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Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes

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European Journal of Clinical Microbiology & Infectious Diseases Aims and scope Submit manuscript

Abstract

Cystic fibrosis-related diabetes (CFRD) patients suffer from accelerated rates of pulmonary decline compared to cystic fibrosis (CF) patients with normal glucose tolerance (NGT). However, the mechanisms underlying this difference are unknown. While CFRD is associated with increased respiratory infections, a link between infection and enhanced pulmonary dysfunction remains unclear. The development of glucose intolerance is spectral, resulting in impaired glucose tolerance (IGT) prior to the diagnosis of CFRD. Inclusion of IGT patients within the NGT group may diminish the ability to identify correlations with CFRD. With this in mind, this study aimed to determine if the association between CFRD and respiratory infections is correlated with pulmonary decline. Respiratory cultures from 234 CF patients with confirmed diagnosis of NGT or CFRD were analyzed to measure rates of infection, focusing on the two most prevalent bacteria in CF, Staphylococcus aureus and Pseudomonas aeruginosa. Infection status was correlated with pulmonary function and confounding clinical variables including age, gender, blood glucose levels, and CF transmembrane conductance regulator (CFTR) phenotype were considered in multivariate analyses. CFRD patients, particularly those with extremely high blood glucose levels, were more likely than NGT patients to be co-infected with S. aureus and P. aeruginosa, compared to infection with only one pathogen. Co-infection was associated with decreased lung function and increased frequency of pulmonary exacerbations, even after adjustment for confounding variables. Alterations in the microbial community composition, as opposed to the presence of a single pathogen, may account for greater pulmonary decline in CFRD patients.

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References

  1. Ciofu O, Tolker-Nielsen T, Jensen PØ, Wang H, Høiby N (2015) Antimicrobial resistance, respiratory tract infections and role of biofilms in lung infections in cystic fibrosis patients. Adv Drug Deliv Rev 85:7–23. doi:10.1016/j.addr.2014.11.017

    Article  CAS  PubMed  Google Scholar 

  2. O’Sullivan BP, Freedman SD (2009) Cystic fibrosis. Lancet 373:1891–1904

    Article  PubMed  Google Scholar 

  3. Lek N, Acerini CL (2010) Cystic fibrosis related diabetes mellitus—diagnostic and management challenges. Curr Diabetes Rev 6(1):9–16. doi:10.2174/157339910790442600

    Article  PubMed  Google Scholar 

  4. Finkelstein SM, Wielinski CL, Elliott GR, Warwick WJ, Barbosa J, Wu SC et al (1988) Diabetes mellitus associated with cystic fibrosis. J Pediatr 112:373–377

    Article  CAS  PubMed  Google Scholar 

  5. Koch C, Rainisio M, Madessani U, Harms HK, Hodson ME, Mastella G et al (2001) Presence of cystic fibrosis-related diabetes mellitus is tightly linked to poor lung function in patients with cystic fibrosis: data from the European Epidemiologic Registry of Cystic Fibrosis. Pediatr Pulmonol 32:343–350. doi:10.1002/ppul.1142

    Article  CAS  PubMed  Google Scholar 

  6. Marshall BC, Butler SM, Stoddard M, Moran AM, Liou TG, Morgan WJ (2005) Epidemiology of cystic fibrosis-related diabetes. J Pediatr 146:681–687. doi:10.1016/j.jpeds.2004.12.039

    Article  CAS  PubMed  Google Scholar 

  7. Milla CE, Warwick WJ, Moran A (2000) Trends in pulmonary function in patients with cystic fibrosis correlate with the degree of glucose intolerance at baseline. Am J Respir Crit Care Med 162:891–895

    Article  CAS  PubMed  Google Scholar 

  8. Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H et al (2014) Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Respir J 43:125–133

    Article  PubMed  Google Scholar 

  9. Parkins MD, Rendall JC, Elborn JS (2012) Incidence and risk factors for pulmonary exacerbation treatment failures in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa. Chest 141:485–493. doi:10.1378/chest.11-0917

    Article  CAS  PubMed  Google Scholar 

  10. Lanng S, Thorsteinsson B, Nerup J, Koch C (1994) Diabetes mellitus in cystic fibrosis: effect of insulin therapy on lung function and infections. Acta Paediatr 83:849–853

    Article  CAS  PubMed  Google Scholar 

  11. Merlo CA, Boyle MP, Diener-West M, Marshall BC, Goss CH, Lechtzin N (2007) Incidence and risk factors for multiple antibiotic-resistant Pseudomonas aeruginosa in cystic fibrosis. Chest 132:562–568. doi:10.1378/chest.06-2888

    Article  PubMed  Google Scholar 

  12. Klepac-Ceraj V, Lemon KP, Martin TR, Allgaier M, Kembel SW, Knapp AA et al (2010) Relationship between cystic fibrosis respiratory tract bacterial communities and age, genotype, antibiotics and Pseudomonas aeruginosa. Environ Microbiol 12:1293–1303. doi:10.1111/j.1462-2920.2010.02173.x

    Article  CAS  PubMed  Google Scholar 

  13. McGuigan L, Callaghan M (2015) The evolving dynamics of the microbial community in the cystic fibrosis lung. Environ Microbiol 17:16–28. doi:10.1111/1462-2920.12504

    Article  PubMed  Google Scholar 

  14. Paganin P, Fiscarelli EV, Tuccio V, Chiancianesi M, Bacci G, Morelli P et al (2015) Changes in cystic fibrosis airway microbial community associated with a severe decline in lung function. PLoS One 10:e0124348. doi:10.1371/journal.pone.0124348

    Article  PubMed  PubMed Central  Google Scholar 

  15. American Diabetes Association (2015) Classification and diagnosis of diabetes. Diabetes Care 38(Suppl):S8–S16. doi:10.2337/dc15-S005

    Article  Google Scholar 

  16. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B (1983) Changes in the normal maximal expiratory flow-volume curve with growth and aging. Am Rev Respir Dis 127(6):725–734

    CAS  PubMed  Google Scholar 

  17. Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G et al (2010) Clinical care guidelines for cystic fibrosis-related diabetes. Diabetes Care 33:2697–2708

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hubert D, Réglier-Poupet H, Sermet-Gaudelus I, Ferroni A, Le Bourgeois M, Burgel P-R et al (2013) Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis. J Cyst Fibros 12:497–503. doi:10.1016/j.jcf.2012.12.003

    Article  PubMed  Google Scholar 

  19. Brennan AL, Gyi KM, Wood DM, Johnson J, Holliman R, Baines DL et al (2007) Airway glucose concentrations and effect on growth of respiratory pathogens in cystic fibrosis. J Cyst Fibros 6:101–109. doi:10.1016/j.jcf.2006.03.009

    Article  CAS  PubMed  Google Scholar 

  20. Wood DM, Brennan AL, Philips BJ, Baker EH (2004) Effect of hyperglycaemia on glucose concentration of human nasal secretions. Clin Sci (Lond) 106:527–533. doi:10.1042/CS20030333

    Article  CAS  Google Scholar 

  21. Baker EH, Clark N, Brennan AL, Fisher DA, Gyi KM, Hodson ME et al (2007) Hyperglycemia and cystic fibrosis alter respiratory fluid glucose concentrations estimated by breath condensate analysis. J Appl Physiol (1985) 102:1969–1975. doi:10.1152/japplphysiol.01425.2006

    Article  CAS  Google Scholar 

  22. Garnett JP, Nguyen TT, Moffatt JD, Pelham ER, Kalsi KK, Baker EH et al (2012) Proinflammatory mediators disrupt glucose homeostasis in airway surface liquid. J Immunol 189:373–380. doi:10.4049/jimmunol.1200718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Philips BJ, Redman J, Brennan A, Wood D, Holliman R, Baines D et al (2005) Glucose in bronchial aspirates increases the risk of respiratory MRSA in intubated patients. Thorax [Internet] 60:761–764

    Article  CAS  Google Scholar 

  24. Baker EH, Janaway CH, Philips BJ, Brennan AL, Baines DL, Wood DM et al (2006) Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease. Thorax 61:284–289. doi:10.1136/thx.2005.051029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Alba-Loureiro TC, Munhoz CD, Martins JO, Cerchiaro GA, Scavone C, Curi R et al (2007) Neutrophil function and metabolism in individuals with diabetes mellitus. Braz J Med Biol Res 40:1037–1044. doi:10.1590/S0100-879X2006005000143

    Article  CAS  PubMed  Google Scholar 

  26. Yano H, Kinoshita M, Fujino K, Nakashima M, Yamamoto Y, Miyazaki H et al (2012) Insulin treatment directly restores neutrophil phagocytosis and bactericidal activity in diabetic mice and thereby improves surgical site Staphylococcus aureus infection. Infect Immun 80(12):4409–4416. doi:10.1128/IAI.00787-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hunt WR, Zughaier SM, Guentert DE, Shenep MA, Koval M, McCarty NA et al (2014) Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes. Am J Physiol Lung Cell Mol Physiol 306(1):L43–L49. doi:10.1152/ajplung.00224.2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Mulrennan S, Baltic S, Aggarwal S, Wood J, Miranda A, Frost F et al (2015) The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes. Sci Rep 5:8931. doi:10.1038/srep08931

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Timothy Murphy, MD for the insightful comments and careful review of this manuscript and Maret Maliniak, MPH for the assistance with patient data acquisition and helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Pediatrics, Emory University, 2015 Uppergate Drive, Atlanta, GA, 30322, USA

    D. H. Limoli, M. K. Khansaheb, B. Helfman, A. A. Stecenko & J. B. Goldberg

  2. Emory+Children’s Center for CF and Airways Disease Research, 2015 Uppergate Drive, Atlanta, GA, 30322, USA

    D. H. Limoli, B. Helfman, A. A. Stecenko & J. B. Goldberg

  3. Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA, 30322, USA

    J. Yang & L. Peng

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  1. D. H. Limoli
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  2. J. Yang
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  4. B. Helfman
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  7. J. B. Goldberg
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Correspondence to J. B. Goldberg.

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Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees.

Funding

DHL is supported by a postdoctoral fellowship (LIMOLI15F0) from the Cystic Fibrosis (CF) Foundation. AAS is a Marcus Professor of Pulmonology. Clinical data collection was done through support from the CF Foundation Emory+Children’s CF Care Center Grant (CC002).

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from each subject enrolled according to the protocol approved by the Emory University Institutional Review Board (IRB00010219 for the adult subjects and IRB00002161 for the pediatric subjects).

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Limoli, D.H., Yang, J., Khansaheb, M.K. et al. Staphylococcus aureus and Pseudomonas aeruginosa co-infection is associated with cystic fibrosis-related diabetes and poor clinical outcomes. Eur J Clin Microbiol Infect Dis 35, 947–953 (2016). https://doi.org/10.1007/s10096-016-2621-0

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  • DOI: https://doi.org/10.1007/s10096-016-2621-0

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