Smoking related interstitial lung diseases

Smoking-related Interstitial Lung
Diseases
The Never-Ending Story of Smoke
and Disease

Diseases
Mostafa Elshazly
MD, FCCP,ERSD,
Professor of Pulmonary Medicine
Chairman of PVRU
Kasr ElAini School Of Medicine
Cairo University

Smoking-related Interstitial Lung Diseases
 Cigarette smoke is a complex mixture of more than 6,000
compounds and causes a variety of pulmonary and systemic
effects in humans .
 Smoking remains the most preventable cause of premature
death and morbidity in the United States and throughout the
developed world .
 Cigarette smoking is the major cause of lung cancer, which in
turn is the leading cause of cancer deaths in both males and
females in the United States .

 Cigarette smoke is a complex mixture of more than 6,000
compounds and causes a variety of pulmonary and systemic
effects in humans .
 Smoking remains the most preventable cause of premature
death and morbidity in the United States and throughout the
developed world .
Cigarette smoking is the major cause of lung cancer, which in
turn is the leading cause of cancer deaths in both males and
females in the United States .

• Smoking-induced lung diseases constitute a complex
group of disorders, varying from the well- known
entity of chronic obstructive pulmonary disease
(COPD) to the more recently described interstitial
lung diseases (ILDs) 1,2
1. Baumgarten Kbet al., Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis. Am J Respir Crit Care Med
1997;155:242–248.
2. Heynemann LE, et al., RB,RB_ILD,and DIP : different entities or part of the spectrum of the same disease process? AJR Am
J Roentgenol 1999;173:1617–1622.

• Smoking-related ILD is a term used to describe the
relationship between
– RB-associated ILD (RB-ILD),
– Desquamative interstitial pneumonia (DIP), and
– Pulmonary Langerhans’ cell histiocytosis (PLCH)
• as interstitial disorders that are etiologically
linked to cigarette smoking 1 .
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; 54:1009–1014.

Copyright © American College of Chest Physicians. All rights reserved.
The Overlap Between Respiratory Bronchiolitis and Desquamative Interstitial Pneumonia in Pulmonary
Langerhans Cell Histiocytosis*: High-Resolution CT, Histologic, and Functional Correlations
Chest. 2003;124(4):1199-1205. doi:10.1378/chest.124.4.1199
Nonproportional Venn diagram illustrating the spectrum of airways and interstitial injury associated with cigarette
smoking. The larger outer circle represents the virtually universal occurrence of RB in smokers. Emphysema will
develop in approximately 20% of these smokers during their lifetime. ILD will develop in a small proportion of
smokers due to DIP or PLCH. In a significant proportion of those in whom DIP or PLCH develops (or overlaps of both),
there is accompanying emphysema (as in the current series). which provides evidence that RBILD, DIP and PLCH form
a spectrum of interstitial patterns of lung injury related to cigarette smoke .

• This direct causative role for smoking in the
pathogenesis of these disorders is based on
significant epidemiological data:
– Consistent preponderance of smokers within this
population
– Potential of disease remission upon smoking cessation
– the existence of similar lesions, namely respiratory
bronchiolitis, in healthy smokers without ILD, and
– the presence of a combination of these lesions in some
affected smokers 1,2 .
1.Ryu JH, Colby TV, Hartman TE, et al. Smoking-related interstitial lung diseases: a concise review. Eur Respir
J 2001; 17: 122–132. 20.Vassalo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Semin Respir
Crit Care Med 2008; 29: 643–650.

• This direct causative role for smoking in the
pathogenesis of these disorders is based on
significant epidemiological data:
– Consistent preponderance of smokers within this
population
– Potential of disease remission upon smoking cessation
– Existence of similar lesions, Respiratory Bronchiolitis, in
healthy smokers without ILD, and
– The presence of a combination of these lesions in some
affected smokers 1,2 .
1.Ryu JH, Colby TV, Hartman TE, et al. Smoking-related interstitial lung diseases: a concise review. Eur Respir
J 2001; 17: 122–132. 20.Vassalo R, Ryu JH. Tobacco smoke-related diffuse lung diseases. Semin Respir
Crit Care Med 2008; 29: 643–650.

• Pathogenesis

• Pathogenesis
• Cigarette smoke can injure the
endothelial and the alveolar epithelial
cells by increasing oxidative stress and
enhancing virus induced parenchymal
inflammation.
• Such injury could lead to abnormal
wound healing and parenchymal
fibrosis in susceptible individuals

Respiratory Bronchiolitis Associated
Interstitial Lung Disease (RB-ILD)
• Is a rare, mild inflammatory pulmonary disorder that occurs
almost exclusively in current or former heavy smokers, usually
between the third and sixth decades, most likely with no
gender predilection.
Sieminska and Kuziemski: Respiratory bronchiolitisinterstitial lung disease. Orphanet Journal of Rare
Diseases 2014 9:106.

• Epidemiology
• The prevalence and incidence of RB-ILD is unknown and has
remained difficult to assess for many years.
• In several earlier case series, the incidence of RB-ILD & DIP,
10%–17% of the study samples 1,2 .
• RB-ILD was recorded separately in only two of these case
series, and accounted for 2% and 13% of cases 3.
1. Bjoraker JA, et al., Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998,
157:199–203. 2.Nicholson AG, et al.,: The prognostic significance of the histologic pattern of interstitial pneumonia in patients presenting
with the clinical entity of cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 2000, 162:2213–2217. 3. Flaherty KR, et al., Clinical
significance of histological classification of idiopathic interstitial pneumonia. Eur Respir J 2002, 19:275–83.

• Epidemiology
• In KSA register of newly diagnosed ILD cases, RB-ILD cases
accounted for 5.5% of all types of IIPs 1 .
• A German pathology review of ILD cases revealed 9.5% of
RB-ILD cases among all types of IIPs 2 .
1.Alhamad EH: Interstitial lung diseases in Saudi Arabia: a single-center study. Ann Thorac Med 2013, 8:33–7.
2. Theegarten D, Müller HM, Bonella F, Wohlschlaeger J, Costabel U: Diagnostic approach to interstitial pneumonias in
a single centre: report on 88 cases. Diagn Pathol 2012, 7:160–171.

• Clinical description
• Insidious onset of
– Exertional dyspnea,
– Symptomatic wheezing, and
– Persistent cough, which may be non-productive.
• Bibasilar end-inspiratory crackles are the most common signs.
Portnoy J, Veraldi KL, Schwarz MI, Cool CD, Curran-Everett D, Cherniack RM, King TE Jr, Brown KK: Respiratory
bronchiolitis-interstitial lung disease:long-term outcome. Chest 2007, 131:664–671.

• Physiologic changes
• Obstructive pattern was the most common pulmonary function
defect (47%)
• Pure restriction or mixed defects were less common (31% and
9%, respectively)
• 13% of patients had normal spirometry data .
Portnoy J, Veraldi KL, Schwarz MI, Cool CD, Curran-Everett D, Cherniack RM, King TE Jr, Brown KK: Respiratory
bronchiolitis-interstitial lung disease:long-term outcome. Chest 2007, 131:664–671.

• Physiologic changes
• Patients with minimal symptoms usually reveal a
mild to moderate decrease in DLco.
• Patients with more severe symptoms, both airway
obstruction and restriction or occasionally an isolated
increase in RV may be found .
Myers JL, Veal CF Jr, Shin MS, Katzenstein AL: Respiratory bronchiolitis causing interstitial lung disease: a
clinicopathological study of six cases. Am Rev Respir Dis 1987, 135:880–4.

• Radiographic findings
• Radiographic findings are usually relatively subtle.
• Normal chest radiographs ( 20% to 28%) .
• Fine reticulonodular interstitial opacities, which are diffuse or
are predominant in basal lung areas . 1, 2
Park JS, et al.,: Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic
correlation. J Comput Assist Tomogr 2002, 26:13–20.
Heyneman LE, et al.,: RB,RB-ILD,DIP different entities or part of the spectrum of the same disease process. Am J Roentgenol
1999, 173:1617–22.

• High-Resolution CT Findings of RB-ILD
– Centrilobular nodular opacities
– Patchy ground-glass opacity
– Bronchial wall thickening
– Upper lobe predominance
– Associated centrilobular emphysema
– Air trapping at expiration
– Findings of fibrosis absent
Park JS, et al.,: Respiratory bronchiolitis-associated interstitial lung disease: radiologic features with clinical and pathologic
correlation. J Comput Assist Tomogr 2002, 26:13–20.
Anil K. Attili, et al., Smoking-related Interstitial Lung Disease: Radiologic-Clinical-Pathologic Correlation. RadioGraphics
2008; 28:1383–1398

– Centrilobular nodular opacities
– Air trapping at expiration
– Findings of fibrosis absent

HRCT image of the upper lung lobes shows centrilobular nodules (white arrows), patchy ground-glass
opacities (black arrow), and mild coexisting centrilobular emphysema (arrowhead).

Histopathologic Findings
 Pigmented macrophages in a
terminal bronchiole and the
adjacent alveoli (arrows),
and
 Moderate Peribronchiolar
inflammation and fibrosis
(arrowhead) are present.

• Bronchoalveolar lavage
– An increased total number of cells with a normal cellular
differential analysis .
– or an increase in the percentage of macrophages.
– A modest increase in neutrophils may also be present.
Hunninghake GW, Crystal RG: Cigarette smoking and lung destruction: accumulation of neutrophils in the
lungs of cigarette smokers. Am Rev Respir Dis 1983, 128:833–838.

• Diagnosis
• It is increasingly accepted that a diagnosis of RB-ILD is secure
when based upon
– Typical HRCT findings (ground-glass opacities and centrilobular
nodules)
– In a current smoker, especially when
– BAL findings (the presence of smokers’ macrophages and the absence
of lymphocytosis) are also compatible.

• Management and disease course
• Smoking cessation is considered the most important factor in
the management of RB-ILD.
• It is also unclear whether patients with RB-ILD benefit from
corticosteroid therapy with regard to the natural history of the
disease.

• The course of RB-ILD is heterogeneous, often with no
functional improvement and with disease progression despite
smoking cessation and treatment 1,2,3 .
• Clinical worsening was common, as well as worsening of
spirometry results and gas exchange, regardless of smoking
status and treatment ordered, including corticosteroids 3.
• RB-ILD is now less commonly regarded as a benign entity.
Moon J, et al.,: Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking
related interstitial lung disease. Thorax 1999, 54:1009–14. 2. Ryu JH, et al.,:Desquamative interstitial pneumonia and
respiratory bronchiolitis–associated interstitial lung disease. Chest 2005, 127:178–184.
3. Portnoy J, Veraldi KL, Schwarz MI, Cool CD, Curran-Everett D, Cherniack RM, King TE Jr, Brown KK: Respiratory
bronchiolitis-interstitial lung disease: long-term outcome. Chest 2007, 131:664–671.

• The course of RB-ILD is heterogeneous, often with no
functional improvement and with disease progression despite
smoking cessation and treatment 1,2,3 .
• Clinical worsening was common, as well as worsening of
spirometry results and gas exchange, regardless of smoking
status and treatment ordered, including corticosteroids 3.
• RB-ILD is now less commonly regarded as a benign
entity.
Moon J, et al.,: Clinical significance of respiratory bronchiolitis on open lung biopsy and its relationship to smoking
related interstitial lung disease. Thorax 1999, 54:1009–14. 2. Ryu JH, et al.,:Desquamative interstitial pneumonia and
respiratory bronchiolitis–associated interstitial lung disease. Chest 2005, 127:178–184.
3. Portnoy J, Veraldi KL, Schwarz MI, Cool CD, Curran-Everett D, Cherniack RM, King TE Jr, Brown KK: Respiratory
bronchiolitis-interstitial lung disease: long-term outcome. Chest 2007, 131:664–671.

Desquamative Interstitial Pneumonia (DIP)

 It was originally defined by Liebow et al. in 1965 1.
 In the following 2 decades it was considered as the putative
early stage of the usual interstitial pneumonia (UIP) 2
 Initially, it was believed that its histological feature was the
desquamation of epithelial cells, but then it was recognized
that the presence of intra-alveolar macrophages was due to an
alveolar filling process 3.
1.Liebow AA, et al.,. Desquamative interstitial pneumonia. Am J Med 1965; 39: 369–404. 2.Tubbs RR, et al. Desquamative
interstitial pneumonitis. Cellular phase of fibrosing alveolitis. Chest 1977; 72: 159–165.3. Ryu JH, et al. Desquamative
interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest 2005; 127: 178–184.

 DIP is associated to tobacco in nearly 80–90% of
patients 1 but, could also be associated
 to many drugs 2
 systemic disorders 3
 environmental exposures 4
 and infections 4
 In addition, it also has been described in children .
1.ATS-ERS. International multidisciplinary consensus. Classification of the IIPs. Am J Respir Crit Care Med 2002;165: 277–30.
2. Corrin B, Price AB. Electron microscopic studies in desquamative interstitial pneumonia associated with asbestos. Thorax
1972; 27:324–331. 3.Abraham JL, Hertzberg MA. Inorganic particles associated with desquamative interstitial pneumonia.
Chest 1981; 80: 67–70. 4. Craig JP, Wells AU, Doffman S, et al. Desquamative interstitial pneumonia, respiratory bronchiolitis
and their relationship to smoking. Histopathol 2004; 45: 275–282

 The average age at the onset of symptoms is about 40
years 1
 Male-Female ratio of 2 : 1 2
 Clinical presentation of DIP is
 Insidious and is characterized by
 Progressive dyspnea and dry cough.
 Inspiratory crackles are present in 60% and
 Digital clubbing in 50% of patients 3.
1.ATS-ERS. International multidisciplinary consensus. Classification of the IIPs. Am J Respir Crit Care Med 2002;165: 277–30.
2. Corrin B, Price AB. Electron microscopic studies in desquamative interstitial pneumonia associated with asbestos. Thorax
1972; 27:324–331. 3.Abraham JL, Hertzberg MA. Inorganic particles associated with desquamative interstitial pneumonia.
Chest 1981; 80: 67–70.

Physiologic changes
 The most common and striking PFT abnormality is marked
reduction in diffusing capacity, with reductions of 50% or
more being common 1 .
 Restrictive defects are also common.
 Patients with advanced disease may have hypoxemia at rest or
with exertion.
Ryu JH, Myers JL, Capizzi SA, Douglas WW, Vassallo R, Decker PA. Desquamative interstitial pneumonia and
respiratory bronchiolitisassociated interstitial lung disease. Chest 2005;127:178–184.

 Radiologic Findings
Chest radiographs are insensitive for detection of DIP and
are reported to be normal in 3%–22% of biopsy-proved
cases 1 .
The radiologic patterns are nonspecific and include patchy
ground glass opacities with a lower lung and peripheral
predominance.
Hartman TE, Primack SL, Swensen SJ, Hansell D, McGuinness G,Mu¨ ller NL. Desquamative interstitial
pneumonia: thin-section CT findings in 22 patients. Radiology 1993;187:787–790.

 Radiologic Findings

Chest radiograph of a patient with desquamative interstitial pneumonia (DIP) showing bilateral interstitial
infiltrates involving mainly the lower lung zones. Mild, localized areas of fibrosis cause a reticular pattern.

 High-Resolution CT Findings
Bilateral patchy ground-glass opacity
Reticular opacities
Subpleural and basal predominance
Honeycombing uncommon
Associated centrilobular emphysema
Anil K. Attili, et al., Smoking-related Interstitial Lung Disease: Radiologic-Clinical-Pathologic Correlation.
RadioGraphics 2008; 28:1383–1398

Bilateral patcReticular opacities
hy ground-glass opacity

 Histologically
The main characteristic of DIP is the presence of pigmented
macrophages within the alveolar spaces that stain in a
nonspecific fashion with PAS-diastase [8].
Minimal to moderate alveolar septal widening usually
accompanies the air-spaces changes.
Honeycombing is rare [16, 32].

Macrophage
accumulations within
most of the distal air
spaces.
The alveolar septa are
thickened by a sparse
inflammatory
infiltrate.
The intraluminal
macrophages in DIP
frequently contain
dusty brown pigment

• Treatment and Outcome
– Smoking cessation is the primary treatment for DIP and
may lead to disease regression
– Oral corticosteroids is generally recommended for
patients with
• Significant symptoms,
• PFT abnormalities, and
• Progressive disease.
– The response to corticosteroids is not uniform

• Treatment and Outcome
• The 5- and 10-yr survival rates are 95.2 and 69.6%,
respectively, for patients with DIP 1 .
• Nevertheless, DIP progresses in some cases and a small
number of patients have a poor outcome 2 .
• Lung transplantation has been performed successfully in
patients with end-stage disease; however, disease recurrence in
the transplanted lung has been reported 3 .
1.Carrington CB et al., . Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med
1978;298:801–809. 2. Hartman TE,et al., Disease progression in usual interstitial pneumonia compared with desquamative
interstitial pneumonia: assessment with serial CT. Chest 1996;110:378–382. 3. Barberis M, Harari S, Tironi A, Lambertico P.
Recurrence of primary disease in a single lung transplant recipient. Transplant Proc 1992;24: 2660–2662.

Pulmonary langerhans cell histiocytosis
 The histiocytic disorders are rare diseases
characterized by abnormal infiltration of certain
organs by cells derived from monocyte/macrophage
or dendritic cell lineage .
 Langerhans Cell Histocytosis (LCH) is a specific
type of histocytic syndrome characterized by
infiltration of tissues with a specific dendritic cell, the
Langerhans cell .
Favara BE, et al: Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell
Proliferations. Reclassification Working Group of the Histiocyte Society. Med Pediatr Oncol 1997, 29(3):157-166.

 Pulmonary Langerhans cell histiocytosis refers to
disease in adults that affects the lung, usually in
isolation and less commonly in addition to other
organ systems .
Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans’-cell histiocytosis. N Engl J Med
2000;342:1969–1978.

 Epidemiology and demographic characteristics
PLCH is a rare disease which occurs almost exclusively in
smokers 1,2 .
Estimated incidence 4-5% of all DLD biopsies 3 .
Affects young adults between the ages of 20 to 40 years1.
No gender predilection 1,4.
1.Vassallo R, et al.,: Clinical outcomes of pulmonary Langerhans’-cell histiocytosis in adults. N Engl J Med 2002,
346(7):484-490. 2. Arico M, et al.,: Langerhans cell histiocytosis in adults. Report from the International Registry of the
Histiocyte Society. Eur J Cancer 2003, 39(16):2341-2348. 3. Gaensler EA, Carrington CB: Open biopsy for chronic diffuse
infiltrative lung disease: clinical, roentgenographic, and physiological correlations in 502 patients. Ann Thorac Surg 1980,
30(5):411-426. 4. Travis WD, et al.,: Pulmonary Langerhans cell granulomatosis (histiocytosis X). A clinicopathologic study
of 48 cases. Am J Surg Pathol 1993, 17(10):971-986

Pathogenesis
• It is possible that smokers with PLCH develop an
amplified inflammatory response induced by
tobacco smoke (and possibly other factors) that
induces activation of multiple cell types in the
lung, including epithelial and immune cells,
resulting in a vicious cycle of inflammation, tissue
injury and tissue remodeling

Pathogenesis
• Whether failure of endogenous anti-inflammatory
mechanisms or additional exogenous insults like
viral infections have a role in promoting smoking
induced PLCH is unknown, and continues to be an
important area of investigation.

The primary event
in the pathogenesis
probably involves
cigarette smoke-
induced
recruitment and
activation of LCs to
the small airways,
a process that may
result from a
variety of potential
mechanisms.
Pathogenesis

Cigarette smoke
activates epithelial cells
and macrophages to
produce cytokines and
chemokines
Cigarette smoke may
also directly activate
LCs.
Langerhans cells
conditioned by
cigarette smoke
may inappropriately
recognize autontigens
in the lungs and
activate adaptive T cell
responses that
secondarily mediate
injury in airway tissues
Pathogenesis

Chronic inflammation
and cytokine
production
(particularly TGF-b)
may promote local
fibroblast activation
and airway-centered
fibrosis.
The combination of
airway centered
inflammation and
tissue remodeling
promote dilatation of
structures distal to
the inflamed small
airways and cystic
formation.
Pathogenesis

 Clinical Features
Ninety percent to 100% of adults with PLCH are current or
former smokers 1.
Prevalence of 3.4%.
Peak occurrence is at 20–40 years of age.
Men and women are equally affected 2.
1.Braier J, et al.,: Outcome in children with pulmonary Langerhans cell Histiocytosis. Pediatric blood & cancer 2004,
43(7):765-769.
2. Seely JM, et al.,: Pulmonary Langerhans Cell Histiocytosis: A Comparative Study of Computed Tomography in Children and
Adults. Journal of thoracic imaging 2010.

 Clinical Features
– Up to 25% of patients are asymptomatic.
– Nonproductive cough and dyspnea.
– Weight loss, fever, night sweats, and anorexia, (33%).
– Spontaneous pneumothorax (10%)
– Crackles and wheezes may occasionally be heard, and in
advanced cases breath sounds are decreased.
1.Braier J, et al.,: Outcome in children with pulmonary Langerhans cell Histiocytosis. Pediatric blood & cancer 2004,
43(7):765-769.
2. Seely JM, et al.,: Pulmonary Langerhans Cell Histiocytosis: A Comparative Study of Computed Tomography in Children
and Adults. Journal of thoracic imaging 2010.

 Pulmonary function and echocardiographic
findings
 PFT findings are variable depending upon the course of the
disease and prevalent anatomical lesions .
 Up to 20% of patients have normal PFT.
 70% of patients have low DLCO, which is the most common
physiologic abnormality observed.
 A restrictive pattern (earlier stages)
 Obstructive pattern (predominant as disease progresses) .
 Pulmonary Hypertension in advanced PLCH are much greater
than in other chronic lung diseases.
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.

 Pulmonary function and echocardiographic
findings
 PFT findings are variable depending upon the course of the
disease and prevalent anatomical lesions .
 Up to 20% of patients have normal PFT.
 70% of patients have low DLCO, which is the most common
physiologic abnormality observed.
 A restrictive pattern (earlier stages)
 Obstructive pattern (predominant as disease progresses) .
 Pulmonary Hypertension in advanced PLCH are much greater
than in other chronic lung diseases.

 Radiographic findings
• CXR is almost always abnormal, although the findings may be
subtle and easy to overlook .
• Reticulonodular infiltrates are predominant in early disease
whereas cystic lesions are more dominant in advanced disease
• Predominantly involving upper and middle lobes with relative
sparing of lung bases.

Radiographic findings

 HRCT Findings of PLCH
• Thin-walled cysts, some confluent or with bizarre shapes.
• Thick-walled cysts.
• Nodules, usually 1–5 mm, centrilobular or peribronchial, may
be cavitary, and seen in association with cysts.
• Progression from three to two to one .
• Upper lobe predominance of nodules and cysts, costophrenic
angles spared.
• Fine reticular opacities.
• Ground-glass opacities.

• Thin-walled cysts, some confluent or with bizarre shapes

• Thick-walled cysts.

• Nodules, usually 1–5 mm, centrilobular or peribronchial, may
be cavitary, and seen in association with cysts

• Upper lobe predominance of nodules and cysts, costophrenic
angles spared.

• Upper lobe predominance of nodules and cysts,
costophrenic angles spared.

 Bronchoalveolar lavage (BAL)
BAL should be performed in all patients as the detection of
> 3% CD1a-positive cells (Langerhans’ cells) in the
appropriate clinical context (supported by consistent chest
HRCT findings) is highly suggestive of PLCH 1,2 .
1.Auerswald U, Barth J, Magnussen H: Value of CD-1-positive cells in bronchoalveolar lavage fluid for the diagnosis of
pulmonary histiocytosis X. Lung 1991, 169(6):305-309.
2. Chollet S, Soler P, Dournovo P, Richard MS, Ferrans VJ, Basset F: Diagnosis of pulmonary histiocytosis × by
immunodetection of Langerhans cells in bronchoalveolar lavage fluid. Am J Pathol 1984, 115(2):225-232.

 Histopathologic Findings
 Lung biopsy is necessary for a definitive diagnosis
• A key histologic feature is the presence of cellular
peribronchiolar nodules containing Langerhans cells and
inflammatory cells in the early stages (15).
• LCs stain positive for S100, CD1a, and HLA–DR at
immunohistochemical analysis.

 Histopathologic Findings
 Lung biopsy is necessary for a definitive diagnosis
• A key histologic feature is the presence of cellular
peribronchiolar nodules containing Langerhans cells and
inflammatory cells in the early stages 1.
• LCs stain positive for S100, CD1a, and HLA–DR at
immunohistochemical analysis.
Suri et al.: Pulmonary langerhans cell histiocytosis. Orphanet Journal of Rare Diseases 2012
7:16.

a low-power microscopic picture with nodular airway-centered lesions showing
microcystic change

High-power shows diffuse infiltration of lung tissue with Langerhans cells showing vesicular
nuclear chromatin, irregular nuclear contour and moderate amount of pale cytoplasm
devoid of phagocytosed material. Many eosinophils are also intermixed among Langerhans

High-power photomicrographs of a surgical lung biopsy specimen Staining is both nuclear and
cytoplasmic with S100.

 Treatment and Outcome
– Smoking cessation is essential and leads to stabilization of
symptoms in most patients.
– Corticosteroids are the mainstay of medical therapy for
PLCH.
– Lung transplantation is considered for patients with
advanced PLCH associated with severe respiratory
impairment and limited life expectancy.

– Smoking cessation is essential and leads to stabilization
of symptoms in most patients.
– Corticosteroids are the mainstay of medical therapy for
PLCH.

– Smoking cessation is essential and leads to stabilization of
symptoms in most patients.
– Pharmacotherapy with immunosuppressive medication
should be considered for
• Patients with severe disease, or
• Patients in whom progressive decline in lung function occurs.

 Outcomes and prognosis
– The course of PLCH in adults is variable and
unpredictable, ranging from asymptomatic to progressive
debilitating disease that leads to respiratory failure and
death over a period of few years.
– Several factors have been associated with poor outcome
including
• Extremes of age, Prolonged constitutional symptoms,
• Multi-organ involvement,
• Extensive cysts and honeycombing on the radiograph,
• Severely DLCO & obstructive physiology
• prolong treatment with steroid therapy and
• associated pulmonary hypertension

 Outcomes and prognosis
– The course of PLCH in adults is variable and
unpredictable, ranging from asymptomatic to progressive
debilitating disease that leads to respiratory failure and
death over a period of few years.
– Several factors have been associated with poor outcome
including
• Extremes of age, Prolonged constitutional symptoms,
• Multi-organ involvement,
• Extensive cysts and honeycombing on the radiograph,
• Severely DLCO & obstructive physiology
• Prolong treatment with steroid therapy and
• Associated pulmonary hypertension.

Conclusions
• The variety of ILDs associated with cigarette smoking is
wider than generally appreciated, and many forms often
coexist.
• Although key high-resolution CT findings of SR-ILDs can be
recognized, mixed patterns of disease associated with
cigarette smoking may be confusing.
• An integrated clinical, radiologic, and pathologic approach
is necessary for accurate diagnosis of the SR-ILDs.

Conclusions
RB-ILD
DIP
PLCH
AEP
SRIF
CPFE

Smoking related interstitial lung diseases

Smoking related interstitial lung diseases

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