38  Unclassifable Interstitial Lung Disease	675

ductive cough, chest discomfort, reduced exercise capacity, and fatigue are other common symptoms.

Physical examination can reveal crackles on lung auscultation, occasionally digital clubbing, or features of CTD or other multisystem processes [11]. Pulmonary function tests at diagnosis typically show a mild reduction in forced vital capacity (FVC) with an average mean across cohort studies of 72% predicted. Diffusion capacity of the lung for carbon monoxide (DLCO) is moderately reduced with an estimated mean of 47% predicted at the time of diagnosis from a recent meta-analysis [7].

Diagnosis

Clinical Features

A thorough questioning of patients with a suspected ILD is critical, and a comprehensive assessment of symptoms, family history, and exposures becomes even more essential when confronted with an ILD that has been considered unclassifable. The history should include screening for symptoms of CTD, including joint pain, swelling, and stiffness, particularly that lasts at least 1 h. Skin rashes, nodules or thickening, dryness of the eyes or mouth, muscle weakness or muscle pain, diffculties swallowing, and gastroesophageal re ux should similarly be assessed.

A multitude of inhaled antigens or environmental exposures can cause smoking-related ILDs, HP, or occupational ILD (i.e., pneumoconiosis). Patients should be questioned for the presence of these exposures with the establishment of an accurate timeline in order to estimate the likelihood of a causal relationship between the exposure and development of ILD. Recurring symptoms with re-exposure can provide particularly useful information; however, this is likely most informative in patients with more acute non-fbrotic forms of HP. [25] Some exposures such as asbestos can lead to ILD development only decades after the contact, which makes the establishment of a causal relationship very challenging, particularly­ given the coexistence of risk factors for other ILDs (e.g., an older age, male sex, and smoking history that also increase the likelihood of IPF). A detailed history of previous treatments associated with ILD development should include previous radiotherapy, oncologic medications (e.g., bleomycin, immune-checkpoint inhibitors), cardiovascular medications (e.g., amiodarone), and immunosuppressive medications (e.g., methotrexate).

There is a genetic background to several subtypes of ILD, and relatives of patients with ILD are at increased risk of developing ILD [26]. Familial forms of IPF are usually diag-

nosed at a younger age and often progress faster than sporadic forms of IPF [27]. Information on familial forms of other ILD subtypes or familial unclassifable ILD is very limited.

Physical examination should similarly focus on identifcation of features suggesting CTD, sarcoidosis or some other systemic process. This should include assessment for joint in ammation, proximal muscle weakness, Raynaud’s phenomenon, fngertip ulceration, digital fssuring, rash, and skin thickening [28].

Radiology

Conventional chest radiography may show signs of lung fbrosis but is not helpful in differentiating ILD subtypes.

For ILD classifcation, high-resolution contiguous HRCT imaging is needed. Some centres include both inspiratory and expiratory images, which can reveal air trapping that suggests concurrent small airways disease as can be seen in HP. Performing CT in the prone position can be useful to differentiate mild fbrosis and interstitial lung abnormalities from gravity-induced dependent atelectasis [15]. Recent guidelines on the diagnosis of IPF suggest classifying CT patterns for patients with possible IPF as usual interstitial pneumonia (UIP), probable UIP, indeterminate for UIP, and most consistent with a non-IPF diagnosis, [15, 29] while previous guidelines used the categories defnite UIP, possible UIP, and inconsistent with UIP [30].

All of these patterns are observed in patients with unclassifable ILD. Using the previous classifcation approach, two studies reported a defnite UIP pattern in 6–17% of patients with unclassifable ILD, and a possible UIP pattern in 26–50% of patients [10, 31]. Radiological patterns of nonspecifc interstitial pneumonia (NSIP), desquamative interstitial pneumonia, and features typical of fbrotic HP have also been reported in unclassifable ILD patients [11]. CT fndings that are diffcult to allocate to a specifc pattern are common reasons for a case of ILD to remain unclassifable. In these patients, there might be a coexistence of several patterns, or acute changes that obscure the underlying pattern [15].

Laboratory Investigations

With CTD-ILD almost always being a differential diagnosis of unclassifable ILD, serological screening for CTD is recommended [28, 29]. Most experts suggest performing C-reactive protein, erythrocyte sedimentation rate, antinu-

676	S. A. Guler and C. J. Ryerson

clear antibodies, rheumatoid factor, anti-cyclic citrullinated peptide, and a myositis panel in all ILD patients as a baseline evaluation. Further serological tests are performed based on the clinical presentation [29].

Some experts advocate measurement of serum precipitins, performance of lymphocyte proliferation tests, and specifc inhalation challenge testing for the diagnosis of HP. These tests may be helpful in the context of a subtle exposure of uncertain signifcance; however, the sensitivity and specifcity of these tests is limited and they are otherwise of uncertain clinical utility [25].

Bronchoscopy with bronchoalveolar lavage is rarely diagnostic in the workup of a patient with ILD. However, in some cases bronchoalveolar lavage can identify underlying infection or malignancy. Cellular analysis might be helpful to phenotype patients with unclassifable ILD, for example, with bronchoalveolar lavage lymphocytosis signifying features of autoimmunity, or prompting a more thorough search for an unidentifed antigen causing HP. Overall, bronchoalveolar lavage is a low risk procedure that can be performed in some patients that would not qualify for SLB [32].

Pathology

Conventional transbronchial biopsy produces small biopsies of the lung parenchyma with the potential to diagnose sarcoidosis or organizing pneumonia, but rarely other lung parenchymal disorders. Transbronchial lung cryobiopsies (TBLC) provide larger tissue samples resulting in a higher diagnostic yield compared to conventional transbronchial biopsies [33]. The diagnostic utility of TBLC versus SLB has not been established yet: A recent study showed poor concordance between samples from TBLC and SLB in the same patient (kappa value 0.22) [34]. Nevertheless, TBLC might provide a possibility to get histopathological insight into the phenotype of unclassifable ILD patients with an unfavourable risk-beneft ratio for SLB. Overall TBLC seems to be reasonably safe if performed by experts in well-­ selected patients [33]. Safety information on TBLC in patients not qualifying for SLB is still limited; however, there is evidence that the procedural risk of both transbronchial cryobiopsy and SLB is higher in patients with advanced ILD and for non-elective procedures [35–37].

Histopathological results from SLB integrated with clinical and radiological information on multidisciplinary discus-

sion is the current reference standard for ILD diagnosis; [1] however, up to 10% of biopsied patients still remain unclassifable [38, 39]. This most frequently happens in the context of overlapping histological patterns, and less frequently in biopsies that show only early and mild nonspecifc fbrotic changes or end-stage “burnt-out” fbrosis [16].Approximately one quarter of patients in previous cohorts of unclassifable ILD had a SLB available for diagnosis, [10, 11, 31] indicating that physicians frequently considered the diagnostic beneft from SLB too low to justify the risk of the procedure. Although SLB is a relatively safe procedure with many studies reporting no deaths after SLB, [40] two large administrative database studies estimated the in-hospital mortality risk of elective SLB in patients with ILD at 1.7% [35, 36]. Remarkably, patients undergoing SLB during a non-elective admission had a mortality risk of 16%. These studies emphasize that patients should be carefully selected for SLB, which should be carefully planned and not performed in the context of acute exacerbation. Specifcally, in elderly patients with signifcant comorbidities and severely impaired lung function the potential risk of SLB should be weighed carefully against its potential impact on management and prognosis. Patient preference and overall therapeutic goals usually play an additional important role in this decision.

Progression andPrognosis

Considering the heterogeneous mixture of unclassifable ILD including patients with early/mild and advanced/severe ILD at time of diagnosis, it is unsurprising that outcomes are highly variable among patients and across ILD centres, with overall prognosis intermediate between IPF and non-IPF ILDs. One Danish cohort reported that 13% of patients with unclassifable ILD had reversible disease, 34% had stable but residual disease, and the remainder had progressive lung functional decline. Hyldgaard et al. [11] reported risk factors for mortality include older age, crackles on lung auscultation, lower FVC, and lower DLCO. On CT a higher fbrosis scores, more severe traction bronchiectasis, and larger pulmonary artery diameter are also independent predictors of worse outcomes [10, 11, 31].

In the four cohort studies with available survival information for unclassifable ILD, the estimated 1-year, 2-year, and 5-year survival rates are 84–89%, 70–76%, and 46–70%, respectively (Fig. 38.3) [10, 11, 31, 41].

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38  Unclassifable Interstitial Lung Disease	677

Percent alive

100

80

60

40

Hyldgaard 2016 Jacob 2017

20Ryerson 2013 Thomeer 2004

0

0

1

2

3

4

5

Follow-up, years

Fig. 38.3  Survival of patients with unclassifable interstitial lung disease. The area of the circle is directly proportional to the baseline sample size for each study. The point estimate corresponds to the centre of the circle. (Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Guler SA,

Ellison K, Algamdi M, Collard HR, Ryerson CJ/2018/Heterogeneity in Unclassifable Interstitial Lung Disease. A Systematic Review and Meta-Analysis./ Annals of the American Thoracic Society/15/854–63. Annals of the American Thoracic Society is an offcial journal of the American Thoracic Society)

Phenotyping Unclassifable ILD

Patients with unclassifable ILD have substantial heterogeneity in their clinical presentation, radiological fndings, and pathological features at time of diagnosis [7]. The variable disease severity at diagnosis, and the heterogeneous underlying biology of patients with ILD are likely reasons for the variable disease progression and behaviour of patients with unclassifable ILD [11]. This heterogeneity causes several issues for clinicians and researchers. For example, it is challenging to demonstrate effcacy of an intervention in clinical studies in this population because even if interventions are successful in some unclassifable ILD patients, the “noise” arising from a heterogeneous response to therapy might prohibit detection of a meaningful beneft. In addition, estimating a patient’s prognosis and response to treatment is diffcult as the heterogeneity of the unclassifable ILD population as a whole makes it challenging to extrapolate previous studies to any individual patient.

Phenotyping unclassifable ILD patients for research and clinical practice by grouping patients with similar features reduces heterogeneity and might help to improve under-

standing of the underlying disease mechanisms, disease progression, and response to therapy. For unclassifable ILD the traditional aetiology-based classifcation does not hold because per defnition, the underlying ILD aetiology is unknown; further the identifcation of the aetiology might not be priority, once a thorough diagnostic workup has been performed. Previous guidelines suggested classifying patients with ILD according to their observed or expected disease behaviour, with this particularly applying to the heterogeneous population of patients with unclassifable ILD [1, 11]. Multiple studies have shown that older age, male sex, lower FVC, and lower DLCO are associated with disease progression [10, 11, 42]., regardless of the etiological classifcation; however, it can be challenging to predict future disease progression from patients’ baseline features or from past episodes of worsening. For example, in patients with systemic sclerosis associated ILD (SSc-ILD), future lung functional decline is diffcult to predict from previous changes in lung function [43]. Honeycombing, traction bronchiectasis, and a radiological UIP pattern also predict a more progressive disease behaviour and unfavourable outcome [31, 44].

678	S. A. Guler and C. J. Ryerson

A progressive fbrosing ILD phenotype has been suggested as a potentially useful subgroup, including patients with a variety of diagnoses and certain high-risk features that culminate in a similar disease behaviour to IPF. This

Table 38.1  Proposed features of interstitial pneumonias with autoimmune features

Domains		Features
Clinical domain		Distal digital tip ulcerations
		Mechanic hands (distal digital fssuring)
		In ammatory arthritis or morning stiffness
		≥60 min
		Palmar telangiectasia
		Raynaud phenomenon
		Digital oedema (puffy fngers)
		Gottron’s sign (papules on digital extensor
		surfaces)
Serologic domain		ANA ≥1:320 or ANA nucleolar/centromere
		pattern any titre
		Rheumatoid factor ≥ 2× upper limit of
		normal
		Positive anti-CCP, -dsDNA, -SSA, -SSB,
		-RNP, -Sm, -Scl-70, -tRNA synthetase,
		-PM-Scl, -MDA-5
Morphologic domain
Radiological		Nonspecifc interstitial pneumonia (NSIP)
patterns
		Organizing pneumonia (OP)
		Lymphoid Interstitial Pneumonia (LIP)
Pathological		NSIP, OP, LIP
patterns
		Interstitial Lymphoid aggregates with
		germinal centres
		Diffuse lymphoplasmacytic infltration
		Multicompartment involvement
			Pleural or pericardial effusion/
			thickening
			Airway disease
			Pulmonary vasculopathy

Adapted from: An offcial European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features [47]

approach has already been validated in randomized controlled trials including patients with fbrotic ILDs other than IPF and previous progression, defned by a combination of decline in FVC, worsening of radiological changes, and increase in symptoms [45, 46]. The concept of progressive fbrosing ILD is also potentially useful for very rare ILD subtypes that have overlapping clinical and morphological features, and also applies to nonspecifc strategies that likely apply to a wide range of ILD patients (e.g., oxygen, pulmonary rehabilitation). The potential downside of this “lumping” approach is the likely increase in heterogeneity of cohorts, which can be a concern for understanding specifc biological mechanisms and study of new targeted therapies.

One way to phenotype patients with unclassifable ILD is to identify patients with features of autoimmunity. A previous research statement from the ATS and ERS proposed the label of interstitial pneumonia with autoimmune features (IPAF) could be used to indicate patients with ILD who have relatively specifc features of a CTD, but without meeting specifc criteria for a defned CTD [47]. Suggested criteria for IPAF include at least one feature from at least two out of the three clinical, serologic, and morphologic domains (Table 38.1, Fig. 38.4) [47]. Some cohort studies report that approximately 20% of their unclassifable ILD patients fall in the IPAF category [48, 49].

The diagnostic dichotomy with the most signifcant management implication is differentiation between IPF and non-­ IPF ILD given the different prognosis and pharmacotherapy used in these two populations. It is therefore frequently clinically helpful to integrate the available demographic, serological, radiological, and histopathological features to suggest whether the overall presentation is more consistent with an IPF-like biology or if a non-IPF ILD is more likely. Several individual factors have been associated with an IPF diagnosis (e.g., older age, male sex, a history of smoking cigarettes; Fig. 38.5) [50–54]. Although there is no standardized way to integrate these features in a diagnostic model, experienced clinicians are able to incorporate these into an overall gestalt

Fig. 38.4  Proposed concept
		Unclassifiable ILD
for determining the likelihood
of autoimmunity in patients
with unclassifable interstitial
lung disease (ILD). Interstitial
pneumonias with autoimmune
features requires at least one		Clinical domain
feature from at least two
domains (Table 38.1)					ILD associated
ILD without	Interstitial pneumonia with autoimmune features
autoimmunity					with CTD
	Serologic		Morphologic
	domain		domain

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38  Unclassifable Interstitial Lung Disease																																									679
															Favors
Demographics				non-IPF ILD																												IPF							OR		95%-CI
1Age > 60 years																																							4.6		2.9-7.6
2Age, years*																																							1.04		1.01-1.07
1Male sex																																							6.4		4.3-9.8
2Male sex*																																							3.85		1.73-8.61
1Ever smoker																																							2.77		1.8-4.5
2Ever smoker*																																							4.09		2.09-8.01
2DLCO, %-predicted*																																							0.96		0.94-0.98
3Antigen exposure																																							0.03		0.01-0.09
2Antigen exposure*																																							0.7		0.33-1.5
Serology
3Positive precipitating antibodies																																							0.31		0.2-0.5
1Positive antinuclear antibodies																																							0.2		0.1-0.4
1Auto-antibody positivity																																							0.19		0.1-0.37
2Auto-antibody positivity*																																							0.66		0.33-1.33
Chest CT scan																																							5.46		1.37-21.8
4Definite/probable UIP pattern
4Honeycombing																																							11.5		2.97-44
Histopathology
5Fibroblastic score																																							8.3		1.98-60
6Germinal centres																																							0.34		0.18-0.63
7Organizing pneumonia																																							0.28		0.1-0.78
7Granulomas																																							0.12		0.02-0.82
7Centrilobular fibrosis																																							0.04		0-0.4
0.01				0.1						1																									10				100
						Odds ratio, 95% confidence interval

Fig. 38.5  Selected diagnostic characteristics favouring IPF and non-­ IPF ILDs. (1) Guler et al. 2018 [66]; (2) Walsh et al. 2019 [55]; (3) Lacasse et al. 2003 [50]; (4) Hunninghake et al. 2003 [51]; (5) Flaherty et al. 2003 [52]; (6) Song et al. 2009 [53]; (7) Takemura et al. 2012

(chronic HP versus IPF) [54] *Physician rated likelihood of IPF [55]. 95% CI 95% confdence interval, ANA antinuclear antibody, CTD connective tissue disease, ILD interstitial lung disease, IPF idiopathic pulmonary fbrosis, OR odds ratio, UIP usual interstitial pneumonia

likelihood of IPF. Typically, respiratory physicians consider an IPF working diagnosis if the diagnostic confdence for IPF is 70–89%. Patients with a working diagnosis of IPF and a defnite IPF diagnosis (≥90% diagnostic confdence) have a similar prognosis, and the approach of a working diagnosis can facilitate management decisions [13, 55].

Management andTreatment

Non-pharmacological management strategies typically apply to all ILD subtypes and should be similarly offered to patients with unclassifable ILD. Smoking cessation and avoidance of potentially causative agents are crucial. Patients should be instructed to avoid potential exposures if HP cannot be confdently excluded. Work-place safety with protection from occupational exposures is also important. Medications that might cause ILD should be exchanged for alternatives wherever possible, although continuation of such medications that clearly lack a relationship with ILD onset or worsening

may be appropriate. Annual in uenza vaccinations and pneumococcal vaccination every 5 years are generally recommended, as well as management of comorbidities and symptom management strategies.

Oxygen supplementation and pulmonary rehabilitation can relieve symptoms and improve exercise capacity, among other benefts [56, 57]. Lung transplantation is an option for some patients, but is contraindicated in many patients with fbrotic ILD. Frail patients with advanced impairment might beneft from prioritizing symptom management over ILD-­ specifc pharmacotherapy, and palliative care might offer great support for patients and caregivers [58].

Pharmacotherapy choices in fbrotic ILD are challenging, with an absence of direct data to support any specifc approach. All recommendations for ILD-targeted medications are therefore off-label and should be considered on a case-by-case basis ideally after careful review by an experienced multidisciplinary team. When it is considered appropriate, pharmacotherapy in unclassifable ILD generally consists of either antifbrotic and/or immunosuppressive therapy.