Cigarette smoking prompts the recruitment of inflammatory cells to small airways, even in the absence of clinical lung disease, that develops in a minority of cases.
Interstitial lung abnormalities (ground-glass opacities (GGO), cysts or centrilobular nodules) are present in 53,7% of smokers[1].
Main characteristics of smoking-related interstitial lung diseases (ILD) are summarized.
1.Smoking-related ILD pattern - Inflammatory
Cigarette smoking is a risk factor for lung disease and an accepted primary cause of respiratory bronchiolitis interstitial lung disease (RB-ILD), desquamative interstitial pneumonia (DIP) and pulmonary Langerhans’ cell histiocytosis (PLCH).
Evidence reveals a direct role for cigarette smoking in these ILD, witnessed by the temporal relationship between disease onset-progression, resolution-cessation and recurrence-resumption.
1.1.RB-ILD
RB is a histological marker of smoking, universal in smokers: accumulation of pigmented macrophages on respiratory bronchioles and neighbouring alveoli. RB-ILD is the clinicopathologic ILD counterpart[2].
HRCT reveals bronchial wall thickening, fine centrilobular nodules and patchy areas of GGO (bilateral and upper lung fields).
The prognosis is good.
1.2.DIP
DIP is associated with smoking in 2/3 of cases and is observed in the 4th-5th decade.
Represents alveolar accumulation of macrophages, hyperplasia of type II pneumocytes and variable diffuse alveolar wall thickening[2].
The main finding on HRCT is GGO affecting middle, lower and peripheral lung zones and irregular linear opacities. Small parenchymal cysts may coexist. It is more diffuse, comparing with RB-ILD, with a bronchiolocentric and more patchy tendency.
1.3.PLCH
PLCH is rare, affecting patients in their 3rd-4th decade and >90% of them are active or former smokers.
Histology is characterized by an accumulation of Langerhans cells in peribronchiolar location. There’s also RB with intra-alveolar macrophage accumulation (DIP-like reaction).
The striking abnormalities on HRCT are bilateral nodules and cysts, sparing lung bases. Nodules with or without cavitation predominate in early disease, are usually <10mm diameter. As time passes, they transform into thick-walled cysts and later in thin-walled cysts. In advanced states, only coalescent cysts are observed. Emphysema may be seen, being challenging to differentiate from coalescent cysts.
A BAL fluid with ≥5% CD1a-positive cells is virtually diagnostic.
1.4.Our Experience
Our hospital evaluated 851 patients with ILD between 2014 and 2018. Of which, 33 had a definitive diagnosis of RB-ILD (9% former smokers and 91% current smokers) and the main HRCT findings were centrilobular nodules.
10 cases were confirmed as DIP (all smokers), and GGO was the most common pattern on HRCT.
Only 5 cases of PLCH were evaluated, all exposed to cigarette smoke (1 former smoker), with cysts as the dominant finding on HRCT.
2.Smoking-related ILD pattern - Remodelling & Fibrosis
2.1.AEF, SRIF, RB with fibrosis
Emphysema is defined as permanent enlargement of airspaces distal to the terminal bronchiole with the destruction of alveolar walls[2,3].
The definition historically excludes obvious fibrosis, but the presence of microscopic fibrosis is common, especially in paraseptal emphysema.
The coexistence of fibrosis and emphysema has been coined differently by distinct authors, representing the same pattern, namely “SRIF”, “RB with fibrosis”, “AEF”[2].
It’s a common histological finding, identified in 45,3% of cases based on a survey, characterized by interstitial fibrosis limited to the subpleural and peribronchiolar interstitium, with the maintenance of lung architecture and emphysema[4]. Many patients with SRIF on histology, had normal HRCT[1].
On HRCT, there are thin-walled cysts, with various sizes, combined with reticulations and GGO, sparing subpleural regions, affecting deeper parenchyma, with predominance in the upper lobes and upper and middle portion of lower lobes.
It may be difficult to distinguish from UIP.
Most patients are asymptomatic or mildly symptomatic, with a stable clinical course. Superimposed chronic interstitial pneumonia must be suspected when there’s clinical progression.
2.2.UIP
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause and UIP is the histopathological pattern[5]. Occurs primarily in older adults with a strong association with smoking (odds ratio of 1,6-2,9), that harms survival[2,4].
Patterns of bibasilar peripheral fibrosis are seen on HRCT.
Honeycombing is the cornerstone for the diagnosis of UIP and specific for pulmonary fibrosis.
- HRCT appearance is of subpleural clustered cystic small airspaces, of similar diameters (3–10 mm), with well-defined walls[3].
- For pathologists, represents destroyed and fibrotic lung tissue comprising abundant cystic airspaces with thick fibrous walls, with loss of acinar architecture[3].
It is associated with progressive worsening and poor prognosis. Therefore, the use of the term “honeycomb” on reports must be conscious, since it dictates the diagnosis of UIP and consequent treatment with a bad prognosis.
2.3.NSIP
Nonspecific Interstitial Pneumonia (NSIP) is the 2nd most frequent pattern of ILD, affecting middle-aged adults. The two main subtypes are fibrotic (fNSIP) and cellular.
There is a well-known association with autoimmune diseases, though not all patients with biopsy-proven fNSIP exhibit autoimmune features. Among those, several are smokers and ex-smokers, therefore a causative effect is purposed.
Spatial and temporal homogeneity are essential for the diagnosis. On imaging, there are GGO (symmetric and bilateral), fine reticulations, pulmonary volume loss and traction bronchiectasis. Immediate subpleural sparing has great specificity.
Biopsy reveals interstitial thickening owing to uniform fibrosis and mild chronic inflammation with preservation of lung structures.
May be difficult to distinguish fNSIP from DIP, even on biopsy. Progression of fibrosis is a clue to suggest fNSIP, since fibrosis in DIP is rare, but the distinction based on early HRCT is challenging.
A pattern of NSIP overlapping with UIP is also found in smokers - in a study of biopsy-proven NSIP, 26% had overlap, of which 2/3 were smokers[2,6].
2.4.CPFE
Combined pulmonary fibrosis and emphysema (CPFE) is a broad term, reflecting patterns of emphysema with interstitial fibrosis. It affects old males, who are heavy smokers.
HRCT images show emphysema with upper-zone predominance and fibrosis on lower lobes. Some authors define CPFE as ≥10% of emphysema on images. Any pattern of fibrosis is possible (including AEP, NSIP and, most commonly, UIP) and some findings suggest that prognosis is dependent on fibrosis type, with 8% of patients diagnosed with IPF meeting criteria for CPFE[7].
Comparing with IPF, there is a higher risk of developing pulmonary hypertension and lung cancer (which influences survival).
3.Diagnostic challenges and Treatment –Radiologists can make a difference
3.1.SRIF vs UIP
The definition of honeycombing on HRCT seems straightforward, but in practice is subjective with an only moderate interobserver agreement, posing a diagnostic challenge.
Watanabe et al. reported that wall thickness of cysts on SRIF was significantly thinner than on honeycombing, although, accurate measurement of walls in clustered cysts is difficult[8].
Otani et al. proposed that clustered cysts of irregular size and shape were more frequent in SRIF and round cysts of similar size were present more often in UIP. Also, cysts in SRIF involved subpleural parenchyma lesser than UIP[1].
The coexistence of UIP and SRIF is also possible, rendering the differentiation even more problematic.
3.2.Treatment
Smoking cessation is always an essential component of treatment. Management includes supportive care plus treatment of comorbidities and complications[9], namely chronic obstructive pulmonary disease (COPD). For DIP or severe COPD, lung transplantation is an option.
For predominantly inflammatory ILD, persistent or severe abnormalities can be managed with corticosteroids or other immunosuppressive medications.
Two antifibrotic medications (nintedanib and pirfenidone) are recommended for IPF, slowing the rate of decline in forced vital capacity and in disease progression[5].
Other ILDs besides IPF have fibrotic phenotype; some may be initially inflammatory and then progress to a fibrotic pattern. Increasing evidence suggests similar genetic and pathophysiological mechanisms between IPF and other fibrotic ILDs, so antifibrotics might be effective if there are features of fibrosis[10].
Considering the overlap between IPF and other HRCT patterns in smokers, the impact on therapy choice for pulmonologists is frequently based on the accuracy of radiologists’ description. IPF or CPFE with a UIP pattern of fibrosis, in particular, should be readily diagnosed, as they now have antifibrotic drugs available.