Shifting Landscape of Airway Infection in Early Cystic Fibrosis

Airway infection plays a critical role in the pathogenesis and progression of cystic fibrosis (CF) lung disease (1). Historically, we believed that CF airway microbiology followed a reasonably predictable course of infection, commencing with Staphylococcus aureus and Haemophilus influenzae soon after birth and continuing into early childhood, then progressing to persistent infection with gram-negative organisms, most notably Pseudomonas aeruginosa (2). We have witnessed dramatic changes in CF care and treatment over the last 20 years, and it is reasonable to speculate that current clinical practice has influenced the prevalence and types of infections we are observing in our young patients with CF.

In this issue of the Journal, Breuer and colleagues (pp. 590–599) reexamine the epidemiology of lower airway infection in a modern cohort of almost 400 infants and young children diagnosed by newborn screening, followed at two Australian CF centers (3). During the 18-year study period, detection of P. aeruginosa, S. aureus, and H. influenzae by BAL decreased significantly, and these changes appeared to be associated with the increased use of oral and inhaled antipseudomonal antibiotics (ciprofloxacin and inhaled tobramycin), azithromycin, and inhaled mucolytic therapies (hypertonic saline and dornase alfa). In the United States, early diagnosis of CF by newborn screening is also temporally associated with reductions in P. aeruginosa infections (4).

One additional treatment strategy that likely had an effect on the microbiology results is the routine use of chronic antistaphylococcal antibiotics at both participating sites. Amoxicillin–clavulanic acid, which all patients received from diagnosis to 2 years of age, may have altered not only the detection of S. aureus but also that of H. influenzae, which is usually susceptible to this antibiotic (5). This certainly limits the generalizability of these results, as U.S. CF Care Centers rarely prescribe antistaphylococal prophylaxis to infants and young children. Although prior studies have suggested the use of antistaphylococal prophylaxis leads to an increase in the prevalence of P. aeruginosa (6), this was not observed within the Australian cohort (3). However, this may have been mitigated by the frequent use of antibiotics targeting P. aeruginosa over the study period. At one of the Australian sites, for example, treatment of pulmonary exacerbations routinely included antipseudomonal antibiotics, regardless of whether patients were culture positive for P. aeruginosa.

Advances in CFTR (CF transmembrane conductance regulator) modulators are likely to further affect airway microbiology. Highly effective CF transmembrane conductance regulator modulators offer significant promise for altering infection in CF. The GOAL (G551D Observational) study found that initiation of ivacaftor therapy was associated with a reduction in culture positivity of both P. aeruginosa and Aspergillus (7). Similarly, reductions in P. aeruginosa infections have been reported in other studies after treatment with ivacaftor (8, 9). In 2019, the CF community is anticipating the approval of a triple combination of highly efficacious CF transmembrane conductance regulator modulators that could eventually benefit more than 80% of people with CF (10). With the intentions of studying and ultimately prescribing these modulators early in infancy, it is very likely that the epidemiology of early infection will be changed to an even greater extent.

In their cohort, the reduction in the prevalence of the bacterial pathogens has led to the emergence of Aspergillus as the most commonly detected pathogen from the lower airways among young children with CF (3). This study raises important questions regarding the increased prevalence of Aspergillus and the clinical implications of this finding. Certainly, the sampling technique affects the rate of isolation of fungi such as Aspergillus, with BAL and sputum being far superior to oropharyngeal (OP) swabs (11). In fact, many microbiology laboratories do not routinely test for fungi in OP swabs because of low diagnostic yield. Because most CF centers rely on OP samples for pathogen surveillance in younger children with CF, fungi such as Aspergillus will not be detected. This raises the question of whether bronchoscopy and BAL should be performed more routinely to survey for airway infection in infants and young children with CF. Although the arguments for and against this surveillance approach are beyond the scope of this editorial, one randomized controlled study did not provide clear evidence to support the routine use of BAL for the diagnosis and management of pulmonary infection in preschool children with CF compared with the standard practice of providing treatment based on results of OP cultures and clinical symptoms (12). Regardless, there is a need to optimize standardized protocols to identify fungi in respiratory samples including OP swabs collected from younger children. Recent advances in mycological culture and culture-independent molecular methods have led to the increased detection of a range of fungal species in CF respiratory samples (13). However, beyond the difficulties of detecting fungi such as Aspergillus, the more challenging issue is determining their clinical significance. Tracy and Moss recently proposed a set of practical diagnostic criteria for differentiating colonization from infection and active lung disease (13). This is an important distinction, as treatment approaches would likely differ. Another consideration that might explain the increased prevalence of Aspergillus in their cohort is that the use of chronic oral antibiotics, including azithromycin, and inhaled antipseudomonal antibiotics, is associated with an increased prevalence of fungi from CF respiratory samples (14, 15).

The CF Foundation is launching an Infection Research Initiative, committing at least $100 million during the next 5 years as part of a sweeping effort to address the chronic and intractable infections that are a hallmark of CF. The findings from this study support the need for targeted research focused on the acquisition and evolution of airway pathogens early in life, and their relationship with clinical outcomes and treatment. It is vital to have a better understanding of airway infection to optimize treatment and alter the cycle of infection and inflammation and subsequent lung function decline and disease progression in patients with CF.