Discussion
In this large retrospective cohort study, we found that individuals with
CF and frequent fungal detection had higher rates of co-infection withP. aeruginosa and S. maltophilia compared to those with no
or rare detection of fungi. Other clinical characteristics and
outcomes did not differ between those with frequent versus rare fungi
including frequency of ABPA diagnosis, nutritional status, and rate of
pulmonary exacerbations. Lung function (ppFEV1) and lung
function decline were also similar between groups including after
controlling for chronic P. aeruginosa and ABPA.
In individuals with ABPA however, frequent fungal detection was
associated with lower lung function (ppFEV1) compared to
those with ABPA but rare fungal detection. Individuals with
ABPA/frequent fungi had higher rates of co-infection with P.
aeruginosa and S. maltophilia ; more CFRD diagnoses; and higher
IgE values compared to those with ABPA/rare fungi and compared to those
without ABPA regardless of fungal categorization. Individuals with ABPA/
frequent fungi also had a trend towards more rapid lung function decline
during follow-up. Interestingly, we found equal proportions of ABPA
among the rare and frequent fungal groups.
As expected, those with ABPA had higher absolute eosinophils and IgE
values, markers of T-helper cells type 2 (Th2), typical of allergic or
hypersensitivity responses. We did not detect a difference in
eosinophils or IgE between the frequent and rare fungal groups.
Interestingly, 60% of the rare group and 55% of the frequent group had
a diagnosis of asthma over the entire study, which is higher than the
general population as well as previously published literature on
patients with CF.19, 20 Furthermore, in the baseline
period, more individuals in the rare group had asthma, while in the
follow up period, more individuals in the frequent group had asthma. .
While the follow up period had more time to collect data and is likely
more robust, the significance of this finding is unclear. Asthma
diagnoses were documented based upon coding in our electronic medical
record; thus diagnoses may reflect institutional practices, regional
effects and allergens, or another unknown confounding variable.
Individuals with frequent fungal infection had higher rates of chronicP. aeruginosa co-infection and more P. aeruginosadetection overall compared to the rare fungus group. A similar pattern
was seen in those with ABPA and frequent fungi, having the highest
proportion of individuals with chronic P. aeruginosa infection
when compared to the other three groups. This may be related to the use
of aggressive antibiotic therapy in P. aeruginosa eradication
protocols, allowing for shifts in biodiversity by creating a less
competitive airway environment for fungal species.11,
21 Other studies and authors have suggested that biofilms created byP. aeruginosa and/or Aspergillus may be initially
favorable and synergistic for fungal spores to
germinate.22 However, other studies have shown thatP. aeruginosa biofilms actually inhibit Aspergillusgrowth, favoring the competition theory.23 There was
no significant differences in MRSA co-infection among any of the groups,
another organism possibly related to more frequent therapies and driven
by microbial management.24 In the follow-up period,
people in our cohort with rare fungi more often isolated P.
aeruginosa prior to later fungal detection, rather than isolating fungi
first, supporting the role of antimicrobial therapies and/or a
synergistic environment in fungal growth, although our numbers were
small.
S. maltophilia was associated with more frequent fungal infection
at baseline and during follow-up. It also had a different longitudinal
pattern than P. aeruginosa , showing that almost 50% isolatedS. maltophilia prior to fungus and vice versa. While one
investigation in the associations with fungi and S. maltophiliahave been seen in people with CF and liver disease, the literature is
still lacking in understanding of how the organisms are
related.25 Our findings are both supportive of and
contrary to existing data, but imply an association between the
acquisition of fungus and subsequent infection with P. aeruginosaand S. maltophilia . Given this, more research is needed to
identify associated risk factors as well as cause and effect
relationships between these organisms.
The association between fungus and lung disease progression has been
examined previously in CF. Studies have shown lower ppFEV1 in those with
chronic fungal infection, yet the definition of chronic varies widely in
the literature. Some investigators have adapted criteria similar to that
of P. aeruginosa classifications, however there are many genera
and species of fungus that make definitions difficult. Furthermore,
given the need for sputum or BAL for fungal culture, detection of fungi
is dependent on the person’s ability to expectorate, further
complicating classification, prevalence, and disease severity. This
likely explains the higher rates of bacteria and fungus isolation in our
cohort when compared to registry data.26
Most studies in the literature focus on Aspergillus orAspergillus fumigatus specifically, excluding other fungal
genera.5, 7, 17 We included all fungi (with the
exception of Candida that is not routinely reported by our
clinical laboratory) as genera such as Scedosporium may also
contribute to CF lung disease.27, 28 However, over
70% of fungal positive cultures in our cohort grew Aspergillus .
Our study was larger than most and included follow-up for a median of 6
years.
Our findings agree with the literature in finding higher morbidity and
worse outcomes in those with ABPA. However, our study was one of the few
comparing ABPA to fungal frequency both as a co-variate and as a
separate group.6, 7 By doing so, we found that those
with both ABPA and frequent fungus appeared to have more severe disease
despite the fact that the presence of fungus in the sputum is not
required for ABPA diagnosis. This dynamic emphasizes the importance of
fungus on inflammation in the CF airway, yet how the pathophysiology of
fungal infections needs further investigation.
This study has several limitations. Most importantly, this was a single
center, retrospective study so we are unable to determine causation
between fungal disease, ABPA and outcomes. Given electronic medical
record limitations, we only evaluated culture results as early as 2004.
It is possible that some individuals isolated fungi before this and thus
meet other fungal group classification. Fungi are also difficult to
isolate in culture.21, 29 Given this, there are likely
individuals who have fungi that were not detected and may account for
those without ABPA in the absence of positive fungal cultures. We tried
to account for this by requiring at least 4 lower airway cultures for
analysis. It is likely that most of the individuals in this study could
spontaneously expectorate, and thus were likely more severely impacted
compared to those who could not expectorate. This may explain the higher
rates of fungi and bacterial pathogens given a more reliable sample than
throat swabs. Furthermore, individuals in the frequent fungal group had
significantly more cultures compared to those with rare fungi which may
lead to surveillance bias. Prospective longitudinal studies are needed
to assess the acquisition of fungus in real time and how use of
antibiotics and co-infections contribute. Mechanistic studies are also
needed to explore the interactions of fungi and other organisms in the
CF airway as well as inflammatory host-responses, specific biomarkers of
fungal disease and allergy, and clinical studies investigating
characteristics regarding the development of ABPA.