings in cystic fibrosis patients receiving vitamin A
supplementation. Graefe’s Arch Clin Exp Ophthalmol 1995; 233:709-713. [PubMed]
Only 26% of 35 patients examined in the Copenhagen clinic had normal
vitamin A status as measured by serum retinol and light sensitivity
but reduced contrast sensitivity. Conjunctival imprints showed dry
eye in 42%; decreased tear stability in 49% and other abnormalities
of low tear production (31%) and increased numbers of dying cells
(23%). In fact 26% were considered to have the criteria for “keratoconjunctivitis
sica”. The authors even suggested that the high incidence
of dry eye could be a primary manifestation of CF.
These findings are more likely the result of suboptimal vitamin
A status particularly as only 26% had normal vitamin A levels. In
studies where vitamin A status is regularly monitored to maintain
normal serum levels, only reduced contrast sensitivity is found
(Ansari et al. 1999 below) and the cause of this is unexplained.
|
Figure
39: Dr Jeanette Dankert-Roelse. |
1995
Dankert-Roelse JE, Meerman GJ. Long term prognosis of patients with
cystic fibrosis in relation to early detection by neonatal screening
and treatment in a cystic fibrosis centre. Thorax 1995; 50:712-718. [PubMed]
Comparative clinical follow up in three birth cohorts of patients
with CF was performed at the Cystic Fibrosis Centre in Groningen.
The first birth cohort (n = 19) was detected by screening and the
two other cohorts were detected clinically, one (n = 30) consisting
of patients born during the screening programme and the other (n
= 32) of patients born during the six years immediately after the
screening programme ended. Patients born during the screening programme
but detected clinically appeared to have a reduced life expectancy
compared with patients detected by screening. The patients detected
by screening showed less deterioration in lung function, a smaller
increase in immunoglobulin levels, and minimal catch-up growth compared
with the non-screened birth cohort of the same age.
Expert management when started immediately after an early diagnosis
of CF by neonatal screening results in important beneficial effects
on the outcome and clinical course of the condition. The institution
of very early treatment may be critical for the outcome and long
term prognosis for most patients with cystic fibrosis. The authors
believe that neonatal screening programmes for cystic fibrosis should
be introduced more widely.
Jeanette Dankert-Roelse
(figure 39) from the Netherlands has been a tireless advocate of
CF neonatal screening since the early Eighties and is still, in
2010, involved in the European CF Society neonatal CF screening
programme. It is a relief that the obvious benefits of neonatal
screening are now accepted and supported by studies that are acceptable
to virtually all.
1996
Armstrong, DS. Grimwood K, Carlin JB, Carzino R, Olinsky A, Phelan
PD.Bronchoalveolar lavage or oropharyngeal cultures
to identify lower respiratory pathogens in infants with cystic fibrosis.
Pediatr Pulmonol 1996; 21:267-275. [PubMed]
A study designed to determine whether oropharyngeal cultures predicted
the presence of pathogens in the lower airways. In children with
CF during 1992-1994, 75 of 90 (83%) infants with CF diagnosed by
neonatal screening had 150 simultaneous bronchoalveolar lavage (BAL)
and oropharyngeal specimens collected for quantitative bacterial
culture at a mean age of 17 months (range, 1-52 months). Ten children
undergoing bronchoscopy for stridor served as controls. Some, in
fact many, of the infants with CF were currently receiving antibiotics
– either anti-Staphylococcal antibiotics (44) or inhaled tobramycin
(11). Total and differential white cell counts and interleukin-8
concentrations were measured in BAL fluid. A subset of bacterial
pathogens was typed by pulsed field gel electrophoresis. A non-linear
relationship with inflammatory markers supported a diagnosis of
lower airway infection when > or = 10(5) colony-forming units/ml
were detected. This criterion was met in 47 (31%) BAL cultures from
37 (49%) children. Staphylococcus aureus (19%), Pseudomonas
aeruginosa (11%), and Hemophilus influenzae (8%) were
the major lower airway pathogens. In oropharyngeal cultures, S.
aureus (47%), Escherichia coli (23%), H. influenzae (15%), and P. aeruginosa (13%) predominated. The sensitivity,
specificity, and positive and negative predictive values of oropharyngeal
cultures for pathogens causing lower respiratory infections were
82%, 83%, 41%, and 97%, respectively. When there was agreement between
paired oropharyngeal and BAL cultures, genetic fingerprinting showed
some strains of the same organism were unrelated. The authors
concluded that oropharyngeal cultures do not reliably predict the
presence of bacterial pathogens in the lower airways of young CF
children.
This is an
important study if only for showing that an alarming number of infants
with CF had infected lower airways even at an average age of only
17 months. In many clinics, such as Copenhagen, children with CF
have frequent cultures, every month or more often - for example
when ever they are unwell. The multiple cultures then available
allow a more accurate assessment of the likelihood of lower respiratory
tract infection over time – rather than the “one off”
correlation as occurred in this and a number of similar studies.
Also this practice of evaluating frequent throat
cultures as an indicator of lower respiratory infection is supported
by Pseudomonas antibody levels which correlate with the culture
results. So if the upper respiratory cultures are repeatedly negative
it is likely that the lower airways are also uninfected - such an
infant will virtually always have negative Pseudomonas antibody
levels.
1996
Doull IJ, Freezer NJ, Holgate ST. Growth of prepubertal children
with mild asthma treated with inhaled beclomethasone dipropionate.
Am J Resp Crit Care Med 1996; 151:1715-1719. [PubMed]
The effect of 7 months inhaled beclomethasone propionate
400 micrograms/day on linear growth and adrenal function in 94 children
aged seven to nine years. Mean regressed daily growth was significantly
decreased during the treatment period 0.79 mm versus
1.14 mm per week. At the end of the seven months study the BDP treated
children had grown significantly less than the children on placebo
(mean 2.66 versus 3.64 mm). There was no catch up over 4 months.
So inhaled
BDP at these relatively modest doses in children with mild asthma
significantly decreased statural growth - a side effect so vigorously
denied for so long by many respiratory paediatricians since the
first reports (Littlewood et al, 1988 above). This is important
in the context of CF as many children are treated, at times unnecessarily,
with inhaled steroids (Balfour-Lynn I M et al. Am J Resp Crit Care
Med 2006; 173:1356-1362), and the doses used may be large and growth
impairment is not a rare finding.
Dr Iolo Doull
is the Director of the Cardiff Paediatric CF Centre. He is heavily
involved in both CF care and research. He has developed a shared
care network for most of Wales which involves he and his team traveling
periodically to the various general hospitals.
1996
Carles S. Desgeorges M. Goldman A. Thiart R. Guittard C. Kitazos
CA. de Ravel TJ. Westwood AT. Claustres M. Ramsay M. First report
of CFTR mutations in black cystic fibrosis patients of southern
African origin. J Med Genet 1996; 33:802-804. [PubMed]
Cystic fibrosis was thought to be rare in the black populations
of Africa and only a few patients have been reported but they had
not been studied at the molecular level. This report, from Michelle
Ramsay’s laboratory, concerns the detection of CFTR mutations
in three black South African patients. One was homozygous for the
3120 + 1G-->A mutation, while the other two were compound heterozygotes
each with this mutation on one chromosome. The other mutations were
G1249E and a previously unreported in frame 54 bp deletions within
exon 17a involving nucleotides 3196-3249 (3196del54).
The 3120 +
1G-->A mutation was first described in black American patients
and has been shown to be a relatively common mutation in this population
(9-14% of CF chromosomes). It was also found in a black CF patient
whose father, the 3120 + 1G-->A carrier, is from Cameroon. These
data suggest that it is an old mutation which accounts for many
of the CFTR mutations in black Africans (Also Pileggi A. 1962; Kulczycki
LL et al, 1964 above and other reports find a low incidence in black
patients).
1996
Brock DJH. Prenatal screening for cystic fibrosis: 5 years’
experience reviewed. Lancet 1996; 347:148-150. [PubMed]
Antenatal screening had been available at two maternity clinics
in Edinburgh, UK, since January, 1992, first on a research basis
and then routinely. 25,000 couples had been screened. The take-up
rates for the two-step and couple models of delivery were very similar
at about 70%. Of 22 high-risk couples identified entirely through
screening, 20 (91%) opted for prenatal diagnosis. Four couples returned
for second and two for third monitored pregnancies. In all eight
cases where affected fetuses were identified, pregnancy was terminated.
David Brock
concluded that “these data remove one of the few remaining
obstacles to a general implementation of prenatal screening for
CF”. However, although prenatal screening was recommended
in the UK by a Health Technology Assessment (Murray et al, 1999)
and after this was accepted in principle by the National Screening
Committee, prenatal screening had not been introduced in the UK
by 2009. Furthermore, antenatal CF screening was discontinued in
the Edinburgh hospitals in 2005 on grounds of both cost and also
the introduction of neonatal screening and the evidence of improving
prognosis for infants with CF diagnosed soon after birth (also Mennie
et al, 1992 above; Livingstone et al, 1994 above).
1996
Bikangaga P, Canny GJ. Benign intracranial hypertension in infants
with cystic fibrosis. Arch Pediatr Adolesc Med 1996; 150:551-552. [PubMed]
Four of 53 (7.7%) newly diagnosed infants with CF in Toronto developed
transient benign raised intracranial pressure during their initial
treatment. This is an apparently benign occurrence according to
previous reports (Roach ES, Sinai SH. Clin Pediatr 1989; 27:371).
Vitamin A deficiency has been described as a cause (Abernathy RS.
AJDC 1976; 130:1360-1362 above) also systemic steroid withdrawal.
Catch up growth after severe malnutrition has also been implicated
but many cases are unexplained. The complication has also been described
with tetracycline antibiotics since the Sixties.
|
Figure
40: Dr David Heaf, |
1996
Cheng K, Smyth RL, Govan JRW, Doherty C, Winstanley C, Denning N,
Heaf DP, Saene H van, Haret CA. Spread of ß-lactam resistant Pseudomonas aeruginosa in a cystic fibrosis clinic. Lancet
1996; 348:639-642. [PubMed]
A high proportion of children attending the Liverpool paediatric
CF centre were found to be chronically infected with a P. aeruginosa that was resistant to ceftazidime and other beta-lactam antibiotics.
Two genomic fingerprinting techniques were used to see if this had
arisen from epidemic spread of a single strain. 92 (76.7%) of the
120 children attending the clinic were infected with P aeruginosa, and 65 (71%) of these 92 infected infants harboured isolates that
were resistant to ceftazidime; 55 of the 65 children harboured the
same epidemic strain - resistant to ceftazidime, azlocillin, and
imipenem, and sensitive to tobramycin and ciprofloxacin.
This study
provides the first molecular evidence of a long-term “outbreak”
of P. aeruginosa in a CF centre. The authors suggested
that careful surveillance of the prevalence of antibiotic resistance
in CF centres should be instituted with measures to prevent cross-infection.
They suggested that anti-Pseudomonal monotherapy “should be
considered with caution”. This lesson had already been learned
in Copenhagen in the early Eighties (Pedersen et al, 1986 above)
and in the past a number of writers had already cautioned against
the use of monotherapy. Most CF centres at the time already followed
the recommendation to use two antibiotics when treating exacerbations
of Pseudomonas infection. However, prior to this outbreak, intravenous
ceftazidime monotherapy had been routine in the Liverpool CF clinic.
This was a very important paper which highlighted the risk of cross
infection with Pseudomonas aeruginosa in CF clinics now
clearly identified by genomic finger printing techniques. Later
this highly transmissible “Liverpool epidemic strain”
of Pseudomonas aeruginosa was reported elsewhere and subsequently
spread to many other CF centres in the UK..
It is cause for concern that, even after experience such as reported
here, there is still discussion as to the use of one or two antibiotics
for the treatment of exacerbations – even to the extent of
a Cochrane review which failed to give firm advice to use two antibiotics!!
(Ephick HE, Tan A. Single versus combination intravenous antibiotic
therapy for people with cystic fibrosis. Cochrane Database of Systematic
Reviews. 2005).
Dr David Heaf (figure 40) is the Director and senior paediatrican
at the Alder Hey Children's Hospital CF Unit in Liverpool. He has
developed an extensive shared care service for children with CF
in the North West of England and North Wales.
1996
Frederiksen B, Lanng S, Koch C, Hoiby N. Improved survival in the
Danish center-treated cystic fibrosis patients: results of aggressive
treatment. Pediatr Pulmonol 1996; 21:153-158. [PubMed]
Survival data for Danish center-treated CF patients, covering the
period 1974-1993. The annual mortality rate for 1989-1993 was 0-1.2%.
Using the age-specific mortality rate for 1989-1993, it was impossible
to calculate the median survival probability because the curve did
not fall below 50% (age up to 45 years); however, it was possible
to show that the survival probability for a newborn CF child to
reach his 45th birthday was 80.4% (confidence interval 76.5-84.6%).
The median age at diagnosis was 0.63 years with no sex difference
(surprisingly there was and still is no neonatal CF screening in
Denmark). The probability of surviving 40 years after the diagnosis
of CF was made was 83.3% (confidence interval 80.1-86.6%).
These survival figures are considerably better than any other published
survival probability at the time. The only item that I would not
agree with the Danish CF centre is their policy of not screening
neonates for CF.
1996
Robinson M, Regnis JA, Bailey DL, King M, Bautovich GJ, Bye PTP.
Effect of hypertonic saline, amiloride, and cough on mucociliary
clearance in patients with cystic fibrosis. Am J Respir Crit Care
Med 1996; 153:1503-1509. [PubMed]
After inhalation of hypertonic (7%) saline alone, and with amiloride,
the amount of radio aerosol cleared from the right lung at 60 and
90 minutes was significantly increased. The authors suggested that
inhaled hypertonic saline was a potentially useful treatment for
CF.
Peter Bye’s
group at St Vincent’s Hospital in Sydney continued their work
on hypertonic saline and eventually carried out a successful clinical
trial of hypertonic saline in adults with CF and eventually confirmed
the value of hypertonic saline treatment (Elkins et al, 2006 below).
Hypertonic 7% saline inhalations were originally reported to double
the rate of removal of bronchial secretions in chronic bronchitis
in an interesting study using radio aerosols (Pavia et al, Am Rev
Respir Dis 1978; 117:199-203). I recall consulting Margaret Hodson
in the early Eighties asking her for any suggestions for treating
a girl with CF who had excessively viscid secretions. She advised
a trial of nebulised hypertonic saline which, from her personal
experience, had proved helpful!
1997
Katznelson D, Szeinberg A, Augarten A, Yahav Y. The critical first
six months in cystic fibrosis: a syndrome of severe bronchiolitis.
Pediatr Pulmonol 1997; 24:134-136. [PubMed]
The
syndrome of infantile bronchiolitis in cystic fibrosis (CF) carries
a high mortality. Fifteen cases of CF encountered over the past
19 years with severe bronchiolitis with onset during the first 6
months of life are described. Treatment includes steroids in high
doses. All patients recovered. Further progress resembled the usual
natural course of CF and showed no evidence of persisting lung damage.
The mechanism of this syndrome is not clear and is probably dependent
on many factors involved in early lung disease in CF. The frequency
of severe bronchiolitis in cystic fibrosis may not be high, but
it continues to be seen in clinical practice today.
This paper is
one of many on CF and a wide range of paediatric subjects by Professor
Daniel Katznelson of the National CF Center, Sheba Medical Center,
Israel.
1996
Colombo C, Battezzi PM, Podda M, Bettinadi N, Giunta A. Ursodeoxycholic
acid for liver disease associated with cystic fibrosis:a double
blind multicenter trial. Hepatology 1996; 23:1484-1490. [PubMed]
A trial of ursodeoxycholic acid by Carla Colombo and colleagues
from MIlan who first reported the use of URSO in people with CF
(Colombo et al, 1990 above). Fifty five patients from 12 CF centres
over one year had either UDCA + taurine, UDCA + placebo, placebo
+ taurine or double placebo. The UDCA treated patients showed better
clinical condition and improved biochemistry; also those treated
with taurine had improved prealbumin levels.
Despite this trial, a Cochrane review, revised in 2009, considered
"There is insufficient evidence to justify its (URSO) routine
use in cystic fibrosis". However, it is reassuring that most
clinicians consider there is clinical evidence and would disagree
with the Cochrane Review and ignore their advice and use URSO at
an early stage if there is any evidence of liver involvement.
1997
Conway SP, Pond MN, Watson A, Etherington C, Robey HL, Goldman MH.
Intravenous colistin sulphomethate in acute respiratory exacerbations
in adult patients with cystic fibrosis. Thorax 1997; 52:987-993. [PubMed]
Intravenous colistin was shown to be an effective safe treatment
for P. aeruginosa associated pulmonary exacerbations in
patients with cystic fibrosis. Assessment of the individual effect
of each treatment regimen suggests a greater efficacy when colistin
is combined with a second antibiotic to which the Pseudomonas shows in vitro sensitivity. It was advised that renal function
should be monitored.
Intravenous
colomycin was first used by Robert Stern who gives an interesting
account of his decision to use of the intravenous route, instead
of the painful intramuscular route, in a wasted girl who already
had an intravenous drip running for hydration purposes. Colomycin
was the only parenteral antibiotic in the early Sixties. Later an
intravenous preparation became available and but was soon replaced
by intravenous gentamicin and then carbenicillin and piperacillin
became available. Stern describes the early developments including
the heparin lock in the early Seventies, the gradual involvement
of the patients with CF in managing their own IV therapy first in
hospital and eventually at home (Stern RC. Intravenous treatment:
where we are and how we got there. In: Doershuk CF, editor. Cystic
Fibrosis in the Twentieth Century. Cleveland: AM Publishing, Ltd,
2001:93-111).
1997
Everard ML, Sly P, Brenan S, Ryan G. Macrolides antibiotics in diffuse
panbronchiolitis and in cystic fibrosis. Eur Respir J 1997; 10:2926. [PubMed]
Mark Everard (figure 41) confirmed with me that this was the first
report from Sheffield UK and Perth Western Australia showing the
anti-inflammatory effect of macrolides in people with cystic fibrosis.
Four of six patients with CF had significant reduction in IL-8 sputum
levels after one month treatment with low dose (200 mg tds) oral
erythromycin. He believes the first report of the use of macrolides
in CF was in a Japanese publication by Nakanishi et al in 1995 –
"A 16-year-old boy was admitted to our hospital because of
coughing, sputum, and exertional dyspnoea. Seven months after birth
cystic fibrosis had been diagnosed. The chest roentgenogram on admission
showed diffuse reticulonodular shadows and overinflation. Pulmonary
function tests revealed obstructive and restrictive impairment.
Erythromycin and Lomefloxacin were administered by mouth, and aminoglycosides
were administered by inhalation. His symptoms were alleviated, and
he is now an outpatient. In Japan, cystic fibrosis is rare, and
this patient is extremely rare because he has grown up to be a 16-year-old.
In this case, low-dose and long-term erythromycin administration
was very effective". (Nakanishi N, Ueda N, Kitade M, Moritaka
T. A case of cystic fibrosis in a Japanese student. Jpn J Thoracic
Dis 1995; 33:771-774.) [PubMed]
The beneficial effect of 600 mg/day of erythromycin for 1 to 12
months in chronic panbronchiolitis in Japanese patients had been
reported previously (Nagai H et al. Respiration 1991; 58:145-9). [PubMed] The effect appeared to be independent of the presence of chronic
Pseudomonas infection and an anti-inflammatory action was suggested
(Fujii T et al. Thorax 1995; 50:1246-52; Hoiby N. Thorax 1994; 49:531-532;
Kudoh S et al. Jpn J Thorac Dis 1987; 25:632-42; Kudoh S. et al.
Am J Respir Crit Care Med 1998; 157:1829-32 below; Kudoh et al,
1998 below).
These were important developments eventually leading to a number
of large clinical trials and the widespread use of azithromycin
in people with CF – undoubtedly one of the major clinical
treatment advances of the Nineties and new Millennium (Equi et al,
2002 below; Saiman et al, 2003 both below). By 2005 nearly 54% of
all the patients on the CF Foundation Registry were taking azithromycin.
|
Figure
41: Dr Mark Everard. |
| |
|
Figure
42: Dr Colin Wallis. |
| |
|
Figure
43: Brenda Button. |
1997
Wallis C, Leung T, Cubbitt D, Reynolds A. Stool elastase as a diagnostic
test for pancreatic function in children with cystic fibrosis. Lancet
1997; 350:1001.[PubMed]
The first published report of faecal pancreatic elastase 1 in children
with CF from Colin Wallis, (figure 42) paediatrician at Great Ormond
Street, London. All non-CF children had normal faecal elastase levels
but 26 of 30 children with CF had undetectable levels. Three of
the others were pancreatic sufficient. Normal levels were reached
by normal infants within 2 weeks.
The test was further evaluated in a larger series of children with
CF in Leeds (Cade et al, 2000 below) and became the accepted method
of determining pancreatic function. The test had a major advantage
over faecal chymotrypsin as it still remained low (negative) in
pancreatic insufficient patients whilst the patient was taking pancreatic
enzyme supplements.
This test was a major advance - a really useful standardised non-invasive
test for accurately confirming the presence of pancreatic insufficiency
without having to stop the pancreatic enzyme treatment of patients
referred to a CF Centre for full investigation - a far cry from
duodenal intubation for tryptic activity which was essential before
the sweat test was introduced during the Fifties; also it was a
major advance on faecal chymotrypsin. However, faecal chymotrypsin
did provide a useful indication as to whether the patient was taking
their pancreatic enzyme supplements – a low chymotrypsin when
thought to be taking pancreatic enzymes suggested non-adherence.
1997
Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Postural
drainage and gastro-oesophageal reflux in infants with cystic fibrosis.
Arch Dis Child 1997; 76:148-150. [PubMed]
First of series of papers from Brenda Button (figure 43), a physiotherapist
from Melbourne, Australia, noting the possible dangers of inhalation
when infants with CF were in the head down position during postural
drainage; infants with CF were known to have an increased incidence
of gastro-oesophageal (GO) reflux. Physiotherapy with and without
head down tilt were compared using 24 hour pH oesophageal monitoring.
Standard physiotherapy with head down tilt was associated with a
significant increase in GO reflux in the infants with CF.
This was an
important study and, with Brenda Button’s subsequent publications,
certainly had a major influence on the techniques of physiotherapy
recommended for CF infants (see also Malfroot & Dab, 1991 above
for earlier studies on reflux in CF infants; Button et al, 2004
also confirmed GO reflux as common and important in adults with
CF).
1997
Drittanti L, Masciovecchio MV, Gabbarini J, Vega M. Cystic fibrosis:
gene therapy or preventive gene transfer? Gene Therapy 1997; 4:1001-1003.[PubMed]
I was very impressed by this, not widely known, paper for it accurately
described the situation clinicians, who followed many patients year
after year, had been observing in the clinic. Patients’ respiratory
function tests are usually stable before chronic infection (usually
Pseudomonas) becomes established but begin a slow deterioration
after chronic Pseudomonas infection becomes established i.e. they
pass the "point of no return" (figure 44 - my figure)..
These authors suggested that before the onset of chronic infection
people with CF can be considered to be in the phase of “CF
Disease” i.e. they have various physicochemical alterations
in the electrolyte and liquid composition of the airway fluid but
no tissue damage. Although they get respiratory infections these
can be eradicated, if treated early with antibiotics and their respiratory
function remains stable. However, eventually a new respiratory infection
is not eradicated and chronic infection of the tissues becomes established.
At this stage the patient then enters the phase of “Lung disease”
where infection and chronic inflammation become established, self
perpetuating and progress independently of the basic CFTR abnormality
– this change is referred to as the “Point of no return”
and there follows a slow deterioration in their condition, the speed
of which is determined by the type and intensity of treatment they
receive.
So the aim of modern treatment is to avoid passing the “Point
of no return” i.e. prevent or delay for as long as possible
the onset of chronic infection of the airways. So it can be appreciated
that if the airway cultures are repeatedly positive for Pseudomonas,
even if the patient has few or even no symptoms (as in the paper
by Konstan et al, above), he already has passed the "Point
of No Return".
In a later paper
Drittanti is one of the authors who state that "The interactivity
between the CFTR gene and cystic fibrosis would be limited to the
initial phase of the disease" (Genetics in Medicine 2000;2:124-130. [PubMed])While the initial phase was related to the CFTR genotype,
the kinetics of the second phase seems to be common to all groups
considered. The hypothesis that the interactivity between the CFTR
gene and CF disease would be limited in time is presented, suggesting
that mutant CFTR would trigger a disease that evolves to become
independent from the CFTR gene itself
|
Figure
44: The Point of No Return.
|
1997
Frederiksen B, Koch C, Hoiby N. Antibiotic treatment at time of
initial colonisation with Pseudomonas aeruginosa postpones
chronic infection and prevents deterioration of pulmonary function
in patients with cystic fibrosis. Pediatr Pulmonol 1997; 23:330-335. [PubMed]
Follow up of the important Valerius et al, 1991 study (above) showing
successful eradication of early infection with P. aeruginosa with nebulised colistin and oral ciprofloxacin. Three months colistin
and ciprofloxacin gave longer freedom from recurrence of infection
than did three weeks treatment.
This study was criticised as historic controls were used. However,
it was already quite obvious that the early eradication treatment
prevented chronic P. aeruginosa infection (Littlewood et
al, 1985; Valerius et al, 1991 above) and most clinicians in Europe
would have regarded it as unethical to involve a placebo group at
this stage; vigorous early eradication treatment was already routine
practice in many European CF clinics. But it is difficult to understand
how three months treatment increases the time to further Pseudomonas
infection as the next episode of infection is usually, but not always,
with a different genotype presumably acquired from the environment
(Munck A et al. Pediatr Pulmonol 2001; 32:288-292). However, also
using genotyping, it was later shown that a minority of Pseudomonas
strains were suppressed but not completely eradicated – so
presumably three months treatment would make this less likely to
happen.
The great delay in the general introduction of early eradication
therapy for Pseudomonas to reduce the prevalence of chronic infection,
particularly in North America, was difficult to understand when
the results of the earlier Copenhagen study were so impressive (Valerius
et al, 1991 above).
Surprisingly, a later Cochrane Systematic review on early eradication
of Pseudomonas aeruginosa, almost a decade later in 2006,
could only conclude that “there is some evidence that antibiotic
treatment of early P. aeruginosa results in short term
eradication but it remains uncertain whether there is clinical benefit
to people with cystic fibrosis” – a conclusion most
experienced clinicians, including Neils Hoiby would fiercely question
(as he and I did in critical letters to the Cochrane reviewers!).
The views of the late Christian Koch summarise the Danish experience
and of most expereinced CF clinicians as to the importance of avoiding
chronic Pseudomonas infection (these are quoted in the comments
on Valerius et al, 1991 above). I'm afraid there are definite downsides
to Evidenced Based Medicine !!!!
1998
Ledson MJ, Tran J, Walshaw MJ. Prevalence and mechanisms of gastro-oesophageal
reflux in adult cystic fibrosis patients. J R Soc Med 1998; 91:7-9. [PubMed]
Fifty adults with CF were surveyed by questionnaire and ten with
reflux symptoms had oesophageal manometry and 24 hour pH recording.
Forty seven patients (94%) had upper gastrointestinal symptoms:
40 (80%) heartburn (27 worse when supine); 26 (52%) regurgitation;
and 28 (56%) dyspepsia. At oesophageal manometry, lower oesophageal
sphincter barrier pressure (LOSBP) was subnormal in 6 of the 10
patients and 3 had uncoordinated peristalsis in the mid-oesophagus.
Eight patients had significant gastroesophageal reflux. Adult CF
patients have high rates of GOR symptoms, diminished LOSBP, and
acid reflux.
This study
re-emphasised the fact that GOR was a frequent and important problem
and a significant cause of symptoms in adults with cystic fibrosis.
The complication had been recognised since first described by Jan
Feigelson (Feigelson & Sauvegrain, 1975 above) and later by
Scott RB et al, 1985 (above); the frequency and importance was again
highlighted in this present paper. Brenda Button in Australia had
already pointed out the problem of the occurrence of reflux in CF
infants in the head down position during physiotherapy (Button et
al, 1997 above) – later she also found reflux to be common
in adults with CF (Button et al, 2004).
Dr Martin Walshaw
(figure 45) was the first Director of the Liverpool CF Centre for
adults and was later joined by Dr Malcolm Ledson (figure 45.1).
The Liverpool CF Centre for adults is now one of the major units
in the UK.
|
|
Figure
45: Dr Martin Walshaw |
Figure
45.1: Dr Malcolm Ledson. |
1998
Kudoh S. Azuma A. Yamamoto M. Izumi T. Ando M. Improvement of survival
in patients with diffuse panbronchiolitis treated with low-dose
erythromycin. Am J Respir Crit Care Med 1998; 157:1829-32. [PubMed]
Diffuse panbronchiolitis (DPB) is a chronic inflammatory disease
of the airways with a high mortality despite treatment with a combination
of antibiotics and the use of supportive therapy. Low-dose erythromycin
therapy (EM) (400 to 600 mg/d) improved the survival and most patients
in Japan have been treated with this regimen since 1984. The authors
compared the survival rates of 498 patients with DPB after dividing
them into three groups (Group a: 1970-1979, Group b: 1980-1984,
Group c: 1985-1990). The survival rate of Group c was significantly
higher than that of Groups a (p < 0.0001) and b (p < 0. 0001).
In Group c (1985-1990), eight of 87 patients died; five (21%) died
in the EM non-treated subgroup (n = 24), and three (5%) died in
the EM-treated subgroup (n = 63). So treatment with erythromycin
was associated with a significant improvement in the survival of
patients with DPB which was more significant in the older than in
the younger patients.
These findings
were the basis for the gradual evaluation of macrolide therapy in
people with cystic fibrosis. The first report of the favourable
effect of erythromycin in DPD was Kudoh S, et al. Clinical effects
of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis.
Jpn J Thorac Dis 1987; 25:632-642. Mark Everard et al, (1997 above)
was the first in the UK to report an effect on sputum inflammatory
markers in cystic fibrosis.
1998
Aris RM, Renner JB, Winders AD, Buell HE, Riggs DB, Lester GE, Ontjes
DA. Increased rate of fractures and severe kyphosis: sequelae of
living into adulthood with cystic fibrosis. Ann Int Med 1998; 128:186-193. [PubMed]
Bone mineral density was measured with dual-energy x-ray absorptiometry,
patient-reported fracture events were confirmed by radiography,
and kyphosis angles were measured by using the Cobb method. Mean
bone mineral densities for the spine, femur, and total body were
severely depressed in patients with cystic fibrosis, averaging 2
SDs below those of age-matched normal controls (P<0.001). Patient
interviews showed that 54 fractures had occurred over 1410 patient-years,
and chest radiographs showed evidence of 14 additional rib and 62
additional vertebral compression fractures. The database (which
covered 1410 patient-years) showed that fracture rates were approximately
twofold greater in women with cystic fibrosis aged 16 to 34 years
(P = 0.015) and men with cystic fibrosis aged 25 to 45 years (P
= 0.04) than in the general population. Vertebral compression and
rib fractures were 100- and 10-fold more common than expected, respectively
(P<0.001 for both comparisons). The mean kyphosis angle (+/-
SD) for this group was markedly abnormal (44 +/- 14 degrees; 62%
> or = 40 degrees) and probably contributed to diminished stature
(mean height loss, 5.8 cm in men with CF and 5.9 cm in women with
cystic fibrosis). Cumulative prednisone dose, body mass index, and
age at puberty were the strongest predictors of bone mineral density.
Although osteoporosis had been mentioned in a number of previous
reports, this was the first major study on osteoporosis in adults
with cystic fibrosis. The study drew attention to the fact that
osteoporosis is almost universal in adults with late-stage CF and
its complications include increased fracture rates and severe kyphosis.
The findings stimulated a great deal of research into osteoporosis
in adults with cystic fibrosis. Later the subject was reviewed in
many publications and in a consensus document from the UK Cystic
Fibrosis Trust (Bone Mineralisation in Cystic Fibrosis. UK Cystic
Fibrosis Trust Bone Mineralisation Working Group. February 2007.
Full text available on the UK CF Trust website (www.cftrust.org,uk)
.
1998
Lowden J, Goodchild MC, Ryley HC, Doull I. Maintenance of growth
in cystic fibrosis despite reduction in pancreatic enzyme supplementation.
Arch Dis Child 1998; 78:377-378. [PubMed]
study
from Cardiff, in the post-fibrosing colonopathy era, further supported
the view that children with CF in the UK were taking unnecessarily
large doses of pancreatic enzyme. Fifteen children with CF on a
mean enzyme intake equivalent to 18,300 U lipase/kg/day were able
to reduce their enzyme supplements to a mean of 8,647 U lipase/kg/day.
There were no changes in energy or fat intake but significant increases
in weight, height and weight for height.
Many
UK patients were taking considerably more enzymes supplements than
the equivalent of 10,000 U lipase/kg/day advised as a result of
the occurrence of fibrosing colonopathy (Mehta A. Lancet 2001;358:1547-1548).
This study from Cardiff supported this and confirmed that in some
patients the doses were not required.
Dr
Iolo Doull (Fig. 45.2) followed Mary Goodchild as the Director
of the Cardiff Paediatric CF centre. He became heavily involved
with CF care and research in the UK and Europe, also in the development
and running of a shared care network for children with CF in most
of Wales.
1998
Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin
may improve lung function in children with cystic fibrosis. Lancet
1998; 351:420. [PubMed]
The second very convincing observational study on macrolides and
CF from the UK (first report by Everard et al, 1997 above) showing
impressive improvement in the respiratory function of severely affected
children given regular azithromycin in addition to their usual treatment.
These impressive observations were followed by a controlled trial
from the Brompton Hospital, London which confirmed the beneficial
effect (Equi et al, 2002 below) and also by a major trial from the
US CF Foundation (Saiman et al, 2003 below).
1998
Conway SP. Transition from paediatric to adult-orientated care for
adolescents with cystic fibrosis. Disability & Rehabilitation
1998; 20:209-216.
The Leeds CF Centre had been running a monthly transition clinic
for the previous 10 years since the adult CF unit was started, first
at Seacroft Hospital in 1988; Dr Conway had been involved since
its inception. All patients should have the opportunity to transfer
to a properly equipped and properly staffed adult cystic fibrosis
centre where they can continue to receive the highest standards
of care from an experienced multidisciplinary team.
In some cities the paediatric and adult CF units are closely related
both geographically and administratively. For example, in Leeds
Dr Conway is the “Lead Clinician” in both the paediatric
and adult CF units. Also in Copenhagen the same team care for both
children and adults. Certainly this arrangement does reduce the
stress experienced by many patients (and their parents) in transferring
to a new hospital and different CF staff. On the other hand some
of the problems of small children and adults with CF are very different.
An ideal is to have a lead clinician involved with both units sharing
the responsibility of the adults with an adult physician and of
the children with a paediatrician.
1998
Cunningham S, Marshall T. Influence of five years of antenatal screening
on the paediatric cystic fibrosis population in one region. Arch
Dis Child 1998; 78:345-348.[PubMed]
The incidence of CF in the five years before and after
antenatal screening was introduced in Edinburgh decreased from 4.6
to 1.6 infants per year – a reduction greater than could be
accounted for by prenatal diagnosis and termination.
Much of the early work on antenatal screening during the Eighties
was done in Edinburgh by David Brock and his colleagues (Brock 1992;
Livingstone et al. 1994; Brock, 1996 all above). It is disappointing
that the antenatal screening which Brock pioneered was eventually
abandoned in Edinburgh and has not been introduced elsewhere in
the UK. The introduction of neonatal CF screening in Scotland and
the steady improvement in prognosis, being two reasons given for
withdrawal of the antenatal screening in Edinburgh. Financial reasons
prevented introduction in England.
1998
Mahadeva R, Webb K, Westerbeek RC, Carroll NR, Dodd ME, Bilton D.
Clinical outcome in relation to care in centres specialising on
cystic fibrosis: cross sectional study. BMJ 1998; 316:1771-1775. [PubMed]
This is one of the few papers which is accepted as supporting the
superiority of CF Centre care to the care received at a general
paediatric clinic in the local hospital. Patients at the adult cystic
fibrosis centre were subdivided into three groups. Those who had
received continuous care from paediatric and adult cystic fibrosis
centres (group A), those who had received paediatric care at their
local hospital then at an adult CF centre (group B) and those who
had received neither paediatric nor adult specialist care (Group
C). Body mass index was 21.3, 20.2 and 18.3 for Groups A B and C
respectively (P<0.001) and the improved nutritional status was
correlated with a higher FEV1 and better chest X-rays (P<0.001
for both). These findings are widely quoted as providing the first
direct evidence that management in cystic fibrosis centres resulted
in a better clinical outcome. This had been appreciated for years
by doctors dealing with people with CF, and indeed by patients and
parents, but is still contested by a minority of general paediatricians
and physicians.
Professor Kevin
Webb (figure 45.4) started the first CF centre for adults at Monsall
Hospital Manchester in 1982; the unit later moved to the purpose-built
Bradbury Unit at Wythenshawe Hospital in 1994. The CF Centre is
one of the largest in the UK and the staff have made major contributions
to improving CF care in the UK.
1997
McIlwaine PM, Wong LT, Peacock D, Davidson AG. Long-term comparative
trial of conventional postural drainage and percussion versus positive
expiratory pressure physiotherapy in the treatment of cystic fibrosis.
J Pediatr 1997; 131:506-508. [PubMed]
Forty patients were randomised to receive either postural drainage
and percussion or PEP mask physiotherapy over one year. Those using
the PEP mask had significantly better respiratory function after
1 year and the authors concluded that this was the more effective
method of physiotherapy.
This study from Professor George Davidson’s CF centre in Vancouver,
Canada had a significant influence on physiotherapy practice in
North America. A subsequent study from this unit, comparing PEP
and Flutter methods, showed PEP to be superior in maintaining pulmonary
function and reducing the need for hospital admissions (McIlwaine
et al. J Pediatr 2001; 138:845-850).
The study was influential in changing the routine physical therapy
practice in North America.
Maggie Mcllwaine is the Senior Physiotherapist at the British Columbia
Children's Hospital, Vancouver CF Centre.
|
|
Figure
45.5: Professor Kevin Webb. |
Figure
45.3: Professor George Davidson |
| |
|
Figure
46: Dr Beryl Rosenstein (right) Professor of Pediatrics at Johns
Hopkins Hospital, Baltimore and Dr Richard Grand (left), Head
of Pediatric Gastroenterology, The Children's Hospital, Boston
with the author at NACF Congress 2008. |
1998
Rosenstein BJ, Cutting GR for the Cystic Fibrosis Consensus Panel.
The diagnosis of cystic fibrosis: a consensus statement. J Pediatr
1998; 132:589-595. [PubMed]
A helpful publication summarising the criteria for
diagnosis as follows - One or more of the characteristic phenotypic
features OR a history of CF in a sibling OR a positive neonatal
screening result AND an increase in sweat chloride concentration
(> 60mmol/l) OR identification of two CF mutations OR demonstration
of abnormal nasal epithelial transport.
1999
Waters DL, Wilcken B, Irwing L, Van Asperen P, Mellis C, Simpson
JM, Brown J, Gaskin KJ. Clinical outcomes of newborn screening for
cystic fibrosis. Arch Dis Child 1999; 80: F1-F7. [PubMed]
An important long term observational study from Sydney of 10 year
follow-up of screened infants with CF, showing significant nutritional
and respiratory benefits from neonatal CF screening first introduced
in 1981 in New South Wales. Fifty seven unscreened CF children (born
1978-1981) are compared with 60 screened infants (born 1981-1984).
Height and weight of screened are consistently better (SDs of 0.3
and 0.4 better respectively) and respiratory function is higher
– FEV1 difference of 9.4% and FVC 8.4% in favour of the screened
infants.
In New South
Wales a more progressive attitude to neonatal CF screening has prevailed
over the years than in the UK. Although Cochrane reviewers considered
this paper unsatisfactory as the controls were historical, most
people accepted that the results were predictable and and provided
further supportive evidence for neonatal CF screening.
1999
Ansari EA, Sahni K, Etherington C, Morton A, Conway SP, Moya E,
Littlewood JM. Ocular signs and symptoms and vitamin A status in
patients with cystic fibrosis treated with daily vitamin A supplements.
Br J Ophthalmol 1999; 83:688-691. [PubMed]
Since the first Leeds studies on vitamin levels in 1978 (Congden
et al, 1981 above), oral supplementation has been guided by annual
monitoring of vitamin levels; also all patients are seen regularly
by a CF specialist dietitian and most have a comprehensive annual
dietary assessment. None of the 28 patients in this study had vitamin
A deficiency, the median value of serum retinol being 48 microg/dl,
range 31-80 microg/dl (normal range 30-80 microg/dl). Dark adaptation
was normal in all patients compared with the control group where
the mean value was 3.4 log units of threshold luminance (95% confidence
interval 2.4-4.0). None of the test group had a value of threshold
luminance 2 SD above the mean value for the control group. Eight
patients had reduced contrast sensitivity. The median value for
serum zinc was 14.2 micromol/ l, range 13-81 micromol/l (normal
range 8-23 micromol/l) and the median value for retinol binding
protein was 36 mg/l, range 13-81 mg/l (normal range 35-58 mg/l).
There was no correlation between dark adaptation and serum retinol,
zinc, or retinol binding protein. Two patients had clinical evidence
of dry eye.
So regular
estimates of plasma vitamin A, together with appropriate supplementation
and expert dietetic review, can maintain normal dark adaptation
in patients with cystic fibrosis. The occurrence of reduced contrast
sensitivity function is well documented in CF and confirmed in this
study but remains an unexplained phenomenon (also Morkeberg et al,
1995 above).
1999
Ramsey BW, Pepe MS, Quan JM, Otto KL, Montgomery AB, Williams-Warren
J, Vasiljev-K M, Borowitz D, Bowman CM, Marshall BC, Marshall S,
Smith AL.. Intermittent administration of inhaled tobramycin in
patients with cystic fibrosis. Cystic Fibrosis Inhaled Tobramycin
Study Group. N Engl J Med 1999; 340:23-30. [PubMed]
One of the most important clinical trials of the decade showing
a significant benefit of inhaled preservative free tobramycin (TOBI)
given during alternate four week cycles for 24 weeks to patients
chronically infected with Pseudomonas aeruginosa. Treated
patients had an average increase of FEV1 of 10% predicted at 20
weeks where as those on placebo had a 2% decline; also the treated
patients had 23% fewer hospital admissions.>
The introduction
of TOBI, supported by this excellent clinical trial, was one of
the major clinical advances of the decade and the culmination of
work started in the late Eighties by Arnold Smith and others (Smith
AL et al. 1989 above). By 2005 nearly 60% of people with CF in the
US CFF Registry were receiving nebulised TOBI.
Although the cost (£10K per annum in the UK) has restricted
the use of the TOBI preparation in the UK, inhaled anti-Pseudomonal
antibiotics (colistin, tobramycin for injection and gentamicin)
have been widely used in the UK for CF patients with chronic Pseudomonas
infection since Margaret Hodson’s important 1981 paper (Hodson
et al, 1981 above).
|
Figure
47: Dr Bruce Montgomery. 2008. |
| |
|
Figure
48: Dr Charlie Howarth. |
Dr Bruce Montgomery
(Figure 47) now Senior Vice President and head of Respiratory Therapeutics
at Gilead Sciences,, was closely involved with the development and
trials of this preparation and has been involved subsequently with
other new treatments including, more recently, nebulised aztreonam
lysine for inhalation.
1999
Howarth CS, Selby PL, Webb AK, Dodd AK, Musson H, McL Niven R, Economu
G, Horrocks AW, Freemont AJ, Mawer EB, Adams EJ. Low bone density
in adults with cystic fibrosis. Thorax 1999; 54:961-967. [PubMed]
An early detailed study of a population of 151 adults aged
15-52 ears with CF from Manchester using DEXA and quantitative computed
tomography and biochemical markers of bone turnover. 34% of adults
with CF had BMD Z scores of -2 or less at one or more skeletal sites.
The respiratory function and physical activity were related to the
BMD Z scores. Markers of bone turnover were negatively related and
vitamin D positively related to the BMD Z scores despite supplementation
with vitamin D.
Dr
Charlie Haworth (figure 48) has major contributions to the increasingly
important bone problems in CF both when working n Manchester and
after moving to Papworth CF Adult centre where he is now Director. Subsequent
reviews and consensus statements on bone problems in CF followed
from North America and the UK.
2005
Aris RM, Merkel PA, Bachrach LK, Borowitz DS, Boyle MP, Elkin S,
Guise TA, Hardin DS, Haworth CS, Hollick MF, JosephM, O'Brien K,
Tullis E, Watts NB, White TB.Consensus statement: Guide to bone
health and disease in cystic fibrosis. J Clin Endocrinol Metab 2005;
90:1888-1896. [PubMed]
2007
Bone mineralisation in cystic fibrosis. Report of the UK Cystic
Fibrosis Trust Bone Mineralisation Working Group. London. Cystic
Fibrosis Trust, february 2007.
Conway S (Chairman), Compston J, Cunliffe H, Dodd M, Elkin S, Haworth
C, Jaffe A, Morton A, Redfern J, Truscott J.
|
Figure
49: CF Trust Consensus |
|
Figure
50: Professor Vera Vavrova receiving the European Cystic Fibrosis
Society Award from the President, Professor Stuart Elborn in
2008. |
|
Figure
51. Dr Garry Connett. |
1999
Vavrova V, Zemkova D, Bartsova J, Zapletal A, Smolikova L. Krebsova
A, Macek M jr. Cystic fibrosis - a disease of adolescents and adults.
[Czech]. Casopis Lekaru Ceskych 1999; 138:654-659. [PubMed]
The summary of this article gives an account of the situation
regarding CF in the CF centre of the Faculty Hospital in Prague
Motol in 1999. 349 patients are followed; also included are the
95 who died since 1985. 126 (36.1%) survived to the age of 18 years.
The median age of death increased from 12.2. years in 1985-1990
to 18.8 years in 1991-1998. Adult status was satisfactory 40.4%,
poor in 33.3% and marginal in 26.3%. Pulmonary function was normal
in 17.5%, and severely affected in 22.8% - the rest between 40-80%
predicted. Modern intensive treatment has improved the prognosis
and quality of life of people with CF.
Professor
Vavrova (figure 50) of Prague published her first paper on CF in
1962 and her most recent in 2009. She has been involved in CF care
and research for nearly 50 years and involved in over 80 papers
dealing with many aspects of the condition. She received the ECFS
Award in 2008.
1999
Sokol RJ, Durie PR. recommendations for the management of liver
and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation
hepatobiliary Disease Consensus Group. J Pediatr Gastroenterol Nutr
1999; 28 Suppl 1:S1-13. [PubMed]
Recommendations of an expert group on management of CF
related liver disease.
1999
Connett GJ, Lucas JS, Atchley JT, Fairhurst JJ, Rolles CJ. Colonic
wall thickeninbg is related to age and not dose of high strength
pancreatic microspheres in child ren with cystic fibrosis. Eur J
Gastro Hepatol 1999; 11:181-183. [PubMed]
Thirty three children with CF, including 25 who had been
receiving high strength pancreatin in the form of Creon 25,000 continuously
for 3 years. Median lipase intake was 19,330 u/kg/day (range 0-59,000).
There was no relationship between enzyme dosage and colonic wall
thickness. The most important relationship of colonic wall thickness
appeared to be with age.
This was a useful report and reassuring that high doses of pancreatic
enzymes, when given in the form of Creon 25,000, did not appear
to cause colonic damage. It had already been evident from the UK
CF Database that many UK patients were taking more than the recommended
equivalent of 10,000 U lipase/kg/day (Mehta A.Lancet 2001; 358:1547-1548).
Obviously it would be unwise to translate these findings to other
brands of high strength enzymes.
Dr Garry Connett
(figure 51) is a Paediatric Respiratory Consultant who succeeded
Dr Chris Rolles as Director of the Southampton Paediatric CF Centre.
He is heavily involved in CF care and clinical research and over
the next ten years published on a wide variety of aspects of cystic
fibrosis.
