Skip to content

Towards breath-based diagnostics for lung infections in cystic fibrosis

by Mavra Nasir, Quantitative Biomedical Science (QBS)

Respiratory infections caused by Pseudomonas aeruginosa and Staphylococcus aureus are the leading cause of morbidity and mortality in cystic fibrosis (CF) patients(1). Accurate microbiological profiling of the lower airways and, consequently, prompt antibiotic treatment, are crucial for delaying chronic infections. In expectorating patients, sputum is cultured for detection of bacterial pathogens. Most children as well as individuals with mild CF disease do not spontaneously expectorate sputum(2,3). In non-expectorating patients, bronchoalveolar lavage (BAL) may be performed to diagnose lower airway infection. However, it is an invasive procedure that requires sedation and cannot be performed frequently. Hence, oropharyngeal (OP) swab cultures are used as surrogate specimens for species identification and antibiotic sensitivity determination. The existing literature is divided on the clinical utility of OP swabs as a reliable surrogate for BAL and sputum. Most studies on children report variable positive predictive values (PPV) ranging from 0.44 to 0.83 for P. aeruginosa and 0.33 to 0.64 for S. aureus(4-7).  In addition, current diagnostic techniques can take up to three days for pathogen identification.

Human breath consists of thousands of volatile molecules that result from cellular metabolic processes, environmental exposures, as well as contributions from the microbiome. Over the last decade, the Food and Drug Administration (FDA) has approved 13 breath tests for use in the clinic. Our work aims to identify putative volatile biomarkers in exhaled breath of CF patients, using two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS), that can guide pathogen identification and antibiotic treatment. Preliminary work involving ex-vivo BAL samples (n = 154) from CF patients were analyzed and a set of 11 volatile biomarkers was able to identify P. aeruginosa a sensitivity and specificity of 0.73 (95% CI 0.46-0.87) and 0.81 (95% CI 0.60-0.94) respectively in the validation set(8). The same set of biomarkers gave a sensitivity and specificity of 0.67 (95% CI 0.38-0.88) and 0.38 (95% CI 0.09-0.76) for S. aureus identification.

To demonstrate clinical translation, we are prospectively collecting breath and sputum from CF patients at CF centers in the United States (New Hampshire and Colorado) and Ireland. Preliminary results from breath show a higher sensitivity for P. aeruginosa and higher specificity for S. aureus compared to OP swabs, suggesting that biomarkers in breath can be used as screening tools to rule-in P. aeruginosa and rule-out S. aureus infections in CF patients.

REFERENCES

  1.        Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005;352(19):1992-2001. doi: 10.1056/NEJMra043184. PubMed PMID: 15888700.
  2.        Radhakrishnan DK, Corey M, Dell SD. Realities of expectorated sputum collection in the pediatric cystic fibrosis clinic. Arch Pediatr Adolesc Med. 2007;161(6):603-6. doi: 10.1001/archpedi.161.6.603. PubMed PMID: 17548767.
  3.        Sagel SD, Kapsner R, Osberg I, Sontag MK, Accurso FJ. Airway inflammation in children with cystic fibrosis and healthy children assessed by sputum induction. Am J Respir Crit Care Med. 2001;164(8 Pt 1):1425-31. doi: 10.1164/ajrccm.164.8.2104075. PubMed PMID: 11704590.
  4.        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(5):267-75. doi: 10.1002/(SICI)1099-0496(199605)21:5<267::AID-PPUL1>3.0.CO;2-K. PubMed PMID: 8726151.
  5.        Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R, Grimwood K, Hiatt P, McCoy K, McNamara S, Ramsey B, Wagener J. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol. 1999;28(5):321-8. PubMed PMID: 10536062.
  6.        Ramsey B, Wentz K, Smith A, Richardson M, Williams-Warren J, Hedges D, Gibson R, Redding G, Lent K, Harris K. Predictive value of oropharyngeal cultures for identifying lower airway bacteria in cystic fibrosis patients. American Review of Respiratory Disease. 1991;144.
  7.        Jung A, Kleinau I, Schonian G, Bauernfeind A, Chen C, Griese M, Doring G, Gobel U, Wahn U, Paul K. Sequential genotyping of Pseudomonas aeruginosa from upper and lower airways of cystic fibrosis patients. Eur Respir J. 2002;20(6):1457-63. PubMed PMID: 12503704.

8.           Nasir M, Bean HD, Smolinska A, Rees CA, Zemanick ET, Hill JE. Volatile molecules from bronchoalveolar lavage fluid can 'rule-in' Pseudomonas aeruginosa and 'rule-out' Staphylococcus aureus infections in cystic fibrosis patients. Sci Rep. 2018;8(1):826. doi: 10.1038/s41598-017-18491-8. PubMed PMID: 29339749; PMCID: PMC5770459.

Leave a Reply

Your email address will not be published. Required fields are marked *