Pulmonary rehabilitation programs have not been evaluated in IPF but are likely to contribu te to overall well-being. Cough \200 Cough is a frequent and troublesome symptom. In cur- rent or ex-smokers produc tive cough may arise from co-existent chronic bronchitis. Gastro-oesophageal re \202 ux di sease (GORD) may be associated with cough. Whilst the role of GORD in the pathogenesis and progression of IPF remains uncertain, symptomatic patients should be treated with a proton pump inhibitor. Transbronchial biopsies do not allow a speci \201 c diagnosis of UIP. Open lung biopsy Surgical biopsy con \201 rmation, when clinical and HRCT features are typ ical of UIP, cannot easily be justi \201 ed. Management and treatment Overview In the majority, UIP will progress over a period of month s and years towards a terminal phase. At the time of diagnosis Conventional anti-tussive agents, such as oral codeine, are widely used, but there is no ev idence of ef \201 cacy. Oral opiates may be used for intractable cough particu- larly in e nd-stage disease. A MILLAR 130 with interferon-gamma 1B (10%), but this trend did not reach statistical signi \201 cance (p=0.08). The hypothesis that interferon-gamma-1B may confer a survival bene \201 t, par- ticularly in patients with milder disease, remains unproven and the results of ongoing rand omized controlled studies are awaited. Pneumothorax Spontaneous pneumothorax or pneumo-mediastinum is a recognized complication of IPF and should be suspected when a patient complains of a sudden increase in breath- lessn ess. Pleurodesis is not a contra-indication to future lung transplantation. Pneumothorax ca n be a late compli- cation of IPF and cause severe breathlessness. In such cases the lung m ay fail to re-expand after insertion of an intercostal drain because of altered lung compli ance and palliative care may be more appropriate. N-acetylcysteine (NAC) A number of in vitro and animal model experiments led to the suggest ion that a redox imbalance may contribute to the development of IPF. The subsequent clinica l obser- vation that lung epithelial lining \202 uid from IPF subjects was deplete of red uced glutathione laid the foundation for clinical trials of NAC. A 12 month double-blind st udy to assess the affects of NAC (600 mg tds) in patients with a con \201 dent UIP diagno- sis analyzed 155 receiving prednisolone (tapering from 0.5 mg/kg a day) and azathioprine ( 2 mg/kg a day). 80 patients received NAC and 75 patients placebo. VC was 9% and DLCO 24% hi gher in the NAC group but no signi \201 cant differences in mortality were found. However, patients in whom the standard regimen with prednisolone and azathioprine was contraindicat ed or \200\230not justi \201 ed \200\231 were excluded from the study and 40% of particip ants were recruited within 6 months of diagnosis. Lung cancer IPF predisposes to non-small cell and small cell lung cancer. Diagnosis and sta ging should be undertaken as for any other patient, although poor lung function from co-exi sting pulmonary \201 brosis makes the possibility of curative treat- ment less likely. Potential disease modifying UIP as the most common form of IIP has/is being studied in more recent trials with recruitment of a virtually homogenous population of patients, albeit at varying stages in the natural history of the disease. Three of these have reported, interf eron-gamma 1B, pirfenidone and N-acetylcysteine, the latter as an adjunct to prednisolone a nd azathioprine, others will follow including endothelin-1 antagonists and TNF-A blockade. Steroid monotherapy More recent studies do not support the use of corticoste- roids in IPF. A meta-analysis concluded that there was no evidence that steroids prolonged survival or i mproved quality of life in this condition. High-dose steroids should not be given (0.5 \200 \2231mg/kg). Key recommendations \200 Steroid monotherapy should not be given. \200 If treatment wit h azathioprine/prednisolone therapy is given, patients should also receive N-acetylcysteine (600mg tds). Treatment should be given within multi-center trials where possible. Steroids and azathioprine There is not substantial evidence for treatment bene \201 t but some clinicians still use this regimen (see BTS guidelines). Lung transplantation \200 A multi-variable analysis from a single center study of 46 pati ents with IPF accepted for transplantation (28 successfully transplanted, 16 died awaiting transplan- tation) suggested that lung transplantation reduced the risk of death by 75%. Cyclophosphamide There is no evidence that oral or pulsed cyclophosphamide is of any long-t erm bene \201 t in terms of survival or quality of life for patients with IPF and it has a signi \201 cant side effect pro \201 le. Transplant should be considered in those patients below who ful \201 l established selecti on criteria for transplant, thus generally excluding those over the age 65 and/or those wit h signi \201 cant co-morbidity. Pirfenidone Pirfenidone is a pyridone which inhibits \201 broblast prolifera- tion and co llagen synthesis in vitro and ameliorates bleo- mycin-induced pulmonary \201 brosis in an imals. A placebo (2:1) controlled, double-blind phase 2 study of pirfenidone therapy in 107 Japanese patients with moderate IPF has recently been reported. Planned for 1 year, the st udy was prematurely stopped at 9 months due to signi \201 cantly greater acute exacerbatio ns in the placebo group. Patients receiving pirfenidone also had signi \201 cantly smaller decline in VC and a small but signi \201 cant improvement in degree of desaturation follo wing a 6MWT at 9 months. Further ran- domised trials of Pirfenidone in IPF are ongoing. Int erferon-gamma 1 Interferon gamma is a Th1 cytokine which down-regulates collagen gene exp ression and suppress products/effects of pro- \201 brotic growth factors. This led to the hypothesis that it might prevent progression of pulmonary \201 brosis initially. A prospe ctive double-blind placebo controlled trial of interferon-gamma-1B in 330 patients reported no signi \201 - cant affect on lung function at any time point. There were more deaths in the placebo group (17%) than those treated Definite UIP (clinico-radiologically or a pathologi- cal diagnosis) should be discussed wit h a transplant center. Advanced UIP (DLCO<39% predicted), or progressive disease (10% or greater decline in FVC du ring 6 months of follow up) should be referred to a transplant center for assessment. AUTHOR \200\231S TIP Don \200\231t miss the transplant window. Further reading American Thoracic Society/European Respiratory Society International Multid isciplinary Consensus Classi \201 cation of the Idiopathic Interstitial Pneumonias. Am J R espir Crit Care Med 2002; 165: 277 \200\223304. Azuma A, Nukiwa T, Tsuboi E, et al. Double blind, placebo- controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: 1040 \200\2231047. CHAPTER 7.1 Usual interstitial pneumonia 131 (ASTP)/American Thoracic Society (ATS)/European Respiratory Society(ERS)/International Soci ety for Heart and Lung Transplantation(ISHLT). Am J Respir Crit Care Med 1998; 158(1): 335 \200\223339. Bradley B, Branley HM, Egan J J, et al. Interstitial lung disease guide- line: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand an d the Irish Thoracic Society. Thorax 2008; 63: (Suppl 5) VI \200\22358. BTS Interstitial lung disease guidelines. Thorax 2008; 63: v1 \200\223v58. Crockett AJ, Cra nston JM, Antic N. Domiciliary oxygen for intersti- tial lung disease. The Cochrane Databas e of Systematic Reviews 2001, Issue 3. Art. No.: CD002883. DOI: 10.1002/14651858. CD002883. Katzenstein AA, Myers JL. Idiopathic pulmonary \201 brosis, clinical relevance of patholo gic classi \201 cation. Am J Respir Crit Care Med 1998; 157: 1301 \200\2231315. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of interferon gamma-1B in patients with idiopathic pulmonary \201 brosis. N Engl J Med 2004; 350: 125 \200\223133. Flaherty KR, King TE Jr, Raghu G, et al. Idiopathic interstitial pneumonia: what is the eff ect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004; 170: 904 \200\223910. Wells AU, Desai SR, Rubens MB, et al. Idiopathic pulmonary \201 brosis: a composite physi ologic index derived from disease extent observed by computed tomography. A J Respir Crit C are Med 2003; 176: 962 \200\223969. International guidelines for the selection of lung transplant candidates. The American Soci ety for Transplant Physicians HISTORY. PHYSICAL EXAMINATION. CXR. BLOOD TESTS. LUNG FUNCTION TESTS Can a diagnosis be made with a high degree of confidence? YES e.g. NO BHL and EN Pulmonary Eosinophilia Coal-workers pneumoconiosis HRCT Can a diagnosis be made with a high degree of confidence? YES e.g. IPF (UIP) Sarcoidosis Subacute HP Lymphangitis carcinomatosis Some rare DPLDs (LCH , AP, LAM) NO Is the patient fit for BAL TBLB? NO YES Do clinical findings and HRCT suggest a condition in which BAL TBLB may be diagnostic or significantly increase diagnostic confidence? YES e.g. Sarcoid Malignancy Acute pulmonary eosinophilia infection COP Subacute HP Some rar e DPLD (AP, LCH) NO e.g. IIP Interstitial pneumonia associated with CTD Is the patient fit for surgical lung biopsy? YES NO Diagnosis of highest probability Confident diagnosis Confident diagnosis Confident diagnosis Abbreviations: BHL \200\223 Bilateral hilar lymphadenopathy EN \200\223 Erythema nodosum LCH \200\223 Langerhans cell histiocytosis AP \200\223 Alveolar protenosis LAM \200\223 Lymphangioleiomyomatosis COP \200\223 Crytptogenic organsing pneumonia HP \200\223 Hypers ensitivity pneumonitis It is anticipated that in many cases of DPLD, a confident diagnosis, or diagnosis of highes t probability will be made locally by the chest physician in conjunction with radiology and pathology colleagues. It is recommended however that regional DPLD centers are established in which regular DPLD multi-disciplinary meetings are held. These centers should have clos e links to local hospitals and the diagnosis and management of a significant proportion of DPLD should be discussed in this setting. Finally, in diagnostically \200\230difficult \200\231 cases of DPLD, the national panel of expert DPLD pathologists (already established ) and radiologists (recommended to be established) may be approached for guidance. Fig. 7.1.3 Generic algorithm for DPL. K REMUND & J EGAN 132 7.2 Non-speci \201 c interstitial pneumonia Introduction NSIP is a speci \201 c histologi cal entity within the classi \201 cation of IIPs. NSIP was \201 rst highlighted by Katze nstein and Fiorelli in a histological review of 110 biopsies taken from patients with inter stitial lung disease. It was recognized that a minority of these biopsies did not re \202 ect the pattern of UIP. The term \200\230non-speci \201 c interstitial pneumonia \200\231 was applied, acknowledging that these biopsies may represent \200\230sampling errors \200 \231 from patients with alternative diagnosis such as extrinsic allergic alveolitis. On HRCT examination the predominant \201 ndings are bilat- eral ground glass opacities as sociated with a moderate reticular pattern and traction bronchiectasis (Fig. 7.2.1). Patchy consolidation can also be present. Honeycombing is rarely seen and when present is thought to represent the \200\230 \201 brosing \200\231 pattern (see Pathologic \201 ndings) o f NSIP. Key points Whether NSIP represents \200\230early \200\231 UIP remains uncertain. \200 Th e survival of patients with advanced \201 brotic NSIP de \201 ned as a DLCO > 35% mirrors that of UIP. UIP could represent a final common pathway of NSIP. In contrast, NSIP is frequently associated with connec- tive tissue diseases. In a retrospective study of 476 patients with systemic sclerosis: \200 80 patients with c linically and radiologically evidence of \201 brosing alveolitis associated with systemic sclerosis underwent surgical biopsy. Fig. 7.2.1 HRCT of the lungs shows at the level of carina diffuse ground glass opacities an d septal lines are not a major \201 nding. 77.5% had the histological pattern of NSIP. In a retrospective analysis by Kinder et al.: \200 88% of patients with biopsy proven idiopathic NSIP meet the criteria for undifferenti ated connective tissue disease. AUTHOR \200\231S TIP A diagnostic algorithm for interpreting HRCT including the anatomical distribution, the presence of honey- combing or reticular lines and extent of ground glass opacities can be used to discriminate between NSIP and UIP. NSIP may represent a speci \201 c pulmonary manifestation of undifferentiated connective tissue disease. Epidemiology \200 The precise incidence and prevalence of NSIP are unknown. In this algorithm the presence/absence of honeycombing is initially evaluated. Honeycombing with a basilar distribution indicates \200\230De \201 nitive UIP \200\231 while honeycom bing with no basilar distribution suggests \200\230Probable UIP \200\231. If honeycomb- in g is not present the detection of septal lines is then evalu- ated. If septal lines are not a major feature this would lead to the diagnosis of \200\230De \201 nitive NSIP \200\231 . If septal lines are a major feature, then the distribution of ground glass opaci- ties is evaluated. A basilar distribution of ground glass opac- ities with septal lines and no hon eycombing is categorized as \200\230Intermediate \200\231 probability of UIP or NSIP. The presence of diffuse or central distribution of ground glass opacities indicates \200\230Po ssible NSIP \200\231. However the interpretation of HRCT in cases of NSIP can still be dif \201 cult. In a study by Aziz et al. the accuracy of interpreting HRCT in diffuse parenchy mal lung disease was found to be variable. The inter-observer accuracy for the diagnosis NS IP between dif- ferent 11 thoracic radiologists was only modest (k = 0.48). The prevalence of NSIP could range from 1 \200\2233/100,000 of the general population. In a highly selected case series of 193 suspected cases of NSIP only 67 (37%) were con \201 rmed as having NSIP after multidisciplinary review. Clinical characteristics and lung function Many of the clinical features of NSIP are compar able to IPF. Cough and shortness of breath with impaired exercise tolerance are the major s ymptoms and usually evolve over several months or years. Clubbing can also be present but i s less frequent when compared to IPF patients. Crackles on auscultation are often detected. The average age at diagnosis is 52 years, which compares to 63 years for IPF patients. 67% are women and 69% have never smoked. Pulmonary function studies show a restrictive pattern in 69% of patients with impaired gas exchange. A DLCO of less than 35% predicted is associ ated with early mortality de \201 ned as death within 2 years. A change in FVC (10% and mo re) is associated with disease progression. Pathologic \201 ndings In a patient with a suspected interstitial pneumonia, to determine the speci \201 c pattern of pulmonary \201 brosis a size- able lung biopsy is required .Therefore transbronchial biop- sies are not helpful. Minimal invasive VATS is the optimal method for diagnosis by providing adequate histological material and should be obtained fro m at least two sites from different lobes. Radiographic \201 ndings The chest radiograph often only shows a subtle increase in opaci ty, typically at the lung bases. In 10% of the patients the chest radiograph is normal. CHAPTER 7.2 Non-speci \201 c interstitial pneumonia 133 NSIP can be subdivided into either \201 brosing or a cellular pattern. Fibrosing NSIP occ urs in 84% of the cases and the cellular pattern occurs in 16%. The hallmark of the NSIP is the temporal homogeneity and the absence of \201 broblast foci, granulomas and eosinophi lic granulocytes. (Figs. 7.2.2 and 7.2.3). However, it can be dif \201 cult to distin- gui sh the \201 brosing NSIP from UIP. concordant UIP compared to the patients with concordant NSIP. These \201 ndings underline the importance to obtain biopsies of at least two sites from different lobes. Cellular NSI P is characterized by a mild to moderate uni- form chronic in \202 ammation with lymphocyt es and type II pneumocyte hyperplasia in the setting of preserved lung architecture. The di fferential diagnosis for cellular NSIP includes hypersensitivity pneumonitis. Cellular NSIP may also represent the cellular form of the term \200\230cryptogenic \201 brosing alveo litis \200\231(CFA). When \201 rst described by Scad- ding, CFA contained a subgroup of p atients who were younger, female and had a cellular pattern on biopsy. These patients were also thought to be steroid responders. In hindsight \200\230cellular NSIP \200\231 probabl y matches \200\230cellular CFA \200\231. Survival The natural history of the NSIP is uncertain because of the absence of prospective studies, however, the survival of NSIP patients is generally thought to be superior to tho se patients with IPF. Combining the diagnostic techniques of HRCT and histology can be help ful for estimating survival in NSIP. Flaherty et al. identi \201 ed a superior survival in patients with both radiologic evidence and histologic evi- dence of NSIP (median survival >9 years) compared to patients with NSIP on HRCT but UIP pattern in the biopsy (median surv ival 5.76 years). Fig. 7.2.2 Low magni \201 cation of a biopsy with temporal uniformity, the absence of hone ycombing and airspace remodeling (hematoxilin and eosin staining, magni \201 cation: x 2.) Management and treatment Patients with NSIP may bene \201 t from immunosuppressive treatme nt. However, appropriate clinical trials have not been performed to date. Based on the clos e association between NSIP and connective tissue diseases, the standard of care would inclu de corticosteroids and immunosup- pressants. A recent double-blind, randomized, placebo- co ntrolled trial of oral cyclophosphamide was performed in 158 patients with scleroderma-rela ted lung disease. In this study pulmonary disease in patients with limited or dif- fuse sys temic scleroderma was de \201 ned as the presence of active alveolitis in bronchoalveolar lavage (neutrophilia >3 %, eosinophilia >2% or both) or ground glass opacities on HRCT or a decreased FVC (45 \200\22385% predicted) and increased Mahler dyspnoea index. Patients wit h history of smoking within preceding 6 months or clinically signi \201 cant pulmonary art erial hypertension requiring drug therapy were excluded. The patients in the cyclophosphami de group had a signi \201 cant but modest bene \201 cial effect on lung function compared to the patients in the placebo group. A mean absolute difference in adjusted 12-month FVC pre- dicted of 2.53% was observed (95% con \201 dence interval, 0.28 to 4.79% (P <0.03)). Six patients died in each group and none death was related to the cyclophosphamide. There w as also an improvement in the dyspnoea index and quality of life was achieved in the cyclop hosphamide group for a period up to 2 years. Among the patients in the cyclophosphamide gro up adverse events as hematuria, leu- kopenia, neutropenia, anemia and pneumonia were more c ommon. A retrospective study by Kondo et al. was performed in 12 patients with \201 brosi ng NSIP and 27 IPF patients. The treat- ment of these patients included steroids in combina tion with cyclophosphamide. After 1 year, 8 NSIP patients had an improvement in their vital capacity (VC predicted 56.7% versus 77.2%, p <0.001) and the other 4 remained stable. The improvement was sustained in 5 patients with long term follow up (mean 91.8 months, range 6 0 \200\223148). One patient died and 2 patients experienced disease progression. Fig. 7.2.3 Advanced interstitial collagen deposition with low cellularity, which resemble \201 brotic NSIP. (Masson \200\223Trichome staining, magni \201 cation: x10.) Fibrosing NSIP shows dense or loose interstitial \201 brosis with chronic in \202 ammati on. However, histopathologic vari- ability between different biopsied lobes may be observed . For example Flaherty et al. have evaluated three histologi- cal permutations of NSIP and UIP. Firstly, \200\230concordant UIP \200\231 was de \201 ned when UIP pattern was exclus ively observed in different lobes. Secondly, \200\230discordant UIP \200\231 was de \201 ned when both UIP and NSIP patterns were found in different lobes. Thirdly, \200\230concor dant NSIP \200\231 was de \201 ned when only histological changes of NSIP were detected. T hese group- ings appear to in \202 uence the clinical outcome. A survival analysis showed a signi \201 cantly better survival for those patients with concordant NSIP compared to pa tients with mixed UIP and NSIP patterns or concordant UIP \201 ndings. The risk of mortal ity was 16.8 times greater in patients with discordant UIP and 24.4 times greater in patien ts with K REMUND & J EGAN 134 However, the toxicity associated with the cyclophospha- mide therapy was signi \201 cant: 21% of the patients had seri- ous adverse effects including haemorrhagic cystitis, leuco- p enia, myelodysplastic syndrome and one patient died because of an opportunistic infection. Therefore less toxic immunosuppressive combinations including steroids with azathioprine or steroids with myco- phenolate mofetil may be an attractive option for the treatment of NSI P. However, little data exist supporting these strategies. Novel therapies, which address c ellular targets of in \202 ammatory responses or \201 brogenic cytokines may be promisin g agents for the future. For example, the application of TNF- antibody therapy may be a r eason- able approach in NSIP based on the association with con- nective tissue disorders. H owever, there is no speci \201 c data to support this approach. Ultimately in patients wit h advanced and progressive disease the surgical treatment of lung transplantation should be considered. Flaherty KR, Thwaite EL, Kazerooni EA, et al. Radiological versus histological diagnosis in UIP and NSIP: survival implications. Thorax 2003; 58: 143 \200\223148. Flaherty KR, Travis WD, Colby GB, et al. Histopathologic variability in usual and non-speci \201 c interstitial pneumonias. Am J Respir Crit Care Med 2001; 164: 1722 \200\2231727. Hartman T, Swensen D, Hansell D, et al. Non-speci \201 c interstitial pneumonia: variable appearances at high-resolution chest CT. Radiology 2000; 217: 701 \200\223705. Jegal Y, Kim DS, Shim TS, et al. Physiology is a stronger predictor of survival than pathol ogy in fibrotic interstitial pneumonia. Am J Respir Crit Care Med 2005; 171: 639 \200\22364 4. Katzenstein AL, Fiorelli RF. Nonspeci \201 c interstitial pneumonia/ \201 brosis. Histol ogic features and clinical signi \201 cance. Am J Surg Pathol 1994; 18: 136 \200\22347. Kinder BW, Collard HR, King TE, et al. Idiopathic non-speci \201 c inter- stitial pneumoni a: lung manifestation of undifferentiated connective tissue disease? Am J Respir Crit Care Med 2007; 176: 691 \200\223697. Kondo Y, Taniguchi H, Yokoi T, et al. Cyclophosphamide and low dose prednisolone in idiopat hic pulmonary \201 brosis and \201 brosing non-speci \201 c interstitial pneumonia. Eu r Respir J 2005; 25: 528 \200\223533. Futher reading American Thoracic Society/European Respiratory Society International Multidi sciplinary Consensus Classi \201 cation of the Idiopathic Interstitial Pneumonias. Am J Re spir Crit Care Med 2002; 165: 277 \200\223304. Latsi PI, du Bois RM, Nicholson AG, et al. Fibrotic idiopathic intersti- tial pneumonia: Th e prognostic value of longitudinal functional trends. Am J Respir Crit care Med 2003; 168: 538 \200\223542. Aziz ZA, Wells AU Hansell DM, et al. HRCT diagnosis of diffuse parenchymal lung disease: in ter-observer variation. Thorax 2004; 59: 506 \200\223511. MacDonald S, Rubens M, Hansell D, et al. Non-speci \201 c interstitial pneumonia and usual interstitial pneumonia: comparative appear- ances at and diagnostic accuracy of thin secti on CT. Radiology 2001; 221: 600 \200\223605. Bouros D, Wells AU, Nicholson AG, et al. Histologic subsets of \201 brosing alveolitis in patients with systemic sclerosis and their relationship to outcome. Am J Respir Crit Care Med 2002; 165: 1581 \200\2231586. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006; 354: 2655 \200\2232666. Chang AC, Yee J, Orringer MB, et al. Diagnostic thoracoscopic lung biopsy: an outpatient ex perience. Ann Thorac Surg 2002; 74: 1942 \200\2231946. Travis WD, Colby TV, Koss MN, et al. Non-Neoplastic Disorders of the Lower Respiratory Trac t, Atlas of Nontumour Pathology. 2002 American Registry of Pathology and the Armed Forced I nstitute of Pathology Washington DC. Costabel U, Du Bois RM, Egan JJ. Diffuse parenchymal lung disease. Progress in Respiratory Research 2007; 36: 160 \200\223174, Karger Switzerland. Travis WD, Hunninghake G, King TE, et al. Idiopathic non-speci \201 c interstitial pneumon ia report of an ATS Project. Am J Respir Crit Care Med 2008 Apr 3; [Epub ahead of print] Egan JJ, Martinez FJ, Wells AU, et al. Lung function estimates in idiopathic pulmonary \201 brosis: the potential for a simple classi \201 ca- tion. Thorax 2005; 60: 270 \200 \223273. This page intentionally left blank A WELLS 136 7.3 Respiratory bronchiolitis-associated interstitial lung disease Introduction Respiratory bronchiolitis-associated interstitial lung disease (RBILD) is a smoking-induced diffuse in terstitial lung process. RBILD is best conceptualized as an exagger- ated form of respirato ry bronchiolitis, a very common incidental \201 nding in cigarette smokers, consisting of an accumulation of pigmented macrophages within respira- tory bronchioles and adjacent alv eoli. It is now generally accepted that the spectra of histologic abnormalities in respirat ory bronchiolitis and RBILD are identical. However, whereas respiratory bronchiolitis is us ually asymptomatic, RBILD, by de \201 nition, manifests as a clinically signi \201 cant d if- fuse lung disease, resulting in cough, shortness of breath and pulmonary function impai rment. smokers, representing respiratory bronchiolitis, include profuse, ill-de \201 ned parenchy mal micronodules, areas of ground-glass attenuation and dependent areas of decreased attenu ation, with occasional background emphysema. The spectrum of HRCT appearances in RBILD is exactly that of respiratory bronchiolitis. Based on the largest HRCT series of patients with a clinico-pathologic diagnosis of RBILD, the most frequent HRCT features are central or peripheral bronchial wall thickening, centri lobular nodules and areas of ground- glass opacity. Emphysema is also common. \200 Areas of hypoattenuation ( \200\230mosaic attenuation \200 \231) are seen in a minority of RBILD cases on inspiratory CT, but are frequent on expirato ry CT in both respiratory bronchiolitis and RBILD. Relationship to smoking Respiratory bronchiolitis and RBILD are both almost invari- ably as sociated with smoking. In the large biopsy series of Fraig, typical respiratory bronchiolit is was seen in all the current smokers and in half of the former smokers but was never pres ent in non-smokers. Based on this and other smaller series, it can be argued that respirato ry bronchiol- itis represents a highly speci \201 c physiologic response to smoking, with no convincing reports of typical respiratory bronchiolitis in non-smokers. RBILD is also st rongly linked to smoking with all patients being current smokers in dour clinical series co ntaining a total of 65 patients, apart from a single non-smoker heavily exposed to solder f umes. In essence, the limited HRCT abnormalities due to respi- ratory bronchiolitis in smokers ar e similar but more extensive in RBILD. Histological features \200 The cardinal histological feature of both respiratory bronchio litis and RBILD is the accumulation of alveolar macrophages in respiratory bronchioles, wit h variable extension into the neighboring alveoli. Macrophages are characterized by brown, \201 nely granular pigmentation (representing constituents of cigarette smoke). A chronic in \202 ammatory cell in \201 ltrate is often present in bronchiolar and surrou nding alveolar walls. Peribron- chial alveolar septal thickening by collagen deposition, ra diating from the involved bronchiole, is more variable. \200 The pulmonary parenchyma dis tant from involved respiratory bronchioles is normal except when there is smoking-related e mphysema. These features do not vary substantially with the global severity of the process and, thus, distinctions between respiratory bronchiolitis and RBILD should not be made histologically , but are wholly based upon symptoms, pul- monary function impairment and HRCT abnormalitie s. \200 A surgical biopsy may be useful when other disease processes require exclusion, b ut should not be used, in isolation, to diagnose RBILD. Fig. 7.3.1 CT scan of patient with biopsy-proven RBILD showing typical features with profus e, ill-de \201 ned parenchymal micronodules, areas of ground-glass attenuation and depende nt areas of decreased attenuation (Courtesy of Dr Fergus Gleeson). Pulmonary function tests Despite the fact that RBILD is bronchiolocentric, restric- tive an d obstructive pulmonary function abnormalities have both been documented. A mixed, predomin antly restrictive ventilatory defect is usual and the carbon mon- oxide diffusing capacity (DLCO) is generally mildly to moderately reduced. The severity of pulmonary function impair ment is crucial in distinguishing RBILD from respira- tory bronchiolitis. Coexistent centri lobular emphysema is a frequent confounder in the interpretation of pulmonary function test s in RBILD, probably explaining the fact that DLCO Imaging features \200 Chest radiographic abnormalities are absent or limited in respirato ry bronchiolitis but tend to be more obvious in RBILD, with bronchial wall thickening, patc hy ground- glass attenuation and reticulo-nodular opacities in most cases. RBILD can not be diagnosed with con \201 dence on chest radiography. Frequent HRCT abnorma lities in healthy CHAPTER 7.3 Respiratory bronchiolitis-associated interstitial lung disease 137 levels were disproportionately reduced in over half the patients with RBILD in the two larg est clinical series. How- ever, emphysema may also accompany limited respiratory bronchioli tis. Thus, the distinction between respiratory bronchiolitis and RBILD on severity grounds requires the integration of clinical, pulmonary function and HRCT data. RBILD can be diagno sed when the combined severity of pulmonary function impairment, HRCT \201 ndings and sym p- toms is indicative of a clinically signi \201 cant interstitial lung disease. HRCT \201 ndings typical of RBILD exclude most other diffuse lung diseases, including the predominantly fibrotic idiopathic interstitial pneumonias (IPF, \201 brotic NSIP). The d istinction between RBILD and sub-acute hypersensitivity pneumonitis on HRCT is sometimes di f \201 cult, as wide- spread poorly formed nodular abnormalities and areas of hypoattenuat ion may co-exist in both diseases. However, the smoking history (RBILD occurs exclusively i n smokers, hypersensitivity pneumonitis is rare in smokers) and BAL profile (lymphcytosis i n hypersensitivity pneumonitis, excess of pigmented macrophages in RBILD) are usually diagn ostic in this context. The management of RBILD is largely driven by the severity of pulmona ry function impairment. Smoking cessation is essential. In mild disease, observation withou t treatment is appropriate. In more severe disease, a trial of corticoste- roid, with or wi thout immunosuppressive drugs, is usual, especially if there is no regression after smoking cessation. However, the risk \200\223bene \201 t ratio of prolonged treatment (with atten dant side effects) is a key consideration. Early withdrawal of treatment in non-responders is usually appropriate. Clinical presentation, natural history and treated course RBILD usually presents between th e third and sixth decades with insidious exertional dyspnoea and persistent cough. However, RBILD may be diagnosed in asymptomatic patients based upon the severity of functional impa irment and chest radiographic or HRCT abnormalities. Bilateral end-inspiratory crackles, wh ich may be predominantly basal, are common, but clubbing is rare. In RBILD and respiratory bronchiolitis alike, a characteristic brown pigmentation of macrophages has been consistent ly observed at BAL, and in RBILD there are increases in mac- rophage numbers, and lower per centages of other per- centages components. A BAL neutrophilia or eosinophilia is rare in R BILD. Further reading Fraig M, Shreesha U, Savici D, et al. Respiratory bronchiolitis: a clin- ic opathologic study in current smokers, ex-smokers, and never- smokers. Am J Surg Pathol 2002 ; 26: 647 \200\223653. AUTHOR \200\231S TIP RBILD is a relatively benign disorder, compared to IPF or \201 broti c NSIP. In most cases, there is functional improve- ment or stability, provided that smokin g cessation is achieved. However, the paucity of longitudinal data, including treatment dat a, in RBILD should be stressed. Accumulated anecdotal experience indicates that a sig- ni \201 cant functional improvement following smoking ces- sation or treatment in RBILD is con \201 ned to a minority of patients. Moon J, du Bois RM, Colby TV, et al. Clinical signi \201 cance of respira- tory bronchioli tis on open lung biopsy and its relationship to smoking related interstitial lung disease. Thorax 1999; 54: 1009 \200\2231014. Myers JL, Veal CF (Jr), Shin MS, et al. Respiratory bronchiolitis caus- ing interstitial lu ng disease: a clinicopathological study of six cases. Am Rev Respir Dis 1987; 135: 880 \200 \223884. Nicholson AG, Colby TV, du Bois RM, et al. The prognostic signi \201 - cance of the histol ogic pattern of interstitial pneumonia in patients presenting with the clinical entity of c ryptogenic \201 bros- ing alveolitis. Am J Respir Crit Care Med 2000; 162: 2213 \200\2232 217. Park JS, Brown KK, Tuder RM, et al. Respiratory bronchiolitis-associ- ated interstitia l lung disease: radiologic features with clinical and pathologic correlation. J Comput Assi st Tomogr 2002; 26: 13 \200\22320. Portnoy J, Veraldi KL, Schwarz MI, et al. Respiratory br onchiolitis- interstitial lung disease: long-term outcome. Chest 2007; 131: 664 \200\223671 . It is not yet clear how often residual functional impairment after cessation of smoking rep resents residual RBILD as opposed to other smoking-related processes such as emphysema. Alt hough in \202 ammation in RBILD may abate with time, a \201 brotic component may result in signi \201 cant residual functional impairment. Remy-Jardin M, Remy J, Boulenguez C, et al. Morphologic effects of cigarette smoking on air ways and pulmonary parenchyma in healthy adult volunteers: CT evaluation and correlation wi th pul- monary function tests. Radiology 1993; 186: 107 \200\223115. Diagnosis and management The formulation of a diagnosis of RBILD requires: (a) that the dis ease presents as a clinically signi \201 cant diffuse lung disease (as opposed to aymptoma tic or mildly symptom- atic respiratory bronchiolitis); and (b) that other diffuse lung dis eases with similar presentations are excluded. Symptoms, clinical signs and the pattern and level of func- tional impairment are highly non-speci \201 c (except in distin- guishing between RBILD and respiratory bronchiolitis) and, thus, HRCT \201 ndings most often provi de discriminatory information. Veeraraghavan S, Latsi PI, Wells AU, et al. Bronchoalveolar lavage findings in idiopathic U IP and NSIP. Eur Respir J 2003; 22: 239 \200\223244. Wells AU, Nicholson AG, Hansell DM. Challenges in pulmonary \201 brosis. 4: smoking-induc ed diffuse interstitial lung diseases. Thorax 2007; 62: 904 \200\223910. Yousem SA, Colby TV, Gaensler EA. Respiratory bronchiolitis- associated interstitial lung d isease and its relationship to desqua- mative interstitial pneumonia. Mayo Clin Proc 1989; 64: 1373 \200\2231380. N HARANI & J MURCHISON 138 7.4 Desquamative interstitial pneumonia Clinical and radiological features \200 Patients typically present with breathlessness an d unless there is co-existing chronic bronchitis, a non-productive cough. Most will have in spiratory crepitations and in one study a fourth of 26 reported cases were clubbed. \200 The plain CXR appearances are non-specific. The most common pattern is bilateral often diff use, occasionally patchy ground-glass opacities and/or reticulo-nodular opacities and in so me cases the CXR is virtually normal. The term desquamative interstitial pneumonia (DIP) was originally coined to re \202 ect th e belief that the intra-alveolar accumulation of cells, characteristic of the disease, repr e- sented desquamated epithelium. It has since become apparent that these cells represent i ntra-alveolar macro- phages laden with brown tobacco-smoke related pigment. Indeed smoking is strongly associated with DIP, as it is with RBILD and it may be that both conditions for m part of a spectrum of smoking-related ILDs. AUTHOR \200\231S TIP DIP is probably part of a spectrum of smoking-related ILDs which inclu des RBILD and Langerhans cell histiocytosis. Normal, restrictive and mild obstructive patterns of lung function have all been described in DIP HRCT scan invariably reveals ground-glass changes that are usually basal and peripheral and sometimes exten- sive (Fig. 7.4.1). The presence of centrilobular ground- glass nodules ma y re \202 ect associated smoking-related RBILD. Epidemiology \200 DIP is a rare disease. \200 The condition occurs almost invariably in current or recent ex-smokers. There is considerable circumstantial evidence indicating tha t cigarette smoke is a causative factor. Only occasionally is the condition seen in those t hat have never smoked; drugs, connective tissue disease or other inhaled irritants have bee n implicated, and there are reports of \200\230idiopathic \200\231 DIP. Co-existing emphysema may also be present (Fig. 7.4.2). Importantly, peripheral honeycomb c ysts are rare, distinguishing DIP from a characteristic usual interstitial pneumonia (UIP) pattern of disease. However architec- tural distortion and minor scarring in the form of li near inter- and intralobular septal thickening and minor bronchi- ectasis or bronchiolectas is may be seen and when associ- ated with ground-glass change is consistent with DIP. DIP is diagnosed most commonly in patients aged 40 \200\22360 years. (a) Fig. 7.4.2 Patchy predominantly peripheral ground glass attenuation due to DIP with associa ted centilobular emphysema (boxed area). Diagnosing DIP \200 The clinical and HRCT features described in a middle- aged smoker may be suggestive of DIP, but are in no way speci \201 c. There are no features on TBB or BAL to reliably distinguish DIP from other ILDs, in particular NSIP, which may present in an i dentical manner. Surgical lung biopsy is therefore always required to make a con \201 dent diagnosis of DIP. (b) AUTHOR \200\231S TIP DIP can only be con \201 dently diagnosed by surgical lung biopsy.