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The Microbiome and Emerging Pathogens in Cystic Fibrosis and Non–Cystic Fibrosis Bronchiectasis Andrew M. Jones, MD, FRCP1

1 Manchester Adult Cystic Fibrosis Centre, University Hospital of South

Manchester NHS Trust, Manchester, United Kingdom Semin Respir Crit Care Med 2015;36:225–235.

Abstract

Keywords

► ► ► ► ►

cystic fibrosis non-CF bronchiectasis microbiology emerging pathogens microbiome

Address for correspondence Andrew M. Jones, MD, FRCP, Manchester Adult Cystic Fibrosis Centre, University Hospital of South Manchester NHS Trust, Southmoor Road, Wythenshawe, Manchester M23 9LT, United Kingdom (e-mail: [email protected]).

Chronic pulmonary sepsis is the predominant cause of morbidity for patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously it was thought that respiratory infection in these patients was mostly limited to a very small number of typical pathogens; however, in recent years there have been increasing reports of infection with other emerging potential pathogens including Burkholderia, Stenotrophomonas, Achromobacter, Ralstonia, Pandoraea, nontuberculous mycobacteria, and fungal species. Furthermore, culture-independent methodologies have established that the lungs of patients with CF and non-CF bronchiectasis comprise mixed microbiological communities of aerobic and anaerobic bacteria, fungal and viral species, collectively referred to as the lung microbiome. This article addresses the clinical relevance of emerging pathogens and the lung microbiome in CF and non-CF bronchiectasis.

Traditionally, it is thought that airway microbiology in cystic fibrosis (CF) and non-CF bronchiectasis is limited to a small number of respiratory pathogens. In CF, these pathogens tend to follow a typical chronological course: in childhood, the usual infecting pathogens are Haemophilus influenzae and Staphylococcus aureus; in adulthood, infection with Pseudomonas aeruginosa dominates (►Fig. 1). In non-CF bronchiectasis, H. influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and P. aeruginosa are the main infecting pathogens. In recent years, increasing numbers of other species are being recognized as potential emerging pathogens in CF, including species of the Burkholderia cepacia complex, Stenotrophomonas, Ralstonia, Achromobacter, Pandoraea, and nontuberculous mycobacteria. The potential reasons for the apparent increasing prevalence of emerging pathogens include the following: 1. Changes in microbiological taxonomy with reassignment of species to new genera 2. An increased use of aggressive eradication therapy for initial infection with “typical” CF pathogens

Issue Theme Cystic Fibrosis and NonCystic Fibrosis Bronchiectasis; Guest Editor: Andrew M. Jones, MD, FRCP

3. A greater use of chronic suppressive antibiotic therapy 4. Application of new molecular techniques for the identification of microorganisms 5. Improved patient survival 6. Increased sputum surveillance No standard definition for infection with these organisms exists and published studies use a variety of definitions, some including patients with single positive cultures while other require multiple positive cultures to meet their definition of infection. This must be borne in mind when interpreting prevalence rates for emerging pathogens from individual studies.

Burkholderia cepacia Complex Pseudomonas cepacia was first described in 1950 by William Burkholder.1 In 1992, several bacteria from the Pseudomonas genus were transferred to a new genus named Burkholderia. These bacteria were renamed B. cepacia, B. gladioli, B. pickettii, B. mallei, B. pseudomallei, B. caryophylii, and B. solanacearum species.2 Subsequently, B. cepacia species has been separated

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DOI http://dx.doi.org/ 10.1055/s-0035-1546752. ISSN 1069-3424.

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Heather Green, MBChB, MRCP1

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Fig. 1 Respiratory infections by age—UK CF Registry 2012 Annual Data Report. 106

into 18 different species, collectively known as the B. cepacia complex (Bcc) (see ►Table 1).3–6 Burkholderia species have been recognized as plant pathogens for over 60 years.1 Over the past few decades, there has also been recognition of these species as opportunistic pathogens in humans. Groups at risk of infection include individuals with immunosuppression, chronic granulomatous disease, and CF.7 B. cepacia was first recognized as an infecting organism in CF in the 1970s.8 An increasing incidence and prevalence of B. cepacia isolates was noted by Isles et al in 1984 at a CF center in Toronto.9 They noted near doubling of the prevalence of B. cepacia–infected patients attending their CF center over a 10-year period. They observed that infected patients followed varying clinical courses and they described a group of patients with high white blood

Table 1 The Burkholderia cepacia complex Burkholderia cepacia Burkholderia multivorans Burkholderia cenocepacia Burkholderia stabiliz Burkholderia vietnamiensis

cell counts, fevers, and severe pneumonic changes on their chest radiographs, who deteriorated rapidly and died; this condition was later named “cepacia syndrome.” By the mid-1980s, it became increasingly apparent that B. cepacia infection was associated with increased morbidity and mortality.10,11 Subsequent studies in the early 1990s provided evidence of person-to-person transmission of B. cepacia infection via strain typing of isolates taken from the index case of infection and their contacts.12 Evaluation of further studies suggested that transmissibility of B. cepacia may be strain dependent with highly transmissible, epidemic strains, such as the Edinburgh/Toronto electrophoretic type 12 (ET12) strain, being most likely to cause cross infection.13,14 The recognition of superinfection, where an existing strain is replaced by a new strain, was described in a case series reported in 1998 of the replacement of existing B. cepacia complex strains with an epidemic Burkholderia cenocepacia ET12 strain and subsequent death of four out of the five superinfected patients.15 The implementation of infection control measures, including segregation of Bcc-infected patients from others with CF, has subsequently controlled the spread of epidemic strains and in turn altered the distribution of Bcc species in CF worldwide. The prevalence of Bcc now ranges from 1 to 8%, and sporadic strains of B. multivorans are now responsible for the majority of new infections.

Burkholderia dolosa

Burkholderia cenocepacia

Burkholderia ambifaria

B. cenocepacia is now well recognized as a potentially transmissible and serious infection in CF patients. Reevaluation of historical isolates from Canadian outbreaks of B. cepacia in Toronto has identified epidemic ET12 B. cenocepacia as the culprit strain.16,17 Other epidemic strains of B. cenocepacia have also been identified.18,19 Studies have reported that infection with B. cenocepacia results in significantly reduced survival and greater rate of decline in forced expiratory volume in one second (FEV1) when compared with P. aeruginosa infection in CF patients (►Fig. 2).20,21 Of all the Bcc species, cases of cepacia syndrome are most commonly, but not exclusively, associated with B. cenocepacia infection. Infection with B. cenocepacia (but not other B. cepacia complex organisms) has also been associated with a poorer outcome following lung transplant in CF patients.22

Burkholderia anthina Burkholderia pyrrocinia Burkholderia ubonesis Burkholderia latens Burkholderia diffusa Burkholderia arboris Burkholderia seminalis Burkholderia metallica Burkholderia contaminans Burkholderia lata Burkholderia pseudomultivorans

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Fig. 2 Survival of CF patients with chronic B. cenocepacia infection and matched controls with chronic P. aeruginosa infection (n ¼ 31 in each group). Reproduced from Jones et al. with permission from BMJ Publishing Group Ltd. 20

Consequently, most transplant centers consider infection with this B. cenocepacia to be a contraindication to transplantation. The implementation of strict infection control measures at CF centers has successfully curtailed the spread of epidemic strains of B. cenocepacia. While acquisition of sporadic strains still occasionally occurs, the incidence and prevalence of Burkholderia species infection in CF has changed, with other species, in particular B. multivorans, now dominating.

Burkholderia multivorans B. multivorans is now responsible for the majority of infections of CF patients with B. cepacia complex. Multicenter studies have shown that the vast majority of infected patients harbor unique strains, supporting the theory that most patients acquire infection from the environment23 and it has been shown that strains isolated from

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the environment are identical to some strains also found in infected patients.24 However, there are a small number of reported cases of shared strains between patients. 23,25–27 In approximately half of cases, initial infection is transient and does not lead to chronic colonisation.20,28 Chronic CF lung infection correlates with changes in metabolism, motility, and biofilm formation of B. multivorans and in vitro models demonstrate an increased virulence in clinical compared with environmental strains.29,30 Clinical studies have failed to demonstrate a difference in survival or rate of FEV1 decline between B. multivorans and P. aeruginosa– infected CF patients.20,21,31 However, unlike P. aeruginosa, in individual cases, B. multivorans is capable of causing necrotizing pneumonia seen in cases of cepacia syndrome.20,32 An example of radiological appearances of cepacia syndrome in a patient with B. multivorans infection is shown in ►Fig. 3.

Burkholderia dolosa B. dolosa infects fewer CF patients than B. cenocepacia or B. multivorans and published studies on this organism are more limited. A retrospective case–control study has reported on the clinical impact of B. dolosa infection following an outbreak in a Boston CF center.31 This study showed that B. dolosa–infected CF patients have accelerated lung function decline compared with patients infected with B. multivorans and P. aeruginosa. Patients were not matched for FEV1 but baseline values between groups were not significantly different, suggesting degree of lung function impairment is not a risk factor for infection with B. multivorans or B. dolosa. This study also showed a significantly higher 18-month mortality in the group of patients infected with B. dolosa compared with patients without Bcc infection. All patients in this study were infected by a genetically identical strain, suggestive of cross infection. This strain was also discovered to be implicated in one of the first studies, suggesting Bcc was capable of cross infection.12,27

Fig. 3 Cepacia syndrome in a Burkholderia multivorans–infected patient with cystic fibrosis. (A) Chest radiograph of a patient with Burkholderia multivorans infection taken when clinically stable. (B) Chest radiograph of the same patient taken when clinically unwell showing widespread acute pulmonary infiltrates in keeping with cepacia syndrome. Seminars in Respiratory and Critical Care Medicine

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Burkholderia gladioli Although not a member of the Bcc, another Burkholderia species, B. gladioli, is occasionally encountered in CF. In one study, only 40% of cases of initial infection progressed to chronic carriage and the clinical impact of chronic infection was variable.33 However, B. gladioli infection is associated with a greater posttransplant mortality and there are several case reports of posttransplant sepsis.34–37

Stenotrophomonas maltophilia S. maltophilia, previously been known as both Pseudomonas maltophilia and Xanthomonas maltophilia, is an aerobic nonfermenting gram-negative rod. It is ubiquitous in aqueous environments and has been isolated from hospital equipment such as nebulizers and oxygen humidifiers.38 This organism can lead to nosocomial infection, particularly in immunocompromised patients, and was first described in the sputum of a CF patient in 1979.39–41 Resistance to multiple antibiotic therapies, including carbapenems, is common. Cotrimoxazole is the antibiotic of choice and strains may also show susceptibility to doxycycline, ciprofloxacin, or piperacillin-tazobactam; colistin has greater in vitro activity than tobramycin.42 Like P. aeruginosa, S. maltophilia is capable of forming a biofilm within airways.43,44 The prevalence of S. maltophilia in CF is variable between CF centers and appears to be increasing. U.S. CF Registry data reported a prevalence of 4% in 1996 increasing to 14% in 2010; in some centers, this organism can be found in the sputum of up to 25% of patients with CF.45,46 Patients are commonly coinfected with P. aeruginosa and Aspergillus, although this is not a consistent finding in all studies.47–50 Chronic infection is not inevitable and a previous study found two-thirds of infected patients subsequently cleared the organism from their sputum by 1 year.48 Given S. maltophilia is isolated intermittently rather than persistently from patients, detection of infection relies on the frequency of collection of sputum samples. Currently, the pathogenicity of S. maltophilia in CF is uncertain. Several studies have concluded that infection with S. maltophilia does not cause accelerated lung function decline when potential confounding variables are taken into account.46,48,50,51 However, other studies have suggested that there is some evidence that S. maltophilia may be pathogenic in CF. Waters et al conducted a large cross-sectional study of patients attending their CF center in Toronto.50 They found that chronic infection, as defined by at least two positive cultures in the preceding 12 months, was found to be an independent risk factor for pulmonary exacerbations requiring hospitalization and antibiotics. This finding remained significant when results were reanalyzed with adjustments for multiple potentially confounding variables including age, baseline FEV1, body mass index, and P. aeruginosa coinfection. Chronically infected patients had a lower mean FEV1 compared with intermittently infected and noninfected patients, but not an accelerated lung function decline. Patients defined as being chronically infected also had an increased pulmonary exacerbation frequency. The finding that S. maltophilia infection is associated with poorer baseline lung function has Seminars in Respiratory and Critical Care Medicine

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been replicated in several other studies.47,49,51,52 In addition, a large retrospective study in 2002 found that infection was more common in older patients, who were found to have more exacerbations, outpatient reviews, and hospitalizations in the 12 months prior to first isolation of S. maltophilia compared with controls.47 While the findings described earlier may be interpreted as evidence of potential pathogenicity, they may alternatively simply reflect that patients with more severe disease are more vulnerable to developing infection with this organism. Waters et al also found that chronically infected patients show a specific immune response to chronic infection with raised antibody titers to S. maltophilia. This was not found to be the case in patients with intermittent infection in the same study.50 Studies have also looked at the potential impact of infection on survival. Goss et al found that infection had no effect on short-term (3-year) survival when adjustments were made for confounding variables.47 Another recent study found that chronic infection was associated with an almost three times increased risk of death or lung transplant in CF patients; however, it should be noted that when the study data were reanalyzed using a time-varying model adjusting for FEV1, a significant difference was no longer found.49 In published studies, the majority of S. maltophilia strains isolated from individuals with CF appear to be unique to the individual patient, although there are occasional reports of shared strains between patients. In a relatively large study involving 183 patients with a positive culture of S. maltophilia, only three patients were found to carry a common strain.53 Shared strains were found in four pairs of patients in a study by Denton et al, with the remaining 33 patients in the study harboring unique strains.38 Marzuillo et al identified 5 shared strains in isolates from 50 CF patients.54 The shared strains were found in groups of two or three patients and none of these strains were isolated from potential waterborne sources in affected patients’ hospital rooms.

Achromobacter Species Achromobacter are aerobic, nonfermenting, gram-negative, bacilli and are widely distributed in the natural environment. The genus Achromobacter currently comprises 6 unnamed species and 15 named species (►Table 2); many are novel species which were assigned names within the past 12 months.55,56 Until recently, the vast majority of Achromobacter infections in CF were thought to be caused by A. xylosoxidans. However, in 2012 it was discovered that increasing the number of gene amplifications performed in multilocus sequencing to 5 allowed species previously designated as A. xylosoxidans to be reassigned as novel species, such as Achromobacter ruhlandii which differs by just 3 16SrRNA polymorphic positions.57 In 2013, Spilker et al were able to further differentiate species by increasing number of genes amplified on sequencing to 7.58 A recent study conducted by the same authors has shown that this level of increased species differentiation can be achieved using the single locus nrdA.59 Using this single locus, 341 CF patients from the United States had their isolates reanalyzed, which had all

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Table 2 Species of Achromobacter Achromobacter aegrifaciens Achromobacter animicus Achromobacter anxifer Achromobacter denitrificans Achromobacter dolens Achromobacter insolitus Achromobacter insuavis Achromobacter marplatensis Achromobacter mucicolens Achromobacter piechaudii Achromobacter pulmonis Achromobacter ruhlandii Achromobacter spanius Achromobacter spiritinus Achromobacter xylosoxidans Note: A further six species are at present unnamed.

been identified as A. xylosoxidans by referring laboratories. This reanalysis showed A. xylosoxidans accounted for only 42% of Achromobacter infections. The second most common Achromobacter species causing infection was A. ruhlandii, accounting for 23.5% of infections followed by A. dolens (17% of infections) with 11 other Achromobacter species accounting for the remaining 17.5% of infections. Achromobacter infections are also occasionally encountered in patients with nonCF bronchiectasis. The prevalence of Achromobacter species infection in CF appears to be increasing but remains under 10% in most CF centers. Annual registry data from the United States reports an overall prevalence (at least one positive culture) of 1.9% in 2005 increasing to 6.8% by 2011.60,61 Age-specific prevalence rates vary and 2012 US registry data shows a peak in the 18- to 24-year-old age group of almost 10%.62 Possible reasons for this apparent increase in prevalence have been outlined earlier. Furthermore, it is possible that current assessments of prevalence are underestimated due to misidentification of Achromobacter species with other gramnegative organisms with a similar morphology such as P. aeruginosa.63 Saiman et al, in 2001, reported that 11% of Achromobacter strains in their study were originally misidentified.64 Currently, the pathogenicity of Achromobacter species remains unclear with conflicting results on clinical outcome from current published studies. Achromobacter are commonly resistant to multiple antibiotics65–67 and A. xylosoxidans, like P. aeruginosa, can create biofilms in sputum, potentially making infections difficult to clear.67,68 In one study, the antibiotics with most activity against clinical isolates of Achromobacter from CF patients were minocycline, piperacillin–tazobactam, imipenem, and meropenem—the most active combinations by synergy testing being meropenem/ciprofloxacin and chloramphenicol/minocycline; isolates were also frequently inhibited

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by high-dose colistin.64 There is some evidence that patients chronically infected with A. xylosoxidans have higher markers of inflammation than uninfected patients (serum interferon gamma and interleukin-6 and sputum tumor necrosis factorα), suggesting that this organism is not an innocent bystander.68 The impact of chronic Achromobacter infection on lung function remains undetermined with published studies reporting conflicting results. Rønne Hansen et al found that patients had a significant decrease in FEV1 and FVC following establishment of chronic infection with A. xylosoxidans.69 Hansen et al also found that patients with rapidly increasing levels of specific antibodies to A. xylosoxidans have steeper FEV1 and FVC decline than noninfected patients. This steeper FEV1 decline was similar to that of patients chronically infected with P. aeruginosa.68 In contrast, other studies have not found an association between A. xylosoxidans infection and accelerated lung function decline.63,65,66,70 There are conflicting reports of antibiotic treatment requirements in association with Achromobacter infection. Tan et al reported that A. xylosoxidans infection was not associated with a greater requirement for intravenous antibiotic treatment70; however, all patients with chronic P. aeruginosa infection received elective courses of intravenous antibiotics every 3 months at the CF center. De Baets et al found increased requirements for intravenous antibiotics in an A. xylosoxidans–infected group of patients than in another cohort with P. aeruginosa infection.63 In this study, patients received only intravenous antibiotics when symptomatic of a pulmonary exacerbation. However, the patients with A. xylosoxidans infection in the study had poorer lung function than those with P. aeruginosa. Risk factors for infection with Achromobacter in CF are uncertain. A. xylosoxidans–infected patients were found to have more pronounced lung damage (defined by higher Brasfield and Bhalla scores of chest radiographs and highresolution computed tomography scans, respectively) at the time of first positive culture in a retrospective case–control study by De Baets et al.63 However, numbers are small in this study with only eight (5.3%) of their CF patient population meeting their definition of chronic colonization. This finding was not reproducible in a later study by Hansen et al, which found patients infected with Achromobacter species had similar lung function to controls.68 There have been several published reports of shared strains of Achromobacter between patients. A multicenter study in 2001 found that five out of seven centers with patients chronically infected with A. xylosoxidans had pairs of individuals with shared strains including two pairs of siblings, one pair of friends, and two pairs with no epidemiological connection.53 Kanellopoulou et al found that five out of nine of infected patients in their study shared the same genotype.71 Similarly, Rønne Hansen et al found that eight out of eighteen Achromobacter species–infected patients in their center shared a common genotype.69 This study originally reported A. xylosoxidans as the infecting species, also known as the Danish epidemic strain, in these patients, but recent reanalysis of these isolates using multilocus sequencing with Seminars in Respiratory and Critical Care Medicine

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amplification of five housekeeping genes has shown that these strains belong to the novel species A. ruhlandii.57 Several other studies have also found clusters of patients with common genotypes of A. xylosoxidans within their study population.66,72,73 Recently, it has been suggested that A. ruhlandii may cause cross infection through indirect person-to-person transmission.74 Hansen et al reported following two separate new instances of A. ruhlandii, Danish epidemic strain, infection in CF patients following indirect contact between individuals known to have chronic A. ruhlandii infection.74 However, many patients in the aforementioned studies harbored their own unique strain of A. xylosoxidans and other studies have shown all patients have genotypically distinct strains.75

Pandoraea Species The genus Pandoraea was first described by Coenye et al in 2000.76 There are currently nine identified Pandoraea species, although only five have been named: P. apista, P. pulmonicola, P. pneumosa, P. sputorum, and P. noribergensis. This genus of gram-negative, motile, bacilli have been mostly isolated from sputa of patients with CF, but have also been found in garden soil, sludge, powdered milk, and water.76 The prevalence of Pandoraea infection in CF, similar to many of the other nonfermenting gram-negative emerging pathogens, is relatively low. Also, like many of the other emerging nonfermenting gram-negative pathogens, this genus of bacteria is capable of growth on B. cepacia complex selective agar, and potential misidentification can occur unless molecular tests are used for diagnostics.76,77 Species from within the Pandoraea genus are typically multiresistant, but these organisms are usually sensitive to cotrimoxazole and imipenem.78–81 The clinical impact of Pandoraea infection is unclear. An in vitro study has shown that the genus increases production of the proinflammatory cytokines interleukin-6 and interleukin-8, which are known to be associated with lung inflammation. This study also found that P. pulmonicola is capable of invading human lung epithelial cells.82 A recent in vivo study using a Galleria mellonella model showed P. pulmonicola to be more virulent than P. apista and P. pneumosa, with an in vivo virulence comparable to B. cenocepacia.83 There is also evidence that chronically infected patients exhibit a specific immune response to infection. Jørgensen et al found rising serum titers of Pandoraea antibodies in six chronically infected patients.80 Of the six patients within this study, four had a greater decline in lung function than would have been expected from their previous measurements. However, the development of allergic bronchopulmonary aspergillosis and the presence of other infecting organisms including P. aeruginosa and M. abscessus in some of these patients made it difficult to attribute lung function decline solely to P. apista infection. Anecdotal evidence from case reports suggests that Pandoraea is not simply an innocent bystander. The study by Jørgensen et al described two patients apparently having replacement of their chronic P. aeruginosa infection with Pandoraea infection (with less frequent culture of Pseudomonas or less Pseudomonas-specific serum antibodies following Seminars in Respiratory and Critical Care Medicine

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establishment of chronic infection with P. apista).80 MartínezLamas et al recently reported a case of a CF patient with significant decline in lung function subsequent to isolation with P. sputorum, which remained in the patient’s sputum on consecutive testing over a 4-year period.78 Pandoraea bacteremia has been reported during a pulmonary exacerbation of a CF patient known to have chronic P. apista infection79; however, it should be noted that this patient had a central venous catheter in place at the time of first positive culture, which may have been the source of bacteremia. Further examples of Pandoraea bacteremia and even subsequent multiorgan failure and death have been reported in patients without CF, which would support the potential virulence of this genus of bacteria.84,85 The ability of Pandoraea species to be transmitted from person to person is unconfirmed, but there have been reports of suspected cross infection. Jørgensen et al described six patients attending their Copenhagen CF center infected with the same strain of P. apista.80 Social contact of these patients, predominantly at winter camps, was thought to have provided the opportunity for cross infection to occur. Following further infection control measures, including segregation for these patients, no further cases of P. apista infection occurred. A recent study found that choice of Pandoraea strain typing methodology might influence study results. In this study, multiple samples from two patients with chronic P. apista infection were analyzed. Each patient was found to have a unique strain of P. apista, but one of the three polymerase chain reaction (PCR) methods used to strain type the organism failed to recognize that the strains from the two patients were distinct.81 It should be noted that the gold standard method of strain typing (pulsed-gel field electrophoresis) was used to analyze isolates in the outbreak reported by Jørgensen et al described earlier.

Ralstonia Species The taxonomy of the Ralstonia genus is rapidly evolving. The genus was first proposed in 1995 and the type species Ralstonia pickettii has previously been known as both Pseudomonas pickettii and R. pickettii.86 There are five currently described species within the Ralstonia genus following reassignment of several species to the genus Cupriavidus. Ralstonia mannitolilytica is most commonly isolated in CF followed by R. pickettii and then Ralstonia respiraculi.87,88 The prevalence of Ralstonia species in CF is unknown, partly due to difficultly in identification of these organisms. Ralstonia is capable of growth on B. cepacia complex selective agar and is therefore can be misidentified as a member of the B. cepacia complex.87,89 In an analysis of sputum isolates referred to the B. cepacia reference laboratory in the University of Michigan,90 Ralstonia species were identified in 72 CF patients over a period of 5 years, in specimens thought to be an organism from the B. cepacia complex. PCR testing of sputum samples provides a more effective way of identifying the organism but is not used to screen all samples routinely. The true prevalence of Ralstonia infection in CF is likely to be low given the few positive samples found in patients included in large studies. Burns et al found just 2 cases of Ralstonia species infection in

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However, patients with R. mannitolilytica as their only chronic infecting organism may have significant radiological disease (see ►Fig. 4). Coenye et al found no evidence of cross infection among the 38 infected patients within their study.87

There are several other bacterial species that are occasionally isolated from samples of patients with CF and/or non-CF bronchiectasis including Serratia marcescens, Inquilinus limosus, Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii. Currently, there are little published data to elucidate whether or not they may have a pathogenic role in individual patients with CF or non-CF bronchiectasis.

Fig. 4 Chest radiograph of an adult patient with cystic fibrosis and Ralstonia mannitolilytica as their only chronic infecting organism.

the 595 patients within their study.91 Using a polyphasic approach, including PCR, Coenye et al found only 42 Ralstonia isolates in a total of 38 patients out of 4,000 specimens.87 Only 3 of these 38 patients had more than one positive culture, suggesting that chronic infection is rare. There is currently no data published on the clinical impact of Ralstonia infection in CF on lung function or pulmonary exacerbation frequency.

Fungal Fungal pathogens are covered extensively in the chapter by Moss in this edition of the journal and therefore will not be further discussed in this present chapter.

Nontuberculous Mycobacteria Nontuberculous mycobacteria pathogens are already covered extensively in the chapter by Park and Olivier in this edition of the journal and therefore will not be further discussed in this present chapter.

Fig. 5 Pie chart showing the microbial diversity in the sputum of an adult with cystic fibrosis. Seminars in Respiratory and Critical Care Medicine

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Anaerobes Recent studies have shown that anaerobic bacteria are commonly detected in significant numbers in lower airway samples from patients with CF and non-CF bronchiectasis both by anoxic culture and molecular-based testing.92,93 Quantitative analyses have shown that the anaerobes are present in significant numbers comparable to those of aerobic bacteria. The most frequently encountered genera are Actinomyces, Gemella, Peptostreptococcus, Prevotella, Streptococcus, and Veillonella. The role of anaerobic species in the pathophysiology of CF and non-CF bronchiectasis remains unresolved. A small case series correlated Streptococcus milleri group bacteria with exacerbations, frequently associated with atypically malodorous sputum, in seven CF patients.94 Prevotella species are able to produce β-lactamases.95 Ulrich and colleagues showed that some patients with CF, but not healthy controls, have antibodies against antigens of Prevotella intermedia and that culture supernatant from P. intermedia is inflammatory and cytotoxic to airway cells.96 In vitro work has shown that some Prevotella species are able to produce quorum sensing molecules that influence the expression of virulence genes in P. aeruginosa.95,97 However, in recent studies, intravenous antibiotic therapy for acute infective exacerbations resulted in an improvement in clinical status despite little alteration in the overall composition of anaerobic bacteria in adults with CF.98,99

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The Microbiome in CF and Non-CF Bronchiectasis Studies using a range of culture-independent molecular techniques designed for characterizing bacterial communities, such as 16S rRNA-gene profiling by terminal restriction fragment length polymorphisms or pyrosequencing, have revealed that the lungs in CF and non-CF bronchiectasis are populated by diverse polymicrobial communities containing aerobic and anaerobic bacteria, fungi, and viruses.100–103 A chart showing an example of the microbial diversity seen in the sputum of a patient with CF is shown in ►Fig. 5. The lung microbiome is unique to an individual patient with CF or bronchiectasis. The diversity of the microbial community narrows in older patients, those with end-stage lung disease, and in association with some bacterial pathogens, such as B. cenocepacia.104 Recent studies have found little change in bacterial community structure during periods of exacerbation and antibiotic treatment in patients with CF and non-CF bronchiectasis.100,105 At present, it remains unclear how changes in the structure and dynamics of the CF lung microbial community influence a patient’s clinical status and disease progression.

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pathology 1950;40:115–118 2 Yabuuchi E, Kosako Y, Oyaizu H, et al. Proposal of Burkholderia

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The microbiome and emerging pathogens in cystic fibrosis and non-cystic fibrosis bronchiectasis.

Chronic pulmonary sepsis is the predominant cause of morbidity for patients with cystic fibrosis (CF) and non-CF bronchiectasis. Previously it was tho...
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