Fig. 1. Inverse relationship between isolation of mucoid P. aeruginosa (but not Staphylococcus aureus or Haemophilus influenzae) and decline in percentage of predicted FEV₁, as compiled from the CF Foundation Patient Registry database for 1998.

mucoid P. aeruginosa (4, 5, 8). Thus, the molecular and cellular connections between lung infection and defects in CFTR have been of great interest as the primary determinant of the overall clinical status of patients with CF.

Despite a complex sputum bacteriology, the progressive decline in pulmonary function that is the hallmark of CF is mostly attributable to a single pathogen, mucoid P. aeruginosa (8). Patients with CF become colonized and sometimes infected with a variety of potential pathogens; S. aureus and nontypable H. influenzae, for example, are common bacterial isolates with pathogenic potential from cultures of CF respiratory tract secretions (Fig. 1). However, there are no compelling data that indicate that either S. aureus or H. influenzae contributes to lung function decline in CF except on the rare occasions when they cause acute pneumonia, empyema, or a similar infection. Indeed, it remains to be determined whether antistaphylococcal therapy in patients with CF confers clinical benefit or harm (9). One unpublished but completed clinical trial of daily antistaphylococcal therapy found no clinical benefit from potent suppression of S. aureus carriage in CF respiratory secretions (H. Stutman, unpublished work). Often after prolonged mucoid P. aeruginosa infection, patients with CF become superinfected with organisms such as Burkholderia cepacia, Aspergillus spp., and atypical mycobacteria (8, 10). In rare instances, patients become infected with virulent microbial pathogens in the absence of P. aeruginosa. Any microbial pathogen can potentially cause serious infection in patients with CF, but only mucoid P. aeruginosa appreciably contributes to the characteristic chronic and progressive decline in pulmonary function (Fig. 1). Studies clearly show that patients with CF harboring only nonmucoid P. aeruginosa and S. aureus maintain >80% of their predicted lung function (2, 3) and that the presence of S. aureus in the absence of mucoid P. aeruginosa actually predicts long-term survival for patients with CF (11).

Fig. 2. Molecular consequences of CFTR mutations. [Reproduced with permission from ref. 17 (Copyright 1995, Lap Chee Tsui)].

The reason that patients with CF initially acquire and fail to eliminate environmental strains of P. aeruginosa is enigmatic. Patients with CF have normal immune function, and the relationship between defects in chloride ion conductance of mutant CFTR and hypersusceptibility to P. aeruginosa infection is not fully elucidated. Recent work supports the idea that, starting at an early age, many patients with CF harbor microbial pathogens in their lungs that can be detected only by invasive techniques such as bronchoalveolar lavage; thus, it may be difficult to know exactly when infection is initiated (12, 13 and 14). Infecting strains of P. aeruginosa do seem to be fairly stable, and most patients harbor a single major clone of P. aeruginosa for many years (15, 16). Little is known about how this otherwise virulent and highly immunogenic pathogen establishes a low-level infection that fails to elicit an appropriate host response leading to prompt bacterial elimination. It is not unreasonable to consider that patients with CF may, in fact, respond to and eliminate many strains of P. aeruginosa until some combination of factors interferes with elimination of one particular strain and chronic infection is initiated. It is not known when the switch to the LPS-rough, mucoid phenotype occurs; however, this change may take place quite early after the initial infection, inasmuch as most patients harbor the nonmucoid phenotype for short periods and the mucoid phenotype for years (1).