Expert Review of Respiratory Medicine

ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20

Smoking associated interstitial lung disease:

update and review

Yaser T Dawod, Noah E Cook, William B Graham, Farah Madhani-Lovely &

Choua Thao

To cite this article: Yaser T Dawod, Noah E Cook, William B Graham, Farah Madhani-Lovely
& Choua Thao (2020): Smoking associated interstitial lung disease: update and review, Expert
Review of Respiratory Medicine, DOI: 10.1080/17476348.2020.1766971

To link to this article: https://doi.org/10.1080/17476348.2020.1766971

Accepted author version posted online: 07

May 2020.

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Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Respiratory Medicine

DOI: 10.1080/17476348.2020.1766971
Article type: Review

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Smoking associated interstitial lung disease: update and review

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Yaser T Dawoda, Noah E Cookb, William B Grahamc, Farah Madhani-Lovelyc, Choua Thao*c
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Section of Pulmonary and Critical Care Medicine, Medstar Washington Hospital Center,

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Washington, DC, USA

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b
Department of Pulmonary and Critical Care Medicine, University of Nevada Las Vegas School of
Medicine, Las Vegas, NV, USA
c
Department of Pulmonary and Critical Care Medicine, Renown Health, Reno, NV, USA

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*Corresponding author:
Choua Thao
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Department of Pulmonary and Critical Care Medicine,

Renown Health, Reno, NV, USA
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Email: cthao@renown.org
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Abstract
Introduction: Smoking-associated interstitial lung disease manifests as several heterogeneous
disorders involving the airways, pleura, and lung parenchyma with various radiological patterns.
The clinical history, radiologic, and pathologic findings are important to distinguish these more
uncommon diseases. A multidisciplinary approach is recommended for diagnosis and to
manage these conditions appropriately.

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Areas covered: This review provides an overview of the epidemiology, risk factors,
pathogenesis, clinical features, diagnosis, and treatment of acute eosinophilic pneumonia, e-

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cigarettes or vaping associated lung injury, respiratory bronchiolitis interstitial lung disease,
desquamative interstitial pneumonitis, pulmonary Langerhans cell histiocytosis, idiopathic

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pulmonary fibrosis, and combined pulmonary fibrosis emphysema.

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Expert opinion: Cigarette smoking is associated with a variety of pathologic conditions that
affect the airways and lungs. E-cigarette use and vaping present new challenges to the clinician.
Consensus between the clinical, radiographic, and pathologic findings are important in

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identifying and differentiating between the various entities to properly diagnose smoking-
related interstitial lung diseases discussed in this review.
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Keywords: Lung disease, interstitial Lung disease, Bronchiolitis, Smoking, Emphysema, Fibrosis,
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Histiocytosis, Langerhans-Cell, Vaping

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Article highlights

• Although COPD remains the most prevalent form of smoking related lung disease, a
multidisciplinary approach is necessary to differentiate and manage these other more
uncommon forms of smoking associated interstitial lung disease
• AEP diagnosis includes BAL eosinophils > 25% with the exclusion of an infectious
etiology
• Elevated levels of vitamin E acetate is the suspected ingredient found in the cartridges

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of E-vaping devices and other electronic nicotine-containing products in identifying

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EVALI
• CPFE consists of upper lobe emphysema and lower lobes fibrosis whose pathogenesis is

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unclear and in comparison to COPD, CPFE patients predominantly showed paraseptal
emphysematous changes associated with other IIP

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• Smoking cessation is the most effective therapy option for the majority of these
smoking related lung diseases, and therefore, should be strongly recommended
• Continued research in genetic testing and its risk factors would assist in the

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susceptibility of certain individuals to smoking related lung diseases
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1. Introduction
Smoking associated interstitial lung diseases are a heterogenous group of disorders that either
directly or indirectly precipitate lung parenchyma pathology. Smoking has been directly
implicated in 80% of chronic obstructive pulmonary disease (COPD) deaths [1-3]. Although
COPD is by far the most common smoking associated lung disease, other rare pulmonary

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diseases have been linked to smoking, including acute eosinophilic pneumonia (AEP),
respiratory bronchiolitis interstitial lung disease (RB-ILD), desquamative interstitial pneumonitis

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(DIP), idiopathic pulmonary fibrosis (IPF), and combine pulmonary fibrosis emphysema (CPFE).
These diseases encompass different pathological processes leading to a spectrum of airway

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changes and radiological findings [4]. Recently, the disease of E-cigarette or Vaping Related

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Lung Injury (EVALI) has become a public health emergency, prompting the CDC to release an
updated guideline for the diagnosis and management of suspected EVALI [5]. The diagnostic
challenge these conditions present to the clinician underscores the importance of a literature
review on this topic.
2.1. Acute Eosinophilic Pneumonia (AEP) U
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AEP is a rapidly developing, non-infectious pneumonia characterized by pulmonary eosinophilic
inflammation and is most commonly observed in smokers. Multiple reports have linked
smoking (tobacco and E-cigarettes smoking) with AEP, particularly following initiation,
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resumption or alteration in smoking habits [6-9]. Indeed, cases of AEP recurrence have been
observed after a smoking challenge test. In patients with a history of AEP who resumed
smoking, a recrudescence of eosinophilia on bronchoalveolar lavage (BAL) samples was
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observed [7,10,11]. Relative risk of developing AEP in the general population is limited,
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however in a retrospective review of 43 cases of AEP in military personnel, smoking was

reported in 91% of individuals [12]. Other identified risk factors for development of AEP are
particular drugs and medications (i.e., daptomycin and piperacillin/tazobactam) [13,14].
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The pathogenesis of AEP is suspected to be a result of inhaled organic and inorganic toxins
found in cigarette smoke, which triggers an IL-5 mediated inflammatory response in the alveoli.
The IL-5 cytokine plays a regulatory role in pulmonary eosinophilia and eosinophils survival in
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lung tissue [15,16]. Studies have also demonstrated a dose dependent relationship between
cigarette smoke exposure and cytokine levels, as well as concentration of macrophages and
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neutrophils in BAL [17].

The patient with AEP presents with respiratory and systemic symptoms that often emulates an
acute infectious process, with symptoms of tachypnea, flushing, cough and hypoxia. Plain chest
radiography most commonly reveals scattered bilateral alveolar opacities [18]. High-resolution
computed tomography (HRCT) findings may show interstitial infiltrates or reticular markings
(Fig. 1), which often evolve into patchy alveolar infiltrates as the disease progresses [19]. The
diagnosis of AEP is made by a history of recent cigarette use in the context of brief febrile
illness, respiratory symptoms and BAL eosinophilia > 25%, with the exclusion of an infectious
etiology (i.e., HIV, Pneumocystis jirovecii, bacterial, and fungal infection) [18].

Treatment of AEP is systemic corticosteroids. A marked improvement should be seen within the
first 48 hours, and confirms the diagnosis. A lack of response to corticosteroids should raise
concern and trigger reevaluation for an alternative diagnosis. Some cases have reported an
improvement with conservative management only. However, due to rapidly progressive

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respiratory failure in most cases of AEP, withholding steroids should only be considered when
the clinician has significant concern for potentially life-threatening complications with steroid

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administration.
The long-term course of the disease is not well elucidated. There are multiple reports of

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smoking tolerance development in patients who resumed smoking after resolution of AEP

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[20,21]. This is in contrast with other reports, where a smoke provocation test was performed
in order to confirm the diagnosis and resulted symptoms recurrence [22].

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2.2. E-Cigarettes or Vaping Associated Lung Injury (EVALI)
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As of December 2019, nearly 2500 cases of EVALI that required hospitalization have been
reported across the United States. The majority of patients were under 35-years-old with a
median age of 24, and male predominance of 67%. While 80% of cases reported using
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tetrahydrocannabinol containing products, 54% also reported using nicotine-containing

products [23-25]. Most recent reports have confirmed 55 deaths due to EVALI. Re-
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hospitalization was noted to be higher in older patients (median age of 45) with at least one
chronic illness [5].
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The underlying pathogenesis of EVALI remains unresolved. Vitamin E acetate has recently been
implicated as a possible ingredient in e-cigarette that is associated with disease development.
This is based on elevated vitamin E acetate levels identified in cartridge samples tested by state
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laboratories, as well as the detection of vitamin E acetate in BAL samples in many of the
confirmed cases [26,27]. Among cases of EVALI that underwent biopsy, pathology findings were
consistent with airway centered acute lung injury with marked mucosal edema and vacuolated
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(foamy) macrophages [28].

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Most cases of EVALI presented with shortness of breath, cough and chest pain along with
constitutional symptoms such as fever, chills, and generalized fatigue. About 80% also reported
gastrointestinal symptoms of nausea, vomiting, diarrhea or abdominal pain. Laboratory studies
show leukocytosis and high erythrocyte sedimentation rates, which are non-specific and can
mimic an infectious etiology [29]. The predominant radiographic findings are basilar ground-
glass opacities which spare the sub-pleural and lobular areas (Fig. 2) [30]. Criteria for the
diagnosis of EVALI has been proposed, requiring a history of e-cigarettes or vaping use within
90 days prior to symptoms, with acute pulmonary infiltrates on imaging, and a negative work-
up for infectious or alternative etiologies [29]. Cell count, cultures, and cytology from BAL may
further aid in diagnosis. Lipid laden macrophages were identified in 7 out of 14 patients who
underwent bronchoscopy with BAL on Oil red O stain [28].
The majority of reported cases of EVALI were treated with systemic corticosteroids, but the
actual efficacy has not been evaluated in a prospective randomized control trial [29,31,32].
Indeed, due to the potential life-threatening progression of the disease, steroids have been
recommended by the American Thoracic Society for patients who experience hypoxia and those

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suspected to have EVALI [33]. As the initial presentation frequently mimics a bacterial or viral

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pneumonia, empiric antibiotics are often administered while a more detailed investigation can
take place.

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2.3. Respiratory Bronchiolitis – Interstitial Lung Disease (RB-ILD)
Respiratory Bronchiolitis (RB) is common among smokers and reflects a mild inflammatory state
that is usually asymptomatic. In tobacco smokers who underwent a lung biopsy for other

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reasons, RB was incidentally identified in 89% of cases [34]. In contrast, RB-ILD is an uncommon
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disease, considered to be a more severe form of RB and classified as an Idiopathic Interstitial
Pneumonia (IIP). It is estimated that RB-ILD represents 2-13% of IIP cases based on reported
international epidemiologic data [35,36]. Almost all patients with RB-ILD have been identified
as active or former smokers [34,37].
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Histologically, RB is characterized by the accumulation of tan-colored pigmented macrophages

in the alveoli, with lymphocytic submucosal and peribronchiolar infiltrates and perialveolar
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fibrosis. The degree of fibrosis in RB-ILD is more extensive than that seen in RB, and is believed
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to play a role in disease development [34]. However, in many cases RB-ILD cannot be
pathologically differentiated from RB, and is therefore dependent on the clinical and
radiographic evidence of ILD for diagnosis [38,39].
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Patients with RB-ILD reports subacute dyspnea, wheezing, and cough that may be productive
[40]. Rarely, RB-ILD present in a more acute pattern [41]. HRCT findings include patchy or
diffuse ground-glass opacities, centrilobular nodules and bronchial wall thickening (Fig. 3) [42].
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Diagnosis is established by the history of current or recent smoking, respiratory symptoms, a

restrictive or a mixed obstructive and restrictive pattern on pulmonary function testing (PFT)
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with a reduced diffusion capacity, and characteristic radiographic findings [39]. Surgical lung or
transbronchial biopsies are not typically needed for diagnosis unless the diagnosis is uncertain.
Smoking cessation is the mainstay of treatment, and often clinical and radiographic
improvement is achieved with no additional interventions [40,43]. Steroids are reserved only
for patients who progress despite smoking cessation, given the mixed data regarding its efficacy
[40,44]. There are limited case reports supporting the use of azathioprine for refractory cases
that did not respond to glucocorticoid therapy [40].
2.4. Desquamative Interstitial Pneumonia (DIP)
DIP is relatively uncommon, with the age of onset between 40 to 60 years and a 2:1 male to
female predominance. Prevalence of smoking among reported cases is as high as 60-87% [45].
DIP was first described histologically in 1965, with large desquamated epithelial cells filling the
alveoli; there were later identified as alveolar macrophages (smoker macrophages) [46]. Diffuse

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involvement of distal air spaces with these distinctive macrophages, along with mild interstitial
thickening and the lack of excessive fibrosis and honeycombing, is characteristic of the disease

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[47].

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The most common symptom of DIP is exertional dyspnea and chronic cough [46]. Chest x-rays
are read as normal in up to one-third of proven cases. HRCT findings are nonspecific, but most

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often show bilateral patchy ground-glass opacities with a peripheral and basal predominance,
with a notable lack of reticulonodular opacities or honeycombing (Fig. 4) [48,49]. Diagnosis can
be challenging and is suspected with a suggestive history of smoking along with the

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radiographic findings. The disease is proven pathologically in only 59% of the cases in which DIP
is suspected [50], therefore biopsy is usually required to confirm the diagnosis.
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While smoking cessation is the central tenet of therapy, patients with DIP may improve,
stabilize or continue to worsen after smoking cessation [51]. Systemic corticosteroids have
been shown to be beneficial, and macrolides may be beneficial in patients with persistent
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disease despite steroids [49,52]. Azathioprine and cyclophosphamide have been used in a
limited number of case reports of refractory cases, with mixed results [53].
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2.5. Pulmonary Langerhans Cell Histiocytosis (PLCH)

PLCH is a rare condition primarily affecting young adults with no gender predominance. While
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there is no clear data regarding the prevalence of the disease, it is estimated PLCH accounts for
3 to 5% of adults with diffuse parenchymal lung disease [54]. Cigarette smoke stimulates the
accumulation of dendritic (Langerhans) cells in the lung parenchyma and suppresses normal
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mechanisms of apoptosis in these cells [55]. Histopathologic findings show clusters of

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Langerhans cells surrounding small bronchioles which obstruct the bronchiolar walls [56].
Extension of cells to the surrounding parenchyma results in an appearance of the stellate
lesions, which is characteristic of the disease [57]. The Langerhans cell expresses CD1a, S100
protein, and CD 207, which is pathognomonic of PLCH [56].
Patients with PLCH present with a nonproductive cough, dyspnea, fatigue, weight loss, and
fever [58]. Extra-pulmonary manifestations can be seen in less than 20% of cases, including
cystic bone lesions, diabetes insipidus or skin rash [59]. HRCT is diagnostic when solid or cystic
nodules are seen involving the upper and mid-lung zones (Fig 5.) and sparing the costophrenic
angles. Honeycombing can also be seen in PLCH [60]. PFT patterns may vary, depending on the
disease morphology. Predominantly nodular disease is associated with a restrictive pattern,
whereas cystic disease is more likely to be associated with airflow obstruction [61,62].
Bronchoscopy is helpful in excluding other causes of nodular cystic lung disease and can
confirm the diagnosis with > 5% of CD1a expression in the lavage cell counts [63]. Surgical lung
biopsy is reserved for patients with an unclear diagnosis despite the above work-up.
Reports suggest 30% of patients with PLCH stabilize or experience resolution of symptoms with

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smoking cessation alone [64]. Systemic corticosteroids are used in patients who are persistently

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symptomatic despite smoking cessation, with mixed data regarding response and duration of
therapy [65,66]. In patients who are refractory to steroids, cladribine and vinblastine have been

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proposed agents based on pediatric population data [67,68]. Patients who progress despite
treatment should be screened for pulmonary hypertension and be referred to a specialized

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center for consideration of enrollment in clinical trials or lung transplant [69,70].

2.6. Idiopathic Pulmonary Fibrosis (IPF)

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IPF is a disease of pulmonary inflammation that results in hyaline and collagen deposition,
forming scar-like tissue throughout the lung parenchyma with an estimated prevalence of 14 to
42.7 per 100,000 people in the United States [71-73]. In a large cohort study, Bellou et al.
reported tobacco smoking and maternal smoking as independent risk factors for IPF (OR 1.79
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and 1.41, respectively) [74]. Environmental and occupational exposures have been implicated,
though confirming a single causative agent is often not achieved. Mineral dust, asbestos, and
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environmental dust have all been described in literature, though specific incidence is difficult to
clarify given concomitant smoking and other factors [75-78]. Gastro-esophageal reflux disease
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(GERD) has also been associated with the development of IPF [79-82]. IPF is fatal and has a
median survival range of 2.5-5 years [83,84].
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Although the pathologic model for disease progression in IPF is still evolving, the current
understanding describes an index injury and slow immune response. The initial injury appears
to be multifaceted from inhalational, recurrent toxin, or gastric acid exposures, or infectious
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agents [85-88]. The site of injury is at the epithelial layer activating pro-fibrotic factors that
stimulate fibroblast migration and collagen matrix deposition [85,87]. On a genetic and
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molecular level, telomerase activity and length, metabolism of reactive oxygen species,
mitochondrial dysfunction, surfactant dysfunction, and a decrease in alveolar cell proliferation
have all been implicated in the pathogenesis of IPF [89,90]. Mutations in TERC, TERN, PARN,
RTELI have also been associated with decreased telomerase length, and in turn, an increased
risk for IPF patients [91-94]. Though the greatest proportions of patients are smokers, familial
IPF has also been described with mutations in TERC and TERT genes attributed to 15% of cases
of familial IPF [92-95]. In summary, the pathogenesis of IPF is a confluence of multiple host-
dependent factors that predispose to dysregulated fibrotic changes.
IPF is a chronic progressive disease that manifests with refractory dry cough, worsening
dyspnea on exertion, dry inspiratory crackles, and digital clubbing [84]. Lung volumes usually
show a restrictive pattern with a decrease diffusion capacity for carbon monoxide [96]. Chest
radiography most frequently shows basilar predominant bilateral reticular opacities, depending
on the extend of the disease on presentation. HRCT is the mainstay of diagnosis, showing a UIP
pattern (Fig. 6) and may obviate the need for surgical lung biopsy [97,98]. Extensive ground-
glass opacities usually suggests an alternative diagnosis. Surgical lung biopsy may be considered

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if the HRCT pattern is nondiagnostic or if an alternative diagnosis (especially chronic
hypersensitivity pneumonitis) is suspected. A multidisciplinary approach with specialists familiar

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with interstitial lung disease is recommended when the diagnosis is uncertain [98].

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Treatment for IPF has evolved significantly over the past decade. Pirfenidone and nintedanib
are two anti-fibrotic drugs approved by the FDA for the treatment of IPF. The ASCEND and

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CAPACITY trials showed pirfenidone reduced the rate of disease progression, measured by force
vital capacity (FVC) and improvement in exercise capacity [99,100]. The INPULSIS trial
demonstrated nintedanib slowed disease progression measured by FVC, and reduced the time

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to first acute exacerbations when compared to placebo [101]. As these trials excluded patients
with an FVC <50% predicted, it is unknown if patients with more advanced diseases would
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benefit from these treatments. However, in a post hoc analysis evaluating the efficacy of
pirfenidone on IPF patients with an advanced lung disease state (FVC <50% predicted and/or
diffusing capacity <35% predicted), subjects treated with pirfenidone demonstrated less decline
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in six minute walk distance as well as improvement in perceived dyspnea [102]. While this
suggests patients with severe IPF may also benefit from treatment with pirfenidone, further
prospective trials are needed to confirm this finding.
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In addition to antifibrotic therapy, patients with IPF should be evaluated for oxygen therapy
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needs, vaccinations, pulmonary rehabilitation, and antacid medication for silent aspiration
[103-105]. Pulmonary hypertension is highly prevalent in individuals with IPF and requires
appropriate screening when clinically indicated [106]. For advanced disease and in patients with
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concomitant pulmonary hypertension, early referral for lung transplant evaluation is

recommended. Treatment for patients with IPF remains a challenge, and with continuing
research as well as novel therapy development, the hope is to improve meaningful clinical
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benefit in the coming years.

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2.7. Combine Pulmonary Fibrosis and Emphysema (CPFE)

CPFE is a syndrome consisting of upper lobe emphysema and lower lobes fibrosis. Prevalence
ranges from 18.8% to 50.9% in individuals with CT findings of pulmonary fibrosis and
emphysematous changes [107]. It has a male predominant pattern. In a retrospective study
assessing the clinical outcomes of individuals with CPFE, all cases were male and smokers, with
an average of 57 pack years [108]. Similarly, a large Greek cohort consisting of 97 CPFE patients
were largely male predominant with a mean of 52 pack years [109]. Cigarette smoking is the
predominant risk factor, although, other exposures including asbestos, silicosis, coal dust
exposure, and hypersensitivity pneumonitis have been associated with development of isolated
emphysematous changes and fibrosis [110-112].
The pathogenesis of CPFE has not been clearly elucidated. In dog models, Hammond and
colleagues evaluated the effect of cigarettes and demonstrated evidence of emphysema and
fibrosis in lung tissue post-mortem [113]. Genetics are suspected to play a role in disease as

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well. Cottin et al. reported a case of a 32-year-old nonsmoker female with CPFE carrying a

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genetic mutation of the SFTPC gene, which may have influenced the development of CPFE
[114]. Additionally, the ABCA3 mutation was identified in a case report of a nonsmoking 41-

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year-old male [115], further suggesting a genetic predisposition to the development of CPFE.
Other plausible molecular pathways include neutrophil elastase and TNF-α [116,117].

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Clinical manifestations on presentation are similar to other forms of smoking related lung
diseases. Common symptoms include cough, dyspnea on exertion, cyanosis, and hypoxemia.
Exam is notable for dry inspiratory crackles and clubbing [118]. Common PFT findings in CPFE

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patients are preserved to mild impairment in spirometric function with remarkable reductions
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in diffusion capacity across many studies [109,119-121]. The preserved to mild impairment of
spirometric function without airflow obstruction is likely the relationship between the
respiratory mechanics of emphysema offsetting the pulmonary fibrosis with traction leading to
the prevention of expiratory airway collapse. There is no consensus definition for the diagnosis
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of CPFE. CT findings should show upper lobe centrilobular and paraseptal emphysema with or
without bullae, and lower lobes fibrosis and reticulation with or without traction bronchiectasis
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(Fig. 7). In comparison to other forms of interstitial lung disease, the UIP pattern appears to be
the most common imaging finding, but other forms of pattern can be present in concurrence
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with other forms of fibrotic lung disease. Moreover, ground-glass opacities have also been
reported as findings in CPFE. In a case series of ten patients with CPFE, two patients with lower
lobe ground-glass opacities had biopsy proven DIP, suggesting other forms of smoking
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associated interstitial lung disease can be seen concomitantly with CPFE [122]. When
comparing the emphysematous changes in CPFE to those in COPD, Lee et al. found that
paraseptal emphysematous changes was more prevalent in CPFE [123]. Careful evaluation of
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the patient’s family history, environmental factors, along with symptoms and radiological
findings should be considered to properly diagnose.
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To date, there is no specific guidelines for the treatment of CPFE. Smoking cessation is the first
line of treatment. Given the preserved to mild impairment of spirometric function without
airflow obstruction, it is unclear if inhaled bronchodilators are beneficial. In a retrospective
study, Oh and colleagues found patients with CPFE treated with inhaled bronchodilators had an
improvement in composite physiologic index [124], suggesting that inhaled bronchodilators
may have some therapeutic benefit. Oxygen therapy should be used for the treatment of
hypoxemia and appropriate vaccinations (i.e., influenza and pneumococcal) should be given.
Immunosuppressive therapy may be considered in individuals with co-existing forms of IIP
[107]. Due to the higher prevalence of pulmonary hypertension and lung cancer in patients with
CPFE, appropriate screening for these comorbidities is indicated. Furthermore, given the higher
risk for mortality when compared to COPD [123], individuals with CPFE should be evaluated
early for lung transplant evaluation.

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3.0 Expert Opinion

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COPD remains and will continue to be the most prevalent form of smoking-related interstitial
lung disease. The preponderance for smoking and electronic smoking or vaping has been

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consistently observed in the lung diseases discussed in this review. Further studies are needed
to understand how some of these diseases tend to be predominant in a younger population.

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With rare exception, smoking cessation is the first therapy for the majority of these diseases
and should be strongly encouraged and facilitated.
In the next five years, we look forward for an improvement in diagnostic testing of the smoking

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associated interstitial lung disease reviewed in this article. Genetic screening of smokers may
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provide better understanding of susceptibility to some of these conditions. Presently, there are
several studies investigating the genetic risk factors in the development of IPF [125]. Another
area of ongoing research is understanding the pathogenesis of EVALI, with particular attention
investigating the in-vivo effects of e-cigarettes in relation to respiratory immune responses
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[126]. Pamrevlumab is a monoclonal antibody against connective tissue growth factor (CTGF)
that has been associated with the dysregulated fibrosis seen in IPF. In a phase II randomized
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controlled trial, patients treated with pamrevlumab showed significantly less decline in FVC in
comparison to placebo (-2.9% vs -7.9%; p=0.033) [127]. This data has now been used to support
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an ongoing phase III trial, assessing the efficacy and safety of pamrevlumab, which may open
more treatment options for IPF patients [128].
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Funding
This paper was not funded.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or

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entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript. This includes employment, consultancies, honoraria, stock

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ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Reviewer disclosures

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Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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References
Papers of special note have been highlighted as:
* of interest
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*** Study on the increased trends in vaping among the adolescents population
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9. Uchiyama H, Suda T, Nakamura Y, et al. Alterations in smoking habits are associated
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