Classification of interstitial lung disease (ILD)

The classification of interstitial lung disease (ILD) can be difficult. ILD is an umbrella term – some say it covers hundreds of conditions or entities. This seems to me as an exaggeration to highlight the complex nature of ILD (especially because no one really knows the exact number).

Nevertheless, we are dealing with many acronyms, many potential causes, a lot of unknowns related to environmental and infectious causes, genetic predisposition etc.

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Can ILD really be classified accurately?

When faced with diagnosing a patient who presents with progressive respiratory symptoms, decline in lung function and interstitial radiological findings, we are keen somehow classify our patient’s condition. To create order in the chaos.

However, ILDs are notoriously hard to differentiate precisely, and the initial diagnosis may change over time in light of new information we receive (i.e. histopathology results, the development of other symptoms consistent with a connective-tissue disease, patient describing family history of ILD, recognizing a relevant occupational exposure etc.).

Broad classifications

Broadly we could classify ILDs as falling within some of these broad categories:

1. Connective-tissue/autoimmune disease
2. Granulomatous inflammatory conditions (such as sarcoidosis)
3. Environmental causes (asbestosis, chronic hypersensitivity pneumonitis)
4. Drug-induced ILD
5. Familial
6. Idiopathic (no cause found)

More often, after careful review and multi-disciplinary team discussion, the diagnosis is one of the following:

1. Some form of idiopathic interstitial pneumonia (see below)
2. Familial interstitial pneumonia
3. Hypersensitivity pneumonitis
4. Sarcoidosis
5. Connective-tissue disease associated interstitial lung disease (CTD-ILD)
6. Drug-induced ILD
7. Something exotic! i.e. some form of vasculitis, eosinophilic lung disease, lymphangioleiomyomatosis (LAM), Langerhans cell histiocytosis (LCH), pulmonary alveolar proteinosis or some other condition you literally never heard about in your life!

Classification of idiopathic interstitial pneumonia

If no cause is found after an extensive search involving clinicians with significant expertise – generally the ILD is diagnosed as an idiopathic interstitial pneumonia (IIP).

In 2013 the American Thoracic and European Respiratory Societies issued a statement regarding the classification IIPs. These are grouped into major (such as idiopathic pulmonary fibrosis – IPF), rare and unclassified (Travis, 2013)

Clinical classifications

Another way ILD can be classified, which has direct clinical implications, is to decide whether the disease is inflammatory or fibrotic. This decision is not always that easy, but helps clinicians navigate uncertainties related to the alphabet soup of acronyms and exotic conditions. Usually a combination of clinical, radiological and bronchoalveolar lavage findings helps to make this distinction.

Importantly, first-line treatment can be decided based on this simple classification: give anti-inflammatory treatment (i.e. corticosteroids) to attempt to stabilize or reverse the ILD or directly go for antifibrotics (nintedanib or pirfenidone) to slow down lung function decline.

Purely fibrotic, progressive lung disease is unlikely to respond to anti-inflammatory or immunosuppressant treatment and early antifibrotic therapy buys the most time for the patient by slowing down decline.

Anti-inflammatory or immunosuppressant therapies can even be detrimental in the case of predominantly fibrotic lung diseases (such as IPF) as shown by the PANTHER-IPF study. However, this finding may actually be underpinned by more complex factors, such as genetic predisposition (which I plan to cover in future posts).

Disease behavior classification

For IIPs, the 2013 ATS/ERS classification goes further than major, rare and unclassifiable. The table below outlines the clinical classification according to disease behavior (Travis, 2013)

“Lumpers” versus “Splitters”

A nicely written article (Wells, 2018) also attempts to classify ILD physicians (treating IPF) into “lumpers” versus “splitters”. Although it’s a slightly funny article, in Prof. Wells’s typical style, it does raise the important point that clinician behavior influences how “deep” the ILD classification will go. I left the reference to this article at the bottom of the page, as it highlights many key issues.

For reference, lumpers are those who look for big picture disease classification over nuances. Splitters are those who believe in the power of detail to distinguish between ILDs. Both approaches are of course legitimate but can be a source of debate.

With regards to IPF, we have 2 major issues in my opinion which have lead to some clinicians being in favor of “lumping”

1. Few therapeutic options

For IPF, in early 2022, we only have two approved antifibrotics (nintedanib and pirfenidone). For other ILDs, especially of the inflammatory variety, the first-line therapy is usually some corticosteroid +/- some second-line or steroid-sparing immunosuppressant. Therefore, clinically we would need to just try to determine which of these treatments would be most likely to help our patient and then monitor the disease behavior over time.

2. The progressive-fibrotic phenotype

Some other forms of pulmonary fibrosis (not IPF) also have a progressive-fibrotic phenotype, despite anti-inflammatory treatment. This means that the progressive lung fibrosis continues over time and in some cases the decline can rival that seen in IPF. In this case, the option would be add-on antifibrotic medication to attempt to slow the decline, and this was shown to work. Therefore, some physicians argue that the fine distinctions between the various forms of ILDs matter less if clinically we would end up recommending the same treatment.

Useful references to help you understand ILD classification better

One good review I found

Mikolasch TA, Garthwaite HS, Porter JC. Update in diagnosis and management of interstitial lung disease . Clin Med (Lond). 2017;17(2):146-153. doi:10.7861/clinmedicine.17-2-146

Prof. Wells’s article (lumpers vs splitters)

Wells AU, Brown KK, Flaherty KR, Kolb M, Thannickal VJ; IPF Consensus Working Group. What’s in a name? That which we call IPF, by any other name would act the same. Eur Respir J. 2018;51(5):1800692. Published 2018 May 17. doi:10.1183/13993003.00692-2018

The 2013 ATS/ERS classification of IIPs

Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748. doi:10.1164/rccm.201308-1483ST