- Email: [email protected]
Which pathogens should we worry about?
Paediatric Respiratory Reviews 31 (2019) 15–17
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
The 2018 Royal Society Of Medicine Cystic Fibrosis Symposium
Which pathogens should we worry about? Andrew M. Jones ⇑ Manchester Adult Cystic Fibrosis Centre, Manchester University Hospitals NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK
a r t i c l e
i n f o
Keywords: Cystic fibrosis Pathogens Emerging pathogens Infection Pseudomonas aeruginosa
a b s t r a c t Aside from the traditional CF pathogens, Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa, there are an increasing number of organisms found to have chronic carriage in patients with cystic fibrosis, including gram-negative bacteria, non-tuberculous mycobacteria, anaerobic bacteria and fungal species. Some of these lower prevalence organisms, such as Burkholderia cenocepacia and Mycobacterium abscessus complex, are recognised as true pathogens associated with significant adverse clinical consequences, whilst for others the relative pathogenicity and need for treatment are unclear. This article will highlight some of the challenges in assessing what is a pathogen in CF and the potential implications of infection with different organisms for individual patients. Ó 2019 Published by Elsevier Ltd.
The microbiological status of a cystic fibrosis (CF) patient is a major determinant of their current health status and subsequent clinical outcome. Historically, there was thought to be a classical narrow spectrum of CF pathogens, with Haemophilus influenzae and Staphylococcus aureus encountered early in childhood, and thereafter, with increasing age, Pseudomonas aeruginosa becoming more common. The number of organisms encountered that are reported as causing chronic infection is increasing, and includes other gramnegative bacteria, such as Achromobacter species, Stenotrophomonas maltophilia, Pandoraea species and Ralstonia species, anaerobic bacteria, such as species of Prevotella, Gemella, Streptococcus and Veillonella, non-tuberculous Mycobacteria, in particular M. abscessus complex and M. avium complex, and fungi, including Aspergillus fumigatus, Scedosporium, Exophiala and Trichosporon species (Table 1). The yield depends on the type of respiratory samples obtained and the culture methodology. For example, prolonged culture and use of specific media, and use of culture independent molecular techniques influence the results provided. When these organisms are encountered in lower respiratory tract secretions from a patient with CF, there are several questions that arise, but primarily, the clinician needs to consider whether this is a potential pathogen that we should worry about. There may be certain behaviours that can be interpreted as potential indications for concern, including likelihood of persistence of infection as opposed to transient carriage, reports of cross-infection ⇑ Address: Manchester Adult Cystic Fibrosis Centre, Manchester University Hospitals NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Fax: +44 0161 291 2080. E-mail address: [email protected] https://doi.org/10.1016/j.prrv.2019.02.007 1526-0542/Ó 2019 Published by Elsevier Ltd.
between patients, influence of transplant outcomes such as persistence in the graft lungs and any ‘‘unusual” behaviour such as episodes of bacteraemia. In addition, the organism may display inherent resistance to many antibiotics and potential virulence may be suggested by in vitro model data. In addition to the behaviour of the organism, other findings that may also be concerning include evidence of a host response to the presence of the organism, such as the development of antibodies, and accelerated clinical decline following acquisition of infection reflected in weight loss and decreased lung function. In considering the published literature concerning the lower prevalence organisms to elucidate their clinical consequences, there are a number of potential pitfalls that should be taken into consideration. Evidence is commonly limited to a few case studies or small cohort studies with outcomes examined over short intervals. There is often a lack of suitable controls, there may not be a uniform definition of ‘chronic infection’, and there may be multiple confounders to take into account, such as the influence of comorbidities and co-infections. For many organisms there is no clear evidence to guide effective treatment regimens and no defined breakpoints for antibiotic susceptibility testing. The available literature is subject to a potential reporting and publication bias, with authors more likely to write up and submit cases with a deleterious outcome in relation to an organism, and similarly for journals to publish such cases. The literature is further complicated by changes in taxonomy for organisms, and reallocation of species to new genera, thus limiting the usefulness of historical reports. Furthermore, in vitro model data may not reflect in vivo behaviour and clinical data from infection in non-CF patients may not reflect the consequences of infection in CF.
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A.M. Jones / Paediatric Respiratory Reviews 31 (2019) 15–17
Table 1 Examples of low prevalence organisms associated with chronic colonisation in CF. Gram-negative bacteria Achromobacter species Acinetobacter species Burkholderia cepacia complex Burkholderia gladioli Elizabethkingia species Inquilinus limosus Pandoraea species Ralstonia species Serratia species Stenotrophomonas maltophilia Non-tuberculous mycobacteria Mycobacterium abscessus complex Mycobacterium avium complex Anaerobic bacteria Actinomyces species Fusobacterium species Gemella species Prevotella species Rothia species Streptococcus species Veillonella species Fungal species Exophiala dermatitidis Lomentospora prolificans Pneumocystis jirovecii Scedosporium species Trichosporon species
Knowledge of optimal treatment strategies and new challenges associated with CF infections continues to evolve, even for the ‘classical’ CF pathogens such as S. aureus. The use of prophylactic anti-Staphylococcal antibiotics in childhood remains controversial. An ongoing UK Registry based study, CF START (www.cfstart.org. uk), hopes to finally resolve this issue. The phenotypic behaviour expressed by different strains of organisms may influence their clinical consequences for patients with CF. For Staph. aureus, small colony variant isolates, generally considered to be related to poor clinical outcomes, can be encountered in CF [1]. Methicillinresistant strains are also encountered and have been associated with worsening progression of lung disease [2]. Strains of Staph. aureus exhibiting virulence factors such as the Panton–Valentine Leucocidin toxin (PVL+ve) have been associated with increased rates of unusual complications, with lung abscesses described in a number of case reports of CF patients [3,4]. Whilst an increasing prevalence of some of the organisms encountered in CF may at least in part be related to improved techniques for their detection and identification, others seem to have a true rise in incidence. There is currently concern with increasing numbers of M. abscessus complex infections in patients with CF [5]. These organisms are notoriously difficult to treat and macrolide antibiotics constitute an essential component of optimal treatment regimens. One of the different M. abscessus complex subspecies, M. abscessus subspecies abscessus, possesses the erm gene that encodes for naturally inducible macrolide resistance, whilst M. abscessus subspecies massilliense has a non-functioning erm gene. One study in non-CF patients with M. abscessus complex infection reported significantly higher success rates for treatment in patients who harboured M. abscessus subspecies massilliense than those who were infected with M. abscessus subspecies abscessus, [6]. A recent retrospective study from a CF centre in France found similar discrepancies in treatment success between M. abscessus subspecies abscessus and M. abscessus subspecies massilliense [7]. International guidelines recommend speciation of M. abscessus complex and testing isolates for sensitivity to macrolides, cefoxitin and amikacin [8].
Fungal species are often isolated from the respiratory secretions of patients with CF and, outside of the hypersensitivity reaction associated with Aspergillus fumigatus, allergic bronchopulmonary aspergillosis, the clinical relevance of airway colonisation with fungi is often unclear. The concept of aspergillus bronchitis is recognised [9], but as with other fungal species there are no clinical studies that have demonstrated benefits of treatment intervention, other than small case studies [10]. The clinical relevance of carriage of an organism in the respiratory tract in CF may also have important consequences in those patients who are listed for lung transplantation. Patients with B. cenocepacia infection are excluded from lung transplant programs in many countries due to poor posttransplant outcomes. Whilst the impact of fungi in the airways of an immunocompetent CF host is unclear, some fungi, including Aspergillus fumigatus and Scedosporium species and Lomentospora prolificans, can cause challenging infective complications in patients post-lung transplantation. Although the presence of particular pathogens, for example B. cenocepacia, have been clearly shown to cause worsening of CF lung disease, the airways of CF patients are not generally populated by a single organism, but by many different species [11]. Cultureindependent microbiological analyses applied to CF samples have provided insights into the complexity of the microbiota of the lower respiratory tract in CF. A narrowing of airway bacterial community diversity is associated with older patients and is seen in those with greater impairment of lung function [12,13]. Whether there is a causal factor in this relationship, and any future implications for treatment strategies, requires further research. The CF airways are not only colonised by aerobic species. There are steep oxygen gradients within CF lungs and relatively high levels of anaerobic bacteria can be readily identified using specialist culture and molecular identification methodologies. The clinical significance of their presence remains unclear. Although a recent study has reported a relative increase in the abundance of anaerobic bacteria at the onset of exacerbations [14], other studies have demonstrated a correlation between a greater abundance of anaerobes and higher body mass index and FEV1 levels, lower levels of inflammation and increased clinical stability [15,16]. P. aeruginosa remains the primary pathogen in CF, as it influences the clinical outcome for the majority of patients with CF. Clinical teams therefore utilise strategies to detect early infection and commence eradication therapy to defer the progression to chronic carriage, apply measures to prevent cross-infection, and for those who eventually develop chronic infection institute long term antibiotic treatment with inhaled antibiotics and oral (predominantly macrolides) agents to minimise the impact of chronic P. aeruginosa on infective exacerbations and the progression of CF lung disease. Other gram-negative pathogens including Ralstonia, Achromobacter, Pandoraea, and Burkholderia species are also encountered but assume a much lower prevalence than P. aeruginosa. These organisms commonly display in vitro resistance to many antibiotics. The prevalence, rates of conversion from initial to chronic carriage and subsequent clinical consequences differ from species to species. Within the Burkholderia cepacia complex, B. cenocepacia has much more severe clinical consequences than the most frequently encountered Burkholderia species, B. multivorans [17]. However, cases of cepacia syndrome, although classically associated with B. cenocepacia infection, are also occasionally described in association with B. multivorans infection [17]. In-vitro data suggest that virulence also may differ between species of Pandoraea [18]. There are reports both of cross-infection and also of data to suggest a potential pathogenic role for at least some of these organisms in patients with CF [19–21].
A.M. Jones / Paediatric Respiratory Reviews 31 (2019) 15–17
SUMMARY Chronic airway infection leading to progressive lung damage and respiratory failure is the major cause of the premature mortality for patients with cystic fibrosis. P. aeruginosa remains by far the most prevalent chronic pathogen in CF, but many other organisms are also increasingly encountered. The relative pathogenicity differs from organism to organism. Factors including the availability of non-culture molecular detection techniques, use of specialist culture media, an increasing population of older patients and a greater array of inhaled antibiotics licensed for long term use, are likely to contribute to a continued rise in the number of cases of infection with such organisms and present new challenges in CF clinical care. CONFLICT OF INTEREST Nothing to declare in relation to this article. References [1] Wolter DJ, Emerson JC, McNamara S, Buccat AM, Qin X, Cochrane E, et al. Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis 2013;57:384–91. [2] Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA 2010;303:2386–93. [3] Barry PJ, Isalska BJ, Jones AM. Panton-valentine leukocidin-positive Staphylococcus aureus: a potentially significant pathogen in cystic fibrosis. Paediatr Respir Rev 2014;15:22–5. [4] Elizur A, Orschelu RC, Ferkol TW, Atkinson JJ, Dunne WM, Buller RS, et al. Panton-valentine leukocidin-positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis. Chest 2007;131:1718–25. [5] Bryant JM, Grogono DM, Rodriguez-Rincon D, Everall I, Brown KP, Moreno P, et al. Emergence and spread of a humantransmissible multidrug-resistant nontuberculous mycobacterium. Science 2016;354:751–7. [6] Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 2011;183:405–10.
17
[7] Roux AL, Catherinot E, Soismier N, Heym B, Bellis G, Lemonnier L, et al. Comparing Mycobacterium massiliense and Mycobacterium abscessus lung infections in cystic fibrosis patients. J Cyst Fibros 2015;14:63–9. [8] Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax 2016;71:i1–22. [9] Baxter CG, Dunn G, Jones AM, Webb K, Gore R, Richardson MD, et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol 2013;132:560–6. [10] Shoseyov D, Brownlee KG, Conway SP, Kerem E. Aspergillus bronchitis in cystic fibrosis. Chest 2006;130:222–6. [11] Sibley CD, Grinwis ME, Field TR, Eshaghurshan CS, Faria MM, Dowd SE, et al. Culture enriched molecular profiling of the cystic fibrosis airway microbiome. PLoS One 2011;22702. 6.e22702. [12] Flight WG, Smith A, Paisey C, Marchesi JR, Bull MJ, Norville PJ, et al. Rapid detection of emerging pathogens and loss of microbial diversity associated with severe lung disease in cystic fibrosis. J Clin Microbiol 2015;53:2022–9. [13] Carmody LA, Caverly LJ, Foster BK, Rogers MAM, Kalikin LM, Simon RH, et al. Fluctuations in airway bacterial communities associated with clinical states and disease stages in cystic fibrosis. PLoS One 2018;13.. https://doi.org/ 10.1371/journal.pone.0194060. [14] Carmody LA, Zhao J, Kalikin LM, LeBar W, Simon RH, Venkataraman A, et al. The daily dynamics of cystic fibrosis airway microbiota during clinical stability and at exacerbation. Microbiome 2015;3.. https://doi.org/10.1186/s40168015-0074-9. [15] Muhlebach MS, Hatch JE, Einarsson GG, McGrath SJ, Gilipin DF, Lavelle G, et al. Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 2018;52:1800242. https://doi.org/ 10.1183/13993003.00242-2018. [16] Zemanick ET, Wagner BD, Robertson CE, Stevens MJ, Szefler SJ, Accurso FJ, et al. Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. Ann Am Thorac Soc 2015;12:221–9. [17] Jones AM, Dodd ME, Govan JRW, Barcus V, Doherty CJ, Morris J, et al. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis. Thorax 2004;59:948–51. [18] Costello A, Herbert G, Fabunmi L, Schaffer K, Kavanagh KA, Caraher EM, et al. Virulence of an emerging respiratory pathogen, genus Pandoraea, in vivo and its interactions with lung epithelial cells. J Med Microbiol 2011;60:289–99. [19] Green HD, Bright-Thomas R, Kenna DT, Turton JF, Woodford N, Jones AM. Ralstonia infection in cystic fibrosis. Epidemiol Infect 2017;145:2864–72. [20] Degand N, Lotte R, Decondé Le Butor C, Segonds C, Thouverez M, Ferroni A, et al. Epidemic spread of Pandoraea pulmonicola in a cystic fibrosis center. BMC Infect Dis 2015;15.. https://doi.org/10.1186/s12879-015-1327-8. [21] Rønne Hansen C, Pressler T, Høiby N, Gormsen M. Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study. J Cyst Fibros 2006;5:245–51.
Contents lists available at ScienceDirect
Paediatric Respiratory Reviews
The 2018 Royal Society Of Medicine Cystic Fibrosis Symposium
Which pathogens should we worry about? Andrew M. Jones ⇑ Manchester Adult Cystic Fibrosis Centre, Manchester University Hospitals NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK
a r t i c l e
i n f o
Keywords: Cystic fibrosis Pathogens Emerging pathogens Infection Pseudomonas aeruginosa
a b s t r a c t Aside from the traditional CF pathogens, Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa, there are an increasing number of organisms found to have chronic carriage in patients with cystic fibrosis, including gram-negative bacteria, non-tuberculous mycobacteria, anaerobic bacteria and fungal species. Some of these lower prevalence organisms, such as Burkholderia cenocepacia and Mycobacterium abscessus complex, are recognised as true pathogens associated with significant adverse clinical consequences, whilst for others the relative pathogenicity and need for treatment are unclear. This article will highlight some of the challenges in assessing what is a pathogen in CF and the potential implications of infection with different organisms for individual patients. Ó 2019 Published by Elsevier Ltd.
The microbiological status of a cystic fibrosis (CF) patient is a major determinant of their current health status and subsequent clinical outcome. Historically, there was thought to be a classical narrow spectrum of CF pathogens, with Haemophilus influenzae and Staphylococcus aureus encountered early in childhood, and thereafter, with increasing age, Pseudomonas aeruginosa becoming more common. The number of organisms encountered that are reported as causing chronic infection is increasing, and includes other gramnegative bacteria, such as Achromobacter species, Stenotrophomonas maltophilia, Pandoraea species and Ralstonia species, anaerobic bacteria, such as species of Prevotella, Gemella, Streptococcus and Veillonella, non-tuberculous Mycobacteria, in particular M. abscessus complex and M. avium complex, and fungi, including Aspergillus fumigatus, Scedosporium, Exophiala and Trichosporon species (Table 1). The yield depends on the type of respiratory samples obtained and the culture methodology. For example, prolonged culture and use of specific media, and use of culture independent molecular techniques influence the results provided. When these organisms are encountered in lower respiratory tract secretions from a patient with CF, there are several questions that arise, but primarily, the clinician needs to consider whether this is a potential pathogen that we should worry about. There may be certain behaviours that can be interpreted as potential indications for concern, including likelihood of persistence of infection as opposed to transient carriage, reports of cross-infection ⇑ Address: Manchester Adult Cystic Fibrosis Centre, Manchester University Hospitals NHS Foundation Trust, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK. Fax: +44 0161 291 2080. E-mail address: [email protected] https://doi.org/10.1016/j.prrv.2019.02.007 1526-0542/Ó 2019 Published by Elsevier Ltd.
between patients, influence of transplant outcomes such as persistence in the graft lungs and any ‘‘unusual” behaviour such as episodes of bacteraemia. In addition, the organism may display inherent resistance to many antibiotics and potential virulence may be suggested by in vitro model data. In addition to the behaviour of the organism, other findings that may also be concerning include evidence of a host response to the presence of the organism, such as the development of antibodies, and accelerated clinical decline following acquisition of infection reflected in weight loss and decreased lung function. In considering the published literature concerning the lower prevalence organisms to elucidate their clinical consequences, there are a number of potential pitfalls that should be taken into consideration. Evidence is commonly limited to a few case studies or small cohort studies with outcomes examined over short intervals. There is often a lack of suitable controls, there may not be a uniform definition of ‘chronic infection’, and there may be multiple confounders to take into account, such as the influence of comorbidities and co-infections. For many organisms there is no clear evidence to guide effective treatment regimens and no defined breakpoints for antibiotic susceptibility testing. The available literature is subject to a potential reporting and publication bias, with authors more likely to write up and submit cases with a deleterious outcome in relation to an organism, and similarly for journals to publish such cases. The literature is further complicated by changes in taxonomy for organisms, and reallocation of species to new genera, thus limiting the usefulness of historical reports. Furthermore, in vitro model data may not reflect in vivo behaviour and clinical data from infection in non-CF patients may not reflect the consequences of infection in CF.
16
A.M. Jones / Paediatric Respiratory Reviews 31 (2019) 15–17
Table 1 Examples of low prevalence organisms associated with chronic colonisation in CF. Gram-negative bacteria Achromobacter species Acinetobacter species Burkholderia cepacia complex Burkholderia gladioli Elizabethkingia species Inquilinus limosus Pandoraea species Ralstonia species Serratia species Stenotrophomonas maltophilia Non-tuberculous mycobacteria Mycobacterium abscessus complex Mycobacterium avium complex Anaerobic bacteria Actinomyces species Fusobacterium species Gemella species Prevotella species Rothia species Streptococcus species Veillonella species Fungal species Exophiala dermatitidis Lomentospora prolificans Pneumocystis jirovecii Scedosporium species Trichosporon species
Knowledge of optimal treatment strategies and new challenges associated with CF infections continues to evolve, even for the ‘classical’ CF pathogens such as S. aureus. The use of prophylactic anti-Staphylococcal antibiotics in childhood remains controversial. An ongoing UK Registry based study, CF START (www.cfstart.org. uk), hopes to finally resolve this issue. The phenotypic behaviour expressed by different strains of organisms may influence their clinical consequences for patients with CF. For Staph. aureus, small colony variant isolates, generally considered to be related to poor clinical outcomes, can be encountered in CF [1]. Methicillinresistant strains are also encountered and have been associated with worsening progression of lung disease [2]. Strains of Staph. aureus exhibiting virulence factors such as the Panton–Valentine Leucocidin toxin (PVL+ve) have been associated with increased rates of unusual complications, with lung abscesses described in a number of case reports of CF patients [3,4]. Whilst an increasing prevalence of some of the organisms encountered in CF may at least in part be related to improved techniques for their detection and identification, others seem to have a true rise in incidence. There is currently concern with increasing numbers of M. abscessus complex infections in patients with CF [5]. These organisms are notoriously difficult to treat and macrolide antibiotics constitute an essential component of optimal treatment regimens. One of the different M. abscessus complex subspecies, M. abscessus subspecies abscessus, possesses the erm gene that encodes for naturally inducible macrolide resistance, whilst M. abscessus subspecies massilliense has a non-functioning erm gene. One study in non-CF patients with M. abscessus complex infection reported significantly higher success rates for treatment in patients who harboured M. abscessus subspecies massilliense than those who were infected with M. abscessus subspecies abscessus, [6]. A recent retrospective study from a CF centre in France found similar discrepancies in treatment success between M. abscessus subspecies abscessus and M. abscessus subspecies massilliense [7]. International guidelines recommend speciation of M. abscessus complex and testing isolates for sensitivity to macrolides, cefoxitin and amikacin [8].
Fungal species are often isolated from the respiratory secretions of patients with CF and, outside of the hypersensitivity reaction associated with Aspergillus fumigatus, allergic bronchopulmonary aspergillosis, the clinical relevance of airway colonisation with fungi is often unclear. The concept of aspergillus bronchitis is recognised [9], but as with other fungal species there are no clinical studies that have demonstrated benefits of treatment intervention, other than small case studies [10]. The clinical relevance of carriage of an organism in the respiratory tract in CF may also have important consequences in those patients who are listed for lung transplantation. Patients with B. cenocepacia infection are excluded from lung transplant programs in many countries due to poor posttransplant outcomes. Whilst the impact of fungi in the airways of an immunocompetent CF host is unclear, some fungi, including Aspergillus fumigatus and Scedosporium species and Lomentospora prolificans, can cause challenging infective complications in patients post-lung transplantation. Although the presence of particular pathogens, for example B. cenocepacia, have been clearly shown to cause worsening of CF lung disease, the airways of CF patients are not generally populated by a single organism, but by many different species [11]. Cultureindependent microbiological analyses applied to CF samples have provided insights into the complexity of the microbiota of the lower respiratory tract in CF. A narrowing of airway bacterial community diversity is associated with older patients and is seen in those with greater impairment of lung function [12,13]. Whether there is a causal factor in this relationship, and any future implications for treatment strategies, requires further research. The CF airways are not only colonised by aerobic species. There are steep oxygen gradients within CF lungs and relatively high levels of anaerobic bacteria can be readily identified using specialist culture and molecular identification methodologies. The clinical significance of their presence remains unclear. Although a recent study has reported a relative increase in the abundance of anaerobic bacteria at the onset of exacerbations [14], other studies have demonstrated a correlation between a greater abundance of anaerobes and higher body mass index and FEV1 levels, lower levels of inflammation and increased clinical stability [15,16]. P. aeruginosa remains the primary pathogen in CF, as it influences the clinical outcome for the majority of patients with CF. Clinical teams therefore utilise strategies to detect early infection and commence eradication therapy to defer the progression to chronic carriage, apply measures to prevent cross-infection, and for those who eventually develop chronic infection institute long term antibiotic treatment with inhaled antibiotics and oral (predominantly macrolides) agents to minimise the impact of chronic P. aeruginosa on infective exacerbations and the progression of CF lung disease. Other gram-negative pathogens including Ralstonia, Achromobacter, Pandoraea, and Burkholderia species are also encountered but assume a much lower prevalence than P. aeruginosa. These organisms commonly display in vitro resistance to many antibiotics. The prevalence, rates of conversion from initial to chronic carriage and subsequent clinical consequences differ from species to species. Within the Burkholderia cepacia complex, B. cenocepacia has much more severe clinical consequences than the most frequently encountered Burkholderia species, B. multivorans [17]. However, cases of cepacia syndrome, although classically associated with B. cenocepacia infection, are also occasionally described in association with B. multivorans infection [17]. In-vitro data suggest that virulence also may differ between species of Pandoraea [18]. There are reports both of cross-infection and also of data to suggest a potential pathogenic role for at least some of these organisms in patients with CF [19–21].
A.M. Jones / Paediatric Respiratory Reviews 31 (2019) 15–17
SUMMARY Chronic airway infection leading to progressive lung damage and respiratory failure is the major cause of the premature mortality for patients with cystic fibrosis. P. aeruginosa remains by far the most prevalent chronic pathogen in CF, but many other organisms are also increasingly encountered. The relative pathogenicity differs from organism to organism. Factors including the availability of non-culture molecular detection techniques, use of specialist culture media, an increasing population of older patients and a greater array of inhaled antibiotics licensed for long term use, are likely to contribute to a continued rise in the number of cases of infection with such organisms and present new challenges in CF clinical care. CONFLICT OF INTEREST Nothing to declare in relation to this article. References [1] Wolter DJ, Emerson JC, McNamara S, Buccat AM, Qin X, Cochrane E, et al. Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis 2013;57:384–91. [2] Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N, Boyle MP. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA 2010;303:2386–93. [3] Barry PJ, Isalska BJ, Jones AM. Panton-valentine leukocidin-positive Staphylococcus aureus: a potentially significant pathogen in cystic fibrosis. Paediatr Respir Rev 2014;15:22–5. [4] Elizur A, Orschelu RC, Ferkol TW, Atkinson JJ, Dunne WM, Buller RS, et al. Panton-valentine leukocidin-positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis. Chest 2007;131:1718–25. [5] Bryant JM, Grogono DM, Rodriguez-Rincon D, Everall I, Brown KP, Moreno P, et al. Emergence and spread of a humantransmissible multidrug-resistant nontuberculous mycobacterium. Science 2016;354:751–7. [6] Koh WJ, Jeon K, Lee NY, Kim BJ, Kook YH, Lee SH, et al. Clinical significance of differentiation of Mycobacterium massiliense from Mycobacterium abscessus. Am J Respir Crit Care Med 2011;183:405–10.
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[7] Roux AL, Catherinot E, Soismier N, Heym B, Bellis G, Lemonnier L, et al. Comparing Mycobacterium massiliense and Mycobacterium abscessus lung infections in cystic fibrosis patients. J Cyst Fibros 2015;14:63–9. [8] Floto RA, Olivier KN, Saiman L, Daley CL, Herrmann JL, Nick JA, et al. US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis. Thorax 2016;71:i1–22. [9] Baxter CG, Dunn G, Jones AM, Webb K, Gore R, Richardson MD, et al. Novel immunologic classification of aspergillosis in adult cystic fibrosis. J Allergy Clin Immunol 2013;132:560–6. [10] Shoseyov D, Brownlee KG, Conway SP, Kerem E. Aspergillus bronchitis in cystic fibrosis. Chest 2006;130:222–6. [11] Sibley CD, Grinwis ME, Field TR, Eshaghurshan CS, Faria MM, Dowd SE, et al. Culture enriched molecular profiling of the cystic fibrosis airway microbiome. PLoS One 2011;22702. 6.e22702. [12] Flight WG, Smith A, Paisey C, Marchesi JR, Bull MJ, Norville PJ, et al. Rapid detection of emerging pathogens and loss of microbial diversity associated with severe lung disease in cystic fibrosis. J Clin Microbiol 2015;53:2022–9. [13] Carmody LA, Caverly LJ, Foster BK, Rogers MAM, Kalikin LM, Simon RH, et al. Fluctuations in airway bacterial communities associated with clinical states and disease stages in cystic fibrosis. PLoS One 2018;13.. https://doi.org/ 10.1371/journal.pone.0194060. [14] Carmody LA, Zhao J, Kalikin LM, LeBar W, Simon RH, Venkataraman A, et al. The daily dynamics of cystic fibrosis airway microbiota during clinical stability and at exacerbation. Microbiome 2015;3.. https://doi.org/10.1186/s40168015-0074-9. [15] Muhlebach MS, Hatch JE, Einarsson GG, McGrath SJ, Gilipin DF, Lavelle G, et al. Anaerobic bacteria cultured from cystic fibrosis airways correlate to milder disease: a multisite study. Eur Respir J 2018;52:1800242. https://doi.org/ 10.1183/13993003.00242-2018. [16] Zemanick ET, Wagner BD, Robertson CE, Stevens MJ, Szefler SJ, Accurso FJ, et al. Assessment of airway microbiota and inflammation in cystic fibrosis using multiple sampling methods. Ann Am Thorac Soc 2015;12:221–9. [17] Jones AM, Dodd ME, Govan JRW, Barcus V, Doherty CJ, Morris J, et al. Burkholderia cenocepacia and Burkholderia multivorans: influence on survival in cystic fibrosis. Thorax 2004;59:948–51. [18] Costello A, Herbert G, Fabunmi L, Schaffer K, Kavanagh KA, Caraher EM, et al. Virulence of an emerging respiratory pathogen, genus Pandoraea, in vivo and its interactions with lung epithelial cells. J Med Microbiol 2011;60:289–99. [19] Green HD, Bright-Thomas R, Kenna DT, Turton JF, Woodford N, Jones AM. Ralstonia infection in cystic fibrosis. Epidemiol Infect 2017;145:2864–72. [20] Degand N, Lotte R, Decondé Le Butor C, Segonds C, Thouverez M, Ferroni A, et al. Epidemic spread of Pandoraea pulmonicola in a cystic fibrosis center. BMC Infect Dis 2015;15.. https://doi.org/10.1186/s12879-015-1327-8. [21] Rønne Hansen C, Pressler T, Høiby N, Gormsen M. Chronic infection with Achromobacter xylosoxidans in cystic fibrosis patients; a retrospective case control study. J Cyst Fibros 2006;5:245–51.