[ Recent Advances in Chest Medicine ]

Current Concepts in Pathogenesis,

Diagnosis, and Management of
Smoking-Related Interstitial Lung Diseases
Anupam Kumar, MD; Sujith V. Cherian, MD; Robert Vassallo, MD; Eunhee S. Yi, MD; and Jay H. Ryu, MD

Tobacco exposure results in various changes to the airways and lung parenchyma. Although
emphysema represents the more common injury pattern, in some individuals, cigarette smoke
injures alveolar epithelial cells and other lung cells, resulting in diffuse infiltrates and paren-
chymal fibrosis. Smoking can trigger interstitial injury patterns mediated via recruitment and
inappropriate persistence of myeloid and other immune cells, including eosinophils. As our
understanding of the role of cigarette smoke constituents in triggering lung injury continues to
evolve, so does our recognition of the spectrum of smoking-related interstitial lung changes.
Although respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneu-
monia, pulmonary Langerhans cell histiocytosis, and acute eosinophilic pneumonia have a well-
established association with tobacco use, its role and impact on idiopathic pulmonary fibrosis,
combined pulmonary fibrosis and emphysema, and connective tissue disease-related intersti-
tial lung diseases is still ambiguous. Smoking-related interstitial fibrosis is a relatively newly
appreciated entity with distinct histopathologic features but with unclear clinical ramifications.
Increased implementation of lung cancer screening programs and utilization of CT scans in
thoracic imaging have also resulted in increased identification of “incidental” or “subclinical”
interstitial lung changes in smokers, the ensuing impact of which remains to be studied.
CHEST 2018; 154(2):394-408

KEY WORDS: interstitial lung disease; pulmonary fibrosis; smoking

Cigarette smoking is implicated to varying
degrees in a distinct but heterogeneous
group of parenchymal lung diseases
(smoking-related interstitial lung diseases
[ILDs]) in addition to emphysema. Lung
diseases in this spectrum can be grouped into
those that likely have a causal association
with tobacco exposure (respiratory
bronchiolitis-interstitial lung disease
[RB-ILD], desquamative interstitial

ABBREVIATIONS: AEC2 = type 2 alveolar epithelial cells; AEP = acute
eosinophilic pneumonia; CPFE = combined pulmonary fibrosis and
emphysema; CTD-ILD = connective tissue disease-related interstitial
lung disease; DIP = desquamative interstitial pneumonia; GGO =
ground-glass opacity; HRCT = high-resolution CT; ILD = interstitial
lung disease; IPF = idiopathic pulmonary fibrosis; PDGF = platelet-
derived growth factor; PH = pulmonary hypertension; PLCH = pul-
monary Langerhans cell histiocytosis; RA = rheumatoid arthritis; RB =
respiratory bronchiolitis; RB-ILD = respiratory bronchiolitis-interstitial
lung disease; SRIF = smoking-related interstitial fibrosis; UIP = usual
interstitial pneumonia
AFFILIATIONS: From the Division of Pulmonary and Critical Care
Medicine (Dr Kumar), Spectrum Health-Michigan State University
College of Human Medicine, Grand Rapids, MI; Division of
Pulmonary, Critical Care and Sleep Medicine (Dr Cherian), University
of Texas Health Science Center at Houston-McGovern Medical School,
Houston, TX; and the Division of Pulmonary and Critical Care
Medicine (Drs Vassallo and Ryu) and Department of Laboratory
Medicine and Pathology (Dr Yi), Mayo Clinic College of Medicine and
Science, Rochester, MN.
CORRESPONDENCE TO: Anupam Kumar, MD, Division of Pulmonary
and Critical Care Medicine, Spectrum Health-Michigan State
University College of Human Medicine, 100 Michigan St NE, Grand
Rapids, MI 49503; e-mail: anupamkumarmd@gmail.com
Copyright Ó 2017 American College of Chest Physicians. Published by
Elsevier Inc. All rights reserved.
DOI: https://doi.org/10.1016/j.chest.2017.11.023

394 Recent Advances in Chest Medicine [ 154#2 CHEST AUGUST 2018 ]

pneumonia [DIP], pulmonary Langerhans cell
histiocytosis [PLCH], and acute eosinophilic pneumonia
[AEP]) and those in which smoking likely acts in
conjunction with endogenous or exogenous factors but
causality is yet to be established (idiopathic pulmonary
fibrosis [IPF], combined pulmonary fibrosis and
emphysema [CPFE], and connective tissue disease-
related interstitial lung disease [CTD-ILD]). The present
review discusses our current understanding of the
manifold mechanisms by which cigarette smoke
inhalation can trigger and propagate interstitial lung
injury in smokers, as well as the key clinical features that
differentiate these disorders. We also discuss the
potential clinical ramifications of smoking-related
interstitial fibrosis (SRIF) and the downstream impact of
incidentally detected “subclinical” interstitial lung
changes in smokers.
Mechanisms and Spectrum of Cigarette
Smoke-Induced ILDs
Tobacco smoke is a toxic assortment of particulate
matter and various chemicals that induce inflammatory,
genotoxic, proliferative, and other stimuli to lung cells
that extend from the conducting to the gas exchange
zones. Reactive oxidant species, nicotine, and other
toxins in cigarette smoke induce epithelial as well as
endothelial cellular activation, often leading to secretion
of a variety of inflammatory cytokines and chemokines
that secondarily recruit immune cells into various lung
compartments, including small and large airways and
the lung parenchyma.1,2 Emphysema, the more common
parenchymal lung injury pattern associated with
smoking, is associated with alveolar cell apoptosis and
destruction accompanied by loss of lung scaffolding.
Although morphologically very different compared with
lesions observed in smoking-induced diffuse lung
diseases, some of the mechanisms by which smoking
induces emphysema are similar to those involved in
fibrosis and distal lung remodeling.
One cell type that is likely central in the pathogenesis of
both emphysema and lung fibrosis is the alveolar
epithelial stem cell. In the lung, a subset of type 2
alveolar epithelial cells (AEC2) performs the function of
new AEC2 progenitors as well as a source of new type 1
alveolar epithelial cells. In this context, certain
pathogenic events such as telomere dysfunction and
predisposition to cellular senescence may provide
insight into the susceptibility of some smokers to
develop either emphysema or fibrotic interstitial lung
changes (or a combination of both). Telomerase is an
chestjournal.org
enzyme system that performs the essential function of
maintaining telomeres on the ends of chromosomes.3
This cellular function is critical as evidenced by the
predisposition of cells with abnormally short telomeres
to develop a phenotype of senescence and apoptosis.
Studies performed in telomerase knockout mice revealed
an increased susceptibility to cigarette smoke-induced
damage and development of emphysema.4 This finding
may be particularly relevant to understanding
susceptibility to both emphysema and fibrosis because of
the demonstration that up to 10% of patients with
nonfamilial fibrotic idiopathic interstitial pneumonia
(most of whom have IPF have abnormally short
telomere lengths5). Although this study did not perform
correlations between smoking history and telomere
length, it does suggest a common mechanism by which
certain smokers may develop a predisposition to alveolar
epithelial cell senescence and an abnormal lung
regenerative pathway that may lead to the phenotype of
emphysema in some and fibrosis in others (or even both
in some patients).
The induction of alveolar epithelial cellular senescence
by cigarette smoke is potentially also pivotal for the
development of either emphysema or interstitial changes
and fibrosis in certain smokers. Cellular senescence, a
state of replicative arrest brought on by cellular stressors
(including cigarette smoke), results in emergence of the
senescence-associated secretory phenotype.6 The
mediators secreted by these cells include a variety of
cytokines, chemokines, matrix metalloproteinases, and
growth factors that have been implicated in the
pathogenesis of both emphysema and pulmonary
fibrosis.6 It is possible that the induction of senescent
cells in the lungs of predisposed smokers may be
sufficient to drive a subsequent inflammatory and tissue
remodeling response, such that the ensuing
inflammatory cell recruitment becomes a secondary
phenomenon of the aberrant biology, rather than a
primary driver of tissue injury, and may provide some
insight into why antiinflammatory (corticosteroid or
other immunomodulatory) therapy is generally lacking
in therapeutic efficacy in at least some of the tobacco-
induced lung diseases.
Cigarette smoke, or its constituents, can also directly
induce profibrotic factors from lung cells.7,8 Among the
growth factors directly induced by cigarette smoke,
transforming growth factor-beta 1 (TGF-b1) and
platelet-derived growth factor (PDGF)-A and -B are
particularly relevant.8,9 TGF-b1 is essential for matrix
generation (including collagen, fibronectin, and elastin)
395
by fibroblasts and myofibroblasts. PDGF induces
fibroblast and myofibroblast proliferation and thus may
amplify TGF-b1 effects by enhancing the number of cells
available to respond and produce matrix proteins.
Immunohistochemical studies performed on lung biopsy
specimens from patients with smoking-induced diffuse
lung diseases have shown upregulation of both TGF-b1
as well as PDGF, suggesting a role for these factors in
tissue remodeling and fibrosis.10,11
Numerous lines of evidence now also support a key role
for osteopontin, a glycoprotein with cytokine-like
properties, in the pathogenesis of smoking-induced
diffuse lung diseases.12,13 Immunohistochemical studies
on PLCH and DIP lung biopsy specimens revealed
strong osteopontin immunoreactivity in infiltrating
macrophages and CD1aþ cells, as well as AEC2 cells.12
Functionally, osteopontin may be critically involved in
antigen-presenting cell trafficking into the lung and may
also play a critical role in the development of T-helper-
17 polarized responses that subsequently drive
inflammation in certain tobacco-induced lung
diseases.13 Osteopontin, along with other cytokines (eg,
granulocyte-macrophage colony stimulating factor,
TGF-b1) can stimulate the recruitment of Langerhans
cells.10,14 Exposure to tobacco smoke may also enhance
the survival of myeloid cells, including dendritic cells, by
inducing cellular response proteins involved in the
regulation of cell death by apoptosis.15 Recruitment of
myeloid cells with morphologic features similar to
Langerhans cells around small airways is likely an early
event that precedes secondary recruitment of other
inflammatory cells and results in formation of the
bronchiolocentric granulomatous-like lesions
characteristic of PLCH.
Although the potential mechanisms mentioned earlier
provide some insights into the pathogenesis of chronic
forms of lung injury such as fibrosis and emphysema, it
has also become apparent that cigarette smoke can
induce an acute form of lung injury through eosinophil
recruitment and activation in some patients, resulting in
AEP. Constituents of the cytoplasmic granules of the
eosinophil such as eosinophilic cationic proteins,
leukotrienes, and other cytokines cause local tissue
injury and edema of lungs through a variety of
mechanisms. Exaggerated eosinophil response and the
release of these substances can also stimulate mast cell
differentiation and T lymphocyte proliferation.16
Prospective studies on patients with AEP also found
increased tryptase levels, confirming the role of mast
396 Recent Advances in Chest Medicine
cells. Studies on BAL samples of patients with AEP have
also shown increased levels of IL-5 and IL-33, both
potent stimulators of eosinophil recruitment, activation,
and proliferation.16,17 IL-5 levels were also found to
inversely correlate with peripheral eosinophilia,
suggesting its role in recruiting eosinophils from
peripheral blood into the lungs, and that an increase in
blood eosinophil count in a patient with AEP is likely a
marker of resolving inflammation.16,18 The eosinophil
accumulation in AEP causes widespread capillary
endothelial damage and increased vascular permeability,
and it results in diffuse alveolar damage with interstitial
eosinophil infiltration. Although cigarette smoke is
certainly a stimulus for this eosinophil-mediated lung
injury, other extrinsic stimuli can also plausibly
stimulate such a response pattern.19
One of the most compelling arguments linking the
diseases listed in Table 1 with cigarette smoking is the
co-existence of the various aforementioned patterns of
interstitial and airway injuries in the same patient.20
Although smoking clearly can cause these diverse lung
injury patterns, it is not certain why some smokers
develop one specific entity rather than another lesion.
These diverse lung responses to cigarette smoke imply
that there must be additional co-factors (either
endogenous/genetic or exogenous) that result in the
induction of a specific disease phenotype in a given
smoker. Similarly, the extent to which any of these
smoking-induced diffuse lung diseases progress to lung
remodeling and airway and/or parenchymal fibrosis
varies considerably between different individuals and
cannot simply be explained by cumulative tobacco
exposure, implying the need to identify further genetic
factors that interplay with smoking in the determination
of the eventual disease phenotype.
ILDs Causally Associated With Smoking
ILDs in which cigarette smoking has been causally
implicated include RB-ILD, DIP, PLCH, and AEP. SRIF
and “subclinical” interstitial changes in smokers are also
included in this category. The clinical features, including
demographic characteristics and pattern of pulmonary
function test results in these disorders, are summarized
in Table 1.
Respiratory Bronchiolitis-ILD
Respiratory bronchiolitis (RB) is a histopathologic term
that refers to the deposition of pigmented macrophages
in the respiratory bronchioles and peribronchiolar
alveolar spaces.21 Although RB can be considered a
[ 154#2 CHEST AUGUST 2018 ]
chestjournal.org

TABLE 1 ] Summary of Significant Clinical Characteristics of Smoking-Related ILDs

Demographic
Smoking-Related ILD Characteristics Symptoms PFT Results Radiology (CT Scan Features) Key Management Strategies
RB-ILD M ¼ F, 30-60 y Cough, dyspnea Normal, obstructive, GGO  centrilobular nodules Smoking cessation,
restrictive, or mixed (usually upper lobe) corticosteroids in
refractory/progressive
cases
DIP M > F, 40-60 y Cough, dyspnea, hemoptysis Normal, obstructive, GGO with lower lobe Smoking cessation,
(rare) restrictive, or mixed. predominance corticosteroids in
Reduced DLCO (centrilobular nodules are refractory/progressive
rare) cases
SRIF M ¼ F, 40-60 y Cough, dyspnea Obstructive, restrictive, or Centrilobular nodules  GGO Smoking cessation, consider
(diagnosed only with mixed (similar to RB-ILD) steroids in severe cases
histopathology) (no data)
PLCH M ¼ F, 20-40 y Cough, dyspnea, pneumothorax Restriction (initial) and Upper lobe nodules, mix of Smoking cessation.
extrapulmonary (diabetes obstruction (advanced) nodules and bizarre- Cladribine in severe
insipidus, bone cysts) shaped cysts (advanced disease. Consider lung
stages), sparing of transplantation in
costophrenic angle advanced cases
AEP M > F, 20-40 y Acute onset of cough, dyspnea, May not be obtained in acute Bilateral, often diffuse GGO Smoking cessation and
and fever. Respiratory failure illness but can be and reticular opacities. corticosteroids (excellent
in severe cases obstructive, restrictive, or Pleural effusion may be response)
mixed seen
IPF M > F, > 60 y Progressive dyspnea, dry cough Restrictive Basal reticulation, traction Smoking cessation, consider
bronchiectasis, antifibrotic therapy (if UIP/
honeycombing IPF confirmed) or lung
transplantation in suitable
candidates
CPFE M > F, > 60 y Progressive dyspnea, cough Pseudo-normal PFT with Upper lobe emphysema with Smoking cessation, consider
disproportionately low lower lobe fibrosis lung transplantation in
DLCO suitable candidates

AEP ¼ acute eosinophilic pneumonia; CPFE ¼ combined pulmonary fibrosis and emphysema; DIP ¼ desquamative interstitial pneumonia; DLCO ¼ diffusing capacity of the lung for carbon monoxide; F ¼ female;
GGO ¼ ground-glass opacity; ILD ¼ interstitial lung disease; IPF ¼ idiopathic pulmonary fibrosis; M ¼ male; PFT ¼ pulmonary function test; PLCH ¼ pulmonary Langerhans cell histiocytosis; RB-ILD ¼ respiratory
bronchiolitis-interstitial lung disease; SRIF ¼ smoking-related interstitial fibrosis; UIP ¼ usual interstitial pneumonia.
397
tell-tale sign of exposure to tobacco, not all patients with
RB develop clinical manifestations. Thus, RB-ILD is
distinct from RB in that it is a form of interstitial
pneumonia with characteristic clinical, radiologic, and
pathologic features (Table 1).22 Almost all patients with
RB-ILD are current or previous smokers.23-25 However,
the intensity of tobacco exposure can be variable with
occurrence of symptoms even in patients with minimal
exposure.23 It is also interesting to note that RB is a
frequent pathologic finding in smokers (in up to 90% of
patients) who develop spontaneous or recurrent
pneumothorax.26 Aside from cigarette exposure, other
fumes such as solder and fiberglass have also been
implicated in RB-ILD, albeit rarely.24,27
RB-ILD is significantly better characterized on high-
resolution CT (HRCT) scans than plain radiographs.
Characteristic HRCT abnormalities include patchy
ground-glass opacities (GGOs), with or without the
presence of fine centrilobular nodules (Fig 1A). In a
single center-based study, bronchial thickening (central
and peripheral) was the most common finding (90%),
followed by centrilobular nodules (71%) and ground-
glass opacification (67%).25 Other changes that may be
seen include areas of air trapping and emphysema.23,25 It
is unusual to see honeycombing or other changes that
signify fibrosis such as traction bronchiolectasis/
bronchiectasis. The lung parenchymal changes in RB-
ILD do not have a zonal predominance. This finding is
in contrast to DIP, which also presents with diffuse
ground-glass opacification but with lower zone
predominance, although not universal.28-30
A history of smoking with the aforementioned
radiographic changes is usually sufficient to diagnose
RB-ILD. Typical BAL studies reflect an increased
number of macrophages (as in smokers in general) with
Figure 1 – A, High-resolution CT (HRCT) scan of respiratory bronchiolitis-interstitial lung disease. HRCT scan of the chest of a 42-year-old male
smoker demonstrates patchy ground-glass opacities bilaterally, more prominent in the left lung anteriorly. B, Histopathology of respiratory
bronchiolitis-interstitial lung disease. Mild increase in pigmented alveolar macrophages within the bronchiolar lumen and adjacent alveolar spaces with
minimal interstitial fibrosis. Hematoxylin and eosin staining, 100 original magnification.
398 Recent Advances in Chest Medicine
nonspecific changes in other cell lines. Lymphocytic
predominance on BAL in a patient with centrilobular
nodules and subtle GGOs should prompt consideration
of hypersensitivity pneumonitis over RB-ILD.
Transbronchial biopsy is not a reliable diagnostic
modality due to the patchy nature of lung involvement.
Histopathology of RB-ILD shows the presence of
brown-pigmented macrophages in the distal airways (ie,
respiratory bronchioles and adjacent alveolar spaces)
(Fig 1B). The distribution is patchy and without overt
evidence of fibrosis, although mild peribronchiolar
fibrosis may be observed.22,31,32 In addition, patchy
lymphocytic and histiocytic infiltration of the
peribronchiolar interstitium may be seen.31 Whether RB
can be distinguished from RB-ILD based on pathologic
findings is controversial, but RB-ILD tends to have more
alveolar fibrosis than RB.33 Thus, in a patient with
compatible clinicoradiologic features and RB-like
histopathologic changes, a diagnosis of RB-ILD can be
safely secured.
Smoking cessation is the most important
recommendation for a patient with RB-ILD. However,
clinical and physiological improvement following
smoking cessation is delayed and often
incomplete.23,24,34 In a long-term follow-up study by
Portnoy et al,34 75% of the patients survived > 7 years
but with clinical and physiological improvement in only
28% and 10.5% of patients, respectively. In patients with
worsening lung disease, or lack of improvement,
particularly if the clinical presentation (ie, demographic
characteristics, radiology findings) is atypical, a surgical
lung biopsy should be considered for diagnostic
clarification. Second-line treatment for persistent or
progressive RB-ILD is less well established but should be
attempted in the absence of improvement.
[ 154#2 CHEST AUGUST 2018 ]
Corticosteroids are often prescribed for individuals with
progressive RB-ILD, although the evidence that supports
such use is sparse.23,34 A dose in the range of 0.5 to
1 mg/kg of prednisone is typically started with a gradual
taper over months based on benefits and tolerance.
Risks/benefits of long-term therapy with corticosteroids
do not have supportive data and should be carefully
individualized for patients. Some patients may exhibit
worsening of clinical and physiological parameters
despite treatment with corticosteroids and other
immunosuppressant agents.23,24,34 In patients with co-
existing features of air trapping, obstructive lung disease,
or emphysema, inhaled corticosteroids and
bronchodilators could also be considered.
Desquamative Interstitial Pneumonia
DIP was first described by Liebow et al35 in 1965, the
name originally referring to “desquamation” of epithelial
cells. However, the abnormal collections of cells
observed within the alveolar spaces in this disorder are
now known to be accumulations of macrophages and
not desquamated epithelial cells. Hence the term “DIP”
is considered by many to be a misnomer.
DIP, like RB-ILD, has a strong association with current
and previous smoking.30,36 Based on data from several
studies, 60% to 90% of DIP cases are reported in
smokers.30,32,36 However, in contrast to RB-ILD, which
is almost exclusively a smoker’s disease, DIP has been
reported secondary to other causes such as connective
tissue diseases (eg, rheumatoid arthritis [RA], systemic
sclerosis),37,38 occupational exposure (eg, mycotoxins,
dust, solder fumes, flock-workers),24,39-41 drugs (eg,
sirolimus),42 and infections.43
Symptoms of patients with DIP are similar to RB-ILD
(Table 1). However, the pulmonary physiological
Figure 2 – A, HRCT image of desquamative interstitial pneumonia. HRCT scan of the chest of a 32-year-old female smoker demonstrates extensive
patchy ground-glass opacities bilaterally in both lower lobes. B, Histopathology of desquamative interstitial pneumonia. Diffuse and prominent
accumulation of pigmented alveolar macrophages with mild to moderate interstitial fibrosis. Variable amount of chronic inflammatory infiltrates and
lymphoid hyperplasia may be seen (not shown). Hematoxylin and eosin staining, 100 original magnification. See Figure 1 legend for expansion of
abbreviation.
chestjournal.org
impairment tends to be more severe than in RB-ILD
with at least a moderate impairment in gas transfer (as
gauged by a reduced diffusing capacity of the lung for
carbon monoxide).23,31,35 HRCT scanning shows
extensive bilateral GGOs, which may have a peripheral
and basal predominance (Fig 2A). Unlike in RB-ILD,
centrilobular nodules are rarely seen.29 Linear opacities
and reticulation may be seen in up to 60% of patients.30
Long-term radiographic follow-up of DIP may
demonstrate radiographic evolution with development
of honeycombing in up to 10% to 20% of patients.29,44
Thus, the distribution of interstitial abnormalities in DIP
may sometimes be similar to that seen in usual
interstitial pneumonia (UIP), but the degree of ground-
glass opacification and the relative paucity of
honeycomb changes in DIP enables distinction from
UIP.29 Bronchoscopy, as in cases of RB-ILD, is used
primarily to rule out an alternative diagnosis. Kawabata
et al45 reported marked eosinophilia (mean: 18%) and
moderate neutrophilia (mean: 11%) in the BAL fluid of
85% of the patients. Attempts at obtaining tissue
diagnosis (surgical biopsy is preferred over
transbronchial biopsy) should be reserved for ambiguity
in diagnosis or disease worsening despite conventional
treatment.
Pathology of DIP overlaps with that of RB-ILD, the most
striking feature being accumulation of pigmented
macrophages in the small airways and alveoli (Fig 2B).
Key features that differentiate DIP and RB-ILD include
the generally uniform and widespread involvement in
DIP, whereas the macrophage accumulation and fibrotic
changes center along the small airways and adjacent
alveoli (bronchiolocentric) in RB-ILD.31,32 Alveolar
septal thickening occurs due to interstitial inflammation.
Mild to moderate fibrosis may be present. In contrast to
UIP, however, patchiness of fibrosis or temporal
399
heterogeneity with fibroblast foci is not a feature of DIP,
allowing relatively easy differentiation.
In general, most patients with DIP have a good
prognosis, especially if smoking cessation is attained
early in the disease course. Within the limitations of lack
of robust data, results from existing studies suggest an
overall survival approaching 90% at 10 years.23,36
However, progression to respiratory failure is more
likely for patients with DIP than with RB-ILD.23
Whether DIP can progress to UIP is controversial, but
follow-up imaging over the long term may show
evidence of honeycombing and reticulation in some
patients.44
Avoidance of tobacco exposure, both active and passive,
forms the cornerstone for treatment. Smoking cessation
results in clinical improvement in approximately 20% to
50% of patients.36 As in RB-ILD, there is paucity of data
about the efficacy of steroids. Data from previous studies
show that although up to 60% of patients treated with
corticosteroids had clinical improvement, 27% worsened
with this treatment.36 Because untreated patients may
have deterioration of pulmonary function,
corticosteroids and steroid-sparing immunosuppressant
agents remain in use despite lack of concrete data.
Prednisone is typically initiated at a dose of 0.5 to 1 mg/
kg and tapered over a few weeks to months, again based
on clinical response and tolerance. A single case report
of clinical benefit with the use of macrolide therapy for
DIP has been reported.46 Therapy for nonsmoking-
related DIP should be tailored to the underlying
etiology, with an emphasis on avoidance of any form of
irritant exposure. Progressive disease warrants
consideration for lung transplantation, if clinically
appropriate, although recurrence has been reported.47
Pulmonary Langerhans Cell Histiocytosis
PLCH is a nodular and cystic ILD seen typically in
young adults in the age group of 20 to 40 years.48 There
is no sex predilection. Smoking is the strongest risk
factor for development of this condition in adults and is
reported in at least 90% of patients with adult PLCH.
Although the precise mechanism of disease remains
unclear, it is likely that PLCH represents a myeloid
neoplasm with inflammatory properties that is induced
by cigarette smoke in most instances. Cigarette smoke is
likely the trigger that induces disease; however, the
identification of mutations affecting cell cycle pathways,
including the BRAF-V600E mutation (identified in up of
50% of PLCH cases) and MAPK, have now shed light
into novel mechanistic pathways by which this disease
400 Recent Advances in Chest Medicine
develops.49,50 BRAF-V600E and other activating cell
cycle mutations may drive disease activity even in
subjects who quit smoking, which may explain the
observation of disease progression in certain individuals
despite smoking cessation.
Up to 10% of patients with PLCH can be asymptomatic,
and 15% may present with recurrent pneumothorax.51,52
Aside from pulmonary parenchymal involvement,
pulmonary vascular involvement resulting in pulmonary
hypertension (PH) seems to be relatively common in
patients with advanced PLCH.53 For instance, in a
retrospective analysis of 17 patients with advanced
PLCH, echocardiography measurements of pulmonary
artery systolic pressure were > 35 mm Hg and
50 mm Hg in 88% and 50% of patients, respectively.54
Presence of PH is also an independent prognostic factor
for increased mortality in PLCH. Extrapulmonary
involvement characterized by diabetes insipidus, bone
cysts, and skin lesions may be observed in approximately
20% of the patients with PLCH.48
Plain chest radiographs may demonstrate upper lobe-
predominant bilateral lung nodules, especially in the
early stages of the disease, but are not diagnostic. HRCT
scans are superior to plain chest radiographs and
typically reveal upper lobe nodules in early stages. These
nodules later cavitate and ultimately form characteristic
bizarre-shaped thick- and thin-walled cysts (Fig 3A). It
is important to note that the nodules and cystic lesions
can co-exist with intervening normal lung parenchyma
in PLCH.52,55 In advanced disease, there may be
evidence of extensive fibrosis and parenchymal
destruction. Thus, a combination of cystic and nodular
lesions predominantly involving the upper lobes in a
smoker strongly suggests PLCH. Costophrenic angles
are characteristically spared.52 Areas of ground-glass
attenuation, which could represent other coexisting
smoking-related ILDs (RB-ILD/DIP), may also be
observed.20
A combination of smoking history with characteristic
radiographic changes on HRCT scanning allows a
provisional diagnosis of PLCH. In cases in which
confirmation is needed, bronchoscopy with BAL and
transbronchial biopsy may be useful. A BAL count of
Langerhans cells (CD1a stain-positive) > 5% may
indicate PLCH but has poor sensitivity.56
Transbronchial biopsy has a diagnostic yield of 50%,
whereas surgical biopsy results are usually definitive.56,57
Light microscopy revealed granulomatous-like nodules
composed mainly of histiocytes that characteristically
[ 154#2 CHEST AUGUST 2018 ]
Figure 3 – A, HRCT image of pulmonary Langerhans cell histiocytosis. HRCT scan of the chest of a 30-year-old female smoker demonstrates numerous
nodules and cysts, of variable size, shape, and wall thickness, predominantly in the mid and upper lungs. B, Histopathology of pulmonary Langerhans
cell histiocytosis. Nodular lesion containing numerous Langerhans cells well demonstrated by langerin immunohistochemical staining (inset). The
nodule may cavitate (not shown). Hematoxylin and eosin staining, 100 original magnification. See Figure 1 legend for expansion of abbreviation.
stain positive for CD1a antigen or langerin (Fig 3B).
However, concomitant severe PH and diffusion
impairment may be prohibitive for pursuing lung
biopsy.
Smoking cessation can stabilize lung function and
potentially improve physiological and radiographic
abnormalities in PLCH.58,59 For patients with refractory
or progressive PLCH, other therapies (including
corticosteroids, immunosuppressants, and
chemotherapy) have been used, with some evidence of
efficacy based on small series.59-61 Grobost et al62 also
reported improved outcomes (improved dyspnea and
increase in FEV1) in a series of patients with progressive
PLCH who were treated with cladribine. PH may be
amenable to PH-specific therapies.63 However, none of
the therapies for PLCH has been studied in a large-scale
randomized design. It remains to be seen whether
selective inhibitors of BRAF V600 kinase can be effective
in patients with PLCH who exhibit a BRAF-V600E
mutation. In advanced disease, lung transplantation
should be considered. Even with a 20% chance of
recurrence, patients with PLCH tend to perform
satisfactorily following lung transplantation, with almost
50% survival at 10 years following transplantation.64
Smoking-Related Interstitial Fibrosis
SRIF is a relatively recently appreciated entity that has
gained prominence, mostly among pathologists,
although it may have been described earlier using
different terms such as “respiratory bronchiolitis with
fibrosis” or “airspace enlargement with fibrosis.”65,66
Katzenstein et al67 described SRIF as a distinct form of
chronic interstitial fibrosis characterized by uniform
nonfocal deposition of hyalinized collagen in the
alveolar septal walls in smokers. However, its clinical
ramifications are not well understood and likely overlap
chestjournal.org
with RB-ILD and DIP (Table 1). Although the
prevalence of SRIF-related changes in lungs range from
14% to 60% based on various small studies of pathology
specimens, there is a clear increase in occurrence in
those who are heavy smokers.65-67 Both current and
previous smokers are affected.
Although the series reported by Katzenstein et al67 did
not have any distinct radiologic features, Yousem66
reported diffuse micronodules and GGOs, similar to RB-
ILD. Although none of the studies had substantial long-
term follow-up (maximum follow up of 3 years), all the
studies documented relative stability and only mild
progression, if any.66,67 Thus, the natural history of SRIF
may be more favorable in contrast to fibrotic lung
diseases such as UIP or fibrotic nonspecific interstitial
pneumonia.
Due to a lack of well-defined clinical and radiologic
features, SRIF will likely remain a histopathologic
diagnosis. However, it should be considered in the
differential diagnosis of patients who present with
symptoms and radiography similar to RB-ILD and DIP.
On histopathology, it is characterized by hyalinized
deeply eosinophilic collagen with minimal surrounding
inflammation (Fig 4). In contrast to UIP, there is
uniform, predominantly subpleural involvement with
little or no fibroblast foci. There is no temporal
heterogeneity. Honeycombing is rare in SRIF, whereas
emphysema and RB are almost always present.68 The
typical pattern and greater degree of fibrosis in SRIF are
also distinct from RB-ILD/DIP and thus can usually be
distinguished. Collectively, these features allow SRIF to
be distinguished from UIP, fibrotic nonspecific
interstitial pneumonia, and RB-ILD/DIP in most cases.
Smoking cessation is plausibly the main treatment
recommendation for these patients. Data on other
401

Figure 4 – Histopathology of smoking-related interstitial fibrosis. Sub-
pleural interstitial thickening due to prominent refractile collagen
deposition. Hematoxylin and eosin staining, 100 original
magnification.
recommendations are lacking. However, as in RB-ILD/
DIP, a trial of corticosteroids is possibly worthwhile for
patients with significant disease. No studies have
documented the impact of immunosuppressant agents
or antifibrotic medications in patients with SRIF
pathologic findings.
The clinical significance of SRIF is unclear but possibly
lies in the fact that it should be distinguished from other
forms of ILDs. Whether patients with SRIF will evolve to
develop honeycombing and UIP-like changes is unclear
at this time. However, based on data from available
studies, prognosis seems excellent.66,67
Acute Eosinophilic Pneumonia
AEP is characterized by the following: (1) febrile illness
of short duration (# 1 month, often < 1 week); (2)
hypoxemic respiratory failure; (3) diffuse pulmonary
opacities on chest radiography; and (4) pulmonary
eosinophilia-bronchoscopy with BAL showing >
25% eosinophils in the absence of parasitic infections,
atopy, or asthma.18 The cause of AEP remains unknown
in many cases, and some investigators consider it to be
an acute hypersensitivity reaction to an unidentified
inhaled antigen.69 Of note, however, 40% of the patients
have a history of smoking cigarettes.70 Also, an
association between recent onset of cigarette smoking or
recent increase in the number of cigarettes has also been
consistently observed, suggesting a pathogenic role of
tobacco smoke constituents to trigger AEP.19,71
Smoking-related AEP is of greater disease severity and is
less likely to be associated with peripheral eosinophilia at
presentation compared with other forms of AEP.72 It is
also critical to consider other etiologies for similar
presentation: fungal (eg, coccidioidomycosis) and
parasitic infections (eg, ascariasis, strongyloidiasis) can
402 Recent Advances in Chest Medicine
also present in a similar fashion and should be ruled out.
Other causes such as drug or toxin-mediated
eosinophilic processes may also involve the lung
parenchyma and should be considered.73,74
Plain chest radiographs demonstrate a pattern suggestive
of acute pulmonary edema with extensive airspace
opacities and pleural effusions in 50% of the patients.75
CT scans characteristically show bilateral diffuse GGOs
with no lobar predominance76 (Fig 5). Centrilobular
nodules and scattered airspace opacities may also be
rarely seen. Pleural effusion is frequently observed.70
Results of pleural fluid studies typically reveal
eosinophil-predominant exudates (22%-51% in one case
series).75 BAL typically reveals an increased eosinophil
count, with an average of 37% to 54%.70 Directing lavage
to the area of maximal radiographic abnormality on the
CT scan is more likely to demonstrate eosinophilia.
Biopsy is rarely necessary, and the severe respiratory
failure, which affects many patients, precludes it.
However, when performed, the main biopsy findings
include pronounced infiltration of eosinophils in the
interstitium and alveolar spaces with features of diffuse
alveolar damage.70
Patients with AEP have a rapid and striking response to
corticosteroids, with most patients exhibiting significant
clinical improvement within 24 to 48 h.77 Although the
optimal dose of corticosteroids is uncertain, commonly
used dosages of IV methylprednisolone for patients with
respiratory failure include 60 to 125 mg every 6 h until
improvement, followed by initiation of oral prednisone,
which is usually tapered off between 2 and 12 weeks.70
Lower doses of oral prednisone and a shorter course
may suffice in the treatment of those without respiratory
failure.78 The tapering of steroids is tailored to the
patient’s clinical response.
Figure 5 – HRCT image of acute eosinophilic pneumonia. HRCT image
of the chest of a 22-year-old male smoker who began smoking cigarettes
3 weeks earlier demonstrates patchy consolidative and ground-glass
opacities bilaterally along with pleural effusions. See Figure 1 legend for
expansion of abbreviation.
[ 154#2 CHEST AUGUST 2018 ]
The prognosis of AEP is excellent, with complete
radiographic resolution within 1 to 2 months following
initiation of corticosteroids.75,77 Relapse is uncommon
and is usually associated with resumption of cigarette
smoking.71 It is therefore crucial to recommend
avoidance of future cigarette smoking in these patients.
In a recently concluded study of patients with
eosinophilic granulomatosis with polyangiitis,
mepolizumab (an anti-IL-5 monoclonal antibody that
reduces blood eosinophil count) showed an ability to
sustain patients in remission for longer periods, thus
allowing corticosteroid sparing.79 However, there is
currently no evidence to validate its use in patients with
progressive or relapsing AEP.
“Subclinical” or “Incidental” Interstitial Lung
Changes in Smokers
Varying degrees of interstitial lung abnormalities can be
seen in smokers and were often loosely referred to in the
past as the “dirty lung.”80,81 Although the entities
categorized under smoking-related ILDs constitute the
clinically apparent conditions, data from studies on
large cohorts of relatively healthy smokers suggest that
smoking-related interstitial lung changes may be far
more prevalent and of greater significance than
previously recognized. Since the emergence of HRCT
scans and also the increased implementation of lung
cancer screening programs, various interstitial lung
abnormalities, often incidental, are increasingly
detected. Lederer et al82 reported an increase in high-
attenuation areas (ground-glass and reticular
abnormalities) on CT scans in a population-based study
of relatively healthy smokers. The extent of high-
attenuation changes on the CT scan increased with
increase in pack-years.
Based on studies that have spanned more than a decade,
the relative incidence of different types of interstitial
lung changes seem to be variable. For instance, in a
study that included 692 participants of a lung cancer
screening program, RB-related changes were observed in
15.7% of the patients, whereas “other chronic interstitial
pneumonia” and “indeterminate” interstitial changes
were noted in 3.8% and 3%, respectively.83 A
retrospective study in a lung cancer screening
population revealed some form of interstitial lung
abnormality in approximately 10% of their cohort.84
Washko et al85 reported interstitial changes in 8% of the
population of smokers who had an HRCT scan, and
those with interstitial changes had a reduced total lung
capacity and lesser amount of emphysema.
chestjournal.org
Cumulative data from these studies show that even
during a relatively short follow-up period (maximum of
3 years in these studies), nonfibrotic interstitial lung
changes may improve in approximately 50%, whereas
fibrotic interstitial changes are unlikely to regress and
can progress in up to 40% of patients. Another common
theme that emerged from these studies is that a greater
number of pack-years of smoking has an independent
adjusted increased risk for causing both well-defined and
unclassifiable interstitial lung abnormalities in lungs of
smokers.82-84,86 Furthermore, the presence of these
interstitial lung changes is also independently associated
with increased all-cause mortality.87 The downstream
impact of these “subclinical” or “incidental” findings is
unclear; however, such findings are likely to increase the
need for imaging follow-up and downstream referrals to
an ILD specialist.
Although the economic repercussions of increased
identification of these interstitial changes remain to be
studied, it offers the potential advantage of early
diagnosis and an increased impetus for smoking
cessation.88 The approach to these findings depends on
the degree of respiratory impairment (symptoms and
pulmonary function abnormalities) and radiographic
pattern. In most situations, the identification of
incidental smoking-related changes (ie, focal or diffuse
GGOs and centrilobular nodules) provides an
opportunity for emphasis on smoking cessation and
establishment of follow-up. In the symptomatic patient,
pulmonary function testing assessment should be
considered. In individuals with progressive disease and
fibrosis (ie, reticulation, traction bronchiectasis,
honeycombing), further testing and management should
be in line with the standard approach to fibrotic lung
diseases.
Association Between Smoking and Other ILDs
Idiopathic Pulmonary Fibrosis
Our current understanding of key pathways that trigger
cigarette smoke-mediated fibrosis and stimulate its
progression in the lungs was described earlier in this
review (the section entitled “Mechanisms and Spectrum
of Cigarette Smoke-Induced ILDs”). The prevalence of
tobacco use in IPF ranges from 41% to 83%.89 Cigarette
smoking has also been directly implicated in the
pathogenesis of IPF.90 Studies in IPF suggest that
smoking is an independent risk factor with an OR of
1.11 to 3.23 among ever smokers.91 Moreover, there is
also an independent strong association between smoking
403
and the development of familial pulmonary fibrosis (OR:
3.6 [95% CI: 1.3-9.4]).92 Although smoking may directly
promote fibrosis, it is likely that in IPF, cigarette smoke
and other environmental or endogenous profibrotic
stimuli synergize to promote interstitial fibrosis in
predisposed individuals. Furthermore, cigarette smoking
influences the clinical course of IPF. In a study by
Antoniou et al93 of 249 patients with IPF, severity
adjusted survival was higher among nonsmokers
compared with current or ever smokers. In addition,
smoking is also a risk factor for development of acute
exacerbation of IPF. Although these data were recently
contradicted, the conflicting results are likely due to
limitations of lead time bias (early diagnosis in smokers)
and the retrospective nature of some of these studies.94,95
Combined Pulmonary Fibrosis and Emphysema
The association between emphysema and cigarette
smoking is well established. However, when emphysema
and pulmonary fibrosis co-exist in the same patient, it
represents a unique syndrome called CPFE.96 CPFE is
characterized by upper lobe emphysema and lower lobe
interstitial fibrosis. However, these patients have a
different natural history than patients with either
pulmonary fibrosis or emphysema alone.97
A consensus definition for CPFE does not exist. In the
broadest sense, this term should include all patients with
co-existent emphysema and fibrosis on HRCT
scanning.97 Most of the affected patients tend to be male
smokers (with > 40 pack-year smoking history), age >
65 years, and severely symptomatic.98 Because
emphysema is associated with increased lung volumes
and compliance and pulmonary fibrosis with opposite
physiological effects, pulmonary function test results
characteristically show normal or near-normal
spirometry values and preserved lung volumes with
severely reduced diffusing capacity of the lung for
carbon monoxide.97
Mortality in CPFE is significant, with a median reported
survival of 2.1 to 8.5 years, with an increased incidence
of PH and lung cancer in this group.97,99 The presence of
PH portends a poor prognosis, with predicted 1-year
survival rate of 60% in patients with CPFE and PH.99
The prevalence of PH is higher than that reported in IPF
or emphysema.96,97,99 Although the initial studies did
not identify a mortality difference between patients with
CPFE and non-CPFE IPF, a recent analysis showed a
distinctly lower 5-year survival and higher mortality
compared with IPF.100,101 Treatment options are
unfortunately limited and include smoking cessation,
404 Recent Advances in Chest Medicine
oxygen supplementation in hypoxemic patients, and
early referral for lung transplantation. Antifibrotic
medications have not been explored in CPFE, and their
effects on disease progression are unknown.
Connective Tissue Disease-Associated ILD
The impact of cigarette smoking in various types of
CTD-ILD is not clear. Among the various autoimmune
diseases, the association with cigarette smoking is most
established for RA.102,103 Several epidemiologic studies
have shown that the risk of developing seropositive RA
is higher among those with tobacco exposure.102-104
Longer duration and severity of smoking has been
shown to increase the risk for RA (approximate relative
risk of 1.5 times), and the risk remains high even after
smoking cessation.104 Klareskog et al105 reported a
major gene-environment interaction between smoking
and HLA-DR shared epitope (HLA-DR SE) genes that
were evident for seropositive RA. In this study, the
combination of smoking history and the presence of
double copies of HLA-DR SE genes increased the risk
for seropositive RA 21-fold compared with the risk
among nonsmokers. However, specific pathogenetic
interactions by which smoking and other factors
increase the risk of RA and ILD are not well understood.
RA is associated with autoantibodies to various self-
antigens, including citrullinated proteins such as type II
collagen, which is found in the synovial tissues and
lungs. Smoking increases the production of citrulline-
modified proteins secondary to an increase in
peptidylarginine deiminase enzymes that are involved
in the citrullination of native proteins.105 Therefore, in
predisposed individuals, an enhanced production of
anti-cyclic citrullinated peptide antibodies is promoted
by cigarette smoke exposure. How this scenario in turn
leads to enhanced pulmonary inflammation of lung
fibrosis is not yet known.
Moreover, cigarette smoking has an impact on response
to treatment in RA, with smokers typically exhibiting a
poor response to methotrexate and other biologic
disease-modifying antirheumatic drugs compared with
never smokers.106 Hudson et al107 evaluated the effects
of cigarette smoking in a cohort of patients with
systemic sclerosis and found a strong negative
correlation between smoking intensity and spirometry,
as well as a trend toward worsening diffusing capacity of
the lung for carbon monoxide.
CPFE has also been described within the context of
smokers with CTD-ILDs. Patients were younger, more
[ 154#2 CHEST AUGUST 2018 ]
frequently female, and tended to present with a less
severe prognosis.108 The physiological profile was
similar with idiopathic CPFE, but PH was less severe,
raising the hypothesis that the better prognosis of CTD-
ILDs delays the appearance and blunts the severity of
PH in CTD-related CPFE.108
Interestingly, a recent study found that current tobacco
smoking, although of relatively low incidence among
patients in the study cohort, has a negative association in
patients with Sjögren syndrome, as smoking seems to
delay progression of disease-associated humoral and
cellular autoimmunity.109 Despite the protective effects
of tobacco smoking on Sjögren syndrome
manifestations, it is still associated with lung disease,
cardiovascular risk, and malignancy, and should thus be
discouraged.
Conclusions
Cigarette smoking results in manifold changes to the
airways and lung parenchyma. Aside from the
destruction to alveolar walls that results in emphysema,
tobacco smoke is also a well-known trigger for varying
degrees of interstitial changes in the lungs that manifest
in diverse ways in the affected patient population.
Clinically apparent smoking-related ILDs fall into a
spectrum of disorders that likely have a causal
relationship with tobacco use and include RB-ILD, DIP,
a subset of AEP, and PLCH. The fact that cigarette
smoke promotes a profibrotic environment through
certain endogenous and exogenous growth factors also
lends support to its pathogenetic role in conditions such
as IPF and CPFE.
Our understanding of the spectrum of smoking-related
interstitial lung changes continues to evolve with
recognition of novel entities such as SRIF, which despite
distinct histopathologic features, remains of unclear
clinical relevance. We also emphasize the relevance of
appreciating “subclinical” or “incidental” interstitial
changes in relatively healthy smokers. Increased
recognition of these changes on CT scans obtained for
other reasons (especially in a high-risk population such
as patients enrolled in a lung cancer screening program)
will be a source of an increased number of referrals to
ILD specialists. Regardless of the type of ILD, smoking
cessation should continue to be the principal
recommendation for patients whose diagnosis falls into
this category of lung diseases while our knowledge of
the role of other potential therapies continues to
expand.
chestjournal.org
Acknowledgments
Financial/nonfinancial disclosure: None declared.
References
1. Zanetti F, Giacomello M, Donati Y, Carnesecchi S, Frieden M,
Barazzone-Argiroffo C. Nicotine mediates oxidative stress and
apoptosis through cross talk between NOX1 and Bcl-2 in lung
epithelial cells. Free Radic Biol Med. 2014;76:173-184.
2. Stevenson CS, Docx C, Webster R, et al. Comprehensive gene
expression profiling of rat lung reveals distinct acute and chronic
responses to cigarette smoke inhalation. Am J Physiol Lung Cell
Mol Physiol. 2007;293(5):L1183-L1193.
3. Chen R, Zhang K, Chen H, et al. Telomerase deficiency causes
alveolar stem cell senescence-associated low-grade inflammation in
lungs. J Biol Chem. 2015;290(52):30813-30829.
4. Alder JK, Guo N, Kembou F, et al. Telomere length is a
determinant of emphysema susceptibility. Am J Respir Crit Care
Med. 2011;184(8):904-912.
5. Alder JK, Chen JJ, Lancaster L, et al. Short telomeres are a risk
factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci U S A.
2008;105(35):13051-13056.
6. Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates
fibrotic pulmonary disease. Nat Commun. 2017;8:14532.
7. Churg A, Zhou S, Preobrazhenska O, Tai H, Wang R, Wright JL.
Expression of profibrotic mediators in small airways versus
parenchyma after cigarette smoke exposure. Am J Respir Cell Mol
Biol. 2009;40(3):268-276.
8. Checa M, Hagood JS, Velazquez-Cruz R, et al. Cigarette smoke
enhances the expression of profibrotic molecules in alveolar
epithelial cells. PLoS One. 2016;11(3):e0150383.
9. Daniels CE, Wilkes MC, Edens M, et al. Imatinib mesylate inhibits
the profibrogenic activity of TGF-beta and prevents bleomycin-
mediated lung fibrosis. J Clin Invest. 2004;114(9):1308-1316.
10. Asakura S, Colby TV, Limper AH. Tissue localization of
transforming growth factor-beta1 in pulmonary eosinophilic
granuloma. Am J Respir Crit Care Med. 1996;154(5):1525-1530.
11. Uebelhoer M, Bewig B, Kreipe H, Nowak D, Magnussen H, Barth J.
Modulation of fibroblast activity in histiocytosis X by platelet-
derived growth factor. Chest. 1995;107(3):701-705.
12. Prasse A, Stahl M, Schulz G, et al. Essential role of osteopontin in
smoking-related interstitial lung diseases. Am J Pathol. 2009;174(5):
1683-1691.
13. Shan M, Yuan X, Song LZ, et al. Cigarette smoke induction of
osteopontin (SPP1) mediates T(H)17 inflammation in human and
experimental emphysema. Sci Transl Med. 2012;4(117):117ra9.
14. Tazi A, Bonay M, Bergeron A, Grandsaigne M, Hance AJ, Soler P.
Role of granulocyte-macrophage colony stimulating factor (GM-
CSF) in the pathogenesis of adult pulmonary histiocytosis X.
Thorax. 1996;51(6):611-614.
15. Vassallo R, Walters PR, Lamont J, Kottom TJ, Yi ES, Limper AH.
Cigarette smoke promotes dendritic cell accumulation in COPD; a
Lung Tissue Research Consortium study. Respir Res. 2010;11:45.
16. Jhun BW, Kim SJ, Kim K, Lee JE, Hong DJ. Clinical implications of
correlation between peripheral eosinophil count and serum levels
of IL-5 and tryptase in acute eosinophilic pneumonia. Respir Med.
2014;108(11):1655-1662.
17. Mato N, Bando M, Kusano A, et al. Clinical significance of
interleukin 33 (IL-33) in patients with eosinophilic pneumonia.
Allergol Int. 2013;62(1):45-52.
18. Allen JN, Pacht ER, Gadek JE, Davis WB. Acute eosinophilic
pneumonia as a reversible cause of noninfectious respiratory
failure. N Engl J Med. 1989;321(9):569-574.
19. Shorr AF, Scoville SL, Cersovsky SB, et al. Acute eosinophilic
pneumonia among US military personnel deployed in or near Iraq.
JAMA. 2004;292(24):2997-3005.
20. Vassallo R, Jensen EA, Colby TV, et al. The overlap between
respiratory bronchiolitis and desquamative interstitial pneumonia
405
 in pulmonary Langerhans cell histiocytosis: high-resolution CT,
histologic, and functional correlations. Chest. 2003;124(4):
1199-1205.
21. Niewoehner DE, Kleinerman J, Rice DB. Pathologic changes in the
peripheral airways of young cigarette smokers. N Engl J Med.
1974;291(15):755-758.
22. Myers JL, Veal CF Jr, Shin MS, Katzenstein AL. Respiratory
bronchiolitis causing interstitial lung disease. A clinicopathologic
study of six cases. Am Rev Respir Dis. 1987;135(4):880-884.
23. Ryu JH, Myers JL, Capizzi SA, Douglas WW, Vassallo R,
Decker PA. Desquamative interstitial pneumonia and respiratory
bronchiolitis-associated interstitial lung disease. Chest. 2005;127(1):
178-184.
24. Moon J, du Bois RM, Colby TV, Hansell DM, Nicholson AG.
Clinical significance of respiratory bronchiolitis on open lung
biopsy and its relationship to smoking related interstitial lung
disease. Thorax. 1999;54(11):1009-1014.
25. Park JS, Brown KK, Tuder RM, Hale VA, King TE Jr, Lynch DA.
Respiratory bronchiolitis-associated interstitial lung disease:
radiologic features with clinical and pathologic correlation.
J Comput Assist Tomogr. 2002;26(1):13-20.
26. Cottin V, Streichenberger N, Gamondes JP, Thevenet F, Loire R,
Cordier JF. Respiratory bronchiolitis in smokers with spontaneous
pneumothorax. Eur Respir J. 1998;12(3):702-704.
27. Fraig M, Shreesha U, Savici D, Katzenstein AL. Respiratory
bronchiolitis: a clinicopathologic study in current smokers, ex-
smokers, and never-smokers. Am J Surg Pathol. 2002;26(5):
647-653.
28. Elkin SL, Nicholson AG, du Bois RM. Desquamative interstitial
pneumonia and respiratory bronchiolitis-associated interstitial lung
disease. Semin Respir Crit Care Med. 2001;22(4):387-398.
29. Hartman TE, Primack SL, Swensen SJ, Hansell D, McGuinness G,
Muller NL. Desquamative interstitial pneumonia: thin-section CT
findings in 22 patients. Radiology. 1993;187(3):787-790.
30. Godbert B, Wissler MP, Vignaud JM. Desquamative interstitial
pneumonia: an analytic review with an emphasis on aetiology. Eur
Respir Rev. 2013;22(128):117-123.
31. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis-
associated interstitial lung disease and its relationship to
desquamative interstitial pneumonia. Mayo Clin Proc. 1989;64(11):
1373-1380.
32. Craig PJ, Wells AU, Doffman S, et al. Desquamative interstitial
pneumonia, respiratory bronchiolitis and their relationship to
smoking. Histopathology. 2004;45(3):275-282.
33. Churg A, Muller NL, Wright JL. Respiratory bronchiolitis/
interstitial lung disease: fibrosis, pulmonary function, and evolving
concepts. Arch Pathol Lab Med. 2010;134(1):27-32.
34. Portnoy J, Veraldi KL, Schwarz MI, et al. Respiratory bronchiolitis-
interstitial lung disease: long-term outcome. Chest. 2007;131(3):
664-671.
35. Liebow AA, Steer A, Billingsley JG. Desquamative interstitial
pneumonia. Am J Med. 1965;39:369-404.
36. Carrington CB, Gaensler EA, Coutu RE, FitzGerald MX, Gupta RG.
Natural history and treated course of usual and desquamative
interstitial pneumonia. N Engl J Med. 1978;298(15):801-809.
37. Ishii H, Iwata A, Sakamoto N, Mizunoe S, Mukae H, Kadota J.
Desquamative interstitial pneumonia (DIP) in a patient with
rheumatoid arthritis: is DIP associated with autoimmune
disorders? Intern Med. 2009;48(10):827-830.
38. Swartz JS, Chatterjee S, Parambil JG. Desquamative interstitial
pneumonia as the initial manifestation of systemic sclerosis. J Clin
Rheumatol. 2010;16(6):284-286.
39. Lougheed MD, Roos JO, Waddell WR, Munt PW. Desquamative
interstitial pneumonitis and diffuse alveolar damage in textile
workers. Potential role of mycotoxins. Chest. 1995;108(5):
1196-1200.
40. Dvorackova I, Pichova V. Pulmonary interstitial fibrosis with
evidence of aflatoxin B1 in lung tissue. J Toxicol Environ Health.
1986;18(1):153-157.
406 Recent Advances in Chest Medicine
41. Abraham JL, Hertzberg MA. Inorganic particulates associated with
desquamative interstitial pneumonia. Chest. 1981;80(suppl 1):
67-70.
42. Flores-Franco RA, Luevano-Flores E, Gaston-Ramirez C.
Sirolimus-associated desquamative interstitial pneumonia.
Respiration. 2007;74(2):237-238.
43. Iskandar SB, McKinney LA, Shah L, Roy TM, Byrd RP Jr.
Desquamative interstitial pneumonia and hepatitis C virus
infection: a rare association. South Med J. 2004;97(9):890-893.
44. Kawabata Y, Takemura T, Hebisawa A, et al. Desquamative
interstitial pneumonia may progress to lung fibrosis as
characterized radiologically. Respirology. 2012;17(8):1214-1221.
45. Kawabata Y, Takemura T, Hebisawa A, et al. Eosinophilia in
bronchoalveolar lavage fluid and architectural destruction are
features of desquamative interstitial pneumonia. Histopathology.
2008;52(2):194-202.
46. Knyazhitskiy A, Masson RG, Corkey R, Joiner J. Beneficial response
to macrolide antibiotic in a patient with desquamative interstitial
pneumonia refractory to corticosteroid therapy. Chest. 2008;134(1):
185-187.
47. Verleden GM, Sels F, Van Raemdonck D, Verbeken EK, Lerut T,
Demedts M. Possible recurrence of desquamative interstitial
pneumonitis in a single lung transplant recipient. Eur Respir J.
1998;11(4):971-974.
48. Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical
outcomes of pulmonary Langerhans’-cell histiocytosis in adults.
N Engl J Med. 2002;346(7):484-490.
49. Roden AC, Hu X, Kip S, et al. BRAF V600E expression in
Langerhans cell histiocytosis: clinical and immunohistochemical
study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg
Pathol. 2014;38(4):548-551.
50. Kamionek M, Ahmadi Moghaddam P, Sakhdari A, et al. Mutually
exclusive extracellular signal-regulated kinase pathway mutations
are present in different stages of multi-focal pulmonary Langerhans
cell histiocytosis supporting clonal nature of the disease.
Histopathology. 2016;69(3):499-509.
51. Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH.
Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest.
2004;125(3):1028-1032.
52. Abbott GF, Rosado-de-Christenson ML, Franks TJ, Frazier AA,
Galvin JR. From the archives of the AFIP: pulmonary Langerhans
cell histiocytosis. Radiographics. 2004;24(3):821-841.
53. Fartoukh M, Humbert M, Capron F, et al. Severe pulmonary
hypertension in histiocytosis X. Am J Respir Crit Care Med.
2000;161(1):216-223.
54. Chaowalit N, Pellikka PA, Decker PA, et al. Echocardiographic and
clinical characteristics of pulmonary hypertension complicating
pulmonary Langerhans cell histiocytosis. Mayo Clin Proc.
2004;79(10):1269-1275.
55. Kim HJ, Lee KS, Johkoh T, et al. Pulmonary Langerhans cell
histiocytosis in adults: high-resolution CT-pathology comparisons
and evolutional changes at CT. Eur Radiol. 2011;21(7):1406-1415.
56. Harari S, Torre O, Cassandro R, Taveira-DaSilva AM, Moss J.
Bronchoscopic diagnosis of Langerhans cell histiocytosis and
lymphangioleiomyomatosis. Respir Med. 2012;106(9):1286-1292.
57. Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of
bronchoscopy in pulmonary Langerhans cell histiocytosis.
J Bronchology Interv Pulmonol. 2013;20(4):309-312.
58. Negrin-Dastis S, Butenda D, Dorzee J, Fastrez J, d’Odemont JP.
Complete disappearance of lung abnormalities on high-resolution
computed tomography: a case of histiocytosis X. Can Respir J.
2007;14(4):235-237.
59. Elia D, Torre O, Cassandro R, Caminati A, Harari S. Pulmonary
Langerhans cell histiocytosis: a comprehensive analysis of 40
patients and literature review. Eur J Intern Med. 2015;26(5):
351-356.
60. Lazor R, Etienne-Mastroianni B, Khouatra C, Tazi A, Cottin V,
Cordier JF. Progressive diffuse pulmonary Langerhans cell
[ 154#2 CHEST AUGUST 2018 ]
 histiocytosis improved by cladribine chemotherapy. Thorax. 82. Lederer DJ, Enright PL, Kawut SM, et al. Cigarette smoking is
2009;64(3):274-275. associated with subclinical parenchymal lung disease: the Multi-
Ethnic Study of Atherosclerosis (MESA)-Lung study. Am J Respir
61. Mason RH, Foley NM, Branley HM, et al. Pulmonary Langerhans
Crit Care Med. 2009;180(5):407-414.
cell histiocytosis (PLCH): a new UK register. Thorax. 2014;69(8):
766-767. 83. Sverzellati N, Guerci L, Randi G, et al. Interstitial lung diseases in a
lung cancer screening trial. Eur Respir J. 2011;38(2):392-400.
62. Grobost V, Khouatra C, Lazor R, Cordier JF, Cottin V.
Effectiveness of cladribine therapy in patients with pulmonary 84. Jin GY, Lynch D, Chawla A, et al. Interstitial lung abnormalities in
Langerhans cell histiocytosis. Orphanet J Rare Dis. 2014;9:191. a CT lung cancer screening population: prevalence and progression
rate. Radiology. 2013;268(2):563-571.
63. Le Pavec J, Lorillon G, Jais X, et al. Pulmonary Langerhans cell
histiocytosis-associated pulmonary hypertension: clinical 85. Washko GR, Hunninghake GM, Fernandez IE, et al. Lung volumes
characteristics and impact of pulmonary arterial hypertension and emphysema in smokers with interstitial lung abnormalities.
therapies. Chest. 2012;142(5):1150-1157. N Engl J Med. 2011;364(10):897-906.
64. Dauriat G, Mal H, Thabut G, et al. Lung transplantation for 86. Salvatore M, Henschke CI, Yip R, et al. Journal Club: evidence of
pulmonary langerhans’ cell histiocytosis: a multicenter analysis. interstitial lung disease on low-dose chest CT images: prevalence,
Transplantation. 2006;81(5):746-750. patterns, and progression. AJR Am J Roentgenol. 2016;206(3):
487-494.
65. Kawabata Y, Hoshi E, Murai K, et al. Smoking-related changes in
the background lung of specimens resected for lung cancer: a 87. Putman RK, Hatabu H, Araki T, et al. Association between
semiquantitative study with correlation to postoperative course. interstitial lung abnormalities and all-cause mortality. JAMA.
Histopathology. 2008;53(6):707-714. 2016;315(7):672-681.
66. Yousem SA. Respiratory bronchiolitis-associated interstitial lung 88. Borondy Kitts AK, McKee AB, Regis SM, Wald C, Flacke S,
disease with fibrosis is a lesion distinct from fibrotic nonspecific McKee BJ. Smoking cessation results in a clinical lung cancer
interstitial pneumonia: a proposal. Mod Pathol. 2006;19(11): screening program. J Thorac Dis. 2016;8(suppl 6):S481-S487.
1474-1479.
89. Oh CK, Murray LA, Molfino NA. Smoking and idiopathic
67. Katzenstein AL, Mukhopadhyay S, Zanardi C, Dexter E. Clinically pulmonary fibrosis. Pulm Med. 2012;2012:808260.
occult interstitial fibrosis in smokers: classification and significance
90. Baumgartner KB, Samet JM, Stidley CA, Colby TV, Waldron JA.
of a surprisingly common finding in lobectomy specimens. Hum
Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis.
Pathol. 2010;41(3):316-325.
Am J Respir Crit Care Med. 1997;155(1):242-248.
68. Katzenstein AL. Smoking-related interstitial fibrosis (SRIF),
91. Taskar V, Coultas D. Exposures and idiopathic lung disease. Semin
pathogenesis and treatment of usual interstitial pneumonia (UIP),
Respir Crit Care Med. 2008;29(6):670-679.
and transbronchial biopsy in UIP. Mod Pathol. 2012;25(suppl 1):
S68-S78. 92. Steele MP, Speer MC, Loyd JE, et al. Clinical and pathologic
features of familial interstitial pneumonia. Am J Respir Crit Care
69. Badesch DB, King TE Jr, Schwarz MI. Acute eosinophilic
Med. 2005;172(9):1146-1152.
pneumonia: a hypersensitivity phenomenon? Am Rev Respir Dis.
1989;139(1):249-252. 93. Antoniou KM, Hansell DM, Rubens MB, et al. Idiopathic
pulmonary fibrosis: outcome in relation to smoking status. Am J
70. Bhatt NY, Allen JN. Update on eosinophilic lung diseases. Semin
Respir Crit Care Med. 2008;177(2):190-194.
Respir Crit Care Med. 2012;33(5):555-571.
94. Collard HR, Richeldi L, Kim DS, et al. Acute exacerbations in the
71. Uchiyama H, Suda T, Nakamura Y, et al. Alterations in smoking
INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis.
habits are associated with acute eosinophilic pneumonia. Chest.
Eur Respir J. 2017;49(5).
2008;133(5):1174-1180.
95. Kishaba T, Nagano H, Nei Y, Yamashiro S. Clinical characteristics
72. De Giacomi F, Decker PA, Vassallo R, Ryu JH. Acute eosinophilic
of idiopathic pulmonary fibrosis patients according to their
pneumonia: correlation of clinical characteristics with underlying
smoking status. J Thorac Dis. 2016;8(6):1112-1120.
cause. Chest. 2017;152(2):379-385.
96. Cottin V, Nunes H, Brillet PY, et al. Combined pulmonary fibrosis
73. Lepine PA, Dumas A, Boulet LP. Pulmonary eosinophilia from
and emphysema: a distinct underrecognised entity. Eur Respir J.
inhaled colistin. Chest. 2017;151(1):e1-e3.
2005;26(4):586-593.
74. Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG.
97. Jankowich MD, Rounds SI. Combined pulmonary fibrosis and
Acute eosinophilic pneumonia secondary to daptomycin: a report
emphysema syndrome: a review. Chest. 2012;141(1):222-231.
of three cases. Clin Infect Dis. 2010;50(11):e63-e68.
98. Portillo K, Morera J. Combined pulmonary fibrosis and
75. Philit F, Etienne-Mastroianni B, Parrot A, Guerin C, Robert D,
emphysema syndrome: a new phenotype within the spectrum of
Cordier JF. Idiopathic acute eosinophilic pneumonia: a study of 22
smoking-related interstitial lung disease. Pulm Med. 2012;2012:
patients. Am J Respir Crit Care Med. 2002;166(9):1235-1239.
867870.
76. Daimon T, Johkoh T, Sumikawa H, et al. Acute eosinophilic
99. Cottin V, Le Pavec J, Prevot G, et al. Pulmonary hypertension in
pneumonia: thin-section CT findings in 29 patients. Eur J Radiol.
patients with combined pulmonary fibrosis and emphysema
2008;65(3):462-467.
syndrome. Eur Respir J. 2010;35(1):105-111.
77. Rhee CK, Min KH, Yim NY, et al. Clinical characteristics and
100. Ryerson CJ, Hartman T, Elicker BM, et al. Clinical features and
corticosteroid treatment of acute eosinophilic pneumonia. Eur
outcomes in combined pulmonary fibrosis and emphysema in
Respir J. 2013;41(2):402-409.
idiopathic pulmonary fibrosis. Chest. 2013;144(1):234-240.
78. Jhun BW, Kim SJ, Kim K, Lee JE. Outcomes of rapid corticosteroid
101. Zhang L, Zhang C, Dong F, et al. Combined pulmonary fibrosis and
tapering in acute eosinophilic pneumonia patients with initial
emphysema: a retrospective analysis of clinical characteristics,
eosinophilia. Respirology. 2015;20(8):1241-1247.
treatment and prognosis. BMC Pulm Med. 2016;16(1):137.
79. Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo
102. Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the
for eosinophilic granulomatosis with polyangiitis. N Engl J Med.
influence of cigarette smoking on rheumatoid arthritis: results from
2017;376(20):1921-1932.
a population based case-control study, using incident cases. Ann
80. Guckel C, Hansell DM. Imaging the ’dirty lung’—has high Rheum Dis. 2003;62(9):835-841.
resolution computed tomography cleared the smoke? Clin Radiol.
103. Criswell LA, Merlino LA, Cerhan JR, et al. Cigarette smoking and
1998;53(10):717-722.
the risk of rheumatoid arthritis among postmenopausal women:
81. King TE Jr. Smoking and subclinical interstitial lung disease. N Engl results from the Iowa Women’s Health Study. Am J Med.
J Med. 2011;364(10):968-970. 2002;112(6):465-471.

chestjournal.org 407
104. Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking
intensity, duration, and cessation, and the risk of rheumatoid
arthritis in women. Am J Med. 2006;119(6):503.e1-503.e9.
105. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology
of rheumatoid arthritis: smoking may trigger HLA-DR (shared
epitope)-restricted immune reactions to autoantigens modified by
citrullination. Arthritis Rheum. 2006;54(1):38-46.
106. Samara KD, Margaritopoulos G, Wells AU, Siafakas NM,
Antoniou KM. Smoking and pulmonary fibrosis: novel insights.
Pulm Med. 2011;2011:461439.
408 Recent Advances in Chest Medicine
107. Hudson M, Lo E, Lu Y, et al. Cigarette smoking in patients with
systemic sclerosis. Arthritis Rheum. 2011;63(1):230-238.
108. Cottin V, Nunes H, Mouthon L, et al. Combined pulmonary
fibrosis and emphysema syndrome in connective tissue disease.
Arthritis Rheum. 2011;63(1):295-304.
109. Stone DU, Fife D, Brown M, et al. Effect of tobacco smoking
on the clinical, histopathological, and serological
manifestations of Sjogren’s syndrome. PLoS One. 2017;12(2):
e0170249.
[ 154#2 CHEST AUGUST 2018 ]