Comparison of respiratory pathogen colonization and antimicrobial susceptibility in people with cystic fibrosis bronchiectasis versus non-cystic fibrosis bronchiectasis: a protocol for a systematic review

Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene. This gene regulates the activity of sodium and chloride channels across the epithelial cells, thereby facilitating appropriate hydration of mucins and effective muco-ciliary clearance in various organs [1]. Impaired secretion of chloride and bicarbonate ions due to CFTR mutations leads to the formation of thick mucus, which is difficult to clear [2]. This predisposes CF patients to pulmonary bacterial infections caused by Staphylococcus aureus, Pseudomonas aeruginosa, Haemophilus influenzae, or Burkholderia cepacia complex (Bcc) [3]. The inflammatory response to recurrent infections eventually leads to bronchiectasis, characterized by permanent bronchial dilation. This causes bacterial adherence, increased bacterial load, and the development of chronic infection. The bacteria gradually adapt to these conditions by forming biofilms, protecting them from phagocytosis as well as penetration of antibiotics [4].

Besides CF, bronchiectasis is associated with various other conditions such as immunodeficiency disorders, autoimmune diseases, ciliary abnormalities, connective tissue diseases, airway injury, malignancy, inflammatory bowel disease, alpha-1 antitrypsin deficiency, or hypersensitivity (allergic bronchopulmonary aspergillosis). These are collectively termed as non-CF bronchiectasis [5].

There are many similarities between CF and non-CF bronchiectasis. Both are associated with severe airway inflammation, mucus obstruction, reduced lung function, progression over time, and frequent pulmonary exacerbations [6, 7]. However, there are also many differences between the two conditions.

Various biological specimens have been analyzed for identifying bacterial colonization patterns in people with bronchiectasis. Sputum is the preferred specimen for culturing bacteria and is also tested for acid-fast bacilli in non-CF bronchiectasis [5]. Bronchoalveolar lavage (BAL) is reserved for patients who are unable to produce sputum or when sputum does not yield organisms. Epithelial lining fluid (ELF) is another respiratory specimen used for microbiologic analysis.

The major microbiota colonizing the airways are similar in both CF and non-CF bronchiectasis. Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia complex, Haemophilus influenzae, Stenotrophomonas maltophilia, and Achromobacter xylosoxidans are commonly associated with CF bronchiectasis [8] while Haemophilus influenzae, Pseudomonas aeruginosa, Moraxella catarrhalis, or non-tuburculous Mycobacteria (NTM) are the predominant bacterial species associated with non-CF bronchiectasis [5, 9]. Gram-positive bacteria including Streptococcus pneumoniae and Staphylococcus aureus are rarely associated with non-CF bronchiectasis unlike CF bronchiectasis [10]. Further, the core microbiota in both the conditions are similar in childhood but diverge by adulthood [6, 11].

Antibiotics are the mainstay of treatment of bronchiectasis in both CF and non-CF patients. The choice of antibiotics is based on an understanding of the predominant respiratory tract colonizers in individual patients, as well as local antimicrobial susceptibility testing (AST) patterns. The appropriate use of antibiotics is associated with improved pulmonary function and survival [12].

AST may predict the success or failure of specific antibiotics, by sorting out the resistant bacteria from the susceptible ones on the basis of Minimal Inhibitory Concentration (MIC) breakpoints. These are determined by breakpoint committees such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). However, the epidemiological cut-off is determined using the susceptibility data from the wild-type population and does not take into consideration any mutant strains [13], which are commonly encountered in the mucus-obstructed airways of CF patients. Therefore, people with CF bronchiectasis often receive antibiotics in higher doses and for longer duration, compared to non-CF bronchiectasis [14]. So clinicians cannot rely only on such data for prescribing empirical therapy to the CF patients. There are several other factors, responsible for differences in antibiotic susceptibility patterns between CF and non-CF populations. Bacteria in CF airways respond to the deficient oxygen or nutrient conditions by slowing down their growth rate or by altering their metabolism [4], which fosters resistance to several antibiotics. Therefore, antibiotics acting on the cell-wall may not be effective in eradicating bacteria that are not actively dividing or are growing slowly. Many bacteria form biofilms, which make them impervious to antibiotics [15]. In addition, different colonial types of bacteria such as small colony variants (SCV) are observed in the respiratory specimens of CF patients [16, 17], which are often missed in routine laboratory testing. A single specimen from CF patients may contain mixed populations of a single organism with different antibiotic susceptibility profile [18].

Therefore, a detailed comparison of respiratory pathogen colonization in people with CF bronchiectasis and non-CF bronchiectasis, and the antimicrobial susceptibility patterns in them, could improve management of both conditions.

The protocol of this systematic review has been registered in the PROSPERO database, the International prospective register of systematic reviews on July 26, 2020 (CRD42020193859). This protocol is in accordance with the Preferred Reporting Item for Systematic Review and Meta-analysis (PRISMA-P) guidelines (Additional file 1) [19].

To date, there are no locally applicable evidence-based guidelines for antimicrobial treatment of non-CF bronchiectasis patients. In general, treatment is based on extrapolation of evidence in CF bronchiectasis [24, 25]. Hence, comparing the bacterial colonization pattern and antibiotic susceptibility profile in CF bronchiectasis versus non-CF bronchiectasis would aid in improved management of both the conditions. Furthermore, the understanding of the microbiota in both CF and non-CF populations would aid in more personalized treatment approaches. Understanding the antimicrobial susceptibility patterns against specific organisms can facilitate appropriate rather than empiric therapy and hopefully reduce the burden of antimicrobial resistance created by rampant usage of antibiotics.