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INVITED REVIEW SERIES: IDIOPATHIC INTERSTITIAL PNEUMONIA-PART 2: SPECIFIC DISEASE ENTITIES SERIES EDITORS: TAMERA J CORTE, ATHOL U WELLS AND HAROLD R COLLARD

Smoking-related idiopathic interstitial pneumonia: A review GEORGE A. MARGARITOPOULOS,1,2 SERGIO HARARI,3 ANTONELLA CAMINATI3 AND KATERINA M. ANTONIOU1 1

Department of Thoracic Medicine and Laboratory of Molecular and Cellular Pneumonology, Interstitial Lung Disease Unit, University Hospital of Heraklion, Heraklion, 2Department of Respiratory Medicine, General Hospital of Kavala, Kavala, Greece, and 3Respiratory Medicine and Semi-Intensive Therapy Unit, Respiratory Physiopathology and Pulmonary haemodynamics Services, San Giuseppe Hospital-Multimedica, Milan, Italy

ABSTRACT

Table 1

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking-related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitisinterstitial lung disease (RB-ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan’s cell histiocytosis, smokingrelated interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking-related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.

• • • • • • • •

Key words: diagnosis, smoking, therapy.

inflammation,

fibrosis,

nicotine,

Correspondence: Katerina M. Antoniou, Department of Thoracic Medicine, Medical School, University of Crete, Heraklion 71110 Crete, Greece. Email: [email protected] The Authors: George A. Margaritopoulos, MD, PhD, is a Consultant in Respiratory Medicine, General Hospital of Kavala, Greece, and a Scientific Collaborator in the University Hospital of Herakleion and in Molecular and Cellular Pneumonology Laboratory. Antonella Caminati, MD, is a Consultant in Respiratory Medicine, Ospedale San Giuseppe—Multimedica, Milan, Italy. Sergio Harari, MD, is a Consultant in Respiratory Medicine and a Director of the Respiratory Unit at Ospedale San Giuseppe in Milan, Italy. Katerina M. Antoniou, MD, PhD, is an Assistant Professor in the University Hospital of Herakleion, Greece; Head of Molecular and Cellular Pneumonology Laboratory; and Chair of ERS 1.05 Group. Received 20 October 2014; invited to revise 9 December 2014; revised 21 January 2015; accepted 6 May 2015.

Article first published online: 2 July 2015 © 2015 Asian Pacific Society of Respirology

Smoking-related interstitial lung disease

Respiratory bronchiolitis—interstitial lung disease Desquamative interstitial pneumonia Pulmonary Langerhans cell histiocytosis Idiopathic pulmonary fibrosis Rheumatoid arthritis—interstitial lung disease Combined pulmonary fibrosis and emphysema Acute eosinophilic pneumonia Pulmonary haemorrhage syndromes

Abbreviations: BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; CPFE, combined pulmonary fibrosis and emphysema; DILD, diffuse interstitial lung diseases; DIP, desquamative interstitial pneumonia; DLCO, diffusing lung capacity; GGO, ground-glass opacities; HP, hypersensitivity pneumonitis; HRCT, high-resolution computed tomography; IIP, idiopathic interstitial pneumonias; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; NSIP, non-specific interstitial pneumonia; PLCH, pulmonary Langerhans cell histiocytosis; RA, rheumatoid arthritis; RB, respiratory bronchiolitis; RB-ILD, respiratory bronchiolitis-interstitial lung disease; SLB, surgical lung biopsy; SRIF, smoking-related interstitial fibrosis; TGF, transforming growth factor; UIP, usual interstitial pneumonia.

INTRODUCTION Cigarette smoking is the major cause of the development of chronic obstructive pulmonary disease (COPD) and lung cancer.1 Interestingly, during the last decade, cigarette smoking has been also implicated in the pathogenesis of diffuse interstitial lung diseases (DILD) such as respiratory bronchiolitis (RB), RB-associated interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP), pulmonary Langerhans cell histiocytosis (PLCH)2 and other types of interstitial lung disease (ILD) in the context of collagen tissue disorders, mainly in rheumatoid arthritis (RA) (Table 1). Moreover, it is now believed Respirology (2016) 21, 57–64 doi: 10.1111/resp.12576

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that smoking may play a key role in the development and progression of the most devastating form of DILD, namely idiopathic pulmonary fibrosis (IPF).3,4

HOW DOES SMOKING PROMOTE LUNG INFLAMMATION AND FIBROSIS? It is now well recognized that cigarette smoking, most likely acting in a background of genetic predisposition, is implicated in the pathogenesis of smoking-related ILD, either inflammatory or fibrotic. Cigarette smoking leads to exaggerated accumulation of inflammatory cells such as macrophages, neutrophils and Langerhans cells in small airways, distal air spaces and interstitium. This could be due to abnormal production from lung epithelial cells of factors that recruit macrophages such as granulocytemacrophage colony-stimulating factor as well as to increased survival and reduced apoptosis of macrophages.5–10 Smoking also induces the production of transforming growth factor (TGF)-β1, a central mediator with crucial role in the development of lung fibrosis.11,12 According to several lines of evidence, nicotine, an addictive substance identified in cigarettes, is implicated in the development of fibrosis in various organs, lung included. It promotes epithelial and endothelial cell damage, stimulates the production and release of TGF-β1, enhances the recruitment of inflammatory cells and the production of reactive oxygen species and also stimulates the production of collagen, which is the major constituent of the extracellular cell matrix.13 Two further hypotheses regarding the implication of smoking in the pathogenesis of smoking-related ILD have been proposed including abnormal telomere shortening and dysregulation of autophagy. Smoking has been related to telomere shortening,14,15 a phenomenon observed in IPF and associated with its disease progression. Telomere shortening is considered as a marker of cell senescence and IPF is characterized as a disease of accelerated senescence.16 Telomeres shorten successively with each cell division and when they achieve a critical length, activate a p53-dependent mechanism that leads to apoptosis.17 Abnormally short telomeres have been documented in alveolar epithelial cells in IPF and impact on epithelium’s ability to regenerate. One of the main reasons of the abnormal shortening is mutations in the enzyme responsible for maintaining telomere length, namely telomerase, but interestingly abnormal shortening can be documented also in the absence of telomerase mutations,18,19 suggesting that other factors such as cigarette smoking may be responsible for this phenomenon. Autophagy is a highly conserved homeostatic mechanism. The main function is the transport of damaged proteins and organelles such as mitochondria for degradation after fusion with lysosomes. It contributes to cellular homeostasis by (i) providing an alternative source of metabolic fuel; (ii) removing damaged cellular components that are toxic to the cell such as dysfunctional mitochondria or aggregated © 2015 Asian Pacific Society of Respirology

proteins; and (iii) promoting cell death.20 The effect of smoking in autophagic activity has been studied mainly in COPD. Autophagy is enhanced in epithelial cells leading to apoptosis and development of emphysema, whereas it is defective in alveolar macrophages, which may allow for excess accumulation of particles in the setting of cigarette smoking and of various bacteria leading to increased oxidative stress, disease progression and acute exacerbations due to infections.20 In IPF lungs, autophagy has been found decreased, possibly mediated by increased levels of TGF-β1.21 An intriguing hypothesis is that cigarette smoking increases the production and release of TGF-β1, which in turn suppresses autophagy.

Smoking-related idiopathic interstitial pneumonias Respiratory bronchiolitis-interstitial lung disease In the recent revision of the Official American Thoracic Society/European Respiratory Society Statement on the international multidisciplinary classification of the idiopathic interstitial pneumonias (IIP),22 the term smoking-related interstitial pneumonia has been introduced and includes RB-ILD and DIP. RB represents a common histological feature in current and former smokers and indicates a ‘physiologic’ inflammatory response to smoking. The histological hallmark of RB is bronchiolocentric clusters of pigmented macrophages (so-called smoker’s macrophages containing a light brown, finely granular pigment)23,24 (Fig. 1) within respiratory bronchioles extending to adjacent alveolar spaces, associated with a variable but mild amount of non-specific peribronchiolar thickening of the alveolar septa; this interstitial fibrosis is characteristically minimal. RB is clinically asymptomatic and may sometimes cause at most mild (but still subclinical) alteration of lung function (generally minimal small airways dysfunction). RB, RB-ILD and DIP represent a histological spectrum of macrophage accumulation with the distinction depending on the extent and distribution of this accumulation (and also reflected by the pattern of presentation on high-resolution computed tomography (HRCT)). Several authors have suggested the term ‘smoking-related interstitial lung disease’ to indicate the overlap between this spectrum of diseases and outline common clinical, radiological and histological aspects.25–27 Despite these similarities, differences exist in clinical presentation and response to therapy in these entities, and they remain classified separately. Multiple HRCT and histological features may coexist in the same patient including PLCH, RB, DIP and pulmonary fibrosis (usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP)).25–27 In clinical practice, these disorders frequently coexist with the more common sequelae of cigarette smoking-induced lung injury: COPD and lung cancer.28 RB-ILD is a rare condition where the pathologic lesion of RB manifests clinically as an ILD in younger smokers,29 occurring in only 1 patient of the 109 cases Respirology (2016) 21, 57–64

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Figure 1 High magnification illustrating pigmented macrophages, the so-called ‘smoker’s macrophages’ containing a light brown, finely granular pigment (courtesy of Dr. Alberto Cavazza).

with histologically proven RB in the largest biopsy series to date.30 Clinical presentation of RB-ILD consists of cough and insidious onset of exertion dyspnoea in the third to sixth decade of life, often with a male predominance.31–33 The disease is almost present in current or former smokers.24,31–33 Bilateral endinspiratory crackles, predominantly basal, are common. Despite the bronchiolocentric nature of disease in RB-ILD, pulmonary function tests usually reveal a mixed but predominantly restrictive defect, with a mild to moderate reduction in the diffusing lung capacity (DLCO). Airway obstruction is usually mild. The severity of pulmonary function impairment is a crucial feature in distinguishing RB-ILD from RB. Patients with RB-ILD usually have mild symptoms and a favourable prognosis. The manifestations of RB-ILD on HRCT images are exactly those of RB, although they often may be more extensive in RB-ILD, and reflect the histological changes present. Poorly defined centrilobular ground-glass nodules, patchy ground-glass opacities (GGO), bronchial wall thickening are the typical aspects of RB and RB-ILD (Fig. 2). A significant correlation between the extension of micronodules and ground-glass attenuation with the extent of macrophage accumulation in respiratory bronchioles, alveoli and alveolar ducts has been described.31 Mild reticulation in the lower zones is present in RB-ILD.23,34 Areas of hypoattenuation more evident on expiratory HRCT scans (termed ‘mosaic attenuation’) are a cardinal feature of small airways disease and have also been reported in RB-ILD, being more extensive in lower lobes.31 Emphysema in the upper lobes is frequently present Respirology (2016) 21, 57–64

Figure 2 (a) High-resolution computed tomography aspects in a case of respiratory bronchiolitis: poorly defined bilateral centrilobular nodules. (b) Histological features of the same case: the lung biopsy shows peribronchiolar pigmented macrophage accumulation (courtesy of Dr. Alberto Cavazza).

in RB-ILD, but generally limited in extension. There is no arbitrary cut-off in HRCT disease extent at which RB becomes RB-ILD; in this regard, HRCT severity should not be evaluated in isolation, but should be integrated with the degree of pulmonary functional abnormality and clinical symptoms.24,31–33 Radiologically, the most important differential diagnosis of RB-ILD is sub-acute hypersensitivity pneumonitis (HP). Centrilobular nodules, ground-glass attenuation and small airways disease (but not usually bronchial wall thickening) are aspects typically observed on HRCT in patients with sub-acute HP. In these cases, an accurate exposure history is important because HP rarely affects current or recent smokers. In this situation, bronchoalveolar lavage (BAL) is another important semi-invasive diagnostic tool: the observation of smoker’s macrophages and the absence of lymphocytosis suggest the diagnosis of RB-ILD and exclude a case of HP. In clinical practice, the diagnosis of RB-ILD is increasingly achieved without surgical lung biopsy (SLB) on the basis of clinical and imaging features and BAL appearance.22 The prognosis of RB-ILD is generally good, and the disease improves or stabilizes with smoking cessa© 2015 Asian Pacific Society of Respirology

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Figure 3 In this case of desquamative interstitial pneumonia, airspaces are uniformly filled from pigmented macrophages (courtesy of Dr. Alberto Cavazza).

tion. Although prolonged survival can be expected, both clinical and physiological decline may be observed in the long-term patients’ follow-up regardless of current therapeutic interventions.33 A trial of corticosteroid can be suggested when significant disease does not regress after smoking cessation, but merits a careful consideration of the risk/benefit ratio.2,31,33

Desquamative interstitial pneumonia A uniform filling of alveolar spaces by smoker’s macrophages is the histological hallmark of DIP, and at low magnification, the overriding impression is one of diffuse and uniform pulmonary involvement (Fig. 3). The alveolar architecture is generally well preserved with a mild chronic inflammatory cell infiltrate in the interstitium. The association of DIP with smoking is well known,35–37 although there are cases of DIP caused by dust inhalation, drugs and Gaucher disease.26,38–44 Some cases of DIP have been described in children, often due to surfactant protein gene mutations.45,46 DIP usually presents in men in the fourth to sixth decade, with cough and dyspnoea (like RB-ILD does). Digital clubbing frequently develops (in approximately 50% of patients), and crackles are present on pulmonary auscultation. Restrictive defects with a decreased DLCO are commonly observed on pulmonary function tests.26 The reduction in DLCO is a useful guide to the underlying severity of the disease. Hypoxia appears only in the severe stage of disease. The almost invariable HRCT finding of DIP is diffuse ground-glass attenuation,26,47 which is usually bilateral and more or less symmetrical.47,48 The mid and lower zones are frequently affected. The upper zones are also involved in most cases, but the predominance of the disease in the upper lobes is rare (unlike the non-regional nature of patchy groundglass attenuation in RB-ILD).31 There is a predilection for sub-pleural lung, but the distribution of GGO may be also random. Other findings at HRCT include irregular lines together with signs of parenchymal distortion as traction bronchiectasis (aspects that indicate underlying fibrosis).49 Honeycombing is usually absent. It is important to outline that HRCT appearance of DIP is non-specific. Thus in one study, a confident diagnosis of DIP, made from experienced © 2015 Asian Pacific Society of Respirology

Figure 4 High-resolution computed tomography image in a case of desquamative interstitial pneumonia. Patchy bilateral ground-glass opacities are present and associated with reticular abnormalities. In addition, some cystic spaces are present.

thoracic radiologists, was correct in only 59% of cases.50 Cystic spaces may be also present in DIP (Fig. 4). DIP is generally characterized by a relatively stable course; 10-year survival is approximately 70% and no response to treatment is rare. In some patients, there may be spontaneous improvement (possibly related to smoking cessation). Progression to severe fibrosis is uncommon, although a background of coexistent NSIP is frequent. GGO extension on HRCT may diminish over time with smoking cessation and corticosteroids therapy.51 In up to a quarter of patients, however, there may be continued worsening despite steroid therapy and lung transplantation may be necessary in some cases. A confident diagnosis of DIP is generally possible only with SLB: the HRCT appearance of extensive ground-glass attenuation and the BAL profile are both non-specific.2 The presence of DIP-like reaction around a variety of space occupying pulmonary lesions and in some diffuse pulmonary disease also limits the role of small tissue biopsies.44 BAL analysis in DIP typically shows a non-specific increase of alveolar macrophages, and its role in this condition is considered irrelevant; a mild increase in percentage of eosinophils and neutrophils cells may also be observed.

Another aspect linked to smoking exposure: smoking-related interstitial fibrosis Smoking-related interstitial fibrosis (SRIF) is a relatively recent described pathological pattern.52 This term was initially used in the current contest to describe changes observed in non-neoplastic lung parenchyma in lobectomy specimen from smokers with cancer.53 The authors were struck by the frequent finding of prominent, severe fibrosis in association with RB and emphysema in patients clinically asymptomatic. Other terms to indicate the same histological lesion were RB-ILD with fibrosis,54 airspace enlargement with fibrosis55 and RB with fibrosis.56 These incidental HRCT and histological findings in smokers are not regarded as a distinct form of IIP.22 Respirology (2016) 21, 57–64

61 SRIF is characterized by a distinct type of hyalinized interstitial fibrosis that is associated with emphysema and RB.52,53,57 The affected thickened alveolar septa show deposition of dense and eosinophilic collagen often with admixed hyperplastic smooth muscle bundles. This aspect is usually quite marked and easily visible at low magnification. It tends to be more prominent in sub-pleural parenchyma where it is associated with emphysema, but it can also be present in deeper lung, including both centrilobular and other random areas. Smoker’s macrophages are invariably present in the alveolar spaces and are generally numerous. In most patients, SRIF is an incidental finding in lung tissue removed for other reasons and represents a histological pattern without a corresponding clinical presentation.53 Very little correlation data are available with imaging, clinical manifestations and pulmonary function. Mild to moderate obstructive defect was observed and mild to moderate reduction of DLCO may be present. Rarely, patients with SRIF present with respiratory symptoms (shortness of breath and/or cough, the most common) leading to lung biopsy. The most frequent aspects of SRIF on HRCT are micronodular infiltrates and GGO. In some cases, SRIF has a distinctive radiological aspect on HRCT and consists of sharply circumscribed upper zonal and mid-zonal sub-pleural foci of emphysema mixed with reticulation sometimes accompanied by areas of GGO.58 As opposed to RB/RB-ILD, SRIF is often mistaken, either on biopsy or HRCT, for a diffuse fibrosing interstitial pneumonia. Fibrosis in SRIF lacks the patchwork pattern and prominent temporal variability that are characteristic of UIP. In addition, in SRIF, there is no significant architectural distortion, typical of UIP. Rather, the collagen deposition in SRIF thickens and expands alveolar septa, while maintaining their basic architecture.53 The differential diagnosis of SRIF from fibrosing NSIP can be challenging, but attention to the appearance of fibrosis, the amount of the inflammation and the distribution of the changes should suggest the correct diagnosis;59,60 SRIF lacks significant inflammation, and the change is more patchy than in NSIP. Whether SRIF is truly a separate entity from the concept of NSIP is matter for discussion. Little is known about progression of SRIF because of the small numbers of patients in the published studies and the short followup. The disease course generally appears stable over time; some patients may show progression in airflow obstruction, but clinical symptoms (generally mild) usually persist stable.52,58 Large screening studies for lung cancer using HRCT have reported interstitial abnormalities in a significant proportion (2.2–22%) of otherwise asymptomatic smokers.61,62

Other smoking-related interstitial lung diseases Combined pulmonary fibrosis and emphysema Combined pulmonary fibrosis and emphysema (CPFE) is an example of coexisting radiologicalpathological patterns in smokers. In the new classifiRespirology (2016) 21, 57–64

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Figure 5 (a) multiple small, irregularly shaped, cysts of varying sizes with thin walls in the upper lung lobes. (b) High magnification micrograph of Langerhans cell histiocytosis. Langerhans type histiocytes have a reniform (or kidney-shaped) nucleus and stain with CD1α.

cation of IIP, CPFE is considered a distinct phenotype of IPF and not a distinct IIP.22 Some authors consider CPFE a clinical syndrome, characterized by the association of distinct features, including smoking history, severe dyspnoea, unexpected subnormal spirometry, severe decrease in DLCO, hypoxaemia at exercise, frequent presence of pre-capillary pulmonary hypertension and a poor prognosis (more severe than in IPF). Basal crackles are often present on auscultation, and finger clubbing is present in nearly half of patients.63 Characteristic HRCT features of CPFE are centrilobular/paraseptal emphysema in the upper lobes and diffuse interstitial features suggestive of pulmonary fibrosis in the lower lobes.63–65 The risk of developing pulmonary hypertension is much higher in CPFE than in IPF and represents the main independent predictor of mortality in these patients.65,66 The prevalence of lung cancer is high in CPFE.67 This entity could be also observed in the context of CTDs, mainly RA and systemic sclerosis where it presents a trend to less severe outcomes, partly due to early diagnosis because of the underlying collagen disease.68–71

Pulmonary Langherhans cell histiocytosis PLCH is a disease characterized by the polyclonal accumulation of CD1α dendritic cells in the lung (Fig. 5).72 It affects adults in the third and fourth decade of life without gender predilection. The majority of the patients have a current or past © 2015 Asian Pacific Society of Respirology

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smoking history, and importantly, the disease can even affect individuals exposed to second-hand smoking. From the clinical point of view, the presenting symptoms are not characteristic and include breathlessness and dry cough, although 30% can be asymptomatic.73 In few cases, the presenting symptom can be a spontaneous pneumothorax (often recurrent).73 Lung function tests can show either obstructive, restrictive or mixed patterns, and often, there is limited exercise capacity due to the development of pulmonary hypertension.74,75 HRCT findings present a characteristic distribution with a relative sparing of lung bases (Fig. 5). In the early stages, nodules with or without cavitation are observed, whereas in late stages, there are cysts. BAL can reveal the presence of CD1α cells, which if >5% can be diagnostic and in the right clinical and radiological context can obviate the need for SLB.76–78 In terms of treatment, the cornerstone is smoking cessation, which in the majority of the patients can slow or even stop the progression of the disease. In the cases where this is not possible, oral steroids can be used although consistent data on their effect are limited.79 Most of the time, PLCH can coexist with DIP and RB-ILD, and the response seen with the use of steroids may reflect simply the improvement of DIP and RB-ILD rather than the improvement of PLCH per se.27 In progressive disease, the use of immunosuppressive drugs such as cyclophosphamide, methotrexate, vinblastine and chlorodeoxyadenosine has been suggested.80,81 Interestingly, chlorodeoxy adenosive (also called cladribine), which has been used previously for the management of multisystem disease79 and acts directly against monocytes, has been found to be effectively used as a single drug in patients with progressive disease despite smoking cessation and steroid treatment.82,83 Pulmonary hypertension is often an unrecognized complication and can be out of proportion to the degree of pulmonary function impairment. Almost 90% of patients assessed for lung transplantation present pulmonary hypertension, which plainly increases the risk of surgery.84 In terms of treatment, administration of bosentan and/or sildenafil has been suggested.85 Other complication include pneumothorax and respiratory, which require the use of chest tube drainage and pleurodesis and oxygen supplementation respectively.85,86.

CONCLUSION Cigarette smoking is now implicated in the development of DILD, although the exact mechanisms are not still well understood. Recently, however, it has been suggested that smoking can also provoke non-specific interstitial lung abnormalities. Several screening studies for early identification of lung cancer using low-dose CT have shown that nearly 10% of smokers can present with interstitial lung abnormalities, which may progress if the patient continues to smoke.61,62,87 Whether these screening tests can identify smoking-related ILD, including IPF at an early stage, needs to be evaluated in future studies.88,89 Smoking cessation and smoking prevention are © 2015 Asian Pacific Society of Respirology

crucial. These entities present some peculiar characteristics that can be useful in terms of diagnosis and treatment only when the smoking status fits in the diagnostic puzzle.90

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