MICROBIOLOGY
A VARIETY OF PAPERS ON MICROBIOLOGICAL SUBJECTS, PSEUDOMONAS AERUGINOSA, STENOTROPHOMONAS MALTOPHILIA, SERUM ANTIBODIES AND PRECIPITINS, CROSS INFECTION, ENVIRONMENTAL HAZARDS, GUT MICROBIOME, BACTERIOPHAGE THERAPY
(B. CEPACIA COMPLEX IS IN A SEPARATE TOPIC)
SOME EARLY PAPERS
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. In fact 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).
– There is an interesting commentary on this paper by Bonnie Ramsey discussing the gradual increase in importance of P. aeruginosa (Ramsey BW. Pediatrics, 1998; 102: 210). Online version of the original can be downloaded http://pediatrics.aappublications.org/content/102/Supplement_1/210
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 1) 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!
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.
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 Niels 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.
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).
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. aureusfell 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 2)
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.
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 519 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. Niels 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.
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 Niels 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. One point in time studies on Pseudomonas antibodies are of limited value.
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 lung 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 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 immunosuppression 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. [PubMed]) 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.
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.
“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. |
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 3). 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 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.[PubMed]; Brett et al, 1987. [PubMed]; Brett et al, 1988 [PubMed]; Brett et al, 1988. [PubMed]; Brett et al, 1990. [PubMed]; Brett et al, 1992.[PubMed]).
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. It was apparent 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 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 antibiotic 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 grow 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 detected!! 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).
Dr Christian Koch in the clinic. |
In 1997 I had the good fortune to interview the late Dr Christian Koch , 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 and difficult to understand 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.
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. [PubMed]; Henry RL et al. Pediatr Pulmonol 1992;12:158-161. [PubMed]; Hudson VL et al. J Pediatr 1993; 122:854-860. [PubMed]; CF Foundation Registry, 1996; Frederiksen B et al. Pediatr Pulmonol 1997;23:330-335. [PubMed]; Kosorok MR et al, Pediatr Pulmonol 2001; 32:277-287. [PubMed]).
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 appeared to be 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 and prolonged.
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).
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.
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. pyloriantigens 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. [PubMed]). 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. aeruginosaisolates 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 and respected 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; 53:609-615. below [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. pseudomalleiinfection 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] )
A paper by Dr Andy Jones, 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 and 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.
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 an 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.
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.
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 unpasteurized bovine milk were positive for this organism. Consumption of raw unpasteurized 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 unpasteurized milk to minimize the risk of becoming infected with this organism.
– Of practical importance as unpasteurized milk is still available.
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). 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).
So 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 Niels 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.
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. Pediatr Pulmonol 2003; 36:439-446. [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. Eur Respir J 2004; 24:449-452. [PubMed]
A clonal strain of Pseudomonas aeruginosa (PA) was isolated in 1999 at the Royal Children’s Hospital, Melbourne, Australia, after five unrelated children with cystic fibrosis (CF) died from severe lung disease aged <5 yrs. Subsequently, more than half of the patients in the clinic with PA were found to harbour this strain, and segregation measures were instituted at the hospital to prevent further spread. The aim of 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]
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).
– 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. aeruginosainfection 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.
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.cysticfibrosis.org.uk)
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 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 years.
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. aeruginosa 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. aeruginosawas 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 prevalence of chronic Pseudomonas infection in clinics (and the opportunity to become infected) 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. Niels 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 Bath AL, de Eyebrow E Silva FA, Hoffmann A, Vireo MI, Zavesca AP, Ferrari AG, Da Cunha LG Jr, Albano RM, de Endeared 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. gladioliinfection 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).
2007 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 aggressive antibiotic treatment. So we would not agree that treatment decisions should not be based on the results of antibody levels.
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 installment 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. A multicentre trial of IgY was underway by 2012 but no publications had appeared by 2018.
(See also New Treatments Topic)
2008 Mahon 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 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 aeruginosain 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 very 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 even 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.[PubMed]) 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 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! Final report in 2011 below [PubMed].
2009 Millar FA, Simmonds NJ, Hodson ME. Trends in pathogens colonising the respiratory tract of adult patients with cystic fibrosis, 1985-2005. J Cyst Fibros 2009; 8:386-391. [PubMed]
A retrospective analysis of sputum microbiology from adult CF patients (1985 to 2005) using the Royal Brompton Hospital CF database. Infection with Pseudomonas aeruginosa or Staphylococcus aureus between 1985 and 2005 remained stable (77 to 82%, p=0.159; 54 to 47%, p=0.108; respectively). Haemophilus influenzae (48 to 6%; p<0.001), Aspergillus species (18 to 9%; p=0.002) and Burkholderia cepacia complex (9 to 4%; p=0.041) prevalence decreased. Stenotrophomonas maltophilia and MRSA increased (1 to 4%, p=0.02; 1 to 6%, p=0.002, respectively). So P. aeruginosa infection remained stable; there has been a decline in B. cepacia complex, H. influenzae and Aspergillus sp., and only a small increase in S. maltophilia and MRSA. Intensive antibiotic strategies have been employed, which, so far, have not resulted in clinically significant emergence of new pathogens.
This is a useful record of the microbiological situation at the Royal Brompton Hospital in London. Interesting that the prevalence of Aspergillus has fallen as some centres have seen a rise in this fungus over recent years.
2009 Razvi S, Quittell L, Sewall A, Quinton H, Marshall B, Saiman L. Respiratory microbiology of patients with cystic fibrosis in the United States, 1995 to 2005. Chest 2009; 136:1554-1560. [PubMed]
Data from the Cystic Fibrosis Foundation Patient Registry were used to examine trends in the incidence and prevalence of bacterial pathogens isolated from patients with CF in the United States from 1995 to 2005. The number of patients with CF in the patient registry increased from 19,735 in 1995 to 23,347 in 2005. During the study period, the reported annual prevalence of Pseudomonas aeruginosa significantly declined from 60.4% in 1995 to 56.1% in 2005 (p < 0.001). The decline was most marked in children 6 to 10 years old (48.2 to 36.1%) and adolescents 11 to 17 years old (68.9 to 55.5%). Both the incidence (21.7% in 1995 and 33.2% in 2005) and prevalence (37.0% in 1995 and 52.4% in 2005) of methicillin-susceptible Staphylococcus aureus significantly increased and the age-specific prevalence was highest in patients 6 to 17 years old. The prevalence of methicillin-resistant S aureus increased from 0.1% in 1995 to 17.2% in 2005 and from 2002 to 2005 was highest in adolescents 11 to 17 years old. Both the prevalence and incidence of Burkholderia cepacia complex declined, while the prevalence of Haemophilus influenzae, Stenotrophomonas maltophilia, and Alcaligenes xylosoxidans increased. Data from the patient registry suggest that the epidemiology of bacterial pathogens in patients with CF changed during the study period.
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; 65:286-291. [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, shower heads, 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 and the abstract is reproduced in full.
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 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]
To assess the effects of Pseudomonas aeruginosa and Staphylococcus aureus infection on lower airway inflammation and clinical status in young children with cystic fibrosis (CF). The authors studied 111 children age < 6 years who had 2 P aeruginosa-positive oropharyngeal cultures within 12 months. They examined bronchoalveolar lavage fluid (BALF) inflammatory markers (ie, cell count, differential, interleukin [IL]-8, IL-6, neutrophil elastase), CF-related bacterial pathogens, exotoxin A serology, and clinical indicators of disease severity.
Young children with CF with both upper and lower airway P aeruginosa infection had higher neutrophil counts, higher IL-8 and free neutrophil elastase levels, increased likelihood of positive exotoxin A titers, and lower Shwachman scores compared with those with positive upper airway cultures only. S aureus was associated with increased lower airway inflammation, and the presence of both P aeruginosa and S aureus had an additive effect on concentrations of lower airway inflammatory markers. BALF markers of inflammation were increased with the number of different bacterial pathogens detected.
The authors concluded that young children with CF who have upper and lower airway P. aeruginosa infection 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.
This study once more emphasises the importance of S. aureus which seems to receive less attention than P. aeruginosa although it is a serious pathogen for people with CF. The study lends some support to the UK recommendation for long term anti-Staphylococcal treatment for the first 3 years.
2010 Weiss B, Bujanover Y, Yahav Y, Vilozni D, Fireman E, Efrati O. Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study. Pediatr Pulmonol 2010; 45:536-540. [PubMed]
Probiotics reduce intestinal inflammation, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. the authors intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients. A prospective pilot study of 10 CF patients with mild-moderate lung disease and Pseudomonas aeruginosa colonization, were treated with probiotics for 6 months. Pulmonary function tests (PFT’s), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study. The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0. 002). PFT’s have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed. The authors concluded that probiotics reduce pulmonary exacerbations rate in patients with CF and may have a preventive potential for pulmonary deterioration in CF patients.
2010 McPherson H, Rosenthal M, Bush A. Can mucoid Pseudomonas aeruginosa be eradicated in children with cystic fibrosis? Pediatr Pulmonol 2010; 45:566-568. [PubMed] Whilst the non-mucoid strain can be eradicated in the early stages, it is believed that mucoid PsA is difficult, if not impossible, to eradicate. Children aged under 16 with a confirmed diagnosis of CF and mucoid PsA on respiratory tract culture during a defined 9-year period were eligible for inclusion. One hundred sixteen children had the minimum dataset, and of these patients 67 (58%) cleared mucoid PsA for more than 1 year. Of the 67 patients who cleared mucoid PsA for more than 1 year, 38 (57%) patients remained clear of mucoid PsA at the last available culture (median 30, range 2-106 clear cultures, and median 55, 12-103 months clear). The authors concluded that isolation of mucoid PsA does not necessarily equate to lifelong infection and suggest that trials of eradication of mucoid PsA at first isolation are required.
Yes is the reassuring answer – mucoid strains of P. aeruginosa can be eliminated and this conforms to experience of smaller numbers of patients.
2010 Weiss B, Bujanover Y, Yahav Y, Vilozni D, Fireman E, Efrati O. Probiotic supplementation affects pulmonary exacerbations in patients with cystic fibrosis: a pilot study. Pediatr Pulmonol 2010; 45:536-540. [PubMed]
Probiotics reduce intestinal inflammation, and Lactobacillus GG (LGG) reduces pulmonary exacerbation rate cystic fibrosis (CF) patients. the authors intended to determine the effect of a mixed probiotic preparation on pulmonary exacerbations and inflammatory characteristics of the sputum in CF patients. A prospective pilot study of 10 CF patients with mild-moderate lung disease and Pseudomonas aeruginosa colonization, were treated with probiotics for 6 months. Pulmonary function tests (PFT’s), sputum cultures with semi-quantitative bacterial analysis, and sputum neutrophil count and interleukin-8 (IL-8) levels were compared to pre-treatment and post-treatment values. The rate of pulmonary exacerbations was compared to 2 years prior to the study. The exacerbation rate was significantly reduced in comparison to the previous 2 years and to 6 months post-treatment (P = 0. 002). PFT’s have not changed at the end of treatment and during 6 months post-treatment. No change in sputum bacteria, neutrophil count, and IL-8 levels was observed.
The authors concluded that probiotics reduce pulmonary exacerbations rate in patients with CF and may have a preventive potential for pulmonary deterioration in CF patients.
2010 Douglas TA, Brennan S, Berry L, Winfield K, Wainwright CE, Grimwood K, Stick SM, Sly PD. Members of AREST CF and ACFBAL Trial. Value of serology in predicting Pseudomonas aeruginosa infection in young children with cystic fibrosis. Thorax 2010; 65:985-990.[PubMed]
A commercial P. aeruginosa multiple antigen (MAg) ELISA and an in-house exotoxin A (ExoA) ELISA were compared in two populations: a discovery population of 76 children (0. 1-7. 1 years) undergoing annual bronchoalveolar lavage (BAL)-based microbiological surveillance and a test population of 55 children (0. 1-5. 6 years) participating in the Australasian CF Bronchoalveolar Lavage Trial. In the discovery population, P. aeruginosa was cultured from BAL fluid (>=10(5) colony-forming units (cfu)/ml) in 15/76 (19. 7%) children (median age 1. 88 years). Positive MAg and ExoA serological results were found in 38 (50. 0%) and 30 (39. 5%) children, respectively. Positive (PPV) and negative (NPV) predictive values for serology at diagnosing P. aeruginosa infection (>=10(5) cfu/ml) were 0. 14 and 0. 99 respectively (MAg assay) and 0. 11 and 0. 98 (ExoA assay). In the test population, P aeruginosa was cultured from BAL fluid (>=10(5) cfu/ml) in 16/55 (29. 1%) children (median age 1. 86 years) and from oropharyngeal swabs in 32/36 (88. 9%). Positive MAg and ExoA serology was detected in 19 (34. 5%) and 33 (60. 0%) children, respectively. The PPV and NPV of serology were 0. 26 and 0. 94 respectively (MAg assay) and 0. 19 and 0. 98 (ExoA assay) and were marginally higher for oropharyngeal cultures. The authors concluded that measuring serum antibody responses against P aeruginosa is of limited value for detecting early P. aeruginosa infection in young children with CF.
This is one of numerous publications over the past 30 years investigating the association of positive serology and the presence of P. aeruginosa in the airways of children with CF. The first publications were to demonstrate that P. aeruginosa was indeed a significant pathogen (Hoiby et al. Acta Paediatr Scand 1974; 63:843-848. [PubMed]). a fact that was questioned by some in the early days. This present Australian study was part of two important Australian research studies on early P. aeruginosa infection. In the experience of these authors the tests were of limited value in detecting early P. aeruginosa and most would agree, and it is to be expected that there can be early colonisation (which by definition does not significantly involve the tissues in contrast to infection which does) of the airways before there is a significant antibody response from the tissues. However, the Leeds CF centre has been using Pseudomonas antibody results since 1986, when they were developed there by Dr Moira Brett. They find the presence of positive antibody tests an added indication for vigorous antibiotic treatment; also a persisting negative result is reassurance that chronic PA infection is not present. Sometimes an unexpected positive antibody tests leads to a more intensive search for P. aeruginosa, including a bronchoscopy, which would not otherwise have been carried out. Rising serial values in patients with chronic PA infection are an indication for more intensive antibiotic therapy. So experience suggest that single comparison studies of cultures and antibodies, such as the present one, are less valuable than longer term studies with serial estimations.
2010 Mohan K, Lakshman V, Fothergill JL, Ledson MJ, Winstanley C, Walshaw MJ. Empyema due to a highly transmissible Pseudomonas aeruginosa strain in an adult cystic fibrosis patient. J Med Microbiol 2010; 59:614-616. [PubMed]
Despite the predilection of P. aeruginosa for the lungs of CF people, infection of the pleura is much less common and is not well described in the CF population. These authors describe what is believed to be the first case of pleural empyema due to a particularly pathogenic transmissible strain of P. aeruginosa (the Liverpool epidemic strain) in an adult CF patient.
Yet another complication from the Liverpool epidemic strain of P. aeruginosa
2011 Wainwright CE, Vidmar S, Armstrong DS, Byrnes CA, Carlin JB, Cheney J, Cooper PJ, Grimwood K, Moodie M, Robertson CF, Tiddens HA, ACFBAL Study Investigators. Effect of bronchoalveolar lavage-directed therapy on Pseudomonas aeruginosa infection and structural lung injury in children with cystic fibrosis: a randomized trial. JAMA. 306(2):163-71, 2011 Jul 13. [PubMed]
Despite wide use of oropharyngeal cultures to identify pulmonary infection, concerns remain over their diagnostic accuracy. While bronchoalveolar lavage (BAL) is an alternative diagnostic tool, evidence for its clinical benefit is lacking. OBJECTIVE: To determine if BAL-directed therapy for pulmonary exacerbations during the first 5 years of life provides better outcomes than current standard practice relying on clinical features and oropharyngeal cultures. DESIGN, SETTING, AND PARTICIPANTS: The Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) randomized controlled trial, recruiting infants diagnosed with cystic fibrosis through newborn screening programs in 8 Australasian cystic fibrosis centers. Recruitment occurred between June 1, 1999, and April 30, 2005, with the study ending on December 31, 2009. INTERVENTIONS: BAL-directed (n = 84) or standard (n = 86) therapy until age 5 years. The BAL-directed therapy group underwent BAL before age 6 months when well, when hospitalized for pulmonary exacerbations, if Pseudomonas aeruginosa was detected in oropharyngeal specimens, and after P. aeruginosa eradication therapy. Treatment was prescribed according to BAL or oropharyngeal culture results. MAIN OUTCOME MEASURES: Primary outcomes at age 5 years were prevalence of P. aeruginosa on BAL cultures and total cystic fibrosis computed tomography (CF-CT) score (as a percentage of the maximum score) on high-resolution chest CT scan.RESULTS: Of 267 infants diagnosed with cystic fibrosis following newborn screening, 170 were enrolled and randomized, and 157 completed the study. At age 5 years, 8 of 79 children (10%) in the BAL-directed therapy group and 9 of 76 (12%) in the standard therapy group had P. aeruginosa in final BAL cultures (risk difference, -1.7% [95% confidence interval, -11.6% to 8.1%]; P = .73). Mean total CF-CT scores for the BAL-directed therapy and standard therapy groups were 3.0% and 2.8%, respectively (mean difference, 0.19% [95% confidence interval, -0.94% to 1.33%]; P = .74). CONCLUSION: Among infants diagnosed with cystic fibrosis, BAL-directed therapy did not result in a lower prevalence of P. aeruginosa infection or lower total CF-CT score when compared with standard therapy at age 5 years.
This is a major study and the summary is reproduced in full. The results are clear – bronchoscopy guided antibiotic treatment during the first 5 years does not lead to a reduction in the number of infants who have P. Pseudomonas infection nor to a significant difference in CT scores. Perhaps the difference between this study and many previous ones comparing these two methods of bacteriological monitoring was that the children were followed over a prolonged period and it was not just a comparison of the findings of one isolated BAL and one oropharyngeal culture.
2012 Skurnik D, Davis MR Jr, Benedetti D, Moravec KL, Cywes-Bentley C, Roux D, TraficanteDC, Walsh RL, Marylander T, Cassidy SK, Harems CR, Martin TR, Assaultable EL, Vargas SO, Macadam AJ, Lie berm an TD, Cushion R, Li puma JJ, Pier GB, Goldberg JB, Probe GP. Targeting pan-resistant bacteria with antibodies to a broadly conserved surface polysaccharide expressed during infection. J Infect Dis 2012; 205:1709-1718. [PubMed]
The bacterial surface polysaccharide poly-beta-(1-6)-N-acetyl-glucosamine (PNAG) mediates biofilm formation by some bacterial species, and antibodies to PNAG can confer protective immunity. By analyzing sequenced genomes, the authors found that potentially multidrug-resistant bacterial species such as Klebsiella pneumoniae, Enterobacter cloacae, Stenotrophomonas maltophilia, and the Burkholderia cepacia complex (BCC) may be able to produce PNAG. The presence of PNAG on BCC was assessed and antibodies to PNAG were tested using opsonophagocytic assays and for protective efficacy against lethal peritonitis in mice. PNAG is expressed in vitro and in vivo by the BCC, and cystic fibrosis patients infected by the BCC species B. dolosa mounted a PNAG-specific opsonophagocytic antibody response. Antisera to PNAG mediated opsonophagocytic killing of BCC and were protective against lethal BCC peritonitis even during coinfection with methicillin-resistant Staphylococcus aureus. The authors concluded this was a potential new therapeutic options against PNAG-producing bacteria, including even pan-resistant pathogen
This is an interesting approach for it is likely that pan-resistant bacteria are likely to become an ever increasing problem as the age of people with CF increases and they receive repeated courses of antibiotics. BCC remains a serious and often intractable problem. So this different approach is to be welcomed.
2012 Waters V, Atenafu EG, Salazar JG, Lu A, Yau Y, Matukas L, Tullis E, Ratjen F. Chronic Stenotrophomonas maltophilia infection and exacerbation outcomes in cystic fibrosis. J Cyst Fibros 2012; 11:8-13. [PubMed].
Chronic Stenotrophomonas maltophilia infection is a risk factor for pulmonary exacerbation in cystic fibrosis (CF) but its impact on subsequent clinical outcomes is unknown. The aim of this study was to determine the effect of chronic S. maltophilia infection and associated antimicrobial therapy on the recovery of forced expiratory lung volume in 1s (FEV(1)) following pulmonary exacerbation. Patients with chronic S. maltophilia infection did not recover their baseline FEV(1) following 31% of exacerbations and had an overall mean FEV(1) decline of 1.84% predicted after exacerbation. Older (p=0.02), female (p=0.02) patients with lower BMI z score (p=0.002) and Burkholderia cepacia complex infection (p=0.005), but not chronic S. maltophilia infection (p=0.86), had a greater decrease in follow up FEV(1)% pred compared to baseline. The number of days of antibiotic therapy against S. maltophilia during a pulmonary exacerbation was not associated with a significant difference in the FEV(1) recovery (p=0.69) or with a longer time to subsequent pulmonary exacerbation (p=0.56). The authors concluded that although CF patients experience a significant decline in lung function following exacerbation, chronic S. maltophilia infection and associated antimicrobial therapy do not affect subsequent lung function recovery.
S. maltophilia has gradually appeared as a more frequent pathogen as the prevalence of P aeruginosa has been reduced by intensive antibiotic therapy. As happened in the early days when isolations of P. aeruginosa occurred more frequently as S. aureus was tested, initially there were doubts as to the degree of pathogenicity. It is somewhat reassuring that the course of patients infected by S. maltophilia was not significantly different from those with more usual organisms and certainly not comparable with the severe effects of B. cepacia.
2012 Cardines R, Giufre M, Pompilio A, Fiscarelli E, Ricciotti G, Bonaventura GD, Cerquetti M. Haemophilus influenzae in children with cystic fibrosis: antimicrobial susceptibility, molecular epidemiology, distribution of adhesins and biofilm formation. Int j Med Microbiol 2012; 302:45-52. [PubMed]
Haemophilus influenzae commonly infects the respiratory tract of patients with cystic fibrosis (CF), early in childhood. In this investigation, 79 H. influenzae isolates were recovered from the respiratory secretions of 64 CF patients (median age: 5 years) included in a 5-year follow-up study. Fifteen of the 64 patients contributed two or more H. influenzae isolates overtime. Serotyping, antibiotic susceptibility testing, genotyping, detection of both hmwA and hia adhesin genes and hypermutable strains was carried out. Biofilm formation ability was investigated. Most strains (72/79, 91.2%) were nonencapsulated or nontypeable (NTHi). Resistance to ampicillin (13.9%) and imipenem (17.7%) was the most detected. Few isolates (2.5%) exhibited the hypermutable phenotype. The NTHi strains showed 55 different genotypes, but 19 clusters of closely related strains were identified. Nine clusters included strains that cross-colonised several patients over a long-time period (mean: 3.7 years). Most patients with sequential isolates harboured strains genetically unrelated, but persistent colonisation with the same clone was observed in 37.5% of patients. Over 45% of NTHi strains contained hmwA-related sequences, 26.3%, hia, 8.3% both hmwA and hia, while 19.4% lacked both. A significant association was found between occurrence of an adhesive gene (irrespective of which) and both persistence (P<0.0001) and long-term cross-colonisation (P<0.0001). Mean biofilm level formed by the persistent strains was found significantly increased compared to non-persistent ones (P<0.0001). Hia-positive strains produced significantly more biofilm than hmwA-carrying strains (P<0.01). Although a high turnover of NTHi strains in FC patients was observed, distinct clones with increased capacity of persistence or cross-colonisation occurred.
Although H influenzae has not received the same respect as P. aeruginosa from clinicians, there are patients in whom the organism reappears in the same patient on numerous occasions. Any evidence that the organism is recurring should be dealt with by more aggressive treatment – even including a course of intravenous antibiotics. For although if the culture becomes negative after a course of antibiotics but recurs, it is likely that the organism was not eradicate in the first place.
2012 Cargill J, Etherington C, Peckham D, Conway S, Denton M. Bloodstream infections in cystic fibrosis: nine years of experience in both adults and children. J Cyst Fibros 2012; 11:337-339.[PubMed]
The aetiology and outcome of bloodstream infections (BSI) occurring at two regional cystic fibrosis (CF) centres (one adult, one paediatric) between 1998 and 2006. During the study period 1691 blood culture sets were taken. Fifty-seven clinically significant episodes of BSI in 48 people with CF (36 adult, 12 paediatric) were identified, along with 28 other episodes considered to be contamination or not clinically significant. The most common BSIs were caused by coagulase-negative staphylococci (13) Candida spp (10), and Stenotrophomonas maltophilia (8). The majority (82%) of significant BSIs were considered to originate from totally-implantable vascular access devices (TIVADs); only 9% were attributed to the lower respiratory tract. The TIVAD was removed in two-thirds of cases of TIVAD-associated BSI. There were three deaths (60% of cases) attributable to BSI originating from the lower respiratory tract but no deaths attributable to TIVAD-associated BSI.
Most significant BSIs in patients with CF originate from TIVADs. Targeted antimicrobial therapy and appropriate early device removal is associated with good clinical outcome. BSI originating from the lower respiratory tract is associated with poor clinical outcome.
2013 Hubert D. Reglier-Poupet H. Sermet-Gaudelus I. Ferroni A. Le Bourgeois M. Burgel PR. Serreau R. Dusser D. Poyart C. Coste J. Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis. J Cyst Fibros 2013; 12:497-503. [PubMed]
In a retrospective study on 419 sputum producer CF patients (293 adults and 126 children >7years of age), we recorded patient characteristics, lung function, nutritional status, IV antibiotics and hospitalisations, the presence of SA and/or PA and FEV1 decline over 2years.
S. aureus was found in 72% of the patients: MSSA in 68.2% of children and 48.8% of adults; MRSA in 17.5% of children and 17.8% of adults. Sixty percent of MRSA patients and 60.4% of MSSA patients also harboured PA. The rate of deterioration of clinical status of the various groups, as assessed from respiratory function, IV antibiotic courses and hospitalisations, increased in the order: no SA/no PA, MSSA alone, MRSA alone, MSSA/PA, MRSA/PA, and PA alone. Nutritional status did not differ between groups. Results were roughly similar for children and adults.
The yearly FEV1 decline was significantly higher only for MRSA/PA patients (p=0.03) compared to no SA/no PA patients.
Clinical condition of CF patients with MSSA only or MRSA only appeared similar, whereas MRSA/PA patients had more severe respiratory function than MSSA/PA patients. In CF patients, MRSA might be more deleterious than MSSA only when associated with PA.
It is surprising that so many patients are permitted to become chronically infected with a known pathogen such as MSSA when in the majority this can be avoided by eradication therapy.
2013 Wu K, Yau YC, Matukas L, Waters V. Biofilm compared to conventional antimicrobial susceptibility of Stenotrophomonas maltophilia isolates from cystic fibrosis patients. Antimicrob Agents Ch 2013; 7:1546-8. [PubMed]
One hundred twenty-five S. maltophilia isolates from 85 CF patients underwent planktonic and biofilm susceptibility testing against 9 different antibiotics, alone and in double antibiotic combinations. When S. maltophilia isolates were grown as a biofilm, 4 of the 10 most effective antibiotic combinations included high-dose levofloxacin and 7 of the 10 combinations included colistin at doses achievable by aerosolization.
2014 Al-Zubeidi D. Hogan PG. Boyle M. Burnham CA. Fritz SA. Molecular epidemiology of methicillin-resistant Staphylococcus aureus isolated in serial cultures from the respiratory tract of children with cystic fibrosis. Infect Dis J 2014; 33(6):549-53. [PubMed]
Little is known about strain relatedness of methicillin-resistant Staphyloccocus aureus (MRSA) isolated at serial time points from the respiratory tract of patients with cystic fibrosis. The authors identified 54 CF patients with serial MRSA cultures (145 distinct cultures). Over time, 45 (83%) patients maintained the same strain type and 9 (17%) possessed at least 2 distinct strain types.
Data suggest that sustained presence of MRSA in CF patients is most commonly attributable to identical strain types. Acquisition of distinct MRSA strains in the airway is infrequent.
It seems that early eradication of S aureus is not a high priority for som vlinicians in view of the very high incidence of chrnic infection in some clinics. This is unfortunate for S. aureus is a proven dangerous pathogen for people with CF.
2014 Barillova P. Tchesnokova V. Dubbers A. Kuster P. Peters G. Dobrindt U. Sokurenko EV. Kahl BC. Prevalence and persistence of Escherichia coli in the airways of cystic fibrosis patients – an unrecognized CF pathogen?. Int J Med Microbiol 2014; 304(3-4):415-21. [PubMed]
Escherichia coli has not been considered as a significant CF pathogen although at times appearing in the sputum cultures. In a total of 176 patients were observed over 5.6 years, in 45 patients (25.6%) E. coli was cultured at least once. In 19 patients (10.8%) the same E. coli strain was isolated at least 3 times within a period of more than 6 months, with a mean persistence of 29 months. E. coli was occasionally or persistently isolated in a quarter of CF patients, mostly in very young or older patients.
The authors suggest the relatively high bacterial load of E. coli colonisation, the distinct association with the highly virulent extra-intestinal B2 clonal group and phenotypic variability in the long-term colonising strains suggests a previously unrecognised clinical significance of E. coli as a CF pathogen. This confirms the impression that certain people with CF tend to grow E.coli frequently and are presumably chronically infected by the organism.
2014 Gifford AH. Alexandru DM. Li Z. Dorman DB. Moulton LA. Price KE. Hampton TH. Sogin ML. Zuckerman JB. Parker HW. Stanton BA. O’Toole GA. Iron supplementation does not worsen respiratory health or alter the sputum microbiome in cystic fibrosis. J Cyst Fibros 2014; 13(3):311-8.[PubMed]
Iron supplementation for hypoferremic anaemia could potentiate bacterial growth in the cystic fibrosis (CF) lung, but clinical trials testing this hypothesis are lacking. Twenty-two adults with CF and hypoferremic anaemia participated in a randomised, double-blind, placebo-controlled, crossover trial of ferrous sulfate 325mg daily for 6weeks. Ferrous sulfate increased serum iron by 22.3% and transferrin saturation (TSAT) by 26.8% from baseline (p<0.05) but did not affect haemoglobin, sputum iron, Akron PES, and the sputum microbiome. Low-dose ferrous sulfate improved hypoferremia without correcting anaemia after 6 weeks. The authors did not observe significant effects on sputum iron, Akron PES, and the sputum microbiome. Although they did not identify untoward health effects of iron supplementation, they suggest a larger blinded randomised controlled trial would be needed to fully demonstrate safety.
There were discussions in the Eighties as to the need for and the danger of correcting the iron deficiency present in so many people with cystic fibrosis. Although this short term study does little to finally settle the question, harm did not appear to result from iron supplementation which should be given in the presence of clinical iron deficiency anaemia.
2014 Knibbs LD. Johnson GR. Kidd TJ. Cheney J. Grimwood K. Kattenbelt JA. O’Rourke PK. Ramsay KA. Sly PD. Wainwright CE. Wood ME. Morawska L. Bell SC. Viability of Pseudomonas aeruginosa in cough aerosols generated by persons with cystic fibrosis. Thorax 2014; 69(8):740-5.[PubMed]
Using purpose-built equipment, the authors measured viable P aeruginosa in cough aerosols at 1, 2 and 4 m from the subject (distance) and after allowing aerosols to age for 5, 15 and 45 min in a slowly rotating drum to minimise gravitational settling and inertial impaction (duration). Aerosol particles were captured and sized employing an Anderson Impactor and cultured using conventional microbiology. Sputum was also cultured and lung function and respiratory muscle strength measured.
Viable P aeruginosa were detected in cough aerosols from all 19 patients with CF, but not from controls; travelling 4 m in 17/18 (94%) and persisting for 45 min in 14/18 (78%) of the CF group. Marked inter-subject heterogeneity of P aeruginosa aerosol colony counts was seen and correlated strongly (r=0.73-0.90) with sputum bacterial loads. Modelling decay of viable P aeruginosa in a clinic room suggested that at the recommended ventilation rate of two air changes per hour almost 50 min were required for 90% to be removed after an infected patient left the room.
The authors concluded that viable P. aeruginosa in cough aerosols travel further and last longer than recognised previously, providing additional evidence of airborne transmission between patients with CF.
Important information for those organising the management of a CF clinic and fully justifying elaborate arrangements to avoid cross infection which none the less have been questioned by some clinicians.
2014 Lamas A. Luis M. de Valbuena, Ruiz M. Gonzalez-Casbas, Jose Manuel. Suarez, Lucrecia. Subcutaneous implant with etonogestrel (Implanon) for catamenial exacerbations in a patient with cystic fibrosis: a case report. BMC Pulm Med 2014; 14:165. [PubMed]
Women with CF have a more rapid decline in lung function than men for which female hormones have been implicated. A 20 year old woman had impressive cessation of pulmonary exacerbations (PE) that were related to menstrual periods (catamenial = relating to menstruation), and recovery of lung function following the insertion of a subcutaneous implant with 68 mg of etonogestrel (Implanon, Organon Espanola S.A. Laboratories, Madrid, Spain), supporting role of female hormones in the development of PE and in the decline of lung function in this woman with CF.
A report which would encourage clinicians check if exacerbations in their female CF patients were related to their menstrual periods. Although there is an impressive chart in the original article, the improvement also appears to coincide with the introduction of tobramycin solution for inhalation!
2014 Mauch RM. Levy CE. Serum antibodies to Pseudomonas aeruginosa in cystic fibrosis as a diagnostic tool: a systematic review. J Cyst Fibros 2014; 13:499-507. [PubMed]
A systematic literature review of the last 40 years on the research of serum antibodies to Pseudomonas aeruginosa in cystic fibrosis and its utility as a diagnostic tool. 26 studies were assessed. ELISA technique was the most commonly used technique to detect serum P. aeruginosa antibodies. The most consistent results were those in which the response against the antigen St-Ag:1-17 was evaluated. The accuracy levels of the ELISA technique remain controversial, but most studies showed a good correlation between antibody titres and microbiological culture.
The detection of serum antibodies to P. aeruginosa shows capacity for early detection of this pathogen and potential utility and viability of incorporation in the diagnostic routine of patients with cystic fibrosis.
There is now a vast literature on the value (or lack of it) of Pseudomonas antibodies in management of people with cystic fibrosis. In clinics such as Leeds and Copenhagen, these antibodies have been in routine use for many years since the Eighties and the clinicians find their practical value is beyond doubt. This review is useful in summarising the present position as we believe the test should be available in all CF centres.
2014 Michon Anne-Laure, Jumas-Bilaket E, Chiron R, Lamy B, Marchandin H. Advances toward the Elucidation of Hypertonic Saline Effects on Pseudomonas aeruginosa from Cystic Fibrosis Patients. PLoS One 2014;9:e90164; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3938589/pdf/pone.0090164.pdf). [PubMed]
Nebulized hypertonic saline (HTS) has beneficial effects including reducing pulmonary exacerbations in Cystic Fibrosis (CF) patients. Several mechanisms may explain these effects but antimicrobial activity of NaCl remains largely unexplored. The study aimed to measure the antimicrobial effect of NaCl on Pseudomonas aeruginosa isolated from the respiratory tract in CF patients.
it was found that NaCl inhibited the growth of all isolates and killed 38% of tested isolates within concentration range currently used in therapeutics.
The results suggest that anti-pseudomonal activity is another mechanism of action of HTS to add to those already established. The authors noted that further studies are needed to determine the ideal NaCl volume, frequency of administration and mode of administration to optimise the potential bactericidal effects of hypertonic saline therapy in CF.
2014 Yum HK. Park IN. Shin BM. Choi SJ. Recurrent Pseudomonas aeruginosa Infection in Chronic Lung Diseases: Relapse or Reinfection?. Tuber Respir Dis (Seoul) 2014; 77:172-7. [PubMed]
Eighteen patients (83.3% of those examined) had recurrent P. aeruginosa pneumonia caused by the strains with same PFGE pattern. The authors concluded that the most of the recurrent P. aeruginosa infections in chronic lung disease due to various conditions occurred due to the relapse of prior infections.
This was already well known in chronic P. aeruginosa infections when exacerbations occur. However, there is now ample evidence to show that after eradication of early P. aeruginosa in CF subsequent infections are usually by a different strain and are new infections rather than recurrences (Munck A et al. Pediatr Pulmonol 2001; 32(4):288-92. [PubMed]).
Andersen C. Kahl BC. Olesen HV. Jensen-Fangel S. Norskov-Lauritsen N. Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients. Clin Microbiol Infect 2014; 20(5):O285-91.[PubMed]
Of 65 patients chronically infected with S. aureus, 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6-31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003).
When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60-1.61). In conclusion, this shows that 2 weeks of IV antimicrobial treatment can significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.
These findings are to be expected. S. aureus can be eradicated by antibiotic therapy provided it is not allowed to become an established chronic infection – somewhat analogous to P. aeruginosa where eradication of a recently acquired infection is usually successful but eradication of chronic infection virtually never achieved.
2014 Anstead M. Saiman L. Mayer-Hamblett N. Lands LC. Kloster M. Goss CH. Rose L. Burns JL. Marshall B. Ratjen F. Pulmonary exacerbations in CF patients with early lung disease. J Cyst Fibros 2014; 13(1):74-9. [PubMed]
Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease. The authors used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. While increased cough was present in all young patients with PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free.
Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.
This conclusion confirms the observations of many clinicians who tend to treat exacerbations very early in young patients e.g a new cough that doesn’t clear quickly is for many paediatricians, even without any other signs, is an indication for vigorous treatment with IV antibiotics.
2014 Berkebile AR. McCray PB Jr. Effects of airway surface liquid pH on host defense in cystic fibrosis. Int J Biochem Cell Biol 2014; 52:124-9. [PubMed]
Studies in humans and animal models of cystic fibrosis indicate that the pH of airway surface liquid is reduced in the absence of cystic fibrosis transmembrane conductance regulator function. Many aspects of the innate host defence system of the airways are pH sensitive, including antimicrobial peptide/protein activity, the rheological properties of secreted mucins, mucociliary clearance, and the activity of proteases.
This review focuses on how changes in airway surface liquid pH may contribute to the host defence defect in cystic fibrosis soon after birth. The authors suggest understanding how changes in pH impact mucosal immunity may lead to new therapies that can modify the airway surface liquid environment, improve airway defences, and alter the disease course.
2014 Bruzzese E. Callegari ML. Raia V. Viscovo S. Scotto R. Ferrari S. Morelli L. Buccigrossi V. Lo Vecchio A. Ruberto E. Guarino A. Disrupted intestinal microbiota and intestinal inflammation in children with cystic fibrosis and its restoration with Lactobacillus GG: a randomised clinical trial. ONE [Electronic Resource]. 9(2):e87796, 2014.[PubMed]
Intestinal inflammation is a hallmark of cystic fibrosis (CF). Administration of probiotics can reduce intestinal inflammation and the incidence of pulmonary exacerbations. The authors investigated the composition of intestinal microbiota in children with CF and analysed its relationship with intestinal inflammation. They also investigated the microflora structure before and after Lactobacillus GG (LGG) administration in children with CF with and without antibiotic treatment.
Compared with healthy controls, children with CF had significantly different intestinal microbial core structures. The levels of Eubacterium rectale, Bacteroides uniformis, Bacteroides vulgatus, Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Faecalibacterium prausnitzii were reduced in children with CF. A similar but more extreme pattern was observed in children with CF who were taking antibiotics.
Lactobacillus GG administration reduced fecal calprotectin (CLP) and partially restored intestinal microbiota. There was a significant correlation between reduced microbial richness and intestinal inflammation.
The authors concluded CF causes qualitative and quantitative changes in intestinal microbiota, which may represent a novel therapeutic target in the treatment of CF. Administration of probiotics restored gut microbiota, supporting the efficacy of probiotics in reducing intestinal inflammation and pulmonary exacerbations
2014 Di Nardo G. Oliva S. Menichella A. Pistelli R. De Biase RV. Patriarchi F. Cucchiara S. Stronati L.Lactobacillus reuteri ATCC55730 in cystic fibrosis. J Pediatr Gastroenterol Nutr 2014; 58(1):81-6. [PubMed]
The aim of this study was to evaluate in patients with cystic fibrosis (CF) the effect of Lactobacillus reuteri (LR) on the rate of respiratory exacerbations and of the infections of both upper respiratory and gastrointestinal tracts. Prospective randomised, double-blind, placebo-controlled study enrolling 61 patients with CF with mild-to-moderate lung disease at the Regional Center for CF of the Department of Pediatrics, University of Rome “La Sapienza.” All of the patients were not hospital inpatients at the time of the enrolment. Inclusion criteria were forced expiratory volume in the first second (FEV1) >70% predicted; no inhaled or systemic steroids, no anti-inflammatory drugs, antileukotrienes, and mast cell membrane stabilisers; and no serious organ involvement. Exclusion criteria were a history of pulmonary exacerbation or upper respiratory infection in the previous 2 months; changes in medications in the last 2 months; a history of haemoptysis in the last 2 months; and colonisation with Burkholderia cepacia or mycobacteria. Patients were randomly assigned to receive LR (30 patients) in 5 drops per day (10(10) colony-forming units) or placebo (31 patients) for 6 months.
Main outcomes were number of episodes of pulmonary exacerbations and hospital admissions for pulmonary exacerbations, number of gastrointestinal and upper respiratory tract infections. FEV1, fecal calprotectin, and cytokine profile in induced sputum and plasma were assessed at baseline and at the end of the trial.
Pulmonary exacerbations were significantly reduced in the LR group compared with the placebo group (P<0.01; odds ratio 0.06 [95% confidence interval {CI} 0-0.40]; number needed to treat 3 [95% CI 2-7]). Similarly, the number of upper respiratory tract infections (in our series only otitis) was significantly reduced in the LR group compared with the placebo group (P<0.05; odds ratio 0.14 [95% CI 0-0.96]; number needed to treat 6 [95% CI 3-102]). The 2 groups did not differ statistically in the mean number and duration of hospitalisations for pulmonary exacerbations and gastrointestinal infections. There was no significant statistical difference in the mean delta value of FEV1, fecal calprotectin concentration, and tested cytokines (tumour necrosis factor-alpha and interleukin-8) between the 2 groups.
The authors concluded LR reduces pulmonary exacerbations and upper respiratory tract infections in patients with CF with mild-to-moderate lung disease. LR administration may have a beneficial effect on the disease course of CF.
2014 Czy S. Stawinska-Witoszynska B. Madry E. Krzywinska-Wiewiorowska M. Szczepanik M. Walkowiak J. Kwiecien J. Non-invasive detection of Helicobacter pylori in cystic fibrosis–the fecal test vs. the urea breath test. Eur Rev Med Pharmacol Sci 2014; 18:2343-8. [PubMed]
Recently it has been shown that cystic fibrosis (CF) patients have the same prevalence of Helicobacter pylori (HP infection) as the general population, as well as the same spectrum of changes caused by this pathogen. The two most popular noninvasive tests, the urea breath test (UBT) and the fecal test (FT) were assessed in diagnosing HP infection in CF patients.
There was convincing evidence of divergent UBT and FT results in the CF patients, so the authors suggest that UBT is kept as the standard method for HP detection in this population.
The infection has never seemed to be a major practical problem amongst people with cystic fibrosis. But this is useful information and the infection should be considered and not overlooked.
2014 Michon Anne-Laure, Jumas-Bilaket E, Chiron R, Lamy B, Marchandin H. Advances toward the Elucidation of Hypertonic Saline Effects on Pseudomonas aeruginosa from Cystic Fibrosis Patients. PLoS One 2014;9:e90164; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC3938589/pdf/pone.0090164.pdf).[PubMed]
Nebulized hypertonic saline (HTS) has beneficial effects including reducing pulmonary exacerbations in Cystic Fibrosis (CF) patients. Several mechanisms may explain these effects but antimicrobial activity of NaCl remains largely unexplored. The study aimed to measure the antimicrobial effect of NaCl on Pseudomonas aeruginosa isolated from the respiratory tract in CF patients.
it was found that NaCl inhibited the growth of all isolates and killed 38% of tested isolates within concentration range currently used in therapeutics.
The results suggest that anti-pseudomonal activity is another mechanism of action of HTS to add to those already established. The authors noted that further studies are needed to determine the ideal NaCl volume, frequency of administration and mode of administration to optimise the potential bactericidal effects of hypertonic saline therapy in CF.
2014 Moodie M. Lal A. Vidmar S. Armstrong DS. Byrnes CA. Carlin JB. Cheney J. Cooper PJ. Grimwood K. Robertson CF. Tiddens HA. Wainwright CE. Costs of bronchoalveolar lavage-directed therapy in the first 5 years of life for children with cystic fibrosis. Cystic Fibrosis Bronchoalveolar Lavage Study Investigators. J Pediatr 2014;165:564-569[PubMed]
To determine whether bronchoalveolar lavage (BAL)-directed therapy for infants and young children with cystic fibrosis (CF), rather than standard therapy, was justified on the grounds of a decrease in average costs and whether the use of BAL reduced treatment costs associated with hospital admissions.
Mean costs per child during the 5 year study period were Australian dollars (AUD) 92,860 in BAL-directed therapy group and AUD 90,958 in standard therapy group. Mean hospital costs per child during the study period were AUD 57,302 in the BAL-directed therapy group and AUD 66,590 in the standard therapy group.
The authors concluded that BAL-directed therapy did not result in either lower mean hospital admission costs or mean costs overall compared with managing patients with CF by a standard protocol based upon clinical features and oropharyngeal culture results alone.
Following on their previous findings that BAL-directed treatment offers no clinical advantage over standard therapy at age 5 years (Wainwright CE, et al. JAMA. 2011; 306:163-71.[PubMed]) the authors could not recommend flexible bronchoscopy with BAL for the routine management of preschool children with CF on the basis of overall cost savings.
2014 Simoneau T. Bazzaz O. Sawicki GS. Gordon C. Vitamin D status in children with cystic fibrosis. Associations with inflammation and bacterial colonization. Ann Am Thorac Soc 2014; 11(2):205-10.[PubMed]
Patients with cystic fibrosis (CF) have high rates of vitamin D insufficiency. The relation between vitamin D status and inflammation in patients with CF is poorly understood. Vitamin D deficiency was defined as a serum 25(OH)D, less than 20 ng/ml and insufficiency as serum 25(OH)D 20 to 29.9 ng/ml.
Data were collected for 148 children. The mean serum 25(OH)D concentration was 32.4 ng/ml (SD, 8.9). Seven percent (10 of 148) were vitamin D deficient, and 36% (53 of 148) were vitamin D insufficient. Among the pancreatic-sufficient patients, 50% (14 of 28) were vitamin D insufficient/deficient, whereas among pancreatic-insufficient patients, 41% (49 of 120) were vitamin D insufficient/deficient. Pseudomonas aeruginosa was a more common pathogen in the patients who were vitamin D insufficient/deficient (18 of 63 vs. 11 of 85, P = 0.018). There was no difference between vitamin D-sufficient versus -insufficient groups in terms of other bacterial colonisation or inflammatory markers.
The authors concluded that overall, vitamin D insufficiency is common among young children with CF. Vitamin D insufficiency is prevalent even in children who are pancreatic sufficient. In this population, vitamin D insufficiency is associated with a history of Pseudomonas colonisation but not with classic markers of systemic inflammation.
There are obvious limitations to a chart review study of this type and 43% of patients who are insufficient/deficient in vitamin D suggests that the previous monitoring of their nutritional state has not included the recommended monitoring of their fat soluble vitamin levels.
2014 Andersen C, Kahl BC, Olesen HV, Jensen-Fangel S, Nørskov-Lauritsen N. Intravenous antibiotics given for 2 weeks do not eradicate persistent Staphylococcus aureus clones in cystic fibrosis patients. Clin Microbiol Infect. 2014 May;20(5):O285-91. doi: 10.1111/1469-0691.12406. Epub 2013 Nov 4. Full text available
Staphylococcus aureus is the most commonly isolated pathogen in respiratory tract secretions from young patients with cystic fibrosis (CF), and several treatment strategies are used to control the infection. One thousand and sixty-one S. aureus isolates cultured from 2526 samples from 130 CF patients during a 2-year study period were subjected to spa typing. Intervals between positive samples and the occurrence of clone replacements were calculated in relation to courses of IV antimicrobial agents. Of 65 patients chronically infected with S. aureus, 37 received 139 courses of IV antimicrobial agents with activity against S. aureus (mean duration, 15 days; range, 6-31 days). Administration of IV antibiotics increased the time to the next sample with growth of S. aureus: the mean interval between two positive samples was 68 days if IV treatment had been administered, in contrast to 49 days if no IV treatment had been administered (p 0.003). When S. aureus recurred in sputum after IV treatment, the isolate belonged to a different clone in 33 of 114 (29%) intervals, in comparison with 68 of 232 (29%) intervals where IV treatment had not been prescribed (OR 0.98, 95% CI 0.60-1.61). The authors concluded antibiotics significantly suppress chronic staphylococcal infection in CF, but is not associated with the eradication of persistent bacterial clones.
– Fifty percent (65/130) of the CF patients attending the Aarhus CF clinic (one of the two major CF centres in Denmark) were chronically infected with S. aureus. The present findings confirm the expected failure to eradicate chronic S. aureus. As occurs with P. aeruginosa, once chronic infection is established, as appears to be the case in a surprisingly high proportion of these patients, suppression is the best one can achieve – eradication is usually impossible.
It is surprising that in many clinics S. aureus infection is not treated as early and aggressively as is P. aeruginosa, where chronic infection was at one time considered to be inevitable but can usually be avoided by early aggressive antibiotic treatment. It is interesting that the incidence of chronic S. aureus infection in the other Danish CF Centre in Copenhagen was only 14% where a more aggressive anti-staphylococcal policy has been adopted for many years (Dalboge CS et al, 2013[PubMed])
2015 Zemanick ET, Emerson J, Thompson V, McNamara S, Morgan W, Gibson RL, Rosenfeld M; EPIC Study Group. Clinical outcomes after initial pseudomonas acquisition in cystic fibrosis. Pediatr Pulmonol. 2015 Jan;50(1):42-8. doi: 10.1002/ppul.23036. Epub 2014 Mar 18. [PubMed]
To evaluate clinical outcomes associated with initial isolation of Pseudomonas aeruginosa (Pa) in a large U.S. cystic fibrosis (CF) cohort in the current era of widespread early Pa eradication therapy. Participants were children with CF enrolled in the Early Pseudomonas Infection Control (EPIC) Observational Study who had no isolation of Pa from respiratory cultures prior to enrollment. Population-averaged regression models using generalized estimating equation methods were used to estimate the effect of Pa acquisition on endpoints including lung function, growth, pulmonary exacerbation rate, respiratory signs and symptoms, and respiratory cultures.
Eight hundred thirty-eight subjects were observed for a mean 4.6 (SD 1.2) years during which 431 (51%) acquired Pa. There was no statistically significant effect of Pa acquisition on the slopes of FEV1 % predicted or growth parameters. Pulmonary exacerbation rate was statistically significantly greater after Pa acquisition (incident rate ratio 1.40, 95% CI 1.07, 1.84) as were odds of crackles or wheeze on physical exam (OR 1.23, 95% CI 1.00, 1.52). Odds of isolation of MRSA (OR 1.86, 95% CI 1.38, 2.49) and S. maltophilia (OR 2.11, 95% CI 1.49, 2.98) increased after Pa acquisition, while the odds of H. influenzae (OR 0.54, 95% CI 0.46, 0.64) decreased.
In this large U.S. cohort, the authors did not detect an association between acquisition of Pa and deterioration in lung function or nutrition. Pa acquisition was associated with significantly increased pulmonary exacerbation rate and odds of crackles or wheeze. Pa infection may be the cause of these outcomes or a marker of more severe disease.
– This study was rather short term to detect significant disadvantages of acquiring Pseudomonas infection. Also presumably the infection was treated. It has been shown in the case of screened CF infants that early adverse experience may be minimised for years by adequate treatment – but significantly more treatment is required. The presence of crackles or wheeze in young CF children is alarming.
See commentary by Zemanick ET and Laguna TA. Clin Infect Dis 2015; 61(5):716-718. Where the subject is discussed and editorial is available in full.
2015 Reid PA, McAllister DA, Boyd AC, Innes JA, Porteous D, Greening AP, Gray RD. Measurement of serum calprotectin in stable patients predicts exacerbation and lung function decline in cystic fibrosis. Am J Respir Crit Care Med. 2015 Jan 15;191(2):233-6. doi: 10.1164/rccm.201407-1365LE. Free article. [PubMed]
A single measurement of serum calprotectin in stability predicts changes in disease activity manifest by time to next exacerbation and decline in lung function. The authors suggest that measurement of calprotectin in the clinic may allow the identification of patients at high risk of exacerbation and/or lung function decline and allow appropriate tailoring of therapy.
– The full reference to this letter from Scotland contains much useful detail.
2015 O’Neill K; Bradley JM; Johnston E; McGrath S; McIlreavey L; Rowan S; Reid A; Bradbury I; Einarsson G; Elborn JS; Tunney MM. Reduced bacterial colony count of anaerobic bacteria is associated with a worsening in lung clearance index and inflammation in cystic fibrosis. ONE [Electronic Resource]. 10(5):e0126980, 2015. Free PMC article [PubMed]
Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis subjects. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF.
The authors observed an inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only.
The authors consider the results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse lung clearance index. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. They suggest these results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.
– These findings are difficult to understand. It is advised the reader consults the full article which is available.
2015 Kidd TJ; Ramsay KA; Vidmar S; Carlin JB; Bell SC; Wainwright CE; Grimwood K; ACFBAL Study Investigators. Pseudomonas aeruginosa genotypes acquired by children with cystic fibrosis by age 5-years. J Cyst Fibros 2015; 14(3):361-9. [PubMed]
The authors describe Pseudomonas aeruginosa acquisitions in children with CF aged <5-years, eradication treatment efficacy, and genotypic relationships between upper and lower airway isolates and strains from non-CF sources.
Of 168 CF children aged <5-years in a bronchoalveolar lavage (BAL)-directed therapy trial, 155 had detailed microbiological results. Overall, 201/271 (74%) P. aeruginosa isolates from BAL and oropharyngeal cultures were available for genotyping, including those collected before and after eradication therapy. Eighty-two (53%) subjects acquired P. aeruginosa, of which most were unique strains. Initial eradication success rate was 90%, but 36 (44%) re-acquired P. aeruginosa, with genotypic substitutions more common in BAL (12/14) than oropharyngeal (3/11) cultures. Moreover, oropharyngeal cultures did not predict BAL genotypes reliably. The authors concluded children with CF acquire environmental P. aeruginosa strains frequently. However, discordance between BAL and oropharyngeal strains raises questions over upper airway reservoirs and how to best determine eradication in non-expectorating children. – Although following the microbiological state of preschool children by BAL did not appear to offer an advantage over routine management in this important study from Australia (Wainwright CE et al, 2011 – Topics -> Bronchoscopy), the initial P. aeruginosa eradication rate of 90% was impressive.
Jenkins R; Wootton M; Howe R; Cooper R. A demonstration of the susceptibility of clinical isolates obtained from cystic fibrosis patients to manuka honey. Arch Microbiol 2015; 197(4):597-601. [PubMed] (Full article available)
Susceptibility of 56 strains of P. aeruginosa and 55 strains of Burkholderia to manuka honey, tobramycin and colistin using micro broth dilution and E strip was determined. All strains exhibited susceptibility to honey <10 % (w/v); mean susceptibility of Burkholderia (4.6 % w/v) was lower than P. aeruginosa (7.3 % w/v). Synergistic or additive combinations were found with all four strains tested. Combinations of manuka honey with antibiotics can be used to lower the MIC need to successfully inhibit both P. aeruginosa and B. cepacia. The authors suggest the use of honey as a combination agent may be possible for the management of P. aeruginosa and B. cepacia.
– There is now considerable literature on the antibacterial properties of honey including a number by Cooper R A et al from Cardiff in relation to B. cepacia (an early one abstracted in the 2000 section of this website). More recently Rowena Jenkins has published on the subject. As yet (2016) honey has not proved to be of value in the treatment of people with CF although it has been used with success in other infections particularly involving the skin. Professor John Govan of Edinburgh had a PhD student and a chemist working on the anti-bacterial effect of honey but they were unable to identify the active component. One experienced CF physician even tried treating an adult patient with CF with nebulised solution of honey but again without obvious clinical benefit.
Dr Jenkins and her research group intend to investigate the activity of honey with a much larger range of bacteria and antibiotic combinations and to determine the susceptibilities of biofilms, as well as suspension cultures. Clinical studies will also be needed to determine the potential and efficacy of antibiotic and honey combinations for cystic fibrosis patients.
2015 Hoen AG, Li J, Moulton LA, O’Toole GA, Housman ML, Koestler DC, Guill MF, Moore JH, Hibberd PL, Morrison HG, Sogin ML, Karagas MR, Madan JC. Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis. J Pediatr. 2015 Jul;167(1):138-47.e1-3. doi: 10.1016/j.jpeds.2015.02.049. Epub 2015 Mar 26.[PubMed]
A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis.
Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. Findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed.
2016 Davis SD, Ratjen F, Brumback LC, Johnson RC, Filbrun AG, Kerby GS, Doumit M, Belessis Y; Stelzer-Braid S; Mallitt KA; Rawlinson W; Jaffe A. Diagnostic accuracy and distress associated with oropharyngeal suction in cystic fibrosis. J Cyst Fibros 2016; 15(4):473-8. [PubMed]
This study aimed to assess the diagnostic accuracy of oropharyngeal suction (OPS) samples in obtaining airway bacterial cultures in young children with cystic fibrosis (CF), and the level of child distress caused by obtaining OPS samples.Young children with CF undergoing broncho-alveolar lavage (BAL) as part of concurrent research or routine annual surveillance were studied. OPS was performed by stimulating a cough and suctioning the back of the oropharynx in the awake child to replicate clinical practice. BAL of the right upper, middle and lingula lobes was then performed. Samples were sent for standard bacterial culture. The child’s distress during OPS was rated using the Groningen Distress Scale (1=calm, 2=timid/nervous, 3=serious distress but still under control, 4=serious distress with loss of control, 5=panic).
There were 65 paired samples obtained from 39 children (21 boys, mean age on day of first sampling was 34.1 months, SD 19.1 months). For Pseudomonas aeruginosa, specificity, sensitivity, NPV and PPV with 95% CI were 98% (87-99), 75% (20-96), 98% (91-98) and 60% (15-93%) respectively. In all age groups combined, median level of distress was 3 (IQR 2-4), with distress highest in 2 and 3 year olds, with a median of 4 (IQR 3-4).-
The authors concluded OPS has diagnostic utility in determining the absence of organisms in the lower airway, with specificity for P. aeruginosa detection of 98%. However, a positive OPS result is not necessarily a good indicator of lower airway infection. Distress levels were high during OPS, mostly in 2 and 3 year olds. They suggest there is a need for interventions to reduce distress or to find alternative methods which are less distressing.
2016 Dee A. Carter, Shona E. Blair, Nural N. Cokcetin, Daniel Bouzo, Peter Brooks, Ralf Schothauer, Elizabeth J. Harry. Therapeutic Manuka Honey: No Longer So Alternative. Front Microbiol. 2016; 7: 569. Published online 2016 Apr 20. doi: 10.3389/fmicb.2016.00569 Free PMC article. [PubMed]
Medicinal honey research is undergoing a substantial renaissance. From a folklore remedy largely dismissed by mainstream medicine as “alternative”, we now see increased interest by scientists, clinical practitioners and the general public in the therapeutic uses of honey. There are a number of drivers of this interest: first, the rise in antibiotic resistance by many bacterial pathogens has prompted interest in developing and using novel antibacterials; second, an increasing number of reliable studies and casereports have demonstrated that certain honeys are very effective wound treatments; third, therapeutic honey commands a premium price, and the honey industry is actively promoting studies that will allow it to capitalize on this; and finally, the very complex and rather unpredictable nature of honey provides an attractive challenge for laboratory scientists.
In this paper the authors review manuka honey research, from observational studies on its antimicrobial effects through to current experimental and mechanistic work that aims to take honey into mainstream medicine. They outline current gaps and remaining controversies in our knowledge of how honey acts, and suggest new studies that could make honey a no longer “alternative” alternative.
– The free full text of this article is available and reviews relevant work in detail and should be consulted for further information. See also article by Jenkins R et al in the 2015 section of this History.
Dee Carter (figure) is Associate Professor and Head of Microbiology in the University of Sydney. Her interests are ecology and population genetics of pathogenic fungi and symbiotic algae,
Peckham D; Williams K; Wynne S; Denton M; Pollard K; Barton R. Fungal contamination of nebuliser devices used by people with cystic fibrosis. J Cyst Fibros 2016; 15(1):74-7. [PubMed]
A total of 170 nebulisers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on Scel+agar and incubated at 27 degree C for up to 2 weeks.Fungal cultures were positive in 86 (57.7%) patient’s devices. In 28/149 (18.8%), 39/149 (26.2%), 47/149 (31.5%) and 20/149 (13.4%) of subjects Aspergillus species, yeasts, moulds and both yeasts and moulds were isolated respectively. There was no difference in contamination rates between different devices.
Miles Denton (figure) is consultant microbiologist in Leeds and Daniel Peckham (figure) is Professor of Respiratory Medicine and Director of the Regional Adult Cystic Fibrosis Centre, Leeds.
2016 Psoter KJ; DE Roos AJ; Wakefield J; Mayer JD; Bryan M; Rosenfeld M. Association of meteorological and geographical factors and risk of initial Pseudomonas aeruginosa acquisition in young children with cystic fibrosis. Epidemiol Infect 2016; 144(5):1075-83.[PubMed]
Meteorological and geographical factors and risk of initial Pa acquisition in young children with CF were examined using the U.S. Cystic Fibrosis Foundation Patient Registry from 2003 to 2009. The results suggest that environmental factors may play a previously unrecognized role in the aetiology of initial Pa acquisition.
– The authors concluded meteorological and geographical factors, particularly increased temperature, dew point and rainfall were found to be associated with time to initial Pa acquisition in young children with CF. They have published on this subject previously and this paper is a useful source of references on the subject.
2016 Padoan R; Poli P; Colombrita D; Borghi E; Timpano S; Berlucchi M. Acute Scedosporium apiospermum Endobronchial Infection in Cystic Fibrosis. Pediatr Infect Dis J 2016 35(6):701-2. [Pubmed]
Fungi are known pathogens in cystic fibrosis patients. A boy with cystic fibrosis presented with acute respiratory distress. Bronchoscopy showed airways obstruction by mucus plugs and bronchial casts. Scedosporium apiospermum was identified as the only pathogen.
Bronchoalveolar lavage successfully resolved the acute obstruction. Plastic bronchitis is a new clinical picture of acute Scedosporium endobronchial colonisation in cystic fibrosis patients.
The authors concluded nebuliser devices are frequently contaminated by moulds and yeasts and emphasis should be placed on ensuring adequate nebuliser hygiene.
2017 Wettlaufer J, Klingel M, Yau Y, Stanojevic S, Tullis E, Ratjen F, Waters V. Longitudinal study of Stenotrophomonas maltophilia antibody levels and outcomes in cystic fibrosis patients. J Cyst Fibros. 2017 Jan;16(1):58-63. doi: 10.1016/j.jcf.2016.06.007. Epub 2016 Jun 23. [Pubmed]
Previous studies have shown an association between higher Stenotrophomonas maltophilia antibody levels and decreased lung function in patients with cystic fibrosis (CF). The purpose of this study was to assess the serologic response to S. maltophilia over time and to determine whether changes in antibody levels could predict clinical outcomes. Changes in S. maltophilia antibody levels in adult and pediatric patients with CF from 2008 to 2014 were assessed between groups of infection patterns. Regression models accounting for repeated measures were used to assess whether antibody levels could predict subsequent S. maltophilia microbiological status, and whether they are associated with lung function and subsequent pulmonary exacerbation.
A total of 409 S. maltophilia antibody samples from 135 CF patients showed that antibody levels did not change significantly between study visits, regardless of infection group. Higher antibody levels were independently associated with future culture positivity (OR 1.62; 95% CI 1.09, 2.41; p=0.02). While higher antibody levels were not independently associated with decreases in FEV1% predicted, they were associated with an increased hazard ratio for subsequent pulmonary exacerbation (HR 1.3; 95% CI 1.1, 1.6; p<0.001).
The authors concluded S. maltophilia antibody levels may be helpful to identify individuals at risk of exacerbation who may benefit from earlier antimicrobial treatment.
– Interesting but, as was the case with Pseudomonas antibodies, S. maltophilia antibodies are unlikely to be widely used in management of patients infected by this organism.
Berdah L, Taytard J, Leyronnas S, Clement A, Boelle PY, Corvol H. Stenotrophomonas maltophilia: A marker of lung disease severity Pediatr Pulmonol. 2018 Apr;53(4):426-430. doi: 10.1002/ppul.23943. Epub 2018 Jan 4. Free PMC [Pubmed]
While the prevalence of Stenotrophomonas maltophilia lung infection in cystic fibrosis (CF) patients has increased in the last decades, its pathogenicity remains controversial. The aim of this study was to investigate the effects of S. maltophilia initial infection on the progression of lung disease in CF children. This case-control retrospective study took place in a pediatric CF centre. A total of 23 cases defined by at least one sputum culture positive for S. maltophilia, were matched for age, sex, and CFTR mutations to 23 never infected CF controls. The clinical data were collected for 2 years before and after S. maltophilia initial infection and comprised lung function analyses, rates of exacerbations and of antibiotic courses.
Compared with controls, cases had lower lung function (P = 0.05), more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02), and intravenous antibiotic courses (P = 0.04) before S. maltophilia acquisition. In the year following S. maltophilia initial infection, lung function decline was similar in cases and controls but cases remained more severe, with more frequent pulmonary exacerbations (P = 0.01), hospitalizations (P = 0.02) and intravenous antibiotics.
The authors concluded S. maltophilia seems to be a marker of CF lung disease severity and international recommendations to reduce lung infection by this pathogen should rapidly emerge.
Dr. Laura Berdah works at the APHP Hopital Trousseau, CF Center Paris
Caskey S, Stirling J, Moore JE, Rendall JC. Occurrence of Pseudomonas aeruginosa in waters: Implications for patients with cystic fibrosis(CF). Lett Appl Microbiol. 2018 Mar 14. doi: 10.1111/lam.12876. [Epub ahead of print] [Pubmed]
Chronic P. aeruginosa infection is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). Current understanding of risk factors for acquisition is limited and so the aim of this study was to examine a large sample of environmental waters from diverse sources. Environmental water samples [n= 7904] from jacuzzis, hydrants, swimming pools, hot tubs, plunge pools, bottled natural mineral water (NMW), taps, springs, ice machines, water coolers, bores and showers were examined for the presence of P. aeruginosa. P. aeruginosa was detected in 524/7904 (6.6%) waters examined. Hot tubs [51/243; 20.9%], tap water [3/40; 8%] and jacuzzis [432/5811; 7.4%] were the most likely environments where P. aeruginosa was isolated. P. aeruginosa was isolated from bottled water [2/67; 3%]. The authors say their study highlights the ubiquitous nature of P. aeruginosa in the environment. Given CF patients are frequently counselled to make lifestyle changes to minimize P. aeruginosa exposure, these results have important implications. In particular, the occurrence of P. aeruginosa in tap water highlights the need to disinfect the CF patients’ nebuliser after each use.
– A study from John Moore’s unit in Belfast confirming the ubiquitous nature of P. aeruginosa in the environment.
Schultz A, Caudri D. Cough swabs less useful but induced sputum very useful in symptomatic older children with cystic fibrosis. Lancet Respir Med. 2018 Jun;6(6):410-411. doi: 10.1016/S2213-2600(18)30183-8. Epub 2018 May 16.Full text [Pubmed]
Infancy and the early preschool years comprise a vital period when structural changes in the lungs of people with cystic fibrosis begins. Therefore, while Ronchetti and colleagues (abstract above) provide robust evidence for the usefulness of sputum induction in symptomatic older children with cystic fibrosis, future efforts should be focused on developing an accurate non-invasive method for microbiological surveillance in young asymptomatic children. Only small numbers of children younger than 6 years were recruited, and the sample was too small to enable a separate analysis of children younger than 6 years. Also, for most samples taken in the part of the study comparing sputum induction with bronchoalveolar lavage, participants were symptomatic (ie, had respiratory exacerbations)
André Schultzis is a paediatric respiratory physician and the Director of Cystic Fibrosis at Perth Children’s Hospital.
Wood ME, Stockwell RE, Johnson GR, Ramsay KA, Sherrard LJ, Kidd TJ, Cheney J, Ballard EL, O’Rourke P, Jabbour N, Wainwright CE, Knibbs LD, Sly PD, Morawska L, Bell SC. Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei. Thorax. 2018 Apr 7. pii: thoraxjnl-2018-211567. doi: 10.1136/thoraxjnl-2018-211567. [Epub ahead of print] [Pubmed]
The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens the authors measured.
Wood ME, Stockwell RE, Johnson GR, Ramsay KA, Sherrard LJ, Jabbour N, Ballard E, O’Rourke P, Kidd TJ, Wainwright CE, Knibbs LD, Sly PD, Morawska L, Bell SC.F ace Masks and Cough Etiquette Reduce the Cough Aerosol Concentration of Pseudomonas aeruginosa in People with Cystic Fibrosis.Am J Respir Crit Care Med. 2018 Feb 1;197(3):348-355. doi: 10.1164/rccm.201707-1457OC.[Pubmed]
Twenty-five adults with CF and chronic P. aeruginosa infection were recruited. Participants performed six talking and coughing manoeuvres, with or without facemasks (surgical and N95) and hand covering the mouth when coughing (cough etiquette) in an aerosol-sampling device.
Facemasks reduced cough-generated P. aeruginosa aerosols, with the surgical mask providing enhanced comfort. Cough etiquette was less effective at reducing viable aerosols.
Hoo ZH, Edenborough FP, Curley R, Prtak L, Dewar J, Allenby MI, Nightingale JA, Wildman MJ. Understanding Pseudomonas status among adults with cystic fibrosis: a real-world comparison of the Leeds criteria against clinicians’ decision.Eur J Clin Microbiol Infect Dis. 2018 Jan 6. doi: 10.1007/s10096-017-3168-4. [Epub ahead of print] [Pubmed]
Pseudomonas aeruginosa status influences cystic fibrosis (CF) clinical management but no ‘gold standard’ definition exists. The Leeds criteria are commonly used but may lack sensitivity for chronic P. aeruginosa. We compared clinicians’ decision with the Leeds criteria in three adult CF centres. Two independent prospective datasets (Sheffield dataset, n = 185 adults; ACtiF pilot dataset, n = 62 adults from two different centres) were analysed. Clinicians involved in deciding P. aeruginosa status were blinded to the study objectives. Clinicians considered more adults with CF to have chronic P. aeruginosa infection compared to the Leeds criteria. This was more so for the Sheffield dataset (106/185, 57.3% with clinicians’ decision vs. 80/185, 43.2% with the Leeds criteria; kappa coefficient between these two methods 0.72) compared to the ACtiF pilot dataset (34/62, 54.8% with clinicians’ decision vs. 30/62, 48.4% with the Leeds criteria; kappa coefficient between these two methods 0.82). However, clinicians across different centres were relatively consistent once age and severity of lung disease, as indicated by the type of respiratory samples provided, were taken into account. Agreement in P. aeruginosa status was similar for both datasets among adults who predominantly provided sputum samples (kappa coefficient 0.78) or adults > 25 years old (kappa coefficient 0.82). Across three different centres, clinicians did not always agree with the Leeds criteria and tended to consider the Leeds criteria to lack sensitivity. Where disagreement occurred, clinicians tended to diagnose chronic P. aeruginosa infection because other relevant information was considered. These results suggest that a better definition for chronic P. aeruginosa might be developed by using consensus methods to move beyond a definition wholly dependent on standard microbiological results.
– It is surprising that the authors make virtually no mention of Pseudomonas antibodies – shown in numerous previous studies to be an accurate indication of chronic Pseudomonas infection since the early classic studies of Niels Hoiby in the Seventies (Hoiby N et al, Acta Path Microbiol Scand 1973; 81:298-308. [PubMed]; Hoiby N, Acta Pathol Microbiol Immunol Scand 1977; Supplement (262): 1-96. [PubMed])and indeed shown to correlate with the presence of chronic Pseudomonas infection in the original paper describing the Leeds criteria (Lee TWR et al.J Cyst Fibros 2003; 2:29-34.[PubMed].
Dr Zhe Hui Hoo is Clinical Research Fellow, in the Medical Statistics Group, University of Sheffield.
Hurley MN, Fogarty A, McKeever TM, Goss CH, Rosenfeld M, Smyth AR. Early Respiratory Bacterial Detection and Antistaphylococcal Antibiotic Prophylaxis in Young Children with Cystic Fibrosis. Ann Am Thorac Soc. 2018 Jan;15(1):42-48. doi: 10.1513/AnnalsATS.201705-376OC. [Pubmed]
Consensus is lacking regarding anti-staphylococcal antibiotic prophylaxis use for young children with cystic fibrosis. Prophylaxis is recommended in the United Kingdom, but it is recommended against in the United States. To test the hypothesis that anti-staphylococcal antibiotic prophylaxis is associated with a decreased risk of Staphylococcus aureus acquisition but no increased risk of Pseudomonas aeruginosa acquisition. The authors undertook a longitudinal observational study of children with cystic fibrosis who were recruited from birth (or from their first registry entry in the period) and followed until the age of 4 years (1,500 d) using 2000-2009 data from the UK Cystic Fibrosis Trust and Cystic Fibrosis Foundation registries. Children were excluded if they had a positive culture result for S. aureus or P. aeruginosa, or if they were receiving inhaled antibiotics, at the first encounter. Time to first S. aureus and P. aeruginosa detection in the UK/U.S. cohorts was compared using a Cox proportional hazards model. A UK-based analysis compared the same for those receiving flucloxacillin with those who received no prophylaxis. They included the following covariates: sex, age at registry entry, dornase alfa use, genotype, and centre size.
The primary analysis comprised 1,074 UK and 3,677 U.S. children. The risk of first detection was greater in U.S. children than in UK children for S. aureus (hazard ratio [HR], 5.79; 95% confidence interval [CI], 4.85, 6.90; P < 0.001) and P. aeruginosa (HR, 1.92; 95% CI, 1.65, 2.24; P < 0.001). In the UK analysis, we compared 278 children receiving flucloxacillin and 306 receiving no prophylaxis. Flucloxacillin was not associated with a reduced risk of S. aureus detection (HR, 1.22; 95% CI, 0.74, 2.0; P = 0.43), but it was associated with an increased risk of P. aeruginosa detection (HR, 2.53; 95% CI, 1.71, 3.74; P < 0.001). None of the covariates significantly affected the risk estimate in either analysis.
The risk of first detection of S. aureus and P. aeruginosa was greater in the United States than in the United Kingdom. In the United Kingdom, the risk of first P. aeruginosa detection was increased among those receiving flucloxacillin compared with those who received no prophylaxis. The authors consider these observational findings should be examined in randomized controlled trials.
Millar BC, McCaughan J, Rendall JC, Downey DG, Moore JE. Pseudomonas aeruginosa in cystic fibrosis patients with c.1652G›A (G551D)-CFTR treated with ivacaftor-Changes in microbiological parameters.J Clin Pharm Ther. 2018 Feb;43(1):92-100. doi: 10.1111/jcpt.12616. Epub 2017 Sep 22 [Pubmed]
This study shows that microbiological parameters with patients on ivacaftor (IVA) therapy were not detrimentally affected, as there was a lower requirement IV antibiotic therapy and a reduction in the rate and density of mucoid Pseudomonas aeruginosa (M‐PA). Examination of antibiotic susceptibility, as expressed by Relative Resistance Index, against four classes of antibiotic in (a) total PA, (b) Non‐mucoid PA (NM‐PA) and (c) M‐PA, isolated from patients before and after commencement of ivacaftor therapy, showed no reduction in antibiotic susceptibility. Overall, this study suggests an improvement in the microbiology status of patients on IVA therapy.
Following commencement of IVA therapy, patients required less iv antibiotic courses but no change in number of oral antibiotics courses. There was significant reduction in both the rate of isolation and density of M-PA (P = .02; P = .006, respectively). In contrast, there was no significant reduction in both the rate of isolation and density of NM-PA (P = .90; P = .07, respectively). Antimicrobial susceptibility in NM-PA and M-PA was not significantly reduced within any of the antibiotics classes or individual antibiotics examined. Increased susceptibility was noted in the beta-lactam class for NM-PA and M-PA, in particular with ceftazidime.Overall, (i) the requirement for less iv antibiotic therapy, (ii) a reduction in the rate and density of M- PA and (iii) no reduction in antibiotic
Dr. Bronagh Millar is a Research Fellow at the School of Mechanical and Aerospace Engineering, Queens University, Belfast.
Muhlebach MS, Zorn BT, Esther CR, Hatch JE, Murray CP, Turkovic L, Ranganathan SC, Boucher RC, Stick SM, Wolfgang MC. Initial acquisition and succession of the cystic fibrosis lung microbiome is associated with disease progression in infants and preschool children. PLoS Pathog. 2018 Jan 18;14(1):e1006798. doi: 10.1371/journal.ppat.1006798. eCollection 2018 Jan. Free article available [Pubmed]
To better understand the relationship between the lung microbiome and early respiratory disease, the authors characterized the lower airways microbiome using bronchoalveolar lavage (BAL) samples obtained from clinically stable CF infants and pre-schoolers who underwent bronchoscopy and chest computed tomography (CT). Cross-sectional samples suggested a progression of the lower airways microbiome with age, beginning with relatively sterile airways in infancy. By age two, bacterial sequences typically associated with the oral cavity dominated lower airways samples in many CF subjects. The presence of an oral-like lower airways microbiome correlated with a significant increase in bacterial density and inflammation. These early changes occurred in many patients, despite the use of antibiotic prophylaxis in our cohort during the first two years of life. The majority of CF subjects older than four harboured a pathogen dominated airway microbiome, which was associated with a further increase in inflammation and the onset of structural lung disease, despite a negligible increase in bacterial density compared to younger patients with an oral-like airway microbiome.
The authors consider their findings suggest that changes within the CF lower airways microbiome occur during the first years of life and that distinct microbial signatures are associated with the progression of early CF lung disease.
– All children in this study were prescribed amoxicillin-clavulanic acid during the first two years of life, which presumably had some effect on the results, or delayed the onset of lower airways acquisition of oral microbes. Reading of the original paper confirms the importance but great complexity of the subject.
Waters V, Grimwood K. Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros. 2018 Mar 27. pii: S1569-1993(18)30079-1. doi: 10.1016/j.jcf.2018.03.007. [Epub ahead of print] [Pubmed]
Review of the studies of Heltshe et al and Boutin et al. aim to redefine what chronic P. aeruginosa infection means in CF.It is clear, though, that mucoid P. aeruginosa does have an adaptive advantage in early CF infection as mucoidy was associated with an almost three-fold increased risk of transition to chronic infection in this current study. Despite the presence of this risk factor, however, only 13% of P. aeruginosa infected patients went on to develop chronic infection. Although Heltshe et al. did not provide details as to eradication strategies used in this cohort, this low incidence of persistent infection does speak to the overall effectiveness of current antimicrobial treatment for early P. aeruginosa infection.
Boutin et al. took their investigation a step further by using molecular methods, specifically quantitative polymerase chain reaction (qPCR), to define chronic P. aeruginosa infection. Performing P. aeruginosa qPCR on culture negative throat swabs may further improve the diagnosis of lower airway infection in young children with CF who are unable to produce sputum,
Caskey S, Stirling J, Moore JE, Rendall JC. Occurrence of Pseudomonas aeruginosa in waters: Implications for patients with cystic fibrosis(CF). Lett Appl Microbiol. 2018 Mar 14. doi: 10.1111/lam.12876. [Epub ahead of print] [Pubmed]
Chronic P. aeruginosa infection is associated with increased morbidity and mortality in patients with cystic fibrosis (CF). Current understanding of risk factors for acquisition is limited and so the aim of this study was to examine a large sample of environmental waters from diverse sources. Environmental water samples [n= 7904] from jacuzzis, hydrants, swimming pools, hot tubs, plunge pools, bottled natural mineral water (NMW), taps, springs, ice machines, water coolers, bores and showers were examined for the presence of P. aeruginosa. P. aeruginosa was detected in 524/7904 (6.6%) waters examined. Hot tubs [51/243; 20.9%], tap water [3/40; 8%] and jacuzzis [432/5811; 7.4%] were the most likely environments where P. aeruginosa was isolated. P. aeruginosa was isolated from bottled water [2/67; 3%]. The authors say their study highlights the ubiquitous nature of P. aeruginosa in the environment. Given CF patients are frequently counselled to make lifestyle changes to minimize P. aeruginosa exposure, these results have important implications. In particular, the occurrence of P. aeruginosa in tap water highlights the need to disinfect the CF patients’ nebuliser after each use.
– A study from John Moore’s unit in Belfast confirming the ubiquitous nature of P. aeruginosa in the environment.
Ratjen F, Moeller A, McKinney ML, Asherova I, Alon N, Maykut R, Angyalosi G; EARLY study group. Collaborators (12)Eradication of early P. aeruginosa infection in children <7 years of age with cystic fibrosis: The early study. J Cyst Fibros. 2018 Apr 20. pii: S1569-1993(18)30087-0. doi: 10.1016/j.jcf.2018.04.002. [Epub ahead of print] [Pubmed]
Antibiotic eradication treatment is the standard-of-care for cystic fibrosis (CF) patients with early Pseudomonas aeruginosa (Pa)-infection; however, evidence from placebo-controlled trials is limited. This double-blind, placebo-controlled trial randomised CF patients aged 3 months to <7 years (N = 51) with early Pa-infection to tobramycin inhalation solution (TOBI 300 mg) or placebo (twice daily) for 28 days with an optional cross-over on Day 35. Primary endpoint was proportion of patients having throat swabs/sputum free of Pa on Day 29. On Day 29, 84.6% patients in the TOBI versus 24.0% in the placebo group were Pa-free (p < 0.001). At the end of the cross-over period, 76.0% patients receiving TOBI in the initial 28 days were Pa-free compared to 47.8% receiving placebo initially. Adverse events were consistent with the TOBI safety profile with no differences between TOBI and placebo.
The authors concluded TOBI was effective in eradicating early Pa-infection with a favourable safety profile in young CF patients.
– Not mentioned in the summary was that at day 91 more patients receiving TOBI during the initial 28 days (the TOBI/placebo group:19/25 patients, 76%) were Pa free compared with those initially on placebo (placebo/TOBI group: 11/23 patients 47.8 %). This was unfortunate for the latter group and emphasises the point that eradication treatment must be early – the greater the delay in initiating treatment the more the risk of chronic Pa infection as occurred in these placebo-treated children. These facts were already known however apparently the regulatory requirements were now satisfied by this study..
Breuer O, Caudri D, Akesson L, Ranganathan S, Stick SM, Schultz A; AREST CF. The clinical significance of oropharyngeal cultures in young children with cystic fibrosis. 2018 Apr 20. pii: 1800238. doi: 10.1183/13993003.00238-2018. [Epub ahead of print][Pubmed]
In children with cystic fibrosis (CF) the associations between oropharyngeal swabs (OPS) for detection of Pseudomonas and lung disease has not been evaluated. OPS and bronchoalveolar lavage (BAL) samples were obtained annually in children with CF from 2005 to 2017. OPS test characteristics were calculated using BAL as gold standard. Results were related to lung inflammation (BAL neutrophil elastase, interleukin-8), structural lung disease (chest CT PRAGMA-CF scores), respiratory exacerbations, and future detection of Pseudomonas on BAL.
From 181 patients, 690 paired OPS-BAL cultures were obtained. Prevalence of Pseudomonas in BAL was 7.4%. OPS sensitivity was 23.0% and specificity 91.4%, reducing the post-test probability for a positive BAL following negative OPS to 6.3%. Pseudomonas on OPS was not associated with lung inflammation or respiratory exacerbations but was weakly associated with current PRAGMA-CF disease score (p=0.043). Pseudomonas on BAL was associated with positive neutrophil elastase (OR 4.17 CI95% 2.04-8.53, p<0.001), increased interleukin-8 (p<0.001), increased all baseline PRAGMA-CF scores (p<0.001), progression of PRAGMA-CF scores (p<0.05) and increased risk of respiratory exacerbations (IRR 2.11 CI95% 1.15-3.87, p=0.017).
In children with CF oropharyngeal swabs only marginally change the probability of detecting lower airway Pseudomonas and are not associated with lung disease indices nor exacerbations risk.
Ronchetti K, Tame JD, Paisey C, Thia LP, Doull I, Howe R, Mahenthiralingam E. The CF-Sputum Induction Trial (CF-SpIT) to assess lower airway bacterial sampling in young children with cystic fibrosis: a prospective internally controlled interventional trial.Lancet Respir Med.2018 Jun;6(6):461-471. doi: 10.1016/S2213-2600(18)30171-1. Epub 2018 May 16. [Pubmed]
A large study from the Paediatric Unit in Cardiff to assess the pathogen yield from sputum induction compared with that from cough swab and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage in children with cystic fibrosis aged between 6 months and 18 years. Samples from cough swab, sputum induction, and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage were matched for within-patient comparisons. Primary outcomes were comparative pathogen yield between sputum induction and cough swab for stage 1, and between sputum induction, and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage for stage 2. Between Jan 23, 2012, and July 4, 2017, 124 patients were prospectively recruited to the trial and had 200 sputum induction procedures for stage 1. 167 (84%) procedures were successful and the procedure was well tolerated. Of the 167 paired samples, 63 (38%) sputum-induction samples were pathogen positive compared with 24 (14%) cough swabs (p<0·0001; odds ratio [OR] 7·5; 95% CI 3·19-17·98). More pathogens were isolated from sputum induction than cough swab (79 [92%] of 86 vs 27 [31%] of 86; p<0·0001). For stage 2, 35 patients had a total of 41 paired sputum-induction and bronchoalveolar lavage procedures. Of the 41 paired samples, 28 (68%) were positive for at least one of the concurrent samples. 39 pathogens were isolated. Sputum induction identified 27 (69%) of the 39 pathogens, compared with 22 (56%; p=0·092; OR 3·3, 95% CI 0·91-12·11) on single-lobe, 28 (72%; p=1·0; OR 1·1, 95% CI 0·41-3·15) on two-lobe, and 33 (85%; p=0·21; OR 2·2, 95% CI 0·76-6·33) on six-lobe bronchoalveolar lavage.
Conclusions. Sputum induction is superior to cough swab for pathogen detection, is effective at sampling the lower airway, and is a credible surrogate for bronchoalveolar lavage in symptomatic children. A substantial number of bronchoscopies could be avoided if sputum induction is done first and pathogens are appropriately treated. Both sputum induction and six-lobe bronchoalveolar lavage provide independent, sizeable gains in pathogen detection compared with the current gold-standard two-lobe bronchoalveolar lavage. The authors propose that sputum induction and six-lobe bronchoalveolar lavage combined are used as standard of care for comprehensive lower airway pathogen detection in children with cystic fibrosis.
Katherine Ronchetti and Jo-Dee Tame are physiotherapists at the Children’s Hospital for Wales.
Zemanick E, Burgel PR, Taccetti G, Holmes A, Ratjen F5 Byrnes CA, Waters VJ, Bell SC, VanDevanter DR, Stuart Elborn J, Flume PA; Antimicrobial Resistance International Working Group in Cystic Fibrosis. Antimicrobial resistance in cystic fibrosis: A Delphi approach to defining best practices. J Cyst Fibros. 2019 Oct 31. pii: S1569-1993(19)30919-1. doi: 10.1016/j.jcf.2019.10.006. [Epub ahead of print][Pubmed]
Antimicrobial susceptibility testing (AST) is a cornerstone of infection management in cystic fibrosis. However, there is little evidence that AST predicts the clinical outcome of CF antimicrobial treatment. It has been suggested there is a need for careful consideration of current AST use by the CF community.
The authors engaged a group of experts consisting of pulmonary (adult and pediatric) and infectious disease clinicians, microbiologists, and pharmacists representing a broad international experience. We conducted an iterative systematic survey (Delphi) to determine and quantify consensus regarding key questions facing CF clinicians in the use of respiratory culture results including what tests to order, when to obtain them, and how to act upon the results of the testing.
Consensus was reached for many questions but there was not universal agreement to the questions that were addressed. There were some differences with respect to cultures obtained for surveillance compared to when there is clinical worsening. Areas of general consensus include when and how respiratory cultures should be performed, what information should be reported, and when AST should be performed. A key finding is that clinical response to treatment is used to guide treatment decisions rather than AST results.
CONCLUSIONS:
Recommendations are presented regarding questions related to microbiology testing for patients with CF. We have also offered recommendations for priority research questions.
– The Key Recommendations were as follows –
- Surveillance respiratory cultures should be obtained four times per yea
- Respiratory cultures should be obtained at the diagnosis of a pulmonary exacerbation
- Spontaneously or induced expectorated sputum is preferred for respiratory cultures
- Respiratory culture results should report both bacterial genus and species
- Bacterial susceptibility testing should be performed at least once annually, when a new pathogen, or at the time of a pulmonary exacerbation
- Antibiotic selection for treatment is based on bacterial species
- Changes in antibiotic treatment are based on clinical response to treatment and informed by susceptibility testing
Dr Edith Zemanick is in the Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States.
Héry-Arnaud G, Boutin S, Cuthbertson L, Elborn SJ, Tunney MM.The lung and gut microbiome: what has to be taken into consideration for cystic fibrosis? J Cyst Fibros. 2019 Jan;18(1):13-21. doi: 10.1016/j.jcf.2018.11.003. Epub 2018 Nov 25.[Pubmed]
The 15th European Cystic Fibrosis Society (ECFS) Basic Science pre-conference Symposium focused on the topic of the microbiome, asking the question “The lung and gut microbiome: what has to be considered for cystic fibrosis (CF)?” This review gives an overview of the main points raised during the symposium, which dealt with the technical considerations, pathophysiology and clinical implications of the microbiome in CF.
Wood ME, Stockwell RE, Johnson GR, Ramsay KA, Sherrard LJ, Kidd TJ, Cheney J, Ballard EL, O’Rourke P, Jabbour N, Wainwright CE, Knibbs LD, Sly PD, Morawska , Bell SC. Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei. Thorax. 2019 Jan;74(1):87-90. doi: 10.1136/thoraxjnl-2018-211567. Epub 2018 Apr 7.[Pubmed]
The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non-Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured.
Michelle E Wood is Research Assistant at the Lung Bacteria Group, QIMR Berghofer Medical Research Institute, Herston, The Adult Cystic Fibrosis Centre Prince Charles Hospital and the University of Queensland Australia. Professor Scott Bell is the Hon. Group Leader
Lababidi N, Sigal V, Koenneke A, Schwarzkopf K, Manz A, Schneider M. Microfluidics as tool to prepare size-tunable PLGA nanoparticles with high curcumin encapsulation for efficient mucus penetration.Beilstein J Nanotechnol. 2019 Nov 19;10:2280-2293. doi: 10.3762/bjnano.10.220. eCollection 2019.[Pubmed]
Great challenges still remain to develop drug carriers able to penetrate biological barriers (such as the dense mucus in cystic fibrosis) and for the treatment of bacteria residing in biofilms, embedded in mucus. Drug carrier systems such as nanoparticles (NPs) require proper surface chemistry and small size to ensure their permeability through the hydrogel-like systems. We have employed a microfluidic system to fabricate poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with a muco-penetrating stabilizer (Pluronic), with a tunable hydrodynamic diameter ranging from 40 nm to 160 nm. The size dependence was evaluated by varying different parameters during preparation, namely polymer concentration, stabilizer concentration, solvent nature, the width of the focus mixing channel, flow rate ratio and total flow rate. Furthermore, the influence of the length of the focus mixing channel on the size was evaluated in order to better understand the nucleation-growth mechanism. Surprisingly, the channel length was revealed to have no effect on particle size for the chosen settings. In addition, curcumin was loaded (EE% of ≈68%) very efficiently into the nanoparticles. Finally, the permeability of muco-penetrating PLGA NPs through pulmonary human mucus was assessed; small NPs with a diameter of less than 100 nm showed fast permeation, underlining the potential of microfluidics for such pharmaceutical applications.
Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, 66123 Saarbrücken, Germany.
Lindsay Jackson , Valerie Waters. Factors influencing the acquisition and eradication of early Pseudomonas aeruginosa infection in cystic fibrosis. J Cyst Fibros 2020 Nov 7;S1569-1993(20)30883-3.doi: 10.1016/j.jcf.2020.10.008.Online ahead of print. [Pubmed]
In recent years considerable improvements have been made in increasing the life expectancy of patients with cystic fibrosis. New highly effective modulator therapies targeting the underlying defect in the cystic fibrosis transmembrane conductance regulator protein are expected to enhance lifespan even further.However, chronic Pseudomonas aeruginosa pulmonary infections continue to threaten CF patient lung health and mortality rates. Early and aggressive antibiotic eradication therapies targeting P. aeruginosa are standard practice, but these eradication therapies fail in 10-40% of patients. The reasons for P. aeruginosa eradication failure remain unclear.
This review summarizes the evidence to date for pseudomonal acquisition and eradication failure in the cystic fibrosis lung. A complex combination of host and bacterial factors are responsible for initial establishment of P. aeruginosa pulmonary infections. Moreover, host and pseudomonal factors, polymicrobial interactions, and antimicrobial limitations in relation to P. aeruginosa eradication therapy failure are summarized
Both authors are at the Translational Medicine, Hospital for Sick Children, Toronto, Canada.
Dr Lindsay Jackson is Postdoctoral Research Fellow and Medical Writer INVIVO Communications Inc.
Dr Valerie Waters is Staff Physician Division of Infectious Diseases and Associate Professor, Department of Paediatrics also Senior Associate Scientist in the Translational Medicine.
Schwensen HF, Moser C, Perch M, Pressler T, Høiby N. Pseudomonas aeruginosa antibody response in cystic fibrosis decreases rapidly following lung transplantation. J Cyst Fibros. 2020 Feb 7. pii: S1569-1993(20)30044-8. doi: 10.1016/j.jcf.2020.01.012. [Epub ahead of print] [Pubmed]
Specific Pseudomonas aeruginosa (PA) precipitating immunoglobulin G antibodies in serum are correlated with PA biofilm infection and are used as diagnostic and prognostic markers in cystic fibrosis (CF). The aim of this study was to examine the change of PA antibody response in CF patients after bilateral sequential lung transplantation (LTx).
PA antibodies and airway bacteriology were retrospectively evaluated in 20 chronically infected CF patients, who underwent LTx between 2001 and 2016 at Rigshospitalet, Copenhagen. Yearly precipitin counts from one year before LTx and up to five years after LTx were compared. Monthly airway cultures were examined in the five-year period after LTx. In addition, crossed immunoelectrophoresis (CIE) were analysed for each patient for antigenic similarities from time of infection, pre-LTx and post-LTx.
Results: All patients experienced a significant drop in PA antibodies from one year pre-LTx to one year post-LTx (p < 0.0001). The PA antibody level did not differ between those, who became re-infected immediately after LTx, and those, who did not. No patients regained the high pre-LTx precipitin levels in the following five years. The antigenic specificities of the sera post-LTx were in each patient similar to the antigenic specificities at the beginning of infection indicating a decades long memory of their immune response like an “immunological fingerprint”.
The authors concluded that after LTx a significant and continuous reduction in PA antibodies was observed. The reduction was independent of immediate reinfection after LTx. A novel three-factor explanatory model is presented.
From the Department of Clinical Microbiology, Rigshospitalet (Copenhagen University Hospital), Denmark.
Professor Niels Hoiby. the late Dr Christian Koch and their colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection (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]) and introducing more aggressive treatment both for chronic infection (1983 Szaff M, Hoiby N, Flensborg EW. Frequent antibiotic therapy improves survival of cystic fibrosis patients with chronic Pseudomonas aeruginosa infection. Acta Paediatr Scand 1983; 72; 651-657.[PubMed]) and early infection (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]. All these papers are abstracted in the appropriate year section of this history.
Niels Hoiby and his colleagues in Copenhagen have been one of the major influences, well ahead of their time, in recognising the significance of P. aeruginosa infection and introducing more aggressive treatment both for chronic and early infection. No one has made a more significant contribution to the treatment of CF than Niels and his colleagues at the Rigshospitalet in Copenhagen. Certainly they were a major influence on us at the Leeds Regional CF Centre in the Eighties. It was great privilege to be invited to speak at Niels’s celebration of 25 years as Professor at the University in Copenhagen.
Zhang D, Li S, Wang N, Tan HY, Zhang Z, Feng Y. The Cross-Talk Between Gut Microbiota and Lungs in Common Lung Diseases.
Front Microbiol. 2020 Feb 25;11:301. doi: 10.3389/fmicb.2020.00301. eCollection 2020. Free PMC Article [Pubmed]
Emerging findings indicate there is a vital cross-talk between gut microbiota and the lungs, which is known as gut-lung axis. The gut disturbances in lung diseases including allergy, asthma, chronic obstructive pulmonary disease, cystic fibrosis and lung cancer were observed by extensive studies. Investigating how gut microbiota impact other distant organs is of great interest in recent years. Although it has not been fully understood whether the disturbance is the cause or effect of lung diseases, alterations in the gut microbial species and metabolites have been linked to changes in immune responses and inflammation as well as the disease development in the lungs. In this article, we systemically review the role and mechanisms underlying the changes in the constituent of gut microbiota and metabolites in lung diseases. In particular, the roles of gut-lung axis in mediating immune responses and reshaping inflammation are highlighted. Furthermore, we discuss the potential of strategies to manipulate the gut microbiota and metabolites as the therapeutic approach for lung diseases.
D Zhang is at the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
.Sara L Rassoulian Barrett , Elizabeth A Holmes , Dustin R Long, Ryan C Shean, Gilbert E Bautista, Sumedha Ravishankar, Vikas Peddu, Brad T Cookson, Pradeep K Singh, Alexander L Greninger, Stephen J Salipante. Cell Free DNA From Respiratory Pathogens Is Detectable in the Blood Plasma of Cystic Fibrosis Patients. 2020 Apr 23;10(1):6903.doi: 10.1038/s41598-020-63970-0. [Pubmed]
Diagnostically informative microbial cell-free DNA (cfDNA) can be detected from blood plasma during fulminant infections such as sepsis. However, the potential for DNA from airway pathogens to enter the circulation of cystic fibrosis (CF) patients during chronic infective states has not yet been evaluated.
The authors assessed whether patient blood contained measurable quantities of cfDNA from CF respiratory microorganisms by sequencing plasma from 21 individuals with CF recruited from outpatient clinics and 12 healthy controls. To account for possible contamination with exogenous microbial nucleic acids, statistical significance of microbe-derived read counts from CF patients was determined relative to the healthy control population.
In aggregate, relative abundance of microbial cfDNA was nearly an order of magnitude higher in CF patients than in healthy subjects (p = 8.0×10-3). 15 of 21 (71%) CF patients demonstrated cfDNA from one or more relevant organisms. In contrast, none of the healthy subjects evidenced significant microbial cfDNA for any of the organisms examined. Concordance of cfDNA with standard microbiological culture of contemporaneously collected patient sputum was variable.
The authors consider their findings provide evidence that cfDNA from respiratory pathogens are present in the bloodstream of most CF patients, which could potentially be exploited for the purposes of non-invasive clinical diagnosis.
Sara L Rassoulian Barrett is in the Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
Stephen J Salipante is a pathologist and Assistant professor of Laboratory Medicine in the Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.
Geraint B Rogers, Steven L Taylor, Lucas R Hoffman, Lucy D Burr. The impact of CFTR modulator therapies on CF airway microbiology. J Cyst Fibros 2020 May;19(3):359-364. doi: 10.1016/j.jcf.2019.07.008.Epub 2019 Aug [Pubmed]
Major historical advances in cystic fibrosis (CF) respiratory clinical care, including mechanical airway clearance and inhaled medications, have aimed to address the consequences of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. In contrast, CFTR modulator therapies instead target the underlying protein defect that leads to CF lung disease. The extent to which these therapies might reduce susceptibility to chronic lung infections remains to be seen. However, by improving airway clearance, reducing the requirement for antibiotics, and in some cases, through direct antimicrobial effects, CFTR modulators are likely to result in substantial changes in CF airway microbiology. These changes could contribute substantially to the clinical benefit associated with modulator therapies, as well as providing an important indicator of treatment efficacy and residual pathophysiology. Indeed, the widespread introduction of modulator therapies might require us to re-consider our models of CF airway microbiology.
Prof Geraint B Rogers is a molecular microbiologist and microbial ecologist. He is the Director, Microbiome Research at SAHMRI, leads a laboratory based within the Flinders University School of Medicine, Adelaide
Dominic A Hughes, Olga Archangelidi, Matthew Coates, Darius Armstrong-James, Stuart J Elborn, Siobhán B Carr, Jane C Davies. Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study. J Cyst Fibros 2021 May 3;S1569-1993(21)00117-X.doi: 10.1016/j.jcf.2021.04.007.Online ahead of print. [Pubmed]
Background: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection using the UK CF Registry.Full details on PubMed.
Conclusions: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.
Dr Dominic A Hughes is a researcher at the National Heart & Lung Institute, Imperial College London, UK; Royal Brompton and Harefield Hospitals, London, UK
Chan BK, Stanley G, Modak M, Koff JL, Turner PE. Bacteriophage therapy for infections in CF. Pediatr Pulmonol. 2021 Feb;56 Suppl 1: S4-S9. doi: 10.1002/ppul.25190. [Pubmed]
Pseudomonas aeruginosa and Staphylococcus aureus are bacterial pathogens frequently associated with pulmonary complications and disease progression in cystic fibrosis (CF). However, these bacteria increasingly show resistance to antibiotics, necessitating novel management strategies. One possibility is bacteriophage (phages; bacteria-specific viruses) therapy, where lytic phages are administered to kill target bacterial pathogens. Recent publications of case reports of phage therapy to treat antibiotic-resistant lung infections in CF have garnered significant attention. These cases exemplify the renewed interest in phage therapy, an older concept that is being newly updated to include rigorous collection and analysis of patient data to assess clinical benefit, which will inform the development of clinical trials. As outcomes of these trials become public, the results will be a valuable gauge of the potential usefulness of phage therapy to address the rise in antibiotic-resistant bacterial infections. In addition, we highlight the further need for basic research to accurately predict the different responses of target bacterial pathogens when phages are administered alone, sequentially, or as mixtures (cocktails), and whether within-cocktail interactions among phages hold consequences for the efficacy of phage therapy in patient treatment.
Dr Benjamin K Chan is research scientist in the Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut, USA
Renee N Ng, Anna S Tai, Barbara J Chang, Stephen M Stick, Anthony Kicic Overcoming Challenges to Make Bacteriophage Therapy Standard Clinical Treatment Practice for Cystic Fibrosis. Front Microbiol 2021 Jan 11;11:593988.doi: 10.3389/fmicb.2020.593988.eCollection 2020. Free PMC article [Pubmed]
Individuals with cystic fibrosis (CF) are given antimicrobials as prophylaxis against bacterial lung infection, which contributes to the growing emergence of multidrug resistant (MDR) pathogens isolated. Pathogens such as Pseudomonas aeruginosa that are commonly isolated from individuals with CF are armed with an arsenal of protective and virulence mechanisms, complicating eradication and treatment strategies. While translation of phage therapy into standard care for CF has been explored, challenges such as the lack of an appropriate animal model demonstrating safety in vivo exist. In this review, we have discussed and provided some insights in the use of primary airway epithelial cells to represent the mucoenvironment of the CF lungs to demonstrate safety and efficacy of phage therapy. The combination of phage therapy and antimicrobials is gaining attention and has the potential to delay the onset of MDR infections. It is evident that efforts to translate phage therapy into standard clinical practice have gained traction in the past 5 years. Ultimately, collaboration, transparency in data publications and standardized policies are needed for clinical translation.
Renee N Ng is a PhD Candidate at the School of Biomedical Sciences, The University of Western Australia, Perth, WA, Australia
Courtney E Price, George A O’Toole. The Gut-Lung Axis in Cystic Fibrosis. J Bacteriol 2021 Aug 2;JB0031121.doi: 10.1128/JB.00311-21. Online ahead of print.[Pubmed]
Cystic Fibrosis (CF) is a heritable, multi-organ disease that impacts all tissues that normally express CFTR protein. While importance of the airway microbiota has long been recognized, the intestinal microbiota has only recently been recognized as an important player in both intestinal and lung health outcomes for persons with CF (pwCF). Here, we summarize current literature related to the gut-lung axis in CF, with a particular focus on three key ideas: Mechanisms through which microbes influence the gut-lung axis, drivers of microbiota alterations, and the potential for intestinal microbiota remediation.
The authors are at the Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover NH 03755, USA.
Margaret Rosenfeld, Anna V Faino, Frankline Onchiri, Melis A Aksit, Scott M Blackman, Elizabeth E Blue, Joseph M Collaco, William W Gordon, Rhonda G Pace, Karen S Raraigh, Yi-Hui Zhou, Garry R Cutting, Michael R Knowles, Michael J Bamshad, Ronald L Gibson. Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis. J Cyst Fibros 2021 Aug 12;S1569-1993(21)01339-4.doi: 10.1016/j.jcf.2021.07.020.Online ahead of print. [Pubmed]
Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years (“Green 3/4”) resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency.
Dr Margaret Rosenfield is in the Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
Zheng Pang, Qingjun Zhu. Traditional Chinese Medicine is an Alternative Therapeutic Option for Treatment of Pseudomonas aeruginosa Infections. Front Pharmacol 2021 Aug 27;12:737252.doi: 10.3389/fphar.2021.737252.eCollection 2021.Free PMC article [Pubmed]
Pseudomonas aeruginosa is an opportunistic pathogen causing life-threatening infections in cystic fibrosis patients and immunocompromised individuals, and it is a leading cause of nosocomial infections associated with significant morbidity and mortality. Treatment of P. aeruginosa is challenging due to the antibiotic resistance to most of the conventional antibiotics. Development of alternative therapeutic options is urgently demanded for the patients who have antibiotic-resistant infections. Traditional Chinese medicine (TCM) has a clinical history of thousands of years for prevention and treatment of infectious diseases in China, taking advantages of improving clinical outcomes, producing less side effects, inhibiting pathogen, and modulating host immunity. Recent research has revealed a variety of natural products derived from TCM showing significant antimicrobial effects on antibiotic-resistant strains of P. aeruginosa alone or combined with antibiotics in vitro or in animal models, suggesting that TCM is a promising complementary and alternative therapeutic approach for treatment of chronic P. aeruginosa infections. This review summarizes the recent findings attempting to dissect the mechanisms of TCM combating P. aeruginosa infections and highlights the molecular targets of TCM on P. aeruginosa and host.
Both the authors are at the Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, China. Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, China. Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Shandong University of Traditional Chinese Medicine, Jinan, China.
Lo M Sosinski, Christian Martin H, Kerri A Neugebauer, Lydia-Ann J Ghuneim, Douglas V Guzior, Alicia Castillo-Bahena, Jenna Mielke, Ryan Thomas, Marc McClelland, Doug Conrad, Robert A Quinn. A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung J Cyst Fibros 2021 Nov 22;S1569-1993(21)02131-7.doi: 10.1016/j.jcf.2021.11.003.Online ahead of print. [Pubmed]
Background: Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF).
Methods: We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics.
Results: The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications.
Conclusions: ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug’s effects take hold.
Lo M Sosinski is a graduate student in the Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI, USA
Birce Sunman, Nagehan Emiralioglu, Gülsen Hazirolan, Burçin Şener, Beste Ozsezen, Dilber Ademhan Tural, Halime Nayir Buyuksahin, Ismail Guzelkas, Ebru Yalcin, Deniz Dogru, Uğur Özçelik, Nural Kiper Effectiveness of Different Eradication Treatment Protocols for New-Onset Pseudomonas aeruginosa in Children with Cystic Fibrosis. Pediatr Pulmonol 2022 Mar 1. doi: 10.1002/ppul.25876. Online ahead of print [Pubmed]
Objectives: While eradicating new-onset Pseudomonas aeruginosa in children with cystic fibrosis is an important issue, there is no clear evidence about the best treatment approach. This retrospective observational cohort study aims to compare the effectiveness of intravenous therapy versus inhalation with/without oral therapy in the eradication of new-onset P aeruginosa, determine the factors affecting the treatment success and assess lung function at baseline and post-treatment.
Methods: Of 399 children, 110 (140 episodes) with either the first P aeruginosa isolation or a new isolation after at least 1 year free of infection, were included. Different eradication regimens (intravenous therapy or inhaled tobramycin or inhaled tobramycin plus oral ciprofloxacin) were compared. Eradication success was accepted as remaining free of infection with a negative culture for 12 months. Demographic, clinical and microbiological characteristics of children, effectiveness of different eradication strategies, time to a new P aeruginosa isolation, and the relationship between lung function and the type of eradication regimen were determined.
Results: Of 140 episodes, intravenous therapy was administered in 53 and inhalation therapy (in combination with or without oral ciprofloxacin) in 87. Total success rate of eradication was 60.7%. Eradication was achieved in 56.6% of children with intravenous therapy, 59.7% with inhaled tobramycin therapy, 72% with inhaled tobramycin plus oral ciprofloxacin therapy. Success rates of different eradication regimens did not differ significantly (p=0.419). Lung function by the end of the first year was worse in the intravenous group compared to the inhalation group (p=0.017 for FEV1, p=0.015 for FVC).
Conclusion: No advantage of intravenous therapy was demonstrated compared to inhalation therapy in terms of eradication success.
Dr Birce Sunman is in the Department of Pediatric Pulmonology, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara, Turkey
Helen Gavillet, Lauren Hatfield, Damian Rivett, Andrew Jones, Anirban Maitra, Alexander Horsley, Christopher van der Gast Bacterial Culture Underestimates Lung Pathogen Detection and Infection Status in Cystic Fibrosis. Microbiol Spectr 2022 Aug 16;e0041922.doi: 10.1128/spectrum.00419-22.Online ahead of print. Free article [Pubmed]
Microbiological surveillance of airway secretions is central to clinical care in cystic fibrosis (CF). However, the efficacy of microbiological culture, the diagnostic gold standard for pathogen detection, has been increasingly questioned. Here we compared culture with targeted quantitative PCR (QPCR) for longitudinal detection of 2 key pathogens, Pseudomonas aeruginosa and Staphylococcus aureus. Prospectively collected respiratory samples taken from 20 pediatric and 20 adult CF patients over a period of 3-years were analyzed. Patients were eligible if considered free of chronic Pseudomonas infection within 12-months prior to start of study. QPCR revealed high levels of infection with both pathogens not apparent from culture alone. Pseudomonas and Staphylococcus were detected by culture on at least one sampling occasion in 12 and 29 of the patients, respectively. Conversely, both pathogens were detected in all 40 patients by QPCR. Classification of infection status also significantly altered in both pediatric and adult patients, where the number of patients deemed chronically infected with Pseudomonas and Staphylococcus increased from 1 to 28 and 9 to 34, respectively. Overall, Pseudomonas and Staphylococcus infection status classification changed respectively for 36 and 27 of all patients. In no cases did molecular identification lead to a patient being in a less clinically serious infection category. Pathogen detection and infection status classification significantly increased when assessed by QPCR in comparison to culture. This could have implications for clinical care of CF patients, including accuracy of infection diagnosis, relevant and timely antibiotic selection, antimicrobial resistance development, establishment of chronic infection, and cross-infection control.
IMPORTANCE Chronic lung infection is the leading cause of morbidity and early mortality for people with cystic fibrosis (pwCF). Microbiological surveillance to detect lung pathogens is recommended as best practise in CF patient care. Here we studied pathogen detection in 40 pwCF over several years. We found that microbiological culture, the diagnostic gold standard, was significantly disparate to targeted culture-independent approaches for detection and determination of chronic infection status of two important pathogens in CF. Pathogen detection was significantly lower by culture and consequently infection status was also misclassified in most cases. In particular, the extent of chronic infection by both P. aeruginosa and S. aureus not realized with culture was striking. Our findings have implications for the development of infection and clinical care of pwCF. Future longitudinal studies with greater patient numbers will be needed to establish the full extent of the clinical implications indicated from this study.
Helen Gavillet is Senior Research Associate in the Department of Life Sciences, Manchester Metropolitan Universitygrid.25627.34, Manchester, United Kingdom.
Rebecca Weiser, Juliette Oakley, Katherine Ronchetti, Jo-Dee Tame, Sven Hoehn, Tomasz P Jurkowski, Eshwar Mahenthiralingam, Julian T Forton. The lung microbiota in children with cystic fibrosis captured by induced sputum sampling. J Cyst Fibros. 2022 Nov;21(6):1006-1012. doi: 10.1016/j.jcf.2022.01.006. Epub 2022 Jan 22. Free article pubmed.ncbi.nlm.nih.gov/35078737/
Background: Spatial topography of the cystic fibrosis (CF) lung microbiota is poorly understood in childhood. How best to sample the respiratory tract in children for microbiota analysis, and the utility of microbiota profiling in clinical management of early infection remains unclear. By comparison with bronchoalveolar lavage (BAL), we assessed the ability of induced sputum (IS) sampling to characterise the lower airway microbiota.
Methods: Sample sets from IS and two or three matched BAL compartments were obtained for microbiota analysis as part of the CF-Sputum Induction Trial (UKCRN_14615, ISRCTNR_12473810). Microbiota profiles and pathogen detection were compared between matched samples.
Results: Twenty-eight patients, aged 1.1-17.7 years, provided 30 sample sets. Within-patient BAL comparisons revealed spatial heterogeneity in 8/30 (27%) sample sets indicating that the lower airway microbiota from BAL is frequently compartmentalised in children with CF. IS samples closely resembled one or more matched BAL compartments in 15/30 (50%) sets, and were related in composition in a further 9/30 (30%). IS detected 86.2% of the Top 5 genera found across matched BAL samples. The sensitivity of IS to detect specific CF-pathogens identified in matched BAL samples at relative abundance ≥5% varied between 43 and 100%, with negative predictive values between 73 and 100%.
Conclusions: Spatial heterogeneity of the lower airway microbiota was observed in BAL samples and presents difficulties for consistent lung sampling. IS captured a microbiota signature representative of the lower airway in 80% of cases, and is a straightforward, non-invasive intervention that can be performed frequently to aid pathogen diagnosis and understand microbiota evolution in children with CF.
Dr Rebecca Weiser is a Research Associate with Microbiomes Microbes and Informatics Group, Organisms and Environment Division, School of Biosciences, Cardiff University, Sir Martin Evans Building, Park Place, Cardiff, UK
Catherine R Armbruster, Yasmin K Hilliam, Anna C Zemke, Samar Atteih, Christopher W Marshall, John Moore, Junu Koirala, Leah Krainz, Jordan R Gaston , Stella E Lee, Vaughn S Cooper, Jennifer M Bomberger. Persistence and evolution of Pseudomonas aeruginosa following initiation of highly effective modulator therapy in cystic fibrosis. mBio. 2024 Apr 2:e0051924. doi: 10.1128/mbio.00519-24. Online ahead of print. pubmed.ncbi.nlm.nih.gov/38564694/
Today, more than 90% of people with cystic fibrosis (pwCF) are eligible for the highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy called elexacaftor/tezacaftor/ivacaftor (ETI) and its use is widespread. Given the drastic respiratory symptom improvement experienced by many post-ETI, clinical studies are already underway to reduce the number of respiratory therapies, including antibiotic regimens, that pwCF historically relied on to combat lung disease progression. Early studies suggest that bacterial burden in the lungs is reduced post-ETI, yet it is unknown how chronic Pseudomonas aeruginosa populations are impacted by ETI. We found that pwCF remain infected throughout their upper and lower respiratory tract with their same strain of P. aeruginosa post-ETI, and these strains continue to evolve in response to the newly CFTR-corrected airway. Our work underscores the continued importance of CF airway microbiology in the new era of highly effective CFTR modulator therapy.
Importance: The highly effective cystic fibrosis transmembrane conductance regulator modulator therapy Elexakaftor/Tezacaftor/Ivacaftor (ETI) has changed cystic fibrosis (CF) disease for many people with cystic fibrosis. While respiratory symptoms are improved by ETI, we found that people with CF remain infected with Pseudomonas aeruginosa. How these persistent and evolving bacterial populations will impact the clinical manifestations of CF in the coming years remains to be seen, but the role and potentially changing face of infection in CF should not be discounted in the era of highly effective modulator therapy.
Catherine Armbruster is in the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.and the Department of Microbiology and Immunology, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire, USA.