Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates the activity of sodium and chloride channels across the epithelial cells, thereby facilitating appropriate hydration of mucins and effective mucociliary clearance in various organs of the body (1). Impaired secretion of chloride and bicarbonate ions due to CFTR mutation leads to the formation of mucus, which is too thick to be cleared (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 of the body to these recurrent infections eventually leads to bronchiectasis, characterized by permanent bronchial dilation, leading to impaired mucociliary clearance allowing bacterial adherence, increased bacterial load and the development of chronic infection. The bacteria gradually adapt to these conditions by forming biofilms, which ensures protection from phagocytic attack as well as 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 exacerbations and severe inflammation, progress to complications, are associated with impaired mucociliary function leading to mucus obstruction and reduced lung function, predispose to microbial infections, and can cause permanent damage (6, 7). However, there are also many differences between the two. These include the differences in the etiology, age, and lung predominance. Bronchiectasis in CF patients is associated with mutations in the CFTR gene while non-CF bronchiectasis is associated with various underlying conditions like immunodeficiency disorders, ciliary dyskinesis or demonstrates post-infectious etiology. Non-CF bronchiectasis affects mainly older population (age > 60 years) unlike CF patients, which is a genetic disorder thereby manifesting in both children and adults. Furthermore, non-CF bronchiectasis is associated with lower lung lobe predominance as compared to upper lung lobe predominance in CF (7).
Although the core airway microbiota is similar in both CF and non-CF bronchiectasis, particular satellite microbes are associated with specific conditions. Sputum is the preferred specimen for culturing the bacterial organisms, and is also tested for acid-fast bacilli in case of non-CF bronchiectasis (5). However, bronchioalveolar lavage (BAL) is reserved for patients who are unable to produce sputum or whose CT (computed tomography) scan indicates microbial infection but sputum culture is negative. In case of CF bronchiectasis, culture of sputum or BAL or epithelial lining fluid (ELF) guides the antimicrobial therapy. 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). Interestingly, the core microbiota in both the conditions is similar in childhood and eventually diverges by adulthood (6, 11).
Antibiotics are the mainstay of treatment of bronchiectasis in both CF and non-CF patients, the choice of which is based on the understanding of the predominant respiratory tract colonizers as well as the results of local antimicrobial susceptibility testing (AST). The use of antibiotics is associated with substantially less devastating pulmonary disease in these patients, thereby improving their survival (12).
AST is used to predict the success or failure of an antibiotic by sorting out the resistant bacteria from the susceptible ones on the basis of Minimal Inhibitory Concentration (MIC) breakpoints, which are determined by breakpoint committees like European Committee on Antimicrobial Susceptibility Testing (EUCAST) or Clinical & 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 for the bacteria to survive in the mucus obstructed airways of the CF patients and to combat the antibiotic treatment, which is often given for longer duration in CF patients and at doses higher than those in non-CF patients (14). So clinicians cannot rely only on such data for prescribing empirical therapy to the CF patients. Besides this there are several other factors, which may be responsible for the disparity in antibiotic susceptibility profile between the CF and non-CF populations. For instance, in response to the oxygen or nutrient deficit conditions in CF lungs, the bacteria adapt by slowing down their growth rate or by altering their metabolism (4), which fosters resistance to several antibiotics among these microorganisms (e.g. the cell-wall acting antibiotics might not be effective in eradicating such bacteria, which are not actively dividing or are growing slowly) or the bacteria form biofilms, which likewise is responsible for antibiotic resistance (15). In addition to this, different colonial types of bacteria such as small colony variants (SCVs) are observed in the respiratory samples of the CF patients (16)(17), which are often missed in the routine laboratory testing. A single sample from CF patients may contain a mixed population of the same organism with varied antibiotic susceptibility profile thereby requiring utmost caution while culturing the microorganisms and testing for antibiotic susceptibility (18).
Therefore, a detailed insight into the comparison of respiratory pathogen colonization in both the conditions would pave way for improved management strategies of bronchiectasis in both the CF and non-CF populations.
Study Aim and Objectives
This systematic review aims to compare the microbiota and antimicrobial susceptibility profile in CF and non-CF bronchiectasis. We propose to undertake a systematic review of literature to address the following research questions:
What are the bacteria colonizing the respiratory tract in patients with cystic fibrosis bronchiectasis compared to non cystic fibrosis bronchiectasis?
How does the antibiotic susceptibility profile of specific bacteria, differ between CF bronchiectasis and non-CF bronchiectasis patients?