Unclassifiable Interstitial Lung Disease

Clinical Vignette

A previously healthy 68-year-old man presented with a 1-year history of gradually worsening dyspnoea and fatigue. A chest X-ray had demonstrated bilateral basilar abnormalities, and he was treated with moxi oxacin by his family physician with no improvement. The patient had a history of gastroesophageal re ux for which he was on a proton pump inhibitor. He was on no other medication. He had quit smoking ten years earlier after a 30-pack-year smoking history. He reported no symptoms suggestive of connective tissue disease (CTD), no environmental or occupational exposures, and no remarkable family history.

His oxygen saturation was 93% while breathing room air, and decreased to 89% during a 6-min walk test. Physical examination revealed bilateral basal coarse crackles, no digital clubbing, and no signs of connective tissue disease or heart failure. Lung function tests included a forced vital capacity of 81%-pre- dicted and diffusion capacity of the lung for carbon monoxide of 64%-predicted. Blood tests revealed a borderline increased creatinine kinase and C-reactive peptide. Autoimmune serologies included a mildly abnormal anti-cyclic citrullinated peptide and SSA

S. A. Guler (*)

Department of Pulmonary Medicine, Inselspital, University Hospital Bern, Bern, Switzerland

e-mail: sabina.guler@insel.ch

C. J. Ryerson

Department of Medicine, University of British Columbia, Vancouver, BC, Canada

Centre for Heart Lung Innovation, St. Paul’s Hospital, Vancouver, BC, Canada

St. Paul’s Hospital, Vancouver, BC, Canada e-mail: chris.ryerson@hli.ubc.ca

antibody. Serum precipitins were negative. Chest CT demonstrated lower-­lung predominant reticulation, traction bronchiectasis, and some superimposed ground glass with a pattern most suggestive of nonspecifc interstitial pneumonia (Fig. 38.1. A surgical lung biopsy showed features of usual interstitial pneumonia, but with increased numbers of interstitial lymphocytes and both interstitial and airspace giant cells, beyond what would be expected in idiopathic pulmonary fbrosis.

A comprehensive assessment by a rheumatologist concluded there was no evidence of a connective tissue disease. Multidisciplinary discussion concluded an unclear aetiology of the ILD, with a differential diagnosis that included hypersensitivity pneumonitis, connective tissue disease-associated interstitial lung disease, and less likely idiopathic pulmonary fbrosis. The patient was treated with immunosuppressive medications based on the more likely differential diagnoses of hypersensitivity pneumonitis and connective tissue disease-­associated interstitial lung disease. He had initial stabilization in his symptoms and lung function, but eventually had progression of his disease and passed away 6 years after initial presentation.

Introduction

Interstitial lung disease (ILD) is a group of typically rare disorders that are distinct enough to be regarded as separate disease entities. ILDs damage the lung parenchyma in varying degrees of in ammation and fbrosis, with some having a known underlying cause and others where no cause can be identifed [1]. The most common of the idiopathic interstitial pneumonias (IIP) is idiopathic pulmonary fbrosis (IPF). Other common ILDs include fbrotic hypersensitivity pneumonitis (HP), and connective tissue disease-associated ILD (CTDILD). Patients with ILD usually present with nonspecifc respiratory symptoms such as progressive dyspnoea and cough. The classifcation into a specifc ILD subtype can be challenging because the clinical, radiological, and pathological fndings frequently overlap. Accurate ILD classifcation informs prevention, management, and prognosis: Associated

exposures need to be eliminated, the indicated pharmacotherapy differs between ILD subtypes, and prognosis varies vastly. Most importantly, immunosuppressive therapy is frequently recommended for patients with CTD-ILD, [2, 3] whereas patients with IPF are potentially harmed by immunosuppression and are instead treated with antifbrotic medications [4– 6]. Despite its importance, the classifcation of an ILD cannot always be achieved. Even with a thorough investigation for potential aetiologies or features that allow the categorization of the ILD, a subset of ILD patients cannot be provided with a specifc ILD diagnosis and remain unclassifable [7].

The classifcation of the IIPs has evolved substantially since the frst classifcation by the pathologist Averill Abraham Liebow in 1968 [8]. In 2002, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) provided the frst standardized nomenclature and set of diagnostic criteria for the major IIPs [9]. The

authors of this consensus paper acknowledged the diagnostic dilemma of unclassifable ILD with a subset of IIP patients that are not classifable even after a thorough clinical, radiological, and pathological investigations. Mainly based on lack of clinical utility, it was decided against creating an unclassifable ILD category at that time. The updated IIP classifcation consensus statement in 2013 introduced the category of unclassifable ILD, with the caution that the use of the label unclassifable ILD should not be used to justify avoidance of a thorough diagnostic process [1]. Over the last few years multiple cohort studies have described this heterogeneous population, tools to phenotype patients with unclassifable ILD are emerging, and clinical trials investigating pharmacotherapies are ongoing.

In this chapter we address the clinical picture of unclassifable ILD and discuss challenges and potential solutions for the management of these patients.

Defnition

Unclassifable, unclassifed, undefned, and undetermined ILD are terms that have been used to label the group of ILD patients that cannot be provided with a specifc, defned ILD [7]. There are no diagnostic criteria for unclassifable ILD,

and there is no universally accepted defnition of the term. The most consistently used defnition is the absence of a clear diagnosis following a multidisciplinary discussion that includes review of all available clinical, radiological, and pathological information [7, 10, 11]. Some clinicians and researchers have advocated to reserve the term unclassifable ILD to patients where a multidisciplinary team has reviewed results from a complete diagnostic workup including SLB, before calling a case unclassifable. In contrast, cases without a complete evaluation would be called unclassifed ILD. Unclassifed then indicates the possibility of classifying the ILD case later when new information becomes available (e.g., when a patient undergoes SLB) [10, 12]. Notably, patients with unclassifable ILD despite a SLB could similarly still be provided a diagnosis eventually following discovery of new information (e.g., a new diagnosis of rheumatoid arthritis), indicating that the term “unclassifable” is also a temporary designation in some patients.

A more standardized approach to the defnition of unclassifable ILD was proposed in an ontological framework for fbrotic ILD: A confdent diagnosis is defned by having ≥90% diagnostic confdence, a provisional diagnosis by 51–89% confdence, and unclassifable ILD by the absence of a single diagnosis that is more likely than not (i.e., <51% confdence; Fig. 38.2) [13]. Using this approach, it is also

Is there a leading diagnosis that meets guideline criteria or has ≥90% confidence?

No

Is there a leading diagnosis that has >50% confidence?

No

Fig. 38.2  Proposed approach to the classifcation of fbrotic interstitial lung disease (ILD). (Reprinted with permission of the American Thoracic Society. Copyright © 2019 American Thoracic Society. Ryerson CJ, Corte TJ, Lee JS, Richeldi L, Walsh SLF, Myers JL, Behr J, Cottin V, Danoff SK, Flaherty KR, Lederer DJ, Lynch DA, Martinez FJ, Raghu G, Travis WD, Udwadia Z, Wells AU, Collard HR. /2017/ A

Standardized Diagnostic Ontology for Fibrotic Interstitial Lung Disease: An International Working Group Perspective/American journal of respiratory and critical care medicine/196/1249–1254. The

American Journal of Respiratory and Critical Care Medicine is an offcial journal of the American Thoracic Society)