MICROBIOLOGY

1951 Garrard SD, Richmond JB, Hirsch MM. Pseudomonas aeruginosa infection as a complication of therapy in pancreatic fibrosis (Mucoviscidosis). Pediatrics 1951; 8:482-8. [PubMed]
The authors discuss the potential problems of antibiotic prophylaxis - the potential for altering the tracheobronchial flora and the importance of Pseudomonas aeruginosa as an emerging opportunistic infection challenge. They asked the paediatric community to critically examine the clinical recommendation for prolonged antibiotic prophylaxis. They suggested - “Effective antibiotics should be employed judiciously and changed when specifically indicated, based upon cultures of the tracheobronchial secretions. To minimize the appearance of resistant strains, combinations of two antibiotics having different mechanisms of action are desirable”.
This practice is still recommended but still not always heeded by paediatricians. A recent Cochrane Systematic Review failed to find published evidence supporting the use of two intravenous antibiotics rather than monotherapy – however, serious consequences may have been related to the habitual use of intravenous ceftazidime monotherapy in one large UK CF centre (Cheng et al, 1996 below) where a multiresistant P. aeruginosa eventually affected a majority of the patients. So virtually all experienced clinicians would now use two anti-Pseudomonal antibiotics for intravenous antibiotic treatment. This present paper from Chicago, is said to be the first report of Pseudomonas aeruginosa as a significant pathogen in people with CF. However Dorothy Andersen had already noted in 1949 - “those with most severe changes sometimes develop bronchitis due to Ps. pyocyaneus (the old term for Pseudomonas aeruginosa) or other gram negative bacilli, a complication rarely seen before the days of penicillin” (Andersen, 1949 above).

1964 Doggett RG, Harrison GM, Wallis ES. Comparison of some properties of Pseudomonas aeruginosa isolated from infections in persons with and without cystic fibrosis. J Bacteriol 1964; 87:427-431. [PubMed]
One of the early papers discussing the peculiarities of this organism that was isolated with increasing frequency from people with CF, in particular the so-called "mucoid" form. Initially there was considerable discussion about the pathogenicity of P. aeruginosa in CF which initially was questioned by some clinicians. Pseudomonas aeruginosa, isolated from the respiratory tract of a group of patients diagnosed as having CF, attained the ability to produce in its capsule a material which was insoluble in certain organic solvents, such as ethanol. The capsule obtained from P. aeruginosa isolated from infected individuals who did not have CF was ethanol-soluble. This alcohol-insoluble mucoid from the CF P. aeruginosa could be demonstrated to persist after sequential subcultures of the organism. (also Doggett et al, 1966 below).

1966 Doggett RG, Harrison GM, Stillwell RN, Wallis ES. An atypical Pseudomonas aeruginosa associated with cystic fibrosis of the pancreas. J Pediatr 1966; 68:215-221.
Another of the many papers published by Doggett on the atypical “mucoid” Pseudomonas aeruginosa isolated from 43 of 62 cultures from 78 children with CF. It was a highly mucoid variant of the organism which was insoluble in ethanol-benzene (figure 23) and was impossible to eradicate once established (also Doggett et al, 1964 above). The authors observe that “until such a means of control is found … clinics that treat groups of CF children may find it good practice to separate those already having Pseudomonas from those not infected with the organism, especially those having inhalation therapy”.
Doggett is usually credited with recognising the significance of the mucoid form of Pseudomonas in people with CF and the conversion from non-mucoid to mucoid after acquisition of the former but not in people who do not have cystic fibrosis. Also it is interesting that, even at this stage, he was suggesting that segregation of Pseudomonas-positive from Pseudomonas-negative patients would be good practice – some 35 years before such segregation was introduced into all CF centres in the UK – in a few with great reluctance on the part of the clinicians!

Figure 23: Legend below picture. From paper with permission.

1969 Lawson D. Panel discussion on microbiology and chemotherapy of the respiratory tract in cystic fibrosis. Proc 5th Int CF Conference, Cambridge, 1969. Ed. Lawson D. London. Cystic Fibrosis Research Trust 1969:225.
David Lawson was one of the first paediatricians to suggest long term anti-Staphylococcal prophylactic chemotherapy. Eventually this treatment was supported by a controlled trial in CF screened infants in East Anglia, UK (Weaver et al, 1994 below). Prophylactic flucloxacillin is now recommended for all CF infants in the first 3 years by the UK CF Trust’s Expert Antibiotic Group (2002 and 2009) although the findings are not accepted in North America.

I was impressed by David Lawson’s approach and from 1975 all CF children for whom I was responsible were on long term cloxacillin and later flucloxacillin from soon after birth, if screened, or from the time of diagnosis. The results of this policy were reported in 1993 by Kevin Southern at the Madrid ECFS meeting. Of 110 patients attending our unit for all their care at that time only 16 (14.5%) had chronic Staph. aureus infection – individual group prevalence in 0-4 years nil, 5-9 yrs 14.7%, 10-15 yrs 22%; furthermore some of those patients had been referred to our clinic already chronically infected with S. aureus. The Leeds CF centres still have most patients on continuous flucloxacillin and there is a very low prevalence of chronic Staphylococcal infection. It is also interesting that despite the publications suggesting anti-Staphylococcal prophylaxis leads to a higher prevalence of Pseudomonas infection, this does not occur if there is also a policy of regular cultures and early Pseudomonas eradication.
David Lawson, whose daughter had CF, was one of the founders of the UK CF Research Trust in 1964. He maintained that earlier diagnosis, by improved neonatal screening, was essential for improvement of results as by the time the diagnosis was presently made lung damage was already present.

1971 Harboushe C, Iacocca V, Braddock L, Barbero G. Pseudomonas agglutinins in patients with cystic fibrosis. Pediatrics 1971; 48:973-974. [PubMed]
An early study of 32 patients with CF of whom 24 harboured Pseudomonas aeruginosa. Not surprisingly, these 24 patients had the highest anti-Pseudomonal serum agglutinin antibody response when compared with eight CF patients without Pseudomonas and 32 controls.
Although this may appear an obvious finding, at the time of this publication the significance of Pseudomonas in the sputum of people with CF was still not established and some clinicians still doubted its importance i.e. does Pseudomonas invade damaged lungs or cause the damage? The presence of an antibody response, suggesting tissue involvement gave further confirmation as to the importance of P. aeruginosa. Previous studies of immune response had been reported (Diaz F et al. J Inf Dis 1970; 121:269; Huang N et al CF Club Abstracts 1970:19; Doggett RG, Harrison GM 5th CF Conference Cambridge 1969:175).
The whole subject of antibody response was later considerably expanded by the many studies of Neils Hoiby from 1973 onwards (below); he correlated the immune response, as judged by antibodies detected by crossed immunoelectrophoresis, with the patient’s clinical course (Hoiby & Axelsen, 1973; Hoiby, 1977 below); certainly his publications stimulated us in Leeds to develop and use Pseudomonas antibodies from 1986 until the present time, using an ELISA test developed by Dr Moira Brett (Brett et al 1986 below) and more recently using a commercial kit.

Figure 2: Dr David Lawson.

1972 May JR, Herrick NC, Thompson D. Bacterial infection in cystic fibrosis. Arch Dis Child 1972; 47:908-913. [PubMed]
Another more extensive study of precipitins against the common respiratory pathogens in 195 patients with CF and cultures obtained from ninety six. The most common precipitins were against P. aeruginosa - more than any other organism being the most frequent organism isolated from children aged six to ten years. S. aureus was not always the first infection and people with CF seemed susceptible to bronchial infection with any pathogen. The fall in prevalence in older patients suggested failure of many patients with P. aeruginosa to survive into adult life in contrast to those with S. aureus.
This was an early indication that infection with P. aeruginosa may adversely affect the long term prognosis. These authors noted “as Doggett and Harrison (1969 above) suggested, infection with mucoid P. aeruginosa is currently one of the commonest causes of death of patients with cystic fibrosis, and the need to keep them out of hospital away from sources of cross-infection cannot be too strongly emphasised”. It was some decades during and after the Nineties before all paediatricians and physicians accepted this sensible advice!! (also Harboushe et al, 1971 above).

It was some decades during and after the Nineties before all paediatricians and physicians accepted this sensible advice!! (also Harboushe et al, 1971 above).

1972 Mearns MB, Hunt GH, Rushworth R. Bacterial flora of the respiratory tract in patients with cystic fibrosis 1950-1971. Arch Dis Child 1972; 47:902-907. [PubMed]
Experience from the Queen Elizabeth Hospital for Children, London. Bacterial flora of patients observed from 1950 onwards also bacterial precipitins from 102 patients. The frequency of isolation of S. aureus fell and there was a steady increase in P. aeruginosa in the most severely affected patients – the fall in S. aureus was one of the most striking features (figure 3)
Commenting on the view of David Lawson that prophylactic anti-Staphylococcal therapy is indicated, Margaret Mearns cautioned that this could lead to more P. aeruginosa infection – still a point of discussion today. Certainly there is evidence that this is the case if a wide spectrum antibiotic is used unless a regimen of early eradication of P.aeruginosa is routine - as it was not in 1972. However, May et al believe that any respiratory pathogen may cause the initial infection including P. aeruginosa.

Figure 3: Bacterial flora of patients with CF between 1950 and 1971. With permission of the BMJ Publishing Group

1973 Hoiby N, Axelsen NH. Identification and quantitation of precipitins against Pseudomonas aeruginosa in patients with cystic fibrosis by means of crossed immunoelectrophoresis with intermediate gel. Acta Path Microbiol Scand 1973; 81:298-308. [PubMed]
The fourth of 418 papers by Neils Hoiby listed on Medline! A classic study correlating clinical severity, presence of mucoid Pseudomonas aeruginosa and increased precipitins using a new more sensitive technique of crossed immuno-electrophoresis with intermediate gel to identify precipitins against P. aeruginosa from 33 patients with CF. He suggested there was selection of mucoid strains in CF by means of the immune response; also that the persistent infection and multiple precipitins produced against the bacteria could cause a local immune reaction which could enhance the destructive lesions of the respiratory tract. Very much in line with the modern views on inflammatory damage and the use of anti-inflammatory therapy.
Neils Hoiby (figure 7) eventually worked with and became a key member of the Danish CF clinic for over 30 years during which time he became one, if not the, world’s leading authority on Pseudomonas aeruginosa and many other aspects of infection and immunity in CF (also Hoiby, 1977).

1976 Lawson D, Porter J. Serum precipitins against respiratory pathogens in 522 “normal children” and 48 cases of cystic fibrosis treated with cloxacillin. Arch Dis Child 1976; 51:890-891. [PubMed]
Since 1964 David Lawson had treated all children with CF with continuous with the anti-Staphyloccocal antibiotic cloxacillin. He had monitored their serum precipitins since 1968 and compared the results to those of a normal population of 522 children none of whom had S. aureus precipitins in the first 4 years. (Also similar work by Strandvik et al, 1990 below). The findings indicated that the development of precipitins could be prevented by continuous cloxacillin.
David Lawson provides further supportive evidence for long term anti-Staphylococcal therapy; he was definitely “the father” of long term prophylactic anti-staphylococcal therapy which is now recommended in the UK by the CF Trust’s Antibiotic Group (2002 & 2009) - at least for the first 2 years. This recommendation is supported by the trial reported by Weaver et al, 1995 (below) and clinical experience of a low incidence of chronic S. aureus infection in patients on long term flucloxacillin (Southern et al, 1993 below). Nancy Huang also reported the use of long term oxacillin (Huang NN et al, 1963 above).
It has been the practice in the Leeds clinic to give lifelong cloxacillin and later flucloxacillin since soon after this paper of David Lawson’s was published in 1976. Certainly the frequency of isolation of S. aureus falls when taking continuous flucloxacillin – in the Leeds clinic overall prevalence of chronic S. aureus infection was 14% and in children under 10 years only 8.3% (Southern KW et al. In Clinical Ecology of Cystic Fibrosis Escobar C et al. (eds.).Elsevier Scientific Publishers, 1993). In the 2005 CF Foundation Registry 51.8% of patients cultured positive for S. aureus.

1977 Hoiby N. Antibodies against Pseudomonas aeruginosa in serum from normal persons and patients colonised with mucoid or non-mucoid P. aeruginosa: results obtained by crossed immunoelectrophoresis. Acta Pathol Microbiol Immunol Scand 1977; 85:142-148.
Further work from Neils Hoiby expanding his 1973 results (Hoiby 1973 above). Correlating the clinical condition and microbiological status with the antibodies undoubtedly confirmed the importance of P. aeruginosa. This early study was important as, surprisingly, some clinicians (usually paediatricians as there were still few adults with CF) still doubted the importance of, and therefore the need to treat, P. aeruginosa infection. A typical comment at the time was “it is not obvious whether Pseudomonas aeruginosa causes increased degenerative lung disease or whether increased degenerative lung disease provides a milieu in which P. aeruginosa may prosper”.
This paper stimulated me to organise Pseudomonas antibody studies in Leeds for which, thanks to funding from the UK CF Trust, we appointed an immunologist, Dr Moira Brett to develop the service. From the mid-Eighties, these Pseudomonas ELISA tests, which Moira Brett developed, have been used, in addition to cultures, to follow Pseudomonas infection. They have been used in the Leeds CF clinics continuously since 1986 (Brett MM et al, 1986 below) until recently when they were replaced by a commercial test. It is surprising that this very valuable test is not more widely used in the UK as persistent absence of an immunological response almost certainly means that the lower respiratory tract is not infected with Pseudomonas; also a rising antibody titre suggests deterioration of the chest due to Pseudomonas infection in those patients already chronically infected and indicates the need for more aggressive anti-Pseudomonal therapy even if symptoms and signs are few.

1977 Lararya-Cuasay LR, Lipstein M, Huang NN. Pseudomonas cepacia in the respiratory flora of patients with cystic fibrosis. Pediatr Res 1977; 11:502.
One of the earliest reports of Pseudomonas cepacia (later called first Burkholderia cepacia, then Burkholderia cepacia complex) isolated between 1973 and 1976 from 54 patients with cystic fibrosis; many were severely affected and 14 died. The presence of the organism made treatment more difficult.
This was a very early report of P. cepacia which did not appear cause concern at the time - in fact in John Lloyd-Still's 1983 Textbook of Cystic Fibrosis there is very brief mention of P.cepacia as one of the "other gram-negative rods that may infect people with cystic fibrosis". Later Rosenstein & Hall reported pneumonia and septicemia due to Pseudomonas cepacia in a patient with CF (Johns Hopkins Med J 1980; 147:188-189) before the first report from Toronto describing major problems in treating the infection (Gold R et al. J Antimicrob Chemother 1983; 12 Suppl A: 331-336) and before the other major publication from Toronto (Isles A, et al. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-210 below).
The first report from the UK was from the Leeds centre and did not appear until 1990 when we had identified 11 cases since 1984 (Simmonds EJ et al. Arch Dis Child 1990; 65:874-877 below). The tendency for B. cepacia to spread between patients was not generally accepted in the UK until 1993 when John Govan from Edinburgh published definite evidence of patient to patient spread (Govan et al, 1993 below).

This and other publications from Copenhagen stimulated me to organise Pseudomonas antibody studies in Leeds for which, thanks to funding from the UK CF Trust, we appointed an immunologist, Dr Moira Brett to develop the service. From the mid-Eighties, these Pseudomonas ELISA tests, which Moira Brett developed, have been used, in addition to cultures, to follow Pseudomonas infection. They have been used in the Leeds CF clinics continuously since 1986 (Brett MM et al, 1986 below) until recently when they were replaced by a commercial test. It is surprising that this very valuable test is not more widely used in the UK as persistent absence of an immunological response almost certainly means that the lower respiratory tract is not infected with Pseudomonas; also a rising antibody titre suggests deterioration of the chest due to Pseudomonas infection in those patients already chronically infected and indicates the need for more aggressive anti-Pseudomonal therapy even if symptoms and signs are few.

1979 Jenner BM, Landau LI, Phelan PD. Pulmonary candidiasis in cystic fibrosis. Arch Dis Child 1979; 54:555-6. [PubMed]
Despite the frequent and prolonged use of antibiotics, this is the first reported case of pulmonary candidiasis confirmed by lung puncture and treated successfully with 5-flourocytosine. Antibiotics, steroids and intravenous catherisation predisposed to Candida infection.
There are very few reports of Candida in CF as a primary pathogen although it can be isolated from the airways of many patients and is found frequently in dental studies of people with CF. More recently vaginal Candida has been described as a common, significant and under-diagnosed problem in women with CF, considered to be related to the frequent use of antibiotics (Sawyer et al, 1994 below). Also with the more widespread use of intravenous therapy, serious systemic infections have occurred with totally implantable venous access devices (reviewed by Webb AK & Woolnough E. J Roy Soc Med 2006; 99 (Suppl 46):13-16).

1982 Kelly NM, Fitzgerald MX, Tempany E, O'Boyle C, Falkiner FR, Keane CT. Does Pseudomonas cross infection occur between cystic fibrosis patients? Lancet 1982; 2:688-690. [PubMed]
This study from Dr Eddie Tempany’s unit in Dublin (Figure 20) was published long before Pseudomonas was considered to spread between patients in CF clinics and at a time when Pseudomonas positive patients mixed freely with Pseudomonas negative patients in all CF centres, clinics and socially.
Over a 12-month period respiratory Pseudomonas aeruginosa isolated from CF patients were typed by serology and pyocin production to determine whether cross-infection was occurring. Although one strain appeared in four unrelated patients, none of these patients had been in contact with each other and the strains were considered to have been acquired from the environment. However, it is relevant that each of six pairs of siblings with CF shared the same strain, but the pairs of strains were distinct from each other. These results suggested to the authors that the general environment was the most important source of Pseudomonas strains for CF patients and that for cross-infection to occur prolonged intimate contact was required – such as living in the same household.
This was an early study on the possibility of cross infection which at the time was considered to be reassuring. However subsequently, with the advent of genetic testing, cross infection was shown to be relatively common in CF centres and clinics, although in 1982 there were relatively few such large groups of patients with CF in the UK.

1984 Efthimiou J, Smith MJ, Hodson ME, Batten JC. Fatal pulmonary infection Mycobacterium fortuitum in cystic fibrosis. Br J Dis Chest 1984; 78:299-302. [PubMed]
An early, probably the first, report of an atypical Mycobacterium infection in a young adult with cystic fibrosis. The organism was resistant to all antibiotics and the patient died. Atypical mycobacteria were to become an increasing problem in people with CF. In a subsequent paper from Royal Brompton Smith MJ et al (1984 below) made a search to determine the prevalence of atypical mycobacteria in their CF patients – presumably as a result of experience with this patient. (Also Boxerbaum B. Isolation of rapidly growing mycobacteria in patients with cystic fibrosis. J Pediatr 1980; 96:689-691).

1984 Smith MJ, Efthimiou J, Hodson ME, Batten JC. Mycobacterial isolations in young adults with cystic fibrosis. Thorax 1984; 39:369-375. [PubMed]
Seven of 223 patients with CF admitted to the Brompton Hospital over a six year period had Mycobacteria in their sputum. The organisms isolated were Mycobacterium tuberculosis in three patients, M. chelonei in one, M. fortuitum in one, and unidentified Mycobacteria in two. The diagnosis was not suspected on clinical grounds in any of these patients; in one patient, however, night sweats were a prominent feature before diagnosis. In four of the patients direct sputum smear examination did not reveal the organism, which was grown subsequently in culture.

These were early days for appreciating the role of atypical Mycobacteria in CF and the organisms were present in the sputa of patients with cystic fibrosis more often than previously recognised. Therefore the authors recommended that sputum examination and culture for Mycobacteria should be performed periodically in these patients. Subsequently problems with these organisms would become more widely recognised and occur as a problem sometimes after lung transplantation when the patients were on immunosuppressive therapy.
Probably as there were fewer adults at that time and so few CF centres for adults, there were no further reports until one from Dublin in 1990 (Mulherin D, et al. Respir Med 1990; 84:273-276) where the frequency of positive skin reactions was found to be similar as in a control population. One of 43 patients grew an atypical mycobacterium from the sputum.

1984 Isles A, McLuskey I, Corey M. Pseudomonas cepacia infection in cystic fibrosis: an emerging problem. J Pediatr 1984; 104:206-210. [PubMed]
The prevalence of Pseudomonas cepacia infection in a population of approximately 500 patients with CF in the Toronto CF centre, increased from 10% in 1971 to 18% by 1981. The carriage of P. aeruginosa had remained unchanged at 70% to 80% over the same period. Patients infected with P. cepacia had greater impairment of pulmonary function than those with P. aeruginosa alone. A syndrome characterized by high fever, severe progressive respiratory failure, leukocytosis, and elevated erythrocyte sedimentation rate (“cepacia syndrome”) had occurred in eight patients over the previous three years, with a 62% fatality rate. Because P. cepacia strains are uniformly resistant to ticarcillin, piperacillin, and aminoglycosides, and because ceftazidime is ineffective despite in vitro activity, treatment of these infections was very difficult. Prevention of acquisition and effective treatment of P. cepacia in patients with cystic fibrosis had become a major problem in the Toronto clinic.

This paper, which describes the devastating effect of the introduction of B. cepacia into a CF clinic population very clearly, heralded a new era in CF care and was to have a profound permanent effect on the treatment and social life of people with CF and their families.
The potential for spread between people with CF and the serious, often fatal, consequences (the so-called “cepacia syndrome”) were not fully appreciated in the UK until the early Nineties when John Govan’s publication documented definite person to person spread (Govan et al, 1993 below). From 1993 there was a general introduction of infection control measures in CF Centres in the UK; also there was an end to the North American CF holiday camps which were shown to be an important source of acquisition of the B. cepacia infection.

In Leeds we had three patients who developed serious B. cepacia infections some months after visiting Canadian CF camps. In 1990 we published the first UK paper on B. cepacia in CF, having identified 11 patients with the infection over 6 years since 1984 but we found no evidence of obvious cross infection between our patients when we first identified the infection (Simmonds EJ, et al. 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).

1986 Pedersen SS, Koch C, Hoiby N, Rosendal K. An epidemic spread of multiresistant Pseudomonas aeruginosa in a cystic fibrosis centre. J Antimicrob Chemother 1986; 17:505-516. [PubMed]
Early in 1983 an epidemic of a Pseudomonas aeruginosa resistant to aminoglycosides, carbenicillin, ureidopenicillins, ceftazidime, cefsulodin and imipenem occurred in the Danish CF centre. Most of the epidemic could be attributed to a specific nosocomial strain by means of O-grouping and phage- typing. This strain was present in the centre at a low frequency in 1973 and developed resistance during repeated courses of chemotherapy. The epidemic was stopped by isolating the patients with the resistant strains. Restrictive and selective use of antibiotics was not sufficient to eradicate the resistant strains, which persisted in 42% of the patients. The extensive use of the third generation cephalosporins in the clinic was probably responsible for inducing and selecting for the resistant strains. Clustering of patients in the centre facilitated the spread. First-line use of older beta-lactam antibiotics, close bacteriological monitoring and prompt isolation of patients with resistant strains was implemented.
The Danish CF centre was unusual in giving regular 3-monthly courses of IV antibiotics to all their patients who were chronically infected with Pseudomonas aeruginosa (Pedersen et al, 1987 below). It is interesting that in the Liverpool paediatric CF clinic the routine use of ceftazidime monotherapy was associated with the development of a resistant Pseudomonas aeruginosa with epidemic spread amongst the patients there (Cheng et al, 1986 below).

1986 Brett MM, Ghoneim ATM, Littlewood JM, Losowsky MS. Development of enzyme linked immunosorbent assay (ELISA) to detect antibodies to Pseudomonas aeruginosa cell surface antigens in sera of patients with cystic fibrosis. J Clin Path 1986; 39:1124-1129. [PubMed]
Dr Moira Brett was at the time research immunologist at the Leeds CF unit. The 7 most common strains of P. aeruginosa from our patients were used as antigens in the ELISA test that she developed. The test was specific for Pseudomonas aeruginosa with no cross reaction with other gram negative organisms. We suggested the test may be useful in monitoring progress of P. aeruginosa infection in CF patients; and so it proved to be as subsequent publications confirmed (Brett et al, 1986 below; Brett et al, 1987; Brett et al, 1988; Brett et al, 1988; Brett et al, 1990; Brett et al, 1992). The test has been in use in the Leeds clinic since 1986 until recently replaced by a commercial kit.

Figure 35: “Controls” were non-CF children; Group 1 - CF who had never had Pseudomonas; Group 2 - Intermittent isolation of Pseudomonas; Group 3 - Chronic Pseudomonas infection. From the paper with permission of the BMJ Publishing Group.

Figure 36: Dr Moira Brett. Author's photo.

1986 Brett MM, Ghoneim ATM, Littlewood JM. Serum antibodies to Pseudomonas aeruginosa in cystic fibrosis. Arch Dis Child 1986; 61:1114-1120. [PubMed]
Serum IgG antibodies to Pseudomonas aeruginosa cell surface antigens were determined by enzyme linked immunosorbent assay (Brett et al, 1986 above). Titres in patients without CF were low (140-235). Those in patients with cystic fibrosis who were chronically infected by P. aeruginosa were very high (1100-20,500), while patients who grew the organism intermittently had lower titres (160-4400) (figure 35). Longitudinal studies showed that raised titres were observed at a very early stage of infection. High titres were associated with a poor clinical state, while low titres were associated with a better clinical state in both chronic and intermittently infected patients with cystic fibrosis. These results suggested that this test is a specific and sensitive measure of the severity and progress of the different stages of pulmonary infection by P. aeruginosa in patients with cystic fibrosis.

Dr Moira Brett (figure 36) at this time was a research immunologist who worked in Leeds with the CF unit at St James University Hospital from the mid-Eighties until the early Nineties. She developed the ELISA test for Pseudomonas antibodies and published a number of papers on the use of the test (Brett et al, 1986; Brett et al, 1987; Brett et al, 1988; Brett et al, 1988; Brett et al, 1990; Brett et al, 1992). We found the test a valuable aid to clinical management and it has been used continuously in the Leeds CF unit since the first report in 1986. It is surprising that many CF Centres still do not routinely estimate Pseudomonas antibodies in their patients with cystic fibrosis. We came to the view that the persistent absence of antibodies is very strong evidence that the patient does not have an unrecognised pulmonary Pseudomonas infection; a high level confirms that chronic infection is present; a rising level suggests that the intensity of treatment should be increased; a progressively higher level indicates a poor prognosis; an increased level in a patient who has negative respiratory cultures suggests there is Pseudomonas infection present and is an indication for bronchoscopy to identify the organism. Repeatedly negative monthly respiratory cultures (cough swabs or throat swabs) and negative Pseudomonas antibodies are probably a better indication that Pseudomonas is absent from the airways than a "one off" bronchoalveolar lavage.

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 an tibiotic 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 possibility!!

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"
This was certainly one of the most important papers of the decade and confirmed that early Pseudomonas infection could be eradicated with nebulised colomycin. It is difficult to understand why this perfectly 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).

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.

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).

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 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 regular inhaled antibiotics.
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 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 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 when questioned, one of these 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 of the University of Colorado Children's Hospital is heavily involved in both CF care and research in the USA.

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); this policy is supported by the trial of Weaver et al.1994 (above).

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 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 important paper 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 paediatrician 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.

2000 Saiman L, Macdonald N, Burns JL, Hoiby N, Speert DP, Weber D. Infection control in cystic fibrosis: practical recommendations for the hospital, clinic, and social settings. Am J Infect Contr 2000; 28:381-385. [PubMed]
Very detailed report of the findings of a CFF consensus meeting on infection control which included Europeans Neils Hoiby, Gerd Doering and Jim Littlewood. The great detail in this report is a reflection of the increasing realization that cross infection was a common and potentially harmful occurrence in CF centres.

Fig. 15: Professor Lisa Saiman.

Dr. Lisa Saiman (figure 15) is a Professor of Clinical Pediatrics at Columbia University and an Attending Professor of Pediatrics at the Morgan Stanley Children’s Hospital of New York-Presbyterian, Columbia University Medical Center where she has served as the hospital epidemiologist since 1994. She has been the director of the CF Foundation’s CF Referral Center for Susceptibility and Synergy Studies since its inception in 1991. Dr. Saiman served as the co-Principal Investigator of a double-blinded, randomized placebo-controlled, multi-center trial of azithromycin in CF patients infected with Pseudomonas aeruginosa (JAMA 2003; 290:1749-56. belo) [PubMed] )

2000 Israel NR, Khanna B, Cutler A, Perry M, Caplan D, Weatherly M, Gold BD. Seroprevalence of Helicobacter pylori infection in cystic fibrosis and its cross-reactivity with anti-Pseudomonas antibodies. J Pediatr Gastroenterol Nutr 2000; 30:426-431. [PubMed]
The seroprevalence of H. pylori in a cohort of patients with CF and its cross-reactivity with Pseudomonas antibodies were investigated using competitive inhibition assay. The research ELISA and 3 commercial tests initially showed H. pylori seropositivity of 47%, 28%, 24%, and 37%, respectively but post adsorption seropositivity declined to 8%, 0%, 0%, and 15%, respectively – and all these positives were confirmed endoscopically to have H. pylori infection. So cross-reactivity between solid-phase H. pylori antigens and anti-Pseudomonas antibodies occurs in patients with CF. The authors advise that preadsorption of CF sera with Pseudomonas proteins should be used in serologic testing if testing for H. pylori.

This was a useful study as there had been confusion about the prevalence of H. pylori in people with CF since the existence of cross reactivity with Pseudomonas antibodies had been reported from Neils Hoiby’s laboratory in Denmark (Johansen HK et al. Clin Diag Lab Immunol 1995; 2:149-155. 7697522 ). One might perhaps have predicted the expected the prevalence of H pylori in people with CF to be low (8-15%) in view of the numerous courses of antibiotics they receive!
This and subsequent studies (Yahav J et al. Dig Dis Sci 2006; 51:2274-2279). [PubMed] confirm that H. pylori is not a significant problem for people with CF.

2000 Ojeniyi B, Frederiksen B, Hoiby N. Pseudomonas aeruginosa cross-infection among patients with cystic fibrosis during a winter camp. Pediatr Pulmonol 2000; 29:177-181. [PubMed]
In 1990 twenty-seven patients with CF from the Danish Cystic Fibrosis Centre went to a winter camp for a week. The study is based on 22 of these patients. Prior to attending camp, 17 out of the 22 patients harboured Pseudomonas aeruginosa in their sputum, but 5 patients did not. After returning from camp, all 22 patients harboured P. aeruginosa in the sputum. The typing results showed that the 5 CF patients who were free of P. aeruginosa in their sputum prior to the winter camp had acquired P. aeruginosa isolates identical to the P. aeruginosa strains isolated from the other 17 CF patients. The authors concluded that separate holiday camps based on the infection status of the patients with cystic fibrosis are necessary to avoid cross-infection of patients not infected with P. aeruginosa.

This is one of the more conclusive reports of people with CF contracting new P. aeruginosa infection during a holiday with others with CF who were already chronically infected. The report was important for at this time there were still experienced CF physicians who questioned the importance of segregation according to microbiological status (Geddes DM. Of isolates and isolation: Pseudomonas aeruginosa in adults with cystic fibrosis. Lancet 2001; 358:522-523).

2001 McCallum SJ, Corkill J, Gallagher M, Ledson MJ, Hart CA, Walshaw MJ. Superinfection with a transmissible strain of Pseudomonas aeruginosa in adults with cystic fibrosis chronically colonised by P. aeruginosa. Lancet 2001; 358:558-560. [PubMed]
Two further examples, from the Liverpool Adult CF Centre, of a transmissible Liverpool strain of P. aeruginosa shown to be identical by genotyping, infecting patients in the same clinic. Here it was shown to have infected patients already chronically infected with another strain of Pseudomonas. The Liverpool strain (LES strain), was first recognised in the Liverpool paediatric clinic, (Cheng et al. 1996 [PubMed] above) was identified in a number of other UK CF centres in a subsequent survey carried out by Scott and Pitt (J Med Microbiol 2004; 53:609-615below). [PubMed]

2001 Visca P, Cazzola G, Petrucca A, Braggion C. Travel-associated Burkholderia pseudomallei infection (Melioidosis) in a patient with cystic fibrosis: a case report. Clin Infect Dis 2001; 32:E15-6. [PubMed]
In September 1997, a 25-year-old Italian lady with CF spent 3 weeks in Thailand. In August 1998, her pulmonary function rapidly declined, with productive cough and intermittent fever. The chest x-ray films revealed diffuse, small, patchy opacities in the upper lobes. Burkholderia pseudomallei (BP) were isolated from specimens of the patient's sputum and were identified by means of 16S rDNA sequencing. The diagnosis of melioidosis was serologically confirmed. Continuous therapy with ceftazidime and co-trimoxazole and maintenance with co-trimoxazole, doxycycline, and chloramphenicol resulted in eradication of Burkholderia pseudomallei.

This infection appears to be a particular risk for the increasing number of adults with CF travelling aboard to places such as Thailand as they seem to be prone to melioidosis. Subsequently further cases were reported. Burkholderia pseudomallei is an important cause of pneumonia and septicaemia in Thailand particularly in the rainy season when it may get into the water supply and there are now almost 70 cases of the infection causing serious illness reported in people with cystic fibrosis. So going on holiday to Thailand is a risk for a person with CF particularly in the rainy season. B. pseudomallei infection has also been reported by a person with CF in Brazil (Barth AL et al, 2007. [PubMed] below).

2001 Jones AM, Govan JR, Doherty CJ, Dodd ME, Isalska BJ, Stanbridge TN, Webb AK. Spread of a multiresistant strain of Pseudomonas aeruginosa in an adult cystic fibrosis clinic. Lancet 2001; 358:557-558. [PubMed]
A prospective surveillance study in the Manchester adult CF centre showed 22 (14%) of 154 patients with chronic P. aeruginosa had isolates with similar and new pyocin and pulsed-field gel electrophoresis types. Cross-infection by a new multiresistant P. aeruginosa strain had therefore occurred. The authors recommended CF centres should undertake microbiological surveillance of their patients.

A subsequent report from Manchester showed that patients infected with this strain of Pseudomonas required more intensive treatment (Jones AM et al. Thorax 2002; 57:924-925. below [PubMed] )


Fig. 23: Dr Andy Jones.

An important paper by Dr Andy Jones (figure 23), consultant physician at the Manchester Adult CF Centre, that was influential in the eventual introduction of widespread microbiological surveillance of CF centres in the UK. This led to the discovery that cross infection was a common occurrence in many of the large CF centres (Scott & Pitt 2004 below). A similar clinical situation with a transmissible P. aeruginosa had been reported from the Liverpool paediatric CF clinic in 1996 (Cheng K et al, 1996 above).

These papers were influential in the introduction of a more rigorous policy of segregation according to microbiological status in most CF centres but in some not without a degree of reluctance on the part of some CF clinicians for example one senior physician wrote - "There is a real risk of stigmatisation by sputum bacteriology, enhanced anxiety about what may be a relatively benign organism (many adults with CF remain well despite positive cultures of Pseudomonas aeruginosa for decades) and fear of attending a CF centre or any school or social event where another person with CF may be met. There are risks in doing too little but it may be worse to do too much. Geddes DM. Lancet 2001; 358:522-523). Also one paediatrician wrote - "This (segregation) means there will be loss of continuity of care as well as flexibility for the families choosing which days they come to see us". One of his paediatric colleagues described those at the CF Trust responsible for recommending patient segregation as "an unruly bunch of zealots"!! Fortunately only a minority of clinicians held these views!!

2001 Equi AC. Pike SE. Davies J. Bush A. Use of cough swabs in a cystic fibrosis clinic. Archives of Disease in Childhood. 85(5):438-9, 2001. [PubMed]

The authors audited prospectively 322 cough swabs taken from cystic fibrosis children and compared cough swabs with concomitant sputum samples in 30 expectorating patients. A positive cough swab is a strong predictor of sputum culture. However, a negative cough swab does not rule out infection. Persistent symptoms should be further investigated.

A practically useful study as cough swabs are widely used to monitor respiratory pathogens in children with CF in the UK.

2001 Rosenfeld M, Gibson RL, McNamara S, Emerson J, Burns JL, Castile R, Hiatt P, McCoy K, Wilson CB, Inglis A, Smith A, Martin TR, Ramsey BW. Early pulmonary infection, inflammation, and clinical outcomes in infants with cystic fibrosis. Pediatr Pulmonol 2001; 32:356-366. [PubMed]
Forty infants from 3 participating sites over a 2-year period had annual bronchoalveolar lavage (BAL) for culture and measurements of pro- and anti-inflammatory cytokines, semi-annual infant pulmonary function testing, and quarterly clinical evaluations. Both the prevalence of CF pathogens and their density in BAL fluid increased with age. Infants had neutrophilic lower airway inflammation and elevated IL-8 concentrations independent of whether CF pathogens were recovered. Total leukocyte and neutrophil densities and IL-8 concentrations increased with density of CF pathogens in BAL fluid, whether the isolated organism was P. aeruginosa or another pathogen. IL-10 concentrations were similar in CF subjects and non-CF historical controls. Infants generally had suboptimal growth (low weight and height percentiles) and obstructive lung disease (decreased expiratory flows and air trapping). Subjects from whom CF pathogens were isolated at > 105 cfu/ml had the worst air trapping and lowest Brasfield chest X-ray scores. The authors considered that their findings would provide a foundation for future studies of early intervention in CF lung disease, including antimicrobial and anti-inflammatory therapy.

In these infants who were recruited from the CF care centres at each of 3 participating sites there was an alarming frequency of isolation of pathogens from the lower airways. Unfortunately antibiotic prescribing practices were not specified although the values were said merely not to correlate with antibiotic use. Obviously the presence of S. aureus in cultures would be related to whether prophylactic anti-staphyloccocal antibiotics being used an d whether a policy of early eradication of Pseudomonas was practised.
With regard to these patients, by the age of 3 years, no less than 21% of the children had >105 cfu/ml of P. aeruginosa, and 39% of any pathogen. The authors considered that carefully conducted randomized controlled trials in very young patients with CF would help to establish the risk-benefit ratio of therapeutic interventions in this important and vulnerable population.
This ultra cautious attitude shows a radically different approach to that recommended in the UK and many European centres where neonatal screening had been routine for many years and early interventions are the rule e.g. long term flucloxacillin, amoxil with colds and any positive airway cultures, and early eradication therapy for positive P. aeruginosa cultures whether there are symptoms or not etc, etc. (These policies are detailed in the CF Trust consensus documents e,g, Antibiotic Treatment for Cystic Fibrosis. UK CF Trust, 2009). This difference in approach is reflected in the much higher chronic infection rates in young children in the US than in some UK and European CF centres.


Fig. 25: Dr Margaret Rosenfeld

Dr Rosenfeld is Medical Director of the Clinical Research Center and also Medical Director of the Pulmonary Function laboratory at the Seattle Children's Hospital.

2001 Munck A, Bonacorsi S, Mariani-Kurkdjian P, Lebourgeois M, Gerardin M, Brahimi N, Navarro J, Bingen E. Genotypic characterization of Pseudomonas aeruginosa strains recovered from patients with cystic fibrosis after initial and subsequent colonization. Pediatr Pulmonol 2001; 32:288-292). [PubMed]
After early eradication treatment of Pseudomonas aeruginosa subsequent serial isolates were characterized by means of molecular methods to determine whether they were genetically related to the initial strain. Initial colonization was eradicated in all 19 patients and 14. Fourteen patients subsequently acquired a new PA strain with a distinct genotypic profile, suggesting a new source of contamination. Five patients had two PA isolates with identical genotypes, suggesting either previous undetected respiratory tract colonization or a persistent environmental source of contamination.

This was a very important, practically very useful and now oft quoted paper which settled the question as to whether Pseudomonas was eradicated or merely suppressed with initial eradication antibiotic therapy. It showed quite clearly that, in the majority of patients, the Pseudomonas had been eradicated rather than merely being suppressed.


Fig. 26a: Dr Anne Munck

Dr Anne Munck (figure 26a) is paediatrician specializing in gastroenterology, nutrition and cystic fibrosis at the University Hospital Robert Debre, Paris. She is heavily involved in cystic fibrosis care and research and is also treasurer of the European Cystic Fibrosis Society.

2001 Burns JL, Gibson RL, McNamara S, Yim D, Emerson J, Rosenfeld M, Hiatt P, McCoy K, Castile R, Smith AL, Ramsey BW. Longitudinal assessment of Pseudomonas aeruginosa in young children with cystic fibrosis. J Infect Dis 2001; 183:444-452. [PubMed].
This study investigated genotypic and phenotypic changes in P. aeruginosa from oropharynx (OP) and bronchoalveolar lavage fluid (BALF) in a cohort of 40 children with CF during their first 3 years. A high degree of genotypic variability was identified, and each patient had unique genotypes. Early isolates had a phenotype distinct from those of usual CF isolates: generally they were non-mucoid and antibiotic susceptible. Genotype and phenotype correlated between OP and BALF isolates. As determined by culture, 72.5% of patients demonstrated P. aeruginosa during their first 3 years. On the basis of combined culture and serologic results, 97.5% of patients had evidence of infection by age 3 years, which suggests that P. aeruginosa infection occurs early in CF and may be intermittent or undetectable by culture.

This very high incidence of P. aeruginosa is quite atypical of UK experience. We do not believe that so many young children are chronically infected (Lee et al, 2004 below) this is based on numerous serial throat cultures, cough swabs and Pseudomonas antibody levels estimated over years which correlate closely with the degree of respiratory infection (Brett et al, 1986 above). It seems that the longitudinal careful observation of a group of patients often yields important additional information not apparent in even the most sophisticated controlled trials or cross sectional studies.


Fig. 26. Dr Jane Burns

Dr Jane Burns is one of N. America's leading CF microbiologists. Her basic research focuses on the natural history of CF airway infections including the pathogenesis of chronic infection and bacterial antibiotic resistance. Dr. Burns is closely involved with the CF Foundation-funded Therapeutics Development Network (TDN) of clinical trials in CF. She serves as the director of the TDN Core Microbiology Laboratory that performs thousands of cultures of CF specimens from clinical trials in the US each year.

2001 Saiman L. Chen Y. Tabibi S. San Gabriel P. Zhou J. Liu Z. Lai L. Whittier S. Identification and antimicrobial susceptibility of Alcaligenes xylosoxidans isolated from patients with cystic fibrosis. Journal of Clinical Microbiology. 39(11):3942-5, 2001. [PubMed]

A total of 106 strains from 78 patients from 49 CF centers in 22 states were studied. Most (89%) were correctly identified by the referring laboratories as Alcaligenes xylosoxidans. However, 12 (11%) strains were misidentified; these were found to be P. aeruginosa (n = 10), Stenotrophomonas maltophilia (n = 1), and Burkholderia cepacia (n = 1). Minocycline, imipenem, meropenem, piperacillin, and piperacillin-tazobactam were the most active since 51, 59, 51, 50, and 55% of strains, respectively, were inhibited. High concentrations of colistin (100 and 200 microg/ml) inhibited 92% of strains. Chloramphenicol paired with minocycline and ciprofloxacin paired with either imipenem or meropenem were the most active combinations and inhibited 40 and 32%, respectively, of strains. Selective media and biochemical identification proved to be useful strategies for distinguishing A. xylosoxidans from other CF pathogens. Standards for processing CF specimens should be developed, and the optimal method for antimicrobial susceptibility testing of A. xylosoxidans should be determined.

One of an increasing number of pathogens isolated from people with CF.

2001 Moore JE. McIlhatton B. Shaw A. Murphy PG. Elborn JS. Occurrence of Burkholderia cepacia in foods and waters: clinical implications for patients with cystic fibrosis. J Food Protect2001; 64:1076-1078. [PubMed]
Two hundred forty-eight retail "ready-to-eat" foodstuffs in eight food categories and 134 waters categorized into nine types were analyzed for the presence of the Burkholderia cepacia complex of organisms. Of these, 14 of 26 (53.8%) samples of raw un pasteurized bovine milk were positive for this organism. Consumption of raw un pasteurized milk may therefore act as a potential source of infection with this organism, which is of particular concern for patients with cystic fibrosis, where colonization and infection with this organism can lead to a fatal necrotising pneumonia and premature death. In addition to the associated risk of infection from fecal pathogens, patients with cystic fibrosis should therefore avoid the consumption of raw un pasteurized milk to minimize the risk of becoming infected with this organism.

Of practical importance as unadvertised milk is still available.

2002 Moore JE. McIlhatton B. Buchanan J. Gilpin D. Shaw A. Hall V. Murphy PG. Elborn JS. Occurrence of Burkholderia cepacia in the hospital environment. Irish J Med Sci 2002; 171:131-133.15736349. [PubMed]
To determine the prevalence of Burkholderia cepacia from the environment in a regional adult cystic fibrosis (CF) care centre. B. cepacia was not detected from commonly shared items of equipment, staff hands, staff uniforms or toilets. In addition, the organism was not detected in toilet bowls, even in the B. cepacia unit. With regard to positive environments for B. cepacia, 4/10 (40%) of the outside surfaces and inner rims of patients' plastic disposable sputum collection containers and 4/17 (23.5%) of air from patients' rooms, following physiotherapy, were positive. All positive samples originated in the B. cepacia segregation area of the inpatient wards and B. cepacia was not detected in the non-cepacia area of the CF centre. Consequently, these two positive sites should therefore be treated as high risk, where organisms may be potentially transmitted from environment to patient.

A useful study confirming that B.cepacia only appeared to be a potential problem in areas inhabited by CF patients already infected by the organism.

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

This study demonstrates extensive spread of a single, clonal strain of P. aeruginosa in a large pediatric CF clinic. Whether this strain is also more virulent than sporadic isolates remains to be determined however the fatal outcome for 5 of these children suggests this was almost certainly the case. As transmissible strains could emerge elsewhere, the authors suggested that other CF clinics may also need to consider molecular methods of surveillance for cross-infection
This is a really tragic story and further evidence of the potential and at times very real dangers of spread of highly transmissible strains of P. aeruginosa. The fact the 5 children died attests to this strains virulence and this infection also leads to a requirement for more treatments. This is another study recommending to others that molecular methods should be used when studying cross infection in CF centres. It is interesting and of some concern that around this time in some major CF centres, there were still clinicians who doubted the need for segregation even though the first major epidemic had been described in 1996 from Liverpool (Cheng et al, 1996 above)

2002 Jones AM. Dodd ME. Doherty CJ. Govan JR. Webb AK. Increased treatment requirements of patients with cystic fibrosis who harbour a highly transmissible strain of Pseudomonas aeruginosa. Thorax 2002; 57:924-925. [PubMed]
A group of patients who harbour the same highly transmissible strain of Pseudomonas aeruginosa were identified at a cystic fibrosis (CF) centre. Isolates of this strain display a number of unusual phenotypic features including resistance to most typical antipseudomonal antibiotics. A study was undertaken to see if there was a difference in treatment requirements between CF patients with chronic infection with their own unique P aeruginosa strains (group 1) and those who harbour a highly transmissible strain (group 2). Data on treatment requirements for the year 2000 were collected from the case records of CF patients with chronic P aeruginosa infection who had received inpatient treatment. Patients co-infected with Burkholderia cepacia or other highly transmissible strains of P aeruginosa were excluded. There were 2/56 and 3/22 deaths in groups 1 and 2, respectively; these patients were excluded from the analysis. No difference was found between the two groups for mean age, % predicted forced expiratory volume in 1 second (FEV(1)), % predicted forced vital capacity (FVC), and body mass index. Patients in group 2 had a greater median (range) number of intravenous antibiotic days (60 (17-216) v 33 (4-237) days; p=0.01), inpatient days (39 (7-183) v 16 (1-172) days; p<0.01), and inpatient episodes (3 (1-9) v 2 (1-6); p<0.01), and more respiratory exacerbations (mean (SD) 8.2 (3.4) v 6.1 (3.2); p=0.01). Patients who harbour the highly transmissible P aeruginosa strain have a greater treatment burden than patients with CF who harbour their own unique strains. These findings support the need for microbiological surveillance for highly transmissible P aeruginosa and the implementation of infection control measures to prevent cross infection.

Andy Jones has done much to clarify the increased pathogenicity of the highly transmissible P. aeruginosa. Here it is apparent that patients infected with these strains require more intensive treatment.

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

2003 Lee TWR, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros 2003; 2:29-34. [PubMed]
The variable definition of chronic Pseudomonas infection in various publications was problem in comparing experience between CF centres. Patients with CF in Leeds were classified into four groups on the routine culture results over the previous 12 months as follows –

“Chronic”      - more than 50% of cultures positive for Pseudomonas;
“Intermittent” - less than 50% of cultures were positive;
“Free”           - previously had positive but clear for the past year;
“Never”          - patient has never had Pseudomonas.

Many previous studies used different definitions of chronic Pseudomonas infection making comparisons difficult. This definition was agreed by a number of experts including Neils Høiby and later confirmed as useful in a published study from Belgium (Proesmans M et al. Eur Respir J 2006; 27:937-943.[PubMed]).

2003 Robinson P, Carzino R, Armstrong D, Olinsky A. Pseudomonas cross-infection from cystic fibrosis patients to non-cystic fibrosis patients: implications for inpatient care of respiratory patients. J Clin Microbiol 2003; 41: 5741. [PubMed]
A 14-year-old boy with non-CF bronchiectasis secondary to chronic aspiration developed multiresistant Pseudomonas aeruginosa lower respiratory disease following several inpatient periods where accommodation and physiotherapy services were shared with CF patients known to be infected with the genetically identical strain of P. aeruginosa. Cross-infection with P. aeruginosa between CF patients and non-CF patients had not previously been described, and this finding raises significant issues relevant to the treatment of patients with non-CF suppurative lung disease. Spread of a highly transmissible P. aeruginosa to a CF patient already chronically infected with P. aeruginosa had already been described from Liverpool (McCallum SJ et al. Lancet 2001; 358:558-560. above)

The spread of infection to non-CF patients from CF patients is a definite risk in hospital wards, particularly if there are immunocompromised patients mixing with CF patients who have chronic P. aeruginosa infection a situation I have observed on one occasion in the years before cross infection with P. aeruginosa was not considered to be a significant risk.


Fig. 31: Dr Phil Robinson

Dr Phil Robinson (figure 31) is Head of CF services and Respiratory Physician at the Royal Melbourne Children’s Hospital and a leading Australian authority on cystic fibrosis.

2003 Kollberg H, Carlander D, Olesen H, Wejaker PE, Johannesson M, Larsson A. Oral administration of specific yolk antibodies (IgY) may prevent Pseudomonas aeruginosa infections in patients with cystic fibrosis. Pediatr Pulmonol 2003; 35:433-440. [PubMed]
Immunotherapy with specific egg-yolk antibodies (IgY) may be an alternative to antibiotics for the prevention of PA infections. CF patients gargled daily with an IgY-antibody preparation, purified from eggs of hens immunized with Pseudomonas bacteria. These patients were compared to a group who did not gargle with the preparation. Both groups had their first colonization with PA eradicated by antibiotics. The basic treatment for CF was essentially the same in both groups.
In the initial study, the period between the first and second colonization with PA was significantly prolonged for the treated vs. the control group. In the prolonged study, the treated group had only 2.5 sputum cultures positive for PA per 100 months of observation, and none of these patients became chronically colonized with PA. No adverse events were reported. In the control group, 13.7 cultures per 100 months of observation were positive for PA, and 5 (24%) patients became chronically infected with PA. This feasibility study shows that antipseudomonal IgY has the potential to effectively prevent PA colonization without any severe adverse effects


Fig. 33: Prof Hans Kollberg

Hans Kollberg (figure 33) from Uppsala has been attending CF meetings for many years – I first remember him giving a paper on CF in Sweden at the 1980 Toronto CF conference. He has published 79 papers since 1964 many on a wide variety of CF topics. He has been developing this particular technique for some years which now seemed to be showing definite promise. Certainly one of the long distance CF doctors!! Further report of this IgY treatment (Nilsson et al, 2007 below) where 10 year progress is reported; a multicentre trial is planned in 2010 and likely o to be funded..

2003 Jørgensen IM. Johansen HK. Frederiksen B. Pressler T. Hansen A. Vandamme P. Høiby N. Koch C. Epidemic spread of Pandoraea apista, a new pathogen causing severe lung disease in cystic fibrosis patients. Pediatric Pulmonology. 36(5):439-46, 2003 Nov.[PubMed]
We show that Pandoraea apista must be added to the increasing list of pathogens capable of causing chronic lung infection in cystic fibrosis (CF) patients. It is most likely that this strain of P. apista was transmissible among patients with CF, leading to spread of infection from the index patient to 5 other patients exposed during participation in winter camps and/or hospitalization. All patients developed chronic infection with high levels of antibodies, and 4 patients had a downhill course of lung disease. P. apista must therefore be considered a new and sometimes important pathogen for CF patients. Cohort isolation prevented further spread of P. apista in our CF center.

One of the increasing numbers of unusual organism which are significant pathogens for people with CF. Such reports from large CF centres such as Copenhagen are useful for clinician who subsequently encounters such organisms.

2003 Saiman L. Siegel J. Cystic Fibrosis Foundation. Infection control recommendations for patients with cystic fibrosis: microbiology, important pathogens, and infection control practices to prevent patient-to-patient transmission. [Review] [395 refs] Infect Cont Hosp Ep 2003; 24(5 Suppl):S6-52. [PubMed]
Report of a Consensus Development Conference organised by the CF Foundation to which representatives from both USA and Europe were invited. The result is a very detailed paper full of information and nearly 400 references!

2004 Griffiths AL. Armstrong D. Carzino R. Robinson P. Cystic fibrosis patients and families support cross-infection measures. European Respiratory Journal. 24(3):449-52, 2004 Sep. [PubMed]
A clonal strain of Pseudomonas aeruginosa (PA) was isolated in 1999 at the Royal Children's Hospital, Melbourne, Australia, after five unrelated children with cystic fibrosis (CF) died from severe lung disease aged <5 yrs. Subsequently, more than half of the patients in the clinic with PA were found to harbour this strain, and segregation measures were instituted at the hospital to prevent further spread. The aim of this study was to assess CF parent and patient responses to the segregation measures to determine overall support. A questionnaire was sent out to the families of 291 CF children treated at the centre. A 65% response rate was obtained. The majority of parents (85%) and patients > or=12 yrs old (63%) were positive about the segregation measures instituted. A total of 11% of parents and 25% of patients were unsure, and 4% of parents and 12% of children gave negative responses. Those who were not happy listed reasons such as concerns about the emotional impact of not socialising with other CF children, inconclusive evidence about person-person spread of infection and feelings of alienation created in the clinic by the separation. In conclusion, the majority of responding cystic fibrosis patients and their families understand and are supportive of infection control measures instituted at the Royal Children's Hospital, Melbourne, Australia.

This is a sad story of the ravages a highly transmissible strain of Pseudomonas can cause in a major CF clinic. It is not surprising that the vast majority of parents supported the segregation policy as five children had died from the particular Pseudomonas strain.

2004 Lee TW, Brownlee KG, Denton M, Littlewood JM, Conway SP. Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center. Pediatr Pulmonol 2004; 37:104-110. [PubMed]
Tim Lee (figure 34) is a Consultant Paediatrician at the Leeds Regional Paediatric CF Centre. Over the years various management strategies were introduced at the Leeds CF centre in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early nebulised antibiotic treatment of first isolations of P. aeruginosa (1984), intensive intravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991).


Fig. 34: Dr Tim Lee


Fig. 35: Dr Miles Denton
Fig. 35: Dr Miles Denton


Fig. 36. BC consensus document

The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups: never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with </=50% of months with samples positive for P. aeruginosa over the previous 12 months; and chronic P. aeruginosa infection with >50% of months with samples positive for P. aeruginosa over the previous 12 months.
The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. However, the annual incidence and mean age of first positive culture of P. aeruginosa did not alter significantly.
In conclusion, anti-Pseudomonal management strategies were associated with both reduced prevalence of chronic infection and an increase in the mean age of onset of chronic P. aeruginosa infection. The actual incidence of new isolations was not significantly altered suggesting that now most new infections are acquired from the environment.

Miles Denton is the microbiologist at Leeds Teaching Hospitals and the Leeds Regional CF Centre. He is also one of the main advisors on microbiological issues to the UK CF Trust and has published on many aspects of CF in particular a number of papers on Stenotrophomonas maltophilia (Denton M et al. J Clin Microbiol 1998; 36:1953-1959; Denton M et al. J Antimicrob Chemother. 1999; 43:555-558 and others on various aspects of S. maltophilia infection in CF including contamination of nebulisers (J Hosp Inf 2008;68:371), presence in salads (Emerg Inf Dis 2005;11:1157), nebulisers (J Hosp Inf 2003;55:180), implantable venous access devices (J Infect 2002;44:53).

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

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

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

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

This study from a large CF centre in Manchester confirms the more serious prognosis for patients infected with B. cenocepacia than for those infected with B. multivorans.

2004 Courtney JM. Dunbar KE. McDowell A. Moore JE. Warke TJ. Stevenson M. Elborn JS. Clinical outcome of Burkholderia cepacia complex infection in cystic fibrosis adults. J Cyst Fibros 2004; 3:93-98. [PubMed]

Nineteen CF adults infected with BCC and 19 controls infected with Pseudomonas aeruginosa were studied over a 4-year period at the Adult CF Centre in Belfast. The BCC infected group displayed a significantly greater reduction of FEV(1) and BMI compared to the P. aeruginosa infected group. Sixteen patients infected with a single Burkholderia cenocepacia strain had a significantly greater rate of FEV(1) decline compared to those infected with Burkholderia multivorans (n=3) or P. aeruginosa (p=0.01 and p<0.0001, respectively). The rate of BMI decline was significantly greater in patients infected with B. cenocepacia compared to those with P. aeruginosa (p=0.007), but not significantly different in those with B. multivorans (p=0.29). BCC infection is associated with an accelerated decline in pulmonary function and BMI. Infection with a single B. cenocepacia strain was associated with a more rapid decline in lung function than those infected with either B. multivorans or P. aeruginosa.

2004 Blackburn L. Brownlee K. Conway S. Denton M. 'Cepacia syndrome' with Burkholderia multivorans, 9 years after initial colonization. J Cyst Fibros 2004; 3:133-134. [PubMed]

A 16-year-old boy with cystic fibrosis developed 'cepacia syndrome' 9 years after the first isolation of Burkholderia multivorans. It is important to recognise that 'cepacia syndrome' is not restricted to those infected with genomovar type III strains and that rapid, irreversible clinical decline can occur many years after the 1st isolation of Burkholderia cepacia complex (Bcc).

2004 Scott FW, Pitt TL. Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales. J Med Microbiol 2004; 53:609-615. [PubMed]
Most previous studies of cross-infection with P. aeruginosa (PA) among patients with CF in the UK suggested that it is a rare occurrence. However, two recent UK reports of highly transmissible strains of PA in patients in regional centres in Liverpool (Cheng et al, 1996 above) and Manchester (Jones et al, 2001 above) raised questions as to the extent of the problem. These reports prompted the UK CF Trust to fund this nationwide survey to establish the distribution of PA genotypes among these patients. Isolates of PA were requested from over 120 hospitals in England and Wales and a sample size of approximately 20% of the CF patient population in each centre was recommended. In total, 1225 isolates were received from 31 centres (range 1 to 330). Single patient isolates were typed by SpeI macrorestriction and PFGE. A panel of strains of the common genotypes including representatives of reported transmissible strains was assembled and further characterized by fluorescent amplified fragment length polymorphism (FAFLP) genotyping.

The important findings were as follows:-
- At least 72% of all patients harboured strains with unique genotypes.
- Small clusters of related strains were evident in some CF centres, presumably indicating limited transmission of local strains.
- The most prevalent strain was indistinguishable from that previously described as the 'Liverpool' genotype, and accounted for approximately 11% of patient isolates from 15 centres in England and Wales.
- The second most common genotype (termed Midlands 1) was recovered from 86 patients in nine centres
- The third genotype, which matched closely the PFGE profile of Clone C, a genotype originally described in Germany, was found in eight centres and was isolated from 15 patients.
- A fourth genotype, identical to the published Manchester strain, was found in three centres.

FAFLP analysis revealed some microheterogeneity among strains of the Liverpool genotype but all isolates of this genotype were positive by PCR for a strain-specific marker.
These data are mentioned in detail in view of their great importance for clinic routines and suggest that cross-infection with PA has occurred both within and widely between CF centres in England and Wales. The two most common genotypes accounted for more than one-fifth of patients' isolates examined and transmissible genotypes were found in all but three of the 31 CF centres studied. These results emphasize the need for continued surveillance of P. aeruginosa genotypes in CF patients to provide informed infection control policy in treatment centres.

2004 Johansen HK. Nørregaard L. Gøtzsche PC. Pressler T. Koch C. Høiby N. Antibody response to Pseudomonas aeruginosa in cystic fibrosis patients: a marker of therapeutic success?--A 30-year cohort study of survival in Danish CF patients after onset of chronic P. aeruginosa lung infection. Pediatr Pulmonol 2004; 37:427-432. [PubMed]
We studied the effects of increasingly intensive treatment regimens on anti-pseudomonal antibody response and survival in five successive cohorts of a total of 157 Danish cystic fibrosis patients after they had acquired chronic P. aeruginosa lung infection. The time periods were 1971-1975 (N = 21), 1976-1980 (N = 64), 1981-1986 (N = 27), 1987-1993 (N = 26), and 1994-2000 (N = 19). Our study shows that CF patients who are treated intensively have lower antibody responses and longer survival after acquisition of chronic P. aeruginosa lung infection.

The details are given in the full abstract but essentially the steady improvement in survival in Copenhagen over the years associated with an aggressive treatment policy is mirrored by a declining level of Pseudomonas precipitins in the patients over the year s..

2004 O'Carroll MR. Syrmis MW. Wainwright CE. Greer RM. Mitchell P. Coulter C. Sloots TP. Nissen MD. Bell SC. Clonal strains of Pseudomonas aeruginosa in paediatric and adult cystic fibrosis units. Eur Respir J 2004; 24:101-106. [PubMed]
Despite recent reports of clonal strains of Pseudomonas aeruginosa in cystic fibrosis (CF) units, the need for routine microbiological surveillance remains contentious. Sputum was collected prospectively from productive patients attending the regional paediatric and adult CF units in Brisbane, Australia. All P. aeruginosa isolates were typed using pulsed-field gel electrophoresis. Spirometry, anthropometrics, hospitalisations and antibiotic sensitivity data were recorded. The first 100 sputum samples (first 50 patients at each clinic) harboured 163 isolates of P. aeruginosa. A total of 39 patients shared a common strain (pulsotype 2), 20 patients shared a strain with at least one other patient and 41 patients harboured unique strains. Eight patients shared a strain identical to a previously reported Australian transmissible strain (pulsotype 1). Compared with the unique strain group, patients harbouring pulsotype 2 were younger and had poorer lung function. Treatment requirements were similar in these two groups, as were the rates of multi resistance. In conclusion, 59% of patients harboured a clonal strain, supporting the need for routine microbiological surveillance. In contrast to previously described clonal strains, the dominant pulsotype was indistinguishable from non clonal strains with respect to both colonial morphology and multi resistance. The clinical significance of clonal strains remains uncertain and requires longitudinal study.

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

2005 Armstrong DS, Hook SM, Jamsen KM, Nixon GM, Carzino R, Carlin JB, Robertson CF, Grimwood K. Lower airway inflammation in infants with cystic fibrosis detected by newborn screening. Pediatr Pulmonol 2005; 40:500-510. [PubMed]
Further work from the group in Victoria, Australia. Controversy exists over whether the lower airway inflammation that characterizes CF is initiated primarily by the genetic defect or is the result of infection. The authors examined bronchoalveolar lavage in detail from 70 CF children detected by newborn screening and 19 controls with chronic stridor. The presence of infection was associated with elevated inflammatory mediators in the BAL fluid. In contrast, minimal or reduced signs of inflammation accompanied absence or eradication of infection from BAL fluid. The authors concluded that in CF, it is infection initiates and sustains airway inflammation.

This was a clear result i.e. the inflammation is caused by the infection. However, the inflammatory response to infection does seem to be excessive in CF but it seems that the infection occurs first to trigger the abnormal inflammatory response.

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

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

2004 Lang AB. Rüdeberg A. Schöni MH. Que JU. Fürer E. Schaad UB. Vaccination of cystic fibrosis patients against Pseudomonas aeruginosa reduces the proportion of patients infected and delays time to infection. Pediatr Infect Dis J 2004; 23:504-510. [PubMed]
Alois Lang and his colleagues conducted a 10-year retrospective analysis of outcomes in a group patients vaccinated with a new P. aerugiinosa vaccine. In 1989-1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. Their follow up of these 26 from 1989 to 2001 is reported. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. Vaccinated patients and controls were attending a single CF clinic and received the same clinical management throughout the study period. Main outcomes were time to infection, proportion of patients infected, development of P. aeruginosa mucoid phenotype, lung function and body weight. RESULTS: The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients >/=18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study. CONCLUSION: Regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

This abstract is reproduced in detail as the apparently impressive results of this preliminary study prompted an international multicentre trial of the vaccine. Unfortunately the results of this major trial were entirely negative - there being no difference between the treated and control groups either in the prevalence of chronic P. aeruginosa infection or the number of new positive Pseudomonas respiratory cultures. It was possible that the increasing use of anti-Pseudomonas eradication therapy and the fall in the prevelance of chronic Pseudomonas infection contributed to the negative results (unpublished data).

2005 Barben J, Hafen G, Schmid J. Swiss Paediatric Respiratory Research Group. Pseudomonas aeruginosa in public swimming pools and bathroom water of patients with cystic fibrosis. J Cyst Fibros 2005; 4:227-231. [PubMed]
This study aimed to identify the prevalence of Pseudomonas aeruginosa (PA) in public swimming pools and water taps. Water was collected from public indoor and outdoor pools in the area of St. Gallen, Switzerland. In addition, standing and running water was sampled from bathroom water taps of 50 patients with CF. Outdoor pools: In 2002, none of the 72 specimens from 28 pools revealed PA. In 2003, three specimens from 46 pools (7%) revealed PA, each were from a different paddling pool. Indoor pools: two of 128 specimens from 56 pools (4%) identified PA, both were from non-public hydrotherapy pools. Water taps: in winter, none of the 102 specimens was colonized with PA. In summer, only two out of 50 specimens of the standing water were positive for PA but none of the running water revealed PA.

So the prevalence of PA in public swimming pools and bathroom water taps in the eastern part of Switzerland is very low. On hot summer days, outdoor paddling pools and standing tap water can contain PA. This study does not support recommendations to avoid public swimming pools or running tap water if the water is maintained according to hygiene guidelines. However, although the swimming pools in Switzerland are essentially free of bacteria unfortunately this is not general European experience. For example, a report from Northern Ireland found public swimming pools were frequently infected with PA (Moore JE et al. Incidence of Pseudomonas aeruginosa in recreational and hydrotherapy pools. Commun Dis Pub Health 2002; 5:23-26). A ”Which” (a consumer magazine) report in 2002 also showed 35 of 61 samples from UK pools and spas fell outside acceptable bacteriological standards.

2005 Taccetti G, Campana S, Festini F, Mascherini M, Doring G. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Respir J 2005; 26:458-461. [PubMed]
Early antibiotic treatment of lung infection in people with CF has been shown to lead to eradication of Pseudomonas aeruginosa (PA). Early antibiotic therapy leads to a PA free-period of a median (range) of 18 (4-80) months. New acquisition with different PA genotypes occurs in 73% of episodes. It also delays the decline of lung function compared with chronically infected patients. The treatment substantially lowers chronic PA prevalence in CF.

Yet more evidence that early antibiotic therapy of P. aeruginosa infection exerts beneficial effects on the patient's clinical status and is cost-effective compared with conventional antibiotic therapy for chronically infected cystic fibrosis patients.

2005 Panagea S. Winstanley C. Walshaw MJ. Ledson MJ. Hart CA. Environmental contamination with an epidemic strain of Pseudomonas aeruginosa in a Liverpool cystic fibrosis centre, and study of its survival on dry surfaces. J Hosp Infect 205; 59:102-107. [PubMed]
We conducted an environmental survey in the Liverpool adult cystic fibrosis (CF) centre in order to determine the extent of environmental contamination with an epidemic strain of Pseudomonas aeruginosa that colonizes most CF patients in Liverpool, and to identify possible reservoirs and routes of cross-infection. In addition, we studied the survival of this strain on dry surfaces, compared with that of other CF P. aeruginosa strains, to explore factors that might contribute to its high transmissibility. Samples were collected from staff, patients and the environment (drains, bath tubs, showers, dry surfaces, respiratory equipment and air) in the inpatient ward and outpatient clinic. P. aeruginosa strains were tested using a new polymerase chain reaction amplification assay specific for the Liverpool epidemic strain (LES). LES was isolated from patients' hands, clothes and bed linen. Environmental contamination with LES was only detected in close proximity to colonized patients (external surfaces of their respiratory equipment, and spirometry machine tubing and chair) and was short-lived. No persistent environmental reservoirs were found. LES was detected in the majority of air samples from inside patients' rooms, the ward corridor and the outpatient clinic. Survival of LES on dry surfaces was significantly longer than that for some other strains tested, but not compared with other strains shown not to be transmissible. Improved environmental survival on its own, therefore, cannot explain the high transmissibility of this epidemic strain. Our study suggests that airborne dissemination plays a significant role in patient-to-patient spread of LES, and confirms the need to segregate those patients colonized by epidemic P. aeruginosa strains from all other CF patients.

2005 Jones AM, Dodd ME, Govan JR, Doherty CJ, Smith CM, Isalska BJ, Webb AK. Prospective surveillance for Pseudomonas aeruginosa cross-infection at a cystic fibrosis center. Am J Resp Crit Care Med 2005; 171:257-260 .[PubMed]
A 4-year prospective surveillance for Pseudomonas aeruginosa (PA) cross-infection at a large regional adult cystic fibrosis centre (Manchester, UK) showed that, despite purpose-built facilities in a new building and the practice of strict hygiene, PA cross-infection has continued. In contrast, individuals segregated from the cohort of patients with chronic PA infection but who attend the same centre have not acquired infection with transmissible PA strains. Simple infection control measures alone do not prevent the spread of some transmissible PA strains between individuals with cystic fibrosis. However, patient segregation effectively controlled spread of such strains.
These were the same transmissible PA strains described from Manchester (Jones et al, 2001 above; Jones et al, 2002 above).

2006 Lebecque P, Leal T, Zylberberg K, Reychler G, Bossuyt X, Godding V. Towards zero prevalence of chronic Pseudomonas aeruginosa infection in children with cystic fibrosis. J Cyst Fibros 2006; 5:237- 44. [PubMed]
Prevalence of chronic P. aeruginosa infection in one of the seven Belgian CF centres was very low and only half the national level; overall 19.8% for all the children and adults but only 2.8% in patients below 18 years. This was attributed to cohorting patients according to their microbiological status and particularly to the widespread and frequent use of inhaled antibiotics over the previous 15 years; also patients were seen by the same paediatric pulmonologist.

This is an impressive report showing a 2.8% prevalence of chronic P. aeruginosa infection in children at this Belgian CF clinic - a prevalence in stark contrast to many published results – for example the incidence reported in both the US and UK patient registries.

2006 Asherova IK. Feigelson J. Vasilyeva LA. Gabitov VJ. Cystic fibrosis complicated by multiresistant tuberculosis. Acta Paediatrica 2006; 95:1513-4. [PubMed]
Tuberculosis is a rare occurence in CF. Second author is Jean Feigelson of Paris who published his first paper on CF on 1963 ([PubMed].

2006 Yahav J. Samra Z. Blau H. Dinari G. Chodick G. Shmuely H. Helicobacter pylori and Clostridium difficile in cystic fibrosis patients. Digest Dis Sci 2006; 51:2274-9.[PubMed]
Stool specimens from 30 consecutive patients with CF, aged 1-44, and from 30 healthy similarly aged subjects were tested for the H. pylori antigen by specific monoclonal antibodies and for CD toxins by Tox A/B assay and Tox A assay. CF patients were assessed clinically and tested for specific H. pylori serum antibodies and for mutations. In CF patients, the prevalence of H. pylori antigen was 16.6% (5/30), compared to 30% (9/30) in controls. Of the 26 CF patients with PI, only 2 (7.6%) were infected by H. pylori, compared with 3 of the 4 (75%) patients with PS (P=0.001). H. pylori infection was diagnosed in 3 of 5 (60%) CF patients carrying mild mutations, compared to 1 of 25 (4%) CF patients carrying severe mutations (P=0.01). Fourteen of 30 (46.6%) stool specimens from CF patients tested positive in the ToxA/B assay, and 3 of 14 tested positive for ToxA. No significant differences in antibiotic use, severity of lung disease, PI, chronic abdominal pain, or genotype were found between the two groups. None of the controls was positive for CD toxins. Prevalence of H. pylori infection in CF patients was lower than in similarly aged non-CF controls. CF patients with PI or a history of distal intestinal obstruction syndrome and those carrying mutations associated with a severe phenotype were protected against H. pylori infection. Almost half of the CF patients were asymptomatic carriers of CD producing mostly toxin B. More studies are needed to confirm our results in a larger group of CF patients.

This paper confirms the previously reported low incidence of H. pylori in people with CF.

2006 Frederiksen B, Pressler T, Hansen A, Koch C, Hoiby N. Effect of aerosolized rhDNase (Pulmozyme) on pulmonary colonization in patients with cystic fibrosis. Acta Paediatrica 2006; 95:1070-1074. [PubMed]
During one year patients with CF were randomized either to aerosolized Pulmozyme daily or to no Pulmozyme. The number of positive respiratory cultures was higher in the untreated group (82%) compared with the treated group (72%) (p<0.05). The most striking difference was found for Staphylococcus aureus, with a prevalence of 30% in the untreated group compared with 16% in the treated group (p<0.0001). Pulmonary function (FEV1) in the treated group showed a significant increase of 7.3% compared to 0.9% in the untreated group (p<0.05). Long term DNase treatment was beneficial to CF patients without chronic lower respiratory tract infection, with fewer positive respiratory cultures, leading to reduced demand for antibiotics and to improved lung function.

A useful study from Copenhagen showing inhaled rhDNase reduced the likelihood of a positive respiratory culture. This finding provides additional support for starting all patients on the treatment at an early age, where inhaled treatment is practical, as occurs now in some centres.

2006 Festini F, Buzzetti R, Bassi C, Braggion C, Salvatore D, Taccetti G Mastella G. Isolation measures for prevention of infection with respiratory pathogens in cystic fibrosis: a systematic review. J Hosp Infect 2006; 64:1-6. [PubMed]
The aim of this review was to determine what evidence is available to support the efficacy of isolation (or segregation) practices in preventing, delaying or reducing the risk for CF patients of acquiring P. aeruginosa and B. cepacia. In the absence of studies with an experimental, controlled design, the efficacy of isolation practices in preventing the transmission of respiratory pathogens in CF remains unproven. However, the observational studies reviewed seem to support the implementation of isolation (or segregation) measures to reduce the risk of transmission of B. cepacia and P. aeruginosa in CF patients.

There is now certainly enough published to support patient segregation according to microbiological status and a controlled trial would be quite unethical. The delay in introducing patient segregation and the occurrence of cross infection in some CF centres has provided adequate information that the practice is fully justified!!!

2006 Starner TD, Zhang N, Kim G, Apicella MA, McCray PB Jr. Haemophilus influenzae forms biofilms on airway, epithelia: implications in cystic fibrosis. Am J Resp Crit Care Med 2006; 174:213-220. [PubMed]
Non-typeable Haemophilus influenzae (NTHi) commonly infects patients with CF, especially early in childhood and biofilms were common in bronchoalveolar lavage fluid decreasing susceptibility to antibiotics; also respiratory cells exhibited inflammatory and host defence responses-evidence of a dynamic host-pathogen interaction. There are implications both for understanding early CF lung disease pathogenesis and for the treatment of early, asymptomatic colonization of patients with CF with H. influenzae.

H. influenzae at times persists in serial respiratory cultures despite antibiotic treatment or soon reappears after such treatment. It is undoubtedly a pathogen for people with CF who become chronically infected. This warrants vigorous attempts to eradicate the organism, if necessary by intravenous antibiotics if oral treatment fails – an approach analogous to the treatment of early P. aeruginosa. Many CF units would now treat and attempt to eradicate any pathogen grown from the CF airways whether or not there were symptoms which are a very crude indicator of endobronchial infection.

2006 Wood DM, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database of Systematic Reviews. (1):CD004197, 2006. [PubMed]
This search identified 15 trials on the subject but the reviewers considered only 3 trials, involving 69 participants, were eligible for inclusion. The reviewers considered that there was evidence from two randomised controlled trials, of “questionable methodological quality”, that treatment of early P. aeruginosa infection with inhaled tobramycin resulted in microbiological eradication of the organism from respiratory secretions more often than placebo and that this effect may persist for up to 12 months, however incomplete data from one of the trials precluded an accurate analysis.
One randomised controlled trial of oral ciprofloxacin and nebulised colistin versus usual treatment was identified (Valerius et al, 1991 above) but the reviewers considered this trial was of “poor methodological quality”. The results suggested treatment of early infection results in microbiological eradication of P. aeruginosa more often than “usual” treatment, after two years. The reviewers considered that there was insufficient evidence to determine whether antibiotic strategies for the eradication of early P. aeruginosa decrease mortality or morbidity, improve quality of life, or are associated with adverse effects compared to placebo or standard treatment. From the three trials included in this review, there was 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.

The conclusions of this Cochrane review were quite out of keeping with the clinical experience of most CF clinicians and the study was soundly criticised by Prof. Neils Hoiby who regarded further trials as unwarranted. The opinion of an experienced and respected clinician such as the late Christian Koch was representative of current opinion (quoted in entry on Valerius et al, 1991 above). There was by this time of this review (2006) a wealth of evidence that avoidance of chronic P. aeruginosa infection improved clinical condition and increased survival, evidence that the reviewers did not consider (Kerem et al, 1990; Henry et al, 1992; Hudson et al, 1993; Pamucku et al, 1995 above; Frederiksen et al, 1996; CF Foundation Patient Registry 1996; Frederiksen et al, 1997 above; Kosorok et al, 2001). Presumably this evidence was ignored as it did not directly concern eradication of P. aeruginosa.
It is important to stress that eradication of early P. aeruginosa infection, to prevent or delay chronic infection, is one of the most important aspects of therapy and acquisition of chronic infection should now be regarded as avoidable and represent a failure of therapy (Drittanti et al, 1996 above).

2006 Onega Hansen C. Pressler T. Høiby N. Gorse M. Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study. J Cyst Fibros 2006; 5:245-251. [PubMed]
In cystic fibrosis (CF), chronic infection of the airways with Achromobacter xylosoxidans have become more frequent. The pathogenic role of this is yet unclear. METHODS: A retrospective case-control study of all patients chronically infected with A. xylosoxidans for at least 3 years. 15 patients (6 males) with chronic A. xylosoxidans infection were matched by age, FEV(1) and body mass index z-score to 15 controls (7 males) at the time of establishment of chronic infection. Eight patients harboured a common A. xylosoxidans strain, indicating either cross-infection or a common source. CONCLUSION: A. xylosoxidans may lead to a decline in lung function in a subgroup of chronically infected CF patients characterised by a rapid increase in specific precipitating antibodies. Cross-infection may possibly occur.

A useful review from the Copenhagen CF Centre of a relatively new problem in people with CF.

2006 Proesmans M. Brainstems W. Dupont L. Bossuyt X. Verhaeghe J. Hoiby N. de Boeck K. Evaluating the "Leeds criteria" for Pseudomonas aeruginosa infection in a cystic fibrosis centre. Eur Respir J 2006; 27:937-943. [PubMed]
Four separate categories of chronic Pseudomonas aeruginosa (Pa) infection in children with cystic fibrosis (CF) have been previously defined, based on airway cultures taken over the previous year. The aim of the present study was to evaluate this definition in the current authors' paediatric and adult CF clinic using clinical, immunological and lung function parameters. During follow-up, out of 193 patients, 55 (34%) CF patients had never been infected with Pa, 27 (17%) were free of Pa, 29 (18%) were intermittently infected and 51 (31%) were chronically infected. Disease severity markers, such as lung function, were significantly worse in the chronic group, especially in the paediatric population. Differences in adult patients were smaller and no longer significant. Pa antibodies differed strongly between the groups, and were very high (mean+/-sd 55.4+/-5.5) and highly statistically significant from all other groups in the chronic group. They were low and different from all other groups in the never group (1.8+/-0.6). Pa antibodies did not differ between the free of Pa and the intermittent group. In conclusion, the current authors confirmed an agreement between Pseudomonas aeruginosa status according to the new definition and clinical status, as well as with the level of Pseudomonas aeruginosa antibodies.

Although these authors agreed with the Leeds criteria for evaluating pseudomonas infection, there was still considerable differences in the criteria used for chronic PA infection.

2006 Kappler M. Kraxner A. Reinhardt D. Ganster B. Griese M. Lang T. Diagnostic and prognostic value of serum antibodies against Pseudomonas aeruginosa in cystic fibrosis. Thorax 2006; 61:684-688. [PubMed]
A representative cross sectional analysis of serum antibodies against three Pseudomonas antigens (alkaline protease, elastase, and exotoxin A) was performed in 183 patients with CF of mean age 16.7 years and FEV1 85.9% predicted. The results were correlated with microbiological results from the previous 2 years to calculate sensitivity, specificity, positive and negative predictive values. The following 2 years were assessed to determine prognostic predictive values. The authors concluded regular determination of serum antibodies may be useful in CF patients with negative or intermittent but not with positive P aeruginosa status. A rise in antibody titres indicates probable infection and eradication treatment may be initiated even in the absence of microbiological detection of P aeruginosa.

The papers evaluating the use of Pseudomonas antibodies in CF have appeared regularly since the Seventies when Neils Hoiby showed by crossed immunoelectrophoresisi that a rising antibody was a bad sign (Hoiby N, Axelsen NH. Identification and quantitation of precipitins against Pseudomonas aeruginosa in patients with cystic fibrosis by means of crossed immunoelectrophoresis with intermediate gel. Acta Path Microbiol Scand 1973; 81:298-308). [PubMed] In Leeds, influenced by Hoiby's work, we evaluated their use in the mid Eighties (Brett MM, Ghoneim ATM, Littlewood JM. Serum antibodies to Pseudomonas aeruginosa in cystic fibrosis. Arch Dis Child 1986; 61:1114-1120. [PubMed] ) in series of studies by Moira Brett and found them to be very useful. Basically absence of antibodies was reassuring that Pseudomonas was not present and a rising titre in chronically infected patients indicated the need for more aggressive treatment.

2007 Nilsson E, Kollberg H, Johannesson M, Wejaker PE, Carlander D, Larsson A. More than 10 years' continuous oral treatment with specific immunoglobulin Y for the prevention of Pseudomonas aeruginosa infections: a case report. J Med Food 2007; 10:375-378. [PubMed]
Hans Kollberg’s group in Sweden have used orally administered immunoglobulin Y (IgY) preparations for 10 years (Kollberg et al, 2003 above) and the patients treated with IgY had only 2.5 P. aeruginosa-positive sputum cultures per 100 months, and none became chronically infected. In the control group, 13.7 of the cultures per 100 months were positive for PA and 24% of patients became chronically infected.
Despite these findings the treatment is not used elsewhere although eventually the product was recognised with Orphan Medicinal Product Designation by the EMeA in 2008 (see Kollberg H. Pediatr Pulmonol 2008; 43:982). A multicentre clinical trial is proposed for 2010.

2007 Barth AL, de Abreu E Silva FA, Hoffmann A, Vieira MI, Zavascki AP, Ferreira AG, da Cunha LG Jr, Albano RM, de Andrade Marques E. Cystic fibrosis patient with Burkholderia pseudomallei infection acquired in Brazil. Microbiology 2007; 45:4077-80. [PubMed]
Burkholderia pseudomallei are rarely isolated from patients with CF outside known areas of endemicity. These authors report the recovery of B. pseudomallei from the sputum of a cystic fibrosis patient who lives in Brazil and highlight the importance of careful attention to unusual non-fermentative gram-negative rods in cystic fibrosis patients (also Visca et al. 2001 above for Thailand experience).

2007 Bruzzese E, Raia V, Spagnuolo MI, Volpicelli M, De Marco G. Maiuri L, Guarino A. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis. Clinical Nutrition 2007; 26:322-328. [PubMed]
Nineteen children with CF received the probiotic Lactobacillus GG (LGG) for 6 months and then changed to a placebo of oral rehydration solution (ORS) for 6 months; in parallel nineteen received ORS and then changed to LGG. Patients treated with LGG showed a reduction of pulmonary exacerbations (Median 1 vs. 2) and of hospital admissions (Median 0 vs. 1, range 3 vs. 2,). LGG resulted in a greater increase in FEV1 (3.6% +/- 5.2 vs. 0.9% +/- 5; p=0.02) and body weight (1.5 kg +/- 1.8 vs. 0.7 kg +/- 1.8; p=0.02). The authors concluded that Lactobacillus GG reduces pulmonary exacerbations and hospital admissions in patients with CF, that probiotics may delay respiratory impairment and that a relationship exists between intestinal and pulmonary inflammation.

There is an increasing interest on the part of patients, parents and doctors in the role probiotics in treating people with CF (Borowitz D et al, J Pediatr Gastroenterol Nutr 2005; 41:273-285. [PubMed]); however, as yet, few CF clinics advise their routine use, perhaps because the evidence of their value is still sparse; but also there are so many other components to treatment that there is reluctance to add yet another medicine to gain a marginal benefit.

2007 Doring G. Meisner C. Stern M. for the Flagella Vaccine Trial Study Group. A double-blind randomized placebo-controlled phase III study of a Pseudomonas aeruginosa flagella vaccine in cystic fibrosis patients. Proceedings of the National Academy of Sciences of the United States of America. 104(26):11020-5, 2007 Jun 26. [PubMed]
In a double-blind, placebo-controlled, multicenter trial, 483 European patients, 2-18 years of age without P. aeruginosa colonization were randomly assigned to receive four intramuscular injections of a bivalent P. aeruginosa flagella vaccine or placebo over a 14-month period. Patients were evaluated quarterly for P. aeruginosa-positive throat cultures and antipseudomonal serum antibody titers during the study period of 2 years. The vaccine was well tolerated, and the patients developed high and long-lasting serum antiflagella IgG titers. In the intention-to-treat group (all patients enrolled), 82 of 239 vaccinated patients had P. aeruginosa infection and/or antipseudomonal serum titers compared with 105 of 244 patients in the placebo group (P = 0.05; relative risk: 0.80; 95% CI: 0.64-1.00). Analysis of the 381 patients in the per-protocol group, who received all four vaccinations or placebo treatments, revealed 37 of 189 patients with infection episodes in the vaccine group compared with 59 of 192 patients with such episodes in the placebo group (P = 0.02; relative risk: 0.66; 95% CI: 0.46-0.93). P. aeruginosa strains, exhibiting flagella subtypes included in the vaccine, were significantly less frequently isolated from vaccinates than from placebo controls (P = 0.016, relative risk: 0.319; 95% CI: 0.12-0.86). Chronic P. aeruginosa infection was rare because of recent institution of early antibiotic eradication regimes. Active immunization of patients with cystic fibrosis lowers the risk for infection with P. aeruginosa and therefore may contribute to a longer survival of these patients.

As in a similar trial of vaccine to protect against Pseudomonas (Aerugen) the chance of showing a convincing result was reduced the widespread use of early eradication regimens resulting in a falling prevalence of chronic Pseudomonas infection.

2007 Hilliard TN, Sukhani S, Francis J, Madden N, Rosenthal M Balfour-Lynn I, Bush A, Davies JC. Bronchoscopy following diagnosis with cystic fibrosis. Arch Dis Child 2007; 92:898-899. [PubMed]
The authors recently changed their practice and performed bronchoscopy following a diagnosis of cystic fibrosis. On a retrospective review of 25 children, Pseudomonas aeruginosa was detected in bronchoalveolar lavage for the first time in five children (20%) and Staphylococcus aureus in four (16%). Lavage culture was positive in eight of the 18 children without respiratory symptoms. The authors suggest that these findings highlight the potential of bronchoscopy following diagnosis, even in asymptomatic children.

Whether to recommend bronchoscopy in an asymptomatic screened infant with CF is dependent on many factors, not least, where the infant was born and the facilities and skill available for paediatric respiratory investigation. Also, the treatment policy of the unit responsible for the care of the infants. Also there is the potential danger of infecting an, as yet uninfected, infant with the instrument if sterilisation has been faulty; also hospitalisation does present a definite infection risk to infants with CF. If the infants were started on prophylactic flucloxacillin from diagnosis (as is recommended by the UK CF Trust's expert Antibiotic Group 2009), it is very unlikely that S. aureus would have been cultured. Also units where screening has been routine for many years, such as Leeds, have managed to achieve very low levels of chronic Pseudomonas infection using only frequent throat cultures, cough swabs and serum antibody levels to recognise and treat early P. aeruginosa infection. If an infant with CF had repeatedly negative upper respiratory tract cultures and negative Pseudomonas antibody levels it would be very unlikely there would be positive bronchial cultures. So “bronchoscopy for all at diagnosis, although it may be decided is desirable, is definitely a policy that needs careful discussion before being applied generally.

The recent multicentre study completed in 2009 comparing regular bronchoscopy with routine care led by Claire Wainwright of Brisbane does not show a significant advantage for those who have regular bronchoscopies.

2007 Kennedy MP, Coakley RD, Donaldson SH, Aris RM, Hohneker K, Wedd JP, Knowles MR, Gilligan PH, Yankaskas JR. Burkholderia gladioli: five year experience in a cystic fibrosis and lung transplantation center. J Cyst Fibros 2007; 6:267-273. [PubMed]
The impact of infection with Burkholderia gladioli in CF is unknown. Thirty-five patients were culture positive for B. gladioli, including 33 CF patients. Two-thirds of these isolates were susceptible to usual anti-Pseudomonal antibiotics. After acquisition, only 40% of the CF patients became chronically infected; chronic infection was associated with resistance to antibiotics on initial culture and failure of eradication after antibiotic therapy. The impact of acquisition of B. gladioli infection in chronic infection was variable. Three CF patients with chronic infection underwent lung transplantation. One post-transplant patient developed a B. gladioli mediastinal abscess, which was treated successfully. The authors concluded that the majority of patients who culture positive for B. gladioli have CF. B. gladioli infection is often transient and is compatible with satisfactory post-lung transplantation outcomes.

Unfamiliar organisms are periodically isolated from people with CF and reports of experience such as this are helpful in defining their importance for the clinician encountering the infection for the first time.

2007 Fridge JL. Conrad C. Gerson L. Castillo RO. Cox K. Risk factors for small bowel bacterial overgrowth in cystic fibrosis. J Pediatr Gastroenterol Nutr 2007; 44:212-218. [PubMed]
Fifty patients, 25 pancreatic-insufficient CF study patients (mean age, 17 y) and 25 gastrointestinal clinic control patients (mean age, 15 y), completed a glucose-hydrogen breath test after an overnight fast. A positive breath test was defined as a fasting hydrogen > or =15 ppm or a rise of > or =10 ppm hydrogen over baseline during the test. The prevalence of positive breath tests was higher in the CF study group (56%) than in the control group (20%) (P = 0.02). The mean fasting hydrogen levels of patients in the study and control groups were 22 and 5 ppm (P = 0.0001). The mean QOL questionnaire scores were not significantly different between breath test-positive and -negative study patients. The use of azithromycin was associated with an increased risk of a positive breath test. Use of laxatives and inhaled ipratropium was associated with a decreased risk of a positive breath test.

This study confirmed that patients with CF were more likely to have elevated fasting hydrogen levels compared with controls. This suggests a high prevalence of small bowel bacterial overgrowth in CF patients. Also medications commonly used by CF patients may influence intestinal health

2007 De Baets F, Schelstraete P, Van Daele S, Haerynck F, Vaneechoutte M. Achromobacter xylosoxidans in cystic fibrosis: prevalence and clinical relevance. J Cyst Fibros 2007; 6:75-78. [PubMed]
One of the many new pathogens encountered in people with CF. Although there was more need for intravenous antibiotic treatment courses, no faster decline in lung function was observed in A. xylosoxidans positive patients. (Hansen CR, et al. 2006 above from Copenhagen – there were similar findings but more treatment was required particularly in those patients with rising antibodies).

Ratjen F. Walter H. Haug M. Meisner C. Grasemann H. Doring G. Diagnostic value of serum antibodies in early Pseudomonas aeruginosa infection in cystic fibrosis patients. Pediatr Pulmonol 2007; 42:249-255. [PubMed].
Specific serum antibodies could be helpful in defining the status of Pseudomonas aeruginosa infection as well as the response to early intervention treatment in patients with cystic fibrosis (CF). We used 1,791 serum samples from 375 European CF patients with known respiratory microbiology status to define titers of P. aeruginosa antibodies directed against alkaline protease (AP), elastase (ELA), and exotoxin A (ExoA). Pseudomonas antibody titers were also measured in a separate cohort of 56 patients undergoing antibiotic treatment for eradication of P. aeruginosa. At a specificity of 97.5%, the sensitivity was highest for antibodies against AP (85.4%), followed by ELA (76.2%) and ExoA (72.0%). AP, ELA, or ExoA antibody titers were significantly higher (P < 0.001) in patients chronically infected with P. aeruginosa compared to patients with negative cultures. The sensitivity of the combined three ELISAs was higher than that for any single ELISA alone. Based on the newly defined cut-off levels, positive serum antibody titers against at least one of the three antigens were present in 43% of patients with new onset of P. aeruginosa infection. Longitudinal assessment of antibody titers assessed before and after inhaled antibiotic therapy in patients with first P. aeruginosa isolation showed a significant decrease in antibody titers against AP and ExoA in patients clearing P. aeruginosa infection, whereas titers increased in patients in whom antibiotic therapy failed to eradicate the organism. Antibody testing against AP, ELA, and ExoA offers high sensitivity and specificity for the presence of P. aeruginosa in respiratory cultures of CF patients. Although serum antibody titers are on average low at the time of first P. aeruginosa isolation from respiratory specimens, they may be useful to monitor response to therapy. However, because variability between patients is considerable, treatment decisions should not be based on P. aeruginosa antibody levels alone.

Many centres such as Copenhagen and Leeds have been using Pseudomonas antibodies for over 20 years and finding them a very useful, indeed an essential aid, in patient management. The main value in paediatric clinics where most children with CF are not chronically infected by P. aeruginosa they are used as a periodic reassurance that they are not infected by P. aeruginosa. Should they be antibody positive, in the presence of a negative respiratory cultures, a search is made for the organism including by bronchial lavage. In patients who are chronically infected with P. aeruginosa a rising titre is an indication for more agressive antibiotic treatment. So we would not agree that treatment decisions should not be based on the results of antibody levels.

2008 Mahenthiralingam E. Baldwin A. Dowson CG. Burkholderia cepacia complex bacteria: opportunistic pathogens with important natural biology. J Appl Microbiol 2008; 104:1539-1551. [PubMed]
Interaction with plants around their roots and foliage forms the natural habitat for a wide range of gram-negative bacteria such as Burkholderia, Pseudomonas and Ralstonia. During these interactions many of these bacteria facilitate highly beneficial processes such as the breakdown of pollutants or enhancement of crop growth. All these bacterial species are also capable of causing opportunistic infections in vulnerable individuals, especially people with cystic fibrosis (CF). Here we will review the current understanding of the Burkholderia cepacia complex (Bcc) as a group of model opportunistic pathogens, contrasting their clinical epidemiology with their ecological importance. Currently, the B. cepacia complex is composed of nine formally named species groups which are all difficult to identify using phenotypic methods. Genetic methods such as 16S rRNA and recA gene sequence analysis have proven useful for Bcc species identification. Multilocus sequence typing (MLST) is also emerging as a very useful tool for both Bcc strain and species identification. Historically, Burkholderia cenocepacia was the most dominant Bcc pathogen in CF, however, probably as a result of strict infection control practices introduced to control the spread of this species, its prevalence has been reduced. Burkholderia multivorans is the now the most dominant Bcc infection encountered in the UK CF population, a changing epidemiology that also appears to be occurring in the US CF population. The distribution of Bcc species residing in the natural environment may vary considerably with the type of environment examined. Clonally identical Bcc strains have been found to occur in the natural environment and cause infection. The contamination of medical devices, disinfectants and pharmaceutical formulations has also been directly linked to several outbreaks of infection. In the last 10 years considerable progress has been made in understanding the natural biology and clinical infections caused by this fascinating group of bacteria.

An up to date clear review of the B. cepacia complex by Esch Malhenthiralingam of Cardiff, an expert on the subject of BC complex. The summary is reproduced in full.

2008 Nilsson E, Larsson A, Olesen HV, Wejaker PE. Kollberg H. Good effect of IgY against Pseudomonas aeruginosa infections in cystic fibrosis patients. Pediatr Pulmonol 2008; 43:892-899. [PubMed]
This is the most recent instalment of an extended open study of oral prophylactic treatment with egg yolk antibodies against Pseudomonas aeruginosa (anti-Pseudomonas IgY) of 17 Swedish patients with CF. They have been on prophylactic IgY treatment for up to 12 years and altogether for the equivalent of 114 patient years. A group of 23 Danish CF patients served as controls. There has been a total absence of adverse events. Only 29 cultures have been positive for P. aeruginosa (cultures after chronic colonization not included), that is, 2.3/100 treatment months compared to 7.0/100 months in the control group (P = 0.028). In the IgY treated group only one pair of siblings (2/17) has been chronically colonized with P. aeruginosa compared to seven patients (7/23) in the control group. Atypical mycobacteria, S. maltophilia, A. xylosoxidans, and A. fumigatus have appeared only sporadically. There have been no cultures positive for B. cepacia. There was no decrease in pulmonary functions within the IgY group. Body mass index values were normal or close to normal for all IgY treated patients. In conclusion, Anti-Pseudomonas IgY has great potential to prevent P. aeruginosa infections.

Hans Kollberg has relentlessly pursued the value of gargling with Anti-Pseudomonas IgY as a preventive treatment against Pseudomonas and the progress is recorded in a number of publications (Carlander D et al. Immunol Res 2000; 21:1-6. [PubMed] Carlander D et al, Biodrugs 2002; 16:433-437.;[PubMed] Kollberg H et al, 2003 above; Nilsson et al, 2007 above). However, it must be observed that the numbers are small and the cruel lesson of the anti-Pseudomonas Aerugen vaccine trial come to mind where an initial small study showed definite benefit but a large multicentre trail was quite negative.

2008 Mohan K. Fothergill JL. Storrar J. Ledson MJ. Winstanley C. Walshaw MJ. Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat. Thorax 2008; 63:839-840. [PubMed]
Chronic infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown. The first report of interspecies transmission of the LES strain of P. aeruginosa from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.

2008 Ullrich G, Wiedau S, Schulz W, Steinkamp G. Parental knowledge and behaviour to prevent environmental P. aeruginosa acquisition in their children with CF. J Cyst Fibros 2008; 7:231-237. [PubMed]
Most parents displayed erroneous beliefs regarding P. aeruginosa (PA) infection. Families performed a mean of 11 different hygienic measures, e.g. they prevented their child from being the first person to use the bathroom in the morning (72%) or from bathing in gravel pits and standing water (52%). The majority of parents felt markedly (44%) or somewhat (44%) stressed that their child might acquire PA, and many parents felt markedly (16%) or somewhat (43%) restricted and stressed by the hygienic measures. Less stressed parents tended to have more knowledge and undertook fewer measures.
The authors suggest that when informing and teaching parents on the nature of PA infection, caregivers should provide clear recommendations on reasonable actions to be taken. Also, physicians should anticipate and adequately respond to parental fears and misconceptions.

It is understandable that parents seek to prevent their children being exposed unnecessarily to P. aeruginosa which is unfortunately ubiquitous in the environment. Striking a balance between a normal life style and over caution is very difficult for the parents as most of the avoidance recommendation have not been put to any form of trial. However, it seems sensible to reduce exposure to environments which are known to harbour P. aeruginosa. They can be reassured that, provided regular cultures are performed, an early infection with P. aeruginosa can be eradicated by appropriate antibiotic treatment so the early infection is not as potentially disastrous occurrence it was in years gone by.

An article on the CF Trust website (www.cftrust.org.uk) reviews the likely sources of P. aeruginosa in the environment - "The environment as a source of Pseudomonas aeruginosa and some other potential pathogens".” Sept. 2007 by Jim Littlewood with expert advice from Dr Miles Denton.

2008 Jacobs JL, Fasi AC, Ramette A, Smith JJ, Hammerschmidt R, Sundin GW. Identification and onion pathogenicity of Burkholderia cepacia complex isolates from the onion rhizosphere and onion field soil. Appl & Environ Microbiol 2008; 74:3121-3129. [PubMed]
Genotypic identification and pathogenicity characterization were performed on B. cepacia complex isolates from the rhizosphere of onion and organic soils in Michigan. A total of 1,290 isolates, 980 rhizosphere and 310 soil isolates, were assigned to the species B. cepacia (160), B. cenocepacia (480), B. ambifaria (623), and B. pyrrocinia (27). The majority of isolates identified as B. cepacia (85%), B. cenocepacia (90%), and B. ambifaria (76%) were pathogenic in a detached onion bulb scale assay and caused symptoms of water soaking, maceration, and/or necrosis.

This study confirmed that multiple B. cepacia complex species colonize the onion rhizosphere and have the potential to cause sour skin rot disease of the onion. In addition, the onion rhizosphere is a natural habitat and a potential environmental source of B. cenocepacia. Following the introduction of segregation of patients growing B. cepacia most new infections were with such environmentally acquired organisms.

2008 Johansen HK. Moskowitz SM. Ciofu O. Pressler T. Høiby N. Spread of colistin resistant non-mucoid Pseudomonas aeruginosa among chronically infected Danish cystic fibrosis patients. J Cyst Fibros 2008; 7:391-397.[PubMed]
Colistin resistant Pseudomonas aeruginosa have rarely been reported in cystic fibrosis (CF) patients. We performed a 17-year prospective study on colistin susceptibility and compared our findings with clinical variables. The first outbreak started in 1995 and lasted 5 years. It involved 27 CF patients who had inhaled colistin twice daily for a median of 10 years. Colistin resistant isolates persisted in individual patients for a median of 75 days after colistin was withdrawn. A second outbreak started in 2004. It involved 40 patients, 17 of whom were the same as in the first outbreak. Most resistant isolates belonged to two major clones that had similar genotypes in the two outbreaks. The P. aeruginosa isolates were all non-mucoid and they appeared in a group of chronically infected patients that had been admitted to the same ward for antibiotic treatment and had been followed at the same week-days in the outpatient clinic. Patients were individually isolated to avoid cross-infection and colistin inhalation was avoided in the CF outpatient clinic and in the ward after both outbreaks. Since 2004, no further spread has been observed. it is important that the colistin resistant clones do not spread to non-infected patients since colistin is an important antibiotic for eradication of initial and intermittent P. aeruginosa colonisation.

Infrequent resistance even with widespread use of colistin in the Danish CF centre

2008 Barker HC. Haworth CS. Williams D. Roberts P. Bilton D. Clostridium difficile pancolitis in adults with cystic fibrosis. J Cyst Fibro 2008; 7:444-447. [PubMed]
three cases of Clostridium difficile pancolitis in adults with cystic fibrosis (CF) in whom the presenting symptoms were atypical. All three required treatment with systemic steroids, in addition to oral vancomycin and metronidazole to achieve resolution of the colitis. This experience suggests that C. difficile colitis should be considered in individuals with CF presenting with non-specific abdominal symptoms.

There have been sporadic reports of C difficile infection in people with CF. Some have been in patients who have had lung transplants. Also asymptomatic carriage seems to be relatively common in CF. In a minority the infection leads to serious clinical illness as in the cases reported here.

2008 Tunney MM, Field TR, Moriarty TF, Patrick S, Doering G, Muhlebach MS, Wolfgang MC, Boucher R, Gilpin DF, McDowell A, Elborn JS. Detection of anaerobic bacteria in high numbers in sputum from patients with cystic fibrosis. Am J Resp Crit Care 2008; 177:995-1001. [PubMed]
Anaerobic species were isolated 64% of sputum samples from adult patients with CF. Similar anaerobic species were identified in bronchiolar lavage fluid from pediatric patients with CF. Although anaerobes were detected in induced sputum samples from 16 of 20 volunteers, they were present in much lower numbers and were generally different species compared with those detected in CF sputum. All isolates were susceptible to meropenem.
So a range of anaerobic species are present in large numbers in the lungs of patients with CF. If these anaerobic bacteria are contributing significantly to infection and inflammation in the CF lung, informed alterations to antibiotic treatment to target anaerobes, in addition to the primary infecting pathogens, may improve management.

Over the years there have been sporadic reports of anaerobes in the sputum of people with CF (Jeeves & Spencer. J Med Microbiol 1990; 31:271-274. [PubMed]
). As yet there is no definite information as to their importance. Their presence in induced sputum specimens of 16 of 20 volunteers is rather confusing even though their numbers were less than in the CF patients.

2008 Hayes D Jr, Kanga JF, Anstead MI, Kuhn RJ. Novel approach to the eradication of Pseudomonas aeruginosa in an infant with CF after outpatient treatment failure. Pediatr Pulmonol 2008; 43:511-513. [PubMed]
Intravenous continuous infusion of betalactam (CIBL) antibiotic and high dose extended interval (HDEI) aminoglycoside therapy theoretically maximize bacterial killing in treatment of Pseudomonas aeruginosa in pulmonary exacerbations of cystic fibrosis (CF). A 3-month-old female infant with CF failed outpatient eradication of Pseudomonas with subsequent eradication using intravenous CIBL antibiotic and HDEI aminoglycoside therapy. This antibiotic combination should be considered in order to optimize pharmacodynamics for Pseudomonas eradication in CF patients before development of chronic colonization

An important case report from Kentucky of an aggressive and successful eradication of P. aeruginosa – not accepting failure. The use of continuous IV beta lactam (eventually aztreonam here) and intermittent high dose IV tobramycin would be worth further investigation. The fact that failed eradication is receiving attention from a centre in the USA is encouraging and indicates a new approach. It is important to leave no stone unturned when attempting to eradicate P. aeruginosa; this often involves giving intravenous antibiotics to small children with CF who do not appear unwell. In these circumstances it would seem sensible to use the antibiotics in the optimal way as in this report.

2008 Zhou J, Garber E, Saiman L. Survey of infection control policies for patients with cystic fibrosis in the United States. Am J Infect Contr 2008; 36:220-222. [PubMed]
Written infection control policies used at CF care sites in the United States were compared with recently published guidelines (Saiman et al, 2003). Most policies recommended contact precautions for hospitalized patients infected with Burkholderia cepacia complex (73%), multidrug-resistant organisms (63%), and methicillin-resistant Staphylococcus aureus (64%). Socializing among CF patients was discouraged in 80% of inpatient policies and 55% of outpatient policies. Although routine mask use by patients remains an unresolved issue, many policies advocated this practice. Future studies should address barriers to implementation of these evidence-based guidelines and continue to monitor implementation.
That contact precautions were only recommended in 73% of centres even with B. cepacia is rather surprising one would have expected 100%. Permitting contact between people with B. cepacia in a CF centre would raise serious issues in the UK.

2008 Brimicombe RW, Dijkshoorn L, van der Reijden TJ, Kardoes I, Pitt TL, van den Broek PJ, Heijerman HG. Transmission of Pseudomonas aeruginosa in children with cystic fibrosis attending summer camps in The Netherlands. J Cyst Fibros 2008; 7:30-36. [PubMed]
This study aimed to establish the degree of transmission resulting in subsequent infection of P. aeruginosa among 80 children with CF attending holiday camps in The Netherlands. The study was performed in the summer of 2001 in four camps organised simultaneously at different locations. Sputum was collected on day 1 of the holiday, and three and six months later. Different morphotypes of P. aeruginosa from sputum were genotyped by AFLP analysis. Criteria were defined for the degree of evidence of transmission. There were 18 cases of “possible”, 2 cases of “probable” transmission and 1 case of “highly probable” transmission. Two predominant types of P. aeruginosa were found (types 18 and 23). Type 18 was already prevalent on day 1 mostly in younger children and was involved in eleven cases of transmission; type 23 was involved in six cases of transmission among older children.

There was a considerable risk of transmission of P. aeruginosa during these holiday camps for children with CF in The Netherlands. Two genotypes of P. aeruginosa appeared to be easily transmissible, one of which seemed common in the Dutch CF population. Previous work from the Netherlands had shown little evidence of cross infection at camps and at the time the professionals involved considered the benefits of the holidays outweighed the risks of infection. For example in 1995 Hoogkamp-Korstanje et al (J Clin Microbiol 1995; 33:572-575. 7751359) considered that “the risk was comparable with that observed in the community. We conclude that the risk of cross infection is trivial compared with the obvious joy and social benefit derived from a holiday camp”. It is interesting how many years elapsed before these findings were published – holiday in 2001 and publication in 2008. A similar long interval occurred in the paper from Copenhagen (Ojeniyi et al, 2000. [PubMed] when the study in 1990 was reported in 2000. [PubMed]

2008 Wainwright CE, Grimwood K, Carlin JB, Vidmar S, Cooper PJ, Francis PW, Byrnes CA, Whitehead BF, Martin AJ, Robertson IF, Cooper DM, Dakin CJ, Masters IB, Massie RJ, Robinson PJ, Ranganathan S, Armstrong DS, Patterson LK, Robertson CF. Safety of bronchoalveolar lavage in young children with cystic fibrosis. Pediatr Pulmonol 2008; 43:965-972.[PubMed]
As part of Dr Claire Wainwright’s study of bronchoalveolar lavage (BAL) directed therapy, 333 BALs were carried out on 107 children median age 23.5 months (1.6 – 67.5 months); 170 (51%) were for exacerbations. 8.7% were followed by fever and 3% clinically significant episodes. 52% had minor adverse events.
The authors concluded that although adverse events were common they were usually transient and well tolerated. Parents should be warned that infants with respiratory infections had an increased risk of post-BAL fever.

This is an important ongoing study further progress of which was reported by Claire Wainwright at the 2009 NACFC in Minneapolis. The study concluded in 2009 and did not establish a case of managing the respiratory infections using regular bronchoscopies but did provide a vast amount of useful information - undoubtedly one of the studies of the decade!

2009 Ratjen F, Munck A, Kho P, Angyalosi G. Treatment of early Pseudomonas aeruginosa infection in patients with cystic fibrosis: the ELITE trial. Thorax. 2009 Dec 8. [PubMed]
The EarLy Inhaled Tobramycin for Eradication (ELITE) study was designed to assess the efficacy and safety of two regimens (28 and 56 days) of tobramycin inhalation solution (TIS) 300 mg/5 mL (TOBI(R)) twice daily for the treatment of early onset P. aeruginosa infection in CF patients. Children aged 6 months and over with early P. aeruginosa infection were treated for 28 days with TIS twice daily after which they were randomised to either stop or to receive a further 28 days treatment. The primary endpoint was the median time to recurrence of P. aeruginosa (any strain). Secondary endpoints included the proportion of patients free of P. aeruginosa infection one month after cessation of therapy and safety assessments.
The median time to recurrence of P. aeruginosa (any strain) was similar between the two groups. In total, 93% and 92% of the patients were free of P. aeruginosa infection one month after the end of treatment and 66% and 69% remained free after 27 months in the 28-day and 56-day groups, respectively. So treatment with inhaled tobramycin 28 days was an effective and well tolerated therapy for early P. aeruginosa infection in CF patients.

2009 Wainwright CE. France MW. O'Rourke P. Anuj S. Kidd TJ. Nissen MD. Sloots TP. Coulter C. Ristovski Z. Hargreaves M. Rose BR. Harbour C. Bell SC. Fennelly KP. Cough-generated aerosols of Pseudomonas aeruginosa and other Gram-negative bacteria from patients with cystic fibrosis. Thorax. 2009; 64:926-931. [PubMed]
P. aeruginosa was isolated in cough aerosols of 25 subjects (89%), 22 of whom produced sputum samples. P. aeruginosa from sputum and paired cough aerosols were indistinguishable by molecular typing. In four cases the same genotype was isolated from ambient room air. Approximately 70% of viable aerosols collected during voluntary coughing were of particles <or=3.3 microm aerodynamic diameter. P aeruginosa, Burkholderia cenocepacia, Stenotrophomonas maltophilia and Achromobacter xylosoxidans were cultivated from respiratory particles in this size range. Positive room air samples were associated with high total counts in cough aerosols (p = 0.003). The magnitude of cough aerosols was associated with higher forced expiratory volume in 1 s (r = 0.45, p = 0.02) and higher quantitative sputum culture results (r = 0.58, p = 0.008).

One of a number of recent studies showing that during coughing, patients with CF produce viable aerosols of P aeruginosa and other Gram-negative bacteria of respirable size range, suggesting the potential for airborne transmission.

2009 Albini S. Abril C. Franchini M. Hüssy D. Filioussis G. Stenotrophomonas maltophilia isolated from the airways of animals with chronic respiratory disease. Schweizer Archiv fur Tierheilkunde 2009; 151:323-328. [PubMed]
Stenotrophomonas maltophilia (S. maltophilia) is frequently isolated from humans with cystic fibrosis. Seven strains of S. maltophilia isolated from animals are described, of which 5 strains were harvested from 3 horses, a dog and a cat with chronic respiratory disease. Analysis with pulsed field gel electrophoresis revealed that 2 horses, which were boarded in the same clinic but two years apart, harboured the same strain of S. maltophilia.

In recent years S. maltophilia is more frequently isolated from people with CF and although the organism appears to be ubiquitous it is useful to know that animals are one potential source.

2009 Mena KD. Gerba CP. Risk assessment of Pseudomonas aeruginosa in water. Rev Environ Contam T 2009; 201:71-115. [PubMed]
P. aeruginosa is part of a large group of free-living bacteria that are ubiquitous in the environment. This organism is often found in natural waters such as lakes and rivers in concentrations of 10/100 mL to >1,000/100 mL. However, it is not often found in drinking water. Usually it is found in 2% of samples, or less, and at concentrations up to 2,300 mL(-1) (Allen and Geldreich 1975) or more often at 3-4 CFU/mL. Its occurrence in drinking water is probably related more to its ability to colonize biofilms in plumbing fixtures (i.e., faucets, showerheads, etc.) than its presence in the distribution system or treated drinking water. P. aeruginosa can survive in deionized or distilled water (van der Jooij et al. 1982; Warburton et al. 1994). Hence, it may be found in low nutrient or oligotrophic environments, as well as in high nutrient environments such as in sewage and in the human body. P. aeruginosa can cause a wide range of infections, and is a leading cause of illness in immunocompromised individuals. In particular, it can be a serious pathogen in hospitals (Dembry et al. 1998). It can cause endocarditis, osteomyelitis, pneumonia, urinary tract infections, gastrointestinal infections, and meningitis, and is a leading cause of septicemia. P. aeruginosa is also a major cause of folliculitis and ear infections acquired by exposure to recreational waters containing the bacterium. In addition, it has been recognized as a serious cause of keratitis, especially in patients wearing contact lenses. P. aeruginosa is also a major pathogen in burn and cystic fibrosis (CF) patients and causes a high mortality rate in both populations (MOlina et al. 1991; Pollack 1995). P. aeruginosa is frequently found in whirlpools and hot tubs, sometimes in 94-100% of those tested at concentrations of <1 to 2,400 CFU/mL. The high concentrations found probably result from the relatively high temperatures of whirlpools, which favor the growth of P. aeruginosa, and the aeration which also enhances its growth. The organism is usually found in whirlpools when the chlorine concentrations are low, but it has been isolated even in the presence of 3.00 ppm residual free chlorine (Price and Ahearn 1988). Many outbreaks of folliculitis and ear infections have been reportedly associated with the use of whirlpools and hot tubs that contain P. aeruginosa (Ratnam et al. 1986). Outbreaks have also been reported from exposure to P. aeruginosa in swimming pools and water slides. Although P. aeruginosa has a reputation for being resistant to disinfection, most studies show that it does not exhibit any marked resistance to the disinfectants used to treat drinking water such as chlorine, chloramines, ozone, or iodine. One author, however, did find it to be slightly more resistant to UV disinfection than most other bacteria (Wolfe 1990). Although much has been written about biofilms in the drinking water industry, very little has been reported regarding the role of P. aeruginosa in biofilms. Tap water appears to be a significant route of transmission in hospitals, from colonization of plumbing fixtures. It is still not clear if the colonization results from the water in the distribution system, or personnel use within the hospital. Infections and colonization can be significantly reduced by placement of filters on the water taps. The oral dose of P. aeruginosa required to establish colonization in a healthy subject is high (George et al. 1989a). During dose-response studies, even when subjects (mice or humans) were colonized via ingestion, there was no evidence of disease. P. aeruginosa administered by the aerosol route at levels of 10(7) cells did cause disease symptoms in mice, and was lethal in aerosolized doses of 10(9) cells. Aerosol dose-response studies have not been undertaken with human subjects. Human health risks associated with exposure to P. aeruginosa via drinking water ingestion were estimated using a four-step risk assessment approach. The risk of colonization from ingesting P. aeruginosa in drinking water is low. The risk is slightly higher if the subject is taking an antibiotic resisted by P. aeruginosa. The fact that individuals on ampicillin are more susceptible to Pseudomonas gastrointestinal infection probably results from suppression of normal intestinal flora, which would allow Pseudomonas to colonize. The process of estimating risk was significantly constrained because of the absence of specific (quantitative) occurrence data for Pseudomonas. Sensitivity analysis shows that the greatest source of variability/uncertainty in the risk assessment is from the density distribution in the exposure rather than the dose-response or water consumption distributions. In summary, two routes appear to carry the greatest health risks from contacting water contaminated with P. aeruginosa (1) skin exposure in hot tubs and (2) lung exposure from inhaling aerosols. [References: 189]

This is an excellent extensive review of the likely sources of P. aeruginosa which is highly relevant to the care of people with CF.

2009 Sagel SD. Gibson RL. Emerson J. McNamara S. Burns JL. Wagener JS. Ramsey BW. Inhaled Tobramycin in Young Children Study Group. Cystic Fibrosis Foundation Therapeutics Development Network. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatrics 2009; 54:183-188.[PubMed]
Young children with CF (111) who have upper and lower airway P. aeruginosa infection determined by BAL have increased endobronchial inflammation and poorer clinical status compared with those with only upper airway P aeruginosa infection. The independent and additive effects of S. aureus on inflammation support the significance of polymicrobial infection in early CF lung disease.

These findings are not unexpected. The additive effect of S.aureus should increase the efforts to avoid chronic S. aureus infection in addition to P. aeruginosa.

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