Delayed diagnosis is common in interstitial lung diseases (ILDs) and is associated
with decreased quality of life and a poor prognosis (1). Early diagnosis and initiation
of appropriate management could improve patient outcomes (2–5). Studies in idiopathic
pulmonary fibrosis (IPF) demonstrated that antifibrotic therapies also slow down disease
progression in patients with more preserved lung function (3, 5).
Interstitial lung abnormalities (ILAs) found incidentally on computed tomography (CT)
performed for other purposes, such as lung cancer screening or diagnostic cardiac
CT, may facilitate early diagnosis of ILD, allowing for early treatment and removal
of triggers that drive ILD progression. However, ILAs are relatively frequent, especially
in older subjects (6). Systematic evaluation of population-based and lung cancer–screening
cohorts showed a prevalence of ILAs of 4–9% in (former) smokers and 2–7% in never-smokers
(7). With increasing use of CT scans, clinicians are confronted with the question,
“what to do with this person with ILAs?” Risk stratification of ILAs is urgently needed
to differentiate two subsets: 1) ILAs with a high likelihood of progression to clinically
relevant ILD; versus 2) ILAs that pose no such risk and do not need further evaluation
and follow-up.
In this issue of the Journal, Rose and colleagues (pp. 60–68) add another piece of
evidence to the puzzle of risk stratification of ILAs (8). They investigated whether
combining CT data and pulmonary function (spirometry and Dl
CO) could identify subjects with suspected ILD, associated with worse outcomes, within
participants with ILAs in the Genetic Epidemiology of Chronic Obstructive Pulmonary
Disease (COPDGene) cohort, a U.S.-based multicenter prospective cohort study of (current
and former) smokers (9). People with known lung diseases other than COPD or asthma
were excluded. CT scans were assessed for percentage of emphysema and ILAs, defined
per criteria of the Fleischner Society (10). CT scans showing ILAs were scored on
the presence of definite fibrosis. Importantly, Dl
CO was corrected for the percentage of emphysema on CT. For suspected ILD, the authors
used the following definition: presence of ILAs and at least one of the following
three criteria: 1) definite fibrosis on CT; 2) post-bronchodilator FVC < 80% predicted;
or 3) Dl
CO < 70% predicted after adjustment for emphysema.
Ten percent of participants (443 out of 4,360) had ILAs. Of those with ILAs, 239 (54%)
met the criteria of suspected ILD; within this subset, 16% had definite fibrosis on
CT, 57% had an FVC < 80%, and 67% had a Dl
CO < 80% after adjustment for emphysema. The majority (62%) of participants with suspected
ILD met only one criterium, 35% met two criteria, and 3% met all three criteria. Participants
with suspected ILD were more likely to be of self-identified Black or African American
race and had a higher pack-year smoking history. Compared with the ILA group, subjects
with suspected ILD were more likely to have worse clinical endpoints (including quality
of life, 6-minute-walk test, and respiratory exacerbations). Mortality rates were
higher in the suspected ILD than in the ILA group (15% vs. 6%).
This study has several strengths, including the large, multicenter, prospective cohort
design with longitudinal data collection. The authors take the important step of splitting
ILAs in two separate subgroups with vastly different outcomes: ILAs versus suspected
ILD. Although ILA is a CT-defined entity, suspected ILD is defined by a combination
of radiological and physiological abnormalities and could be seen as a potential early
phase in the evolutionary continuum of ILD (11). However, suspected ILD and even definite
ILD is not a diagnosis but merely an umbrella term warranting further investigations,
ideally in an experienced ILD center with a multidisciplinary team discussion (11,
12). Although it feels intuitively correct to refer subjects with suspected ILD for
further work-up and follow-up, it is too early to conclude that people with ILAs without
suspected ILD can be safely discharged from follow-up.
The study also has limitations. First, the COPDGene cohort studied only smokers, implicating
the need to further validate and fine-tune the criteria of suspected ILD in broader
populations. Second, although a Dl
CO < 70% predicted (after adjustment for emphysema) appeared to be the most important
criterium in driving the associations with clinical endpoints, Dl
CO was not measured at baseline but only in the second phase of COPDGene (5 years
after enrollment). Replication of the lung function criteria (and their cut-offs)
is warranted in independent cohorts with contemporaneous imaging, spirometry, and
Dl
CO data. Moreover, it is a concern that the single criterium of an often-variable
measure such as Dl
CO is sufficient to support labeling a person as having suspected ILD. Last, another
potential caveat is the fact that the presence of subpleural reticulation was not
included in the criteria for suspected ILD. This conforms to the Fleischner criteria,
where the division is made in subpleural nonfibrotic ILA and subpleural fibrotic ILA
(characterized by the presence of architectural distortion with traction bronchiectasis
or honeycombing) (10). However, a recent population-based ILA study in China showed
that subpleural reticulation in itself was an independent risk factor for progression
(6).
Strikingly, the distribution of suspected ILD in COPDGene is equal in males and females,
which is not reflecting the prevalence of IPF in registries and studies (13). Furthermore,
there is a considerably lower death rate in subjects with suspected ILD than in patients
with IPF. Besides a potential lead-time bias, this suggests that ILAs likely encompass
the broad spectrum of ILDs. As the presence of connective tissue diseases or occupational
exposures were not an exclusion criterium for participating in the COPDGene cohort,
this may partially explain the survival and sex distribution, where the suspected
ILD could be related to connective tissue disease or exposure. For this group, early
detection of ILD may be most relevant, as immunosuppressive treatments and avoidance
of disease triggers have the potential to reverse, stabilize, or slow down lung function
decline (11). In the current study, self-identified Black race was a risk factor for
suspected ILD. Previous studies have shown that women and people of Black ethnicity
are less likely to receive a diagnosis of IPF and are underrepresented in registries
and clinical trials (13, 14). Identifying suspected ILD in the group of ILAs—according
to the approach by Rose and colleagues—may be a way to improve earlier diagnosis in
broader and more diverse populations.
The results of this study underline that people with ILAs should undergo lung function
testing, in line with previous expert recommendations (7, 10). The question remains,
though, whether people with ILAs can be discharged from follow-up if lung function
is normal and there are no signs of definite fibrosis on CT. Although several studies
have identified blood biomarkers and genetic polymorphisms related to the presence
of ILAs, limited data exist on biomarkers predictive of ILA progression (15, 16).
It would be interesting to link the proposed suspected ILD classification with biomarkers
and genetic data in COPDGene.
Taken together, the findings of Rose and colleagues support that it is time to complement
the CT-based ILA classification with a clinical classification of suspected ILD, also
incorporating lung function and potentially symptoms and blood biomarkers to identify
patients as early as possible in the evolutionary continuum of the different ILDs.
Such a holistic classification would pave the way for clinical trials investigating
the long-term benefits of treating ILDs in the early phases, to improve outcomes for
patients with often still poor prognoses.