Cigarette smoking has a causal association with chronic obstructive pulmonary disease (COPD) and bronchogenic carcinoma, and additionally, cigarette smoking has been attributed to the development and natural history of distinct forms of lung parenchymal disease involving interstitium.
Smoking-Related Interstitial Lung Disease (SR- ILD)
The 2013 American Thoracic Society and European Respiratory Society statement classified RB-ILD and DIP as smoking-related idiopathic interstitial pneumonia (SR-IIP).
RB-ILD and DIP are different entities and not two junctures in a continuum, based on their distinct clinical presentation, radiographic features, histology, response to treatment, and prognosis.
Histologically, DIP is characterized by an alveolar accumulation of macrophages followed by interstitial inflammation and fibrosis.
Even though predominantly a smoker’s disease, with a reported association of close to 90%, DIP has also been associated with other exposures and disease conditions including:
Although adult-onset DIP is not identified with any genetic defects, DIP in children is a distinct clinical entity with a demonstrated genetic mutation in surfactant protein B and C causing dysfunction. It usually portends a poorer prognosis.
In 1965, Liebow et al. first reported about this disease, and due to their interpretation of large cells within alveolar spaces as desquamated epithelial cells from lining walls, named it desquamative interstitial pneumonia. This name has since been proved to be a misnomer, as those cells have been identified as macrophages within air spaces.
The original authors also did not report the distinctive association with smoking which was first highlighted by Carrington et al. in 1978. The most common age of onset is between 40 to 60 years with a reported 2 to1 male to female predominance. The prevalence of smoking among patients is reported anywhere between 60% to 87%. Craig and Tubbs et al. independently reported about a 40% prevalence of nonsmokers in their cohorts.
Respiratory bronchiolitis (RB) primarily involves macrophage accumulation in respiratory bronchioles in response to smoking. That subsequently incites interstitial inflammation and fibrosis in a time sensitive manner. The characteristic findings of pigmented macrophages, therefore, have a distinct bronchiolocentric distribution with centrilobular ground-glass opacities in chest imaging.
As opposed to RB or RBILD, macrophage accumulation in DIP is extensive, diffuse, and uniform within alveolar spaces. The extensive alveolar infiltration of macrophages renders them an eosinophilic stain due to the abundant eosinophilic cytoplasm of the macrophages. Alveolar macrophages often contain a distinct light brown pigmentation that does not stain for hemosiderin and is known conventionally as “smoker’s pigment,” the corresponding macrophages known as “smoker’s macrophages.“ Macrophages of marijuana smoker with DIP tend to have a characteristic smaller golden brown particulate material. In addition, alveolar septa are infiltrated by lymphocytic conglomerates or lymphoid follicles, and even eosinophils. Radiologically, cystic spaces may be present in areas of ground glass opacities. Those small cystic air spaces seen in chest imaging in DIP have been shown to correlate histologically with dilated alveolar ducts and bronchiectasis. 
Overall alveolar architecture is well preserved, but focal interstitial thickening and inflammatory changes are quite common. Toward late-stage disease, production of transforming growth factor beta-1 results in fibrosis around alveolar interstitium. Unlike usual interstitial pneumonia, however, fibroblastic foci are almost never seen. Multinucleated giant cells are also often reported.
An overlap of clinical and histopathological features are common among smoking-related interstitial pneumonia. A clinical, radiological, and pathological consensus during the period of longitudinal follow up, therefore, becomes necessary to characterize a specific form of SR-ILD and pursue appropriate treatment.
Individuals with a history of relevant exposure to cigarettes, inhalational drugs of abuse, and occupational risk factors commonly present with a dry cough and exercise-induced shortness of breath. Although childhood disease has been rarely reported as mentioned above, the most common age of presentation is 40 to 60 years. There is a male predominance in the prevalence of this disease, consistent with its correlation with exposures.
Less than 10% of patients are asymptomatic at diagnosis. Symptoms are however nonspecific including dyspnea on exertion (90%), persistent cough (70%), with or without sputum production (about 40%). Hemoptysis is very rare.
Clinical examination reveals clubbing in 50% of patients, along with coarse rales in bilateral bases.
Peripheral blood may reveal an increase in neutrophil and eosinophil count.
Pulmonary function tests show a restrictive defect, with impaired diffusion capacity unlike usual obstructive pattern in respiratory bronchiolitis.
Chest x-ray may show a reticulonodular infiltrate in lower lung zones but appears fairly subtle and nonspecific. They are reported to be normal in 3% to 22% of biopsy-proven cases.
High-resolution CT chest is the imaging modality of choice. It shows diffuse bilateral lower lobe predominant ground glass changes in a homogenous distribution, and without honeycombing- the last two features distinguishing it from usual interstitial pneumonia or idiopathic pulmonary fibrosis. In progressive disease, cysts and traction bronchiectasis may be seen, but it is not exclusively subpleural. Fibrosis is not as common as in NSIP or UIP.
However advanced DIP is reported to be indistinguishable from NSIP with a temporally uniform pattern of fibrosis beyond the initial accumulation of alveolar macrophages. Sugiyama et al reported that late-stage association at 30%.
Unlike other inhalational lung diseases, the ground glass infiltrates in DIP are more predominant in lower lung zones.
Interestingly in a study reported by Cartier et al., radiologists' diagnosis of DIP based on HRCT was histologically proven in only 59% of cases, emphasizing once again the need for a clinical, radiological, and histological consensus.
Transbronchial biopsy may not yield representative tissue section and have been reported to provide findings consistent with organizing pneumonia in early disease or fibrotic disease in later stages.
A surgical lung biopsy is the gold standard of diagnosis.
In recent years, transbronchial cryobiopsy is being explored as an alternative diagnostic approach with an increase in sample size by non-invasive means.
Studies have shown time and again that considerable overlap exists between RB-ILD and DIP and features of both may be present in differing sections of biopsy. However radiological manifestations in the entire lung field, as well as PFT abnormalities, are markedly different between the two.
The most important intervention after diagnosis is smoking cessation. Similarly if associated with specific occupational exposures, avoidance of exposure is also key to preventing disease progression.
Systemic corticosteroid therapy over months has been reported as the most effective pharmacologic intervention. With corticosteroids and immunosuppressive therapy (azathioprine being the most commonly used agent), most patients remain stable or improve with reports of even complete recovery. However, in separate publications, both Aubry et al. and Kawabata et al. showed that about 25% of patients might continue to progress in spite of corticosteroid therapy, resulting in pulmonary fibrosis. In patients refractory to steroids, there have been reports of successful use of clarithromycin.
There are isolated case reports of the use of azathioprine and cyclophosphamide to treat acute respiratory failure due to DIP. Finally, with progressive and severe lung disease causing hypoxemia, pulmonary hypertension, severe reduction in TLC or DLCO, lung transplantation evaluation is indicated; although, there are reports of recurrence of DIP post lung transplantation.
Other smoking-related idiopathic interstitial pneumonia, such as respiratory bronchiolitis-interstitial lung disease.
Other idiopathic interstitial pneumonia, such as the following:
Mortality of DIP ranges anywhere between 6% to 28%. Although spontaneous improvement has been reported, two-thirds of DIP patients have a progression of disease if left untreated. In a study by Aubry et al., 25% of patients continued to have progressive disease despite corticosteroid therapy.
There are not many longitudinal studies characterizing the rate of disease progression. In one such study, Remy-Jardin et al. reported that ground glass changes, emphysema, and centrilobular nodules increased from 28% to 42%, 26% to 40%, and 33% to 35%, respectively, in current smokers during a mean follow-up period of 5.5 years. In a radiological follow up of DIP in a small group of 14 patients, cysts were found to increase along with new appearance of honeycombing in 35%. This included patients on systemic corticosteroid therapy. Ten-year survival rates are reported at around 70%.
Acute interstitial pneumonitis and diffuse alveolar hemorrhage have also been reported as acute complications of the disease. Particularly there have been reported cases of acute exacerbations after diagnostic video-assisted thoracoscopic surgery.
There is also opinion regarding the progression of DIP into the domain of fibrotic NSIP in advanced stages as far as histopathological features are concerned. Prognosis nevertheless, is better in this group of disease than either NSIP or UIP.
Incidence and prevalence of desquamative interstitial pneumonia are so rare across the population that large population-based randomized controlled trials are not available to guide management and outcomes.
Nevertheless, association with cigarette and marijuana smoking, as well as certain occupational exposures have been proved unequivocally. Once diagnosed; therefore, discontinuation of exposure becomes the single most important intervention, as reiterated by the 2013 American Thoracic Society and European Respiratory Society statement.
As mentioned above, considerable overlap exists between smoking-related interstitial lung diseases like RB, RBILD, DIP and even non-specific interstitial pneumonia. Mixed histopathological features are often reported. A combined clinical, radiological, and histopathological approach to diagnosis as well as a longitudinal follow up becomes necessary to distinguish each of the entities. Prognosis varies between RBILD, DIP, and NSIP in worsening order, and therefore the establishment of a diagnosis early on helps in intervening appropriately and addressing prognosis with patient and families. Mortality is almost never reported for RBILD with disease regression over a period of 30 years from smoking cessation, while DIP has a reported mortality rate of 6% to 28% with disease progression occasionally even on treatment and smoking cessation.
If there is no contraindication, severe disease with activity-induced hypoxemia, pulmonary hypertension, and severe impairment of pulmonary function (DIP or NSIP), should be referred to in the advanced stage for pulmonary transplantation.
|||Godbert B,Wissler MP,Vignaud JM, Desquamative interstitial pneumonia: an analytic review with an emphasis on aetiology. European respiratory review : an official journal of the European Respiratory Society. 2013 Jun 1 [PubMed PMID: 23728865]|
|||Gill A, Bong lung: regular smokers of cannabis show relatively distinctive histologic changes that predispose to pneumothorax. The American journal of surgical pathology. 2005 Jul [PubMed PMID: 15958866]|
|||Tubbs RR,Benjamin SP,Reich NE,McCormack LJ,Van Ordstrand HS, Desquamative interstitial pneumonitis. Cellular phase of fibrosing alveolitis. Chest. 1977 Aug [PubMed PMID: 884976]|
|||Abraham JL,Hertzberg MA, Inorganic particulates associated with desquamative interstitial pneumonia. Chest. 1981 Jul [PubMed PMID: 7249745]|
|||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 Nov [PubMed PMID: 10525560]|
|||Lougheed MD,Roos JO,Waddell WR,Munt PW, Desquamative interstitial pneumonitis and diffuse alveolar damage in textile workers. Potential role of mycotoxins. Chest. 1995 Nov [PubMed PMID: 7587416]|
|||Iskandar SB,McKinney LA,Shah L,Roy TM,Byrd RP Jr, Desquamative interstitial pneumonia and hepatitis C virus infection: a rare association. Southern medical journal. 2004 Sep [PubMed PMID: 15455981]|
|||Sung SA,Ko GJ,Kim JY,Kim MG,Lee JE,Kim GI,Jo SK,Cho WY,Kim HK, Desquamative interstitial pneumonia associated with concurrent cytomegalovirus and Aspergillus pneumonia in a renal transplant recipient. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2005 Mar [PubMed PMID: 15735246]|
|||LIEBOW AA,STEER A,BILLINGSLEY JG, DESQUAMATIVE INTERSTITIAL PNEUMONIA. The American journal of medicine. 1965 Sep [PubMed PMID: 14338290]|
|||Carrington CB,Gaensler EA,Coutu RE,FitzGerald MX,Gupta RG, Natural history and treated course of usual and desquamative interstitial pneumonia. The New England journal of medicine. 1978 Apr 13 [PubMed PMID: 634315]|
|||Carrington CB,Gaensler EA,Coutu RE,Fitzgerald MX,Gupta RG, Usual and desquamative interstitial pneumonia. Chest. 1976 Feb [PubMed PMID: 1248298]|
|||Tazelaar HD,Wright JL,Churg A, Desquamative interstitial pneumonia. Histopathology. 2011 Mar [PubMed PMID: 20854463]|
|||Craig PJ,Wells AU,Doffman S,Rassl D,Colby TV,Hansell DM,Du Bois RM,Nicholson AG, Desquamative interstitial pneumonia, respiratory bronchiolitis and their relationship to smoking. Histopathology. 2004 Sep [PubMed PMID: 15330806]|
|||Akira M,Yamamoto S,Hara H,Sakatani M,Ueda E, Serial computed tomographic evaluation in desquamative interstitial pneumonia. Thorax. 1997 Apr [PubMed PMID: 9196515]|
|||Margaritopoulos GA,Harari S,Caminati A,Antoniou KM, Smoking-related idiopathic interstitial pneumonia: A review. Respirology (Carlton, Vic.). 2016 Jan [PubMed PMID: 26138798]|
|||Sawata T,Bando M,Nakayama M,Mato N,Yamasawa H,Sugiyama Y, Influence of Smoking in Interstitial Pneumonia Presenting with a Non-Specific Interstitial Pneumonia Pattern. Internal medicine (Tokyo, Japan). 2016 [PubMed PMID: 27746429]|
|||Johkoh T,Müller NL,Cartier Y,Kavanagh PV,Hartman TE,Akira M,Ichikado K,Ando M,Nakamura H, Idiopathic interstitial pneumonias: diagnostic accuracy of thin-section CT in 129 patients. Radiology. 1999 May [PubMed PMID: 10228542]|
|||Dias C,Mota P,Neves I,Guimarães S,Souto Moura C,Morais A, Transbronchial cryobiopsy in the diagnosis of desquamative interstitial pneumonia. Revista portuguesa de pneumologia. 2016 Sep-Oct [PubMed PMID: 27134124]|
|||Kligerman S,Franks TJ,Galvin JR, Clinical-Radiologic-Pathologic Correlation of Smoking-Related Diffuse Parenchymal Lung Disease. Radiologic clinics of North America. 2016 Nov [PubMed PMID: 27719975]|
|||Madan R,Matalon S,Vivero M, Spectrum of Smoking-related Lung Diseases: Imaging Review and Update. Journal of thoracic imaging. 2016 Mar [PubMed PMID: 26479130]|
|||Yousem SA,Colby TV,Gaensler EA, Respiratory bronchiolitis-associated interstitial lung disease and its relationship to desquamative interstitial pneumonia. Mayo Clinic proceedings. 1989 Nov [PubMed PMID: 2593722]|
|||Hartman TE,Primack SL,Kang EY,Swensen SJ,Hansell DM,McGuinness G,Müller NL, Disease progression in usual interstitial pneumonia compared with desquamative interstitial pneumonia. Assessment with serial CT. Chest. 1996 Aug [PubMed PMID: 8697837]|
|||Kawabata Y,Takemura T,Hebisawa A,Sugita Y,Ogura T,Nagai S,Sakai F,Kanauchi T,Colby TV, Desquamative interstitial pneumonia may progress to lung fibrosis as characterized radiologically. Respirology (Carlton, Vic.). 2012 Nov [PubMed PMID: 22805187]|
|||Aubry MC,Wright JL,Myers JL, The pathology of smoking-related lung diseases. Clinics in chest medicine. 2000 Mar [PubMed PMID: 10763087]|
|||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 Jul [PubMed PMID: 18628222]|
|||Katzenstein AL, Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2012 Jan [PubMed PMID: 22214972]|
|||Ryu JH,Myers JL,Capizzi SA,Douglas WW,Vassallo R,Decker PA, Desquamative interstitial pneumonia and respiratory bronchiolitis-associated interstitial lung disease. Chest. 2005 Jan [PubMed PMID: 15653981]|
|||Remy-Jardin M,Edme JL,Boulenguez C,Remy J,Mastora I,Sobaszek A, Longitudinal follow-up study of smoker's lung with thin-section CT in correlation with pulmonary function tests. Radiology. 2002 Jan [PubMed PMID: 11756735]|
|||Myers JL,Katzenstein AL, Fibroblasts in focus. American journal of respiratory and critical care medicine. 2006 Sep 15 [PubMed PMID: 16959920]|
|||Monaghan H,Wells AU,Colby TV,du Bois RM,Hansell DM,Nicholson AG, Prognostic implications of histologic patterns in multiple surgical lung biopsies from patients with idiopathic interstitial pneumonias. Chest. 2004 Feb [PubMed PMID: 14769733]|
|||Fan LL,Dishop MK,Galambos C,Askin FB,White FV,Langston C,Liptzin DR,Kroehl ME,Deutsch GH,Young LR,Kurland G,Hagood J,Dell S,Trapnell BC,Deterding RR, Diffuse Lung Disease in Biopsied Children 2 to 18 Years of Age. Application of the chILD Classification Scheme. Annals of the American Thoracic Society. 2015 Oct [PubMed PMID: 26291470]|
|||Langston C,Dishop MK, Diffuse lung disease in infancy: a proposed classification applied to 259 diagnostic biopsies. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society. 2009 Nov-Dec [PubMed PMID: 19323600]|
|||Deutsch GH,Young LR,Deterding RR,Fan LL,Dell SD,Bean JA,Brody AS,Nogee LM,Trapnell BC,Langston C,Albright EA,Askin FB,Baker P,Chou PM,Cool CM,Coventry SC,Cutz E,Davis MM,Dishop MK,Galambos C,Patterson K,Travis WD,Wert SE,White FV, Diffuse lung disease in young children: application of a novel classification scheme. American journal of respiratory and critical care medicine. 2007 Dec 1 [PubMed PMID: 17885266]|
|||Matsuo A,Matsumoto N,Kitamura A,Tsubouchi H,Yanagi S,Nakazato M, Desquamative interstitial pneumonia complicated by diffuse alveolar haemorrhage. Respirology case reports. 2018 Feb [PubMed PMID: 29321935]|
|||Yogo Y,Oyamada Y,Ishii M,Hakuno H,Fujita A,Yamauchi T,Sawafuji M,Kobayashi K,Mukai M,Yamaguchi K, [A case of acute exacerbation of desquamative interstitial pneumonia after video-assisted thoracoscopic surgery (VATS)]. Nihon Kokyuki Gakkai zasshi = the journal of the Japanese Respiratory Society. 2003 Jun [PubMed PMID: 12833843]|
|||Sánchez Varilla JM,Vázquez Martín M,García Dante H,Peñas del Castillo J,Domínguez Plata T, [Acute exacerbation of desquamative interstitial pneumonia after thoracoscopy lung biopsy]. Anales de medicina interna (Madrid, Spain : 1984). 2005 Dec [PubMed PMID: 16523552]|
|||Kadoch MA,Cham MD,Beasley MB,Ward TJ,Jacobi AH,Eber CD,Padilla ML, Idiopathic interstitial pneumonias: a radiology-pathology correlation based on the revised 2013 American Thoracic Society-European Respiratory Society classification system. Current problems in diagnostic radiology. 2015 Jan-Feb [PubMed PMID: 25512168]|
|||Fink L, [Interstitial lung diseases. The pattern is important]. Der Pathologe. 2014 Nov [PubMed PMID: 25319226]|