Further information ATS/ERS. International Multidisciplinary Consensus Classi \201 cation of the Idiopathic Interstitial Pneumonias. Am J Resp Crit Care Med 2002; 165: 277 \200\2233 04 OVERVIEW 261 Table 30.1. Idiopathic interstitial pneumonias: summary of key features Idiopathic pulmonar y \201 brosis (IPF) [previously cryptogenic \201 brosing alveolitis (CFA)] Idiopathic Onset over years HRCT \201 brosis, honeycombing, minimal ground glass, subpleu ral, and basal distribution Histology usual interstitial pneumonia (UIP): areas of intersti tial \201 brosis (made up of foci of proliferating \201 broblasts) interspersed with no rmal lung (temporal and spatial heterogeneity), minimal in \202 ammation Prognosis poor Non-speci \201 c interstitial pneumonia (NSIP) Idiopathic or disease-associated Onset over months \200\223years HRCT diffuse ground glass, \201 ne reticulation, minimal honeycombing Histology varying degrees of in \202 ammatio n and \201 brosis, more uniform appearance than UIP Prognosis variable, can be good Idiopathic or disease-associated Onset over months HRCT areas of consolidation, basal, subp leural, and peribronchial predominance Histology alveolar spaces \200\230plugged \200\231 with granulation tissue, extension into bronchioles Prognosis generally good Cryptogenic organizing pneumonia (COP) [previously idiopathic bronchiolitis obliterans orga nizing pneumonia, BOOP] Acute interstitial pneumonia (AIP) Idiopathic Many similarities to ARDS Onset over days HRCT diffuse ground glass and patchy c onsolidation Histology diffuse alveolar damage: interstitial oedema, intra-alveolar hyaline membranes, followed by \201 broblast proliferation and interstitial \201 brosis Progno sis poor Idiopathic, occurs in smokers Onset over years Symptoms usually mild HRCT centrilobular nod ules, ground glass, thick-walled airways Histology pigmented macrophages in bronchioles Pro gnosis good Respiratory bronchiolitis associated interstitial lung disease (RB-ILD) Desquamative interstitial pneumonia (DIP) Idiopathic, occurs in smokers Onset over weeks \200\223months HRCT ground glass Histology p igmented macrophages in alveolar air spaces (perhaps a more extensive form of RB-ILD), temp orally uniform appearance Prognosis good Lymphoid interstitial pneumonia (LIP) Idiopathic or disease-associated Onset over years HRCT ground glass, often reticulation His tology diffuse interstitial lymphoid in \201 ltrates Prognosis variable 262 CHAPTER 30 Idiopathic interstitial pneumonias Idiopathic pulmonary \201 brosis (IPF): diagnosis De \201 nition Chronic interstitial pn eumonia of unknown cause charac- terized histologically by temporal and spatial heterogenei ty, with areas of \201 brosis and architectural distortion interspersed with areas of nor mal lung. This occurs as different areas of lung are in varying stages of evolu- tion of th e pathological process. The histological appearance of idiopathic pulmonary \201 brosis ( previously known as cryptogenic \201 brosing alveolitis) is usual interstitial pneumonia (UIP). Epidemiology Prevalence \201 gures vary from 6 to 14/100 000, although prevalence may be 175/100 000 in patients >75 years old. Slightly more common in males. Mean age at pr esentation 67. Familial form well described, but very rare. Causes and pathophysiology The development of \201 brosis was previ- ously thought to re \202 ect a response to chronic in \202 ammation resulting from an unknown initial injury. This key role of in \202 amma tion in the pathogenesis of IPF has been questioned, however, based partly on the observati ons that in \202 ammation is not a major feature of pathological specimens, and that respo nses to \200\230anti-in \202 ammatory \200\231 treatment with steroids are often poor. An alternative theory is that repeated alveolar epithelial injury leads directly to wound hea ling and \201 brosis, and this concept of \200\230 \201 brosis without in \202 ammatio n \200\231 has been demonstrated both in animal models and other human diseases. The nature of the lung injury remains obscure: postulated triggers include inhalation of metal dust a nd wood dust, smoking, or expo- sure to the Epstein \200\223Barr virus. Cytokine production (e.g. plasminogen acti- vator inhibitors, matrix metalloproteinases, transforming growth f actor B) by alveolar epithelial cells may play an important role in the development of \201 brosis. Host genetic factors are also likely to be important in modi- fying the wound- healing response. Clinical features \200 Typically presents with gradual onset exertional breathlessness and cough; average of 9 mon ths of symptoms prior to presentation 5% of patients are said to be asymptomatic, although this is likely to be an underestimate Arthralgia occurs in about 20% Fine basal late inspir atory crackles Clubbing in up to 50% Cyanosis and cor pulmonale in severe disease. \200 \200 \200 Investigations \200 Blood tests Raised ESR and CRP and mild anemia may occur; positive rheumatoid factor and/or ANA may occur at low titres in the absence of associated connective tissue disease PFTs Ty pically restrictive pattern with reduced vital capacity and transfer factor; smokers may ex hibit coexisting obstructive defect. Oxygen saturations are frequently reduced, particularl y on exertion; ABGs may demonstrate type I respiratory failure IPF: DIAGNOSIS 263 CXR Peripheral and basal reticular shadowing, may extend to other zones, sometimes with hon eycombing; rarely may be normal HRCT features include bilateral, peripheral, and subpleural reticulation, with honeycombing, traction bronchiectasis, architectural distortion, and mi nimal or no ground-glass change. Predominantly basal initially, more extensive later in dis ease course. Extent of disease on CT corre- lates with physiological impairment. Predominan t ground-glass appear- ance suggests an IIP other than IPF \200\224consider lung biopsy BAL is not routinely required and is rarely helpful. Typically shows neu- trophilia, sometimes mild eosinophilia. Marked eosinophilia (>20%) or lymphocytosis (>50%) should raise possibi lity of alternative diagnosis Lung biopsy (via VATS or thoracotomy) if there is diagnostic doubt Gallium and DTPA scanning are seldom of use in clinical practice. \200 Histology Usual interstitial pneumonia, a \201 brosing pattern character- ized by tempora l and spatial heterogeneity: patches of active \201 broblastic foci (re \202 ecting acut e injury) are interspersed with honeycombing/archi- tectural distortion (re \202 ecting ch ronic scarring) and areas of normal lung, re \202 ecting varying stages of evolution of th e disease process in different areas of lung. Interstitial in \202 ammation is minimal. Si gni \201 cant inter-observer disagreement between expert pathologists regarding the presen ce of a UIP pattern on lung biopsy has been reported, however, and an overall diagnosis tak ing into account clinical, radiological and histological features is recommended. Diagnosis can be con \201 dently made in most cases on the basis of clinical and HRCT \201 ndings . Lung biopsy is not generally required in patients with typical clinical and HRCT features of IPF, but should be considered in the presence of unusual features (e.g. predominant gro und glass/nodules/ consolidation/upper lobe involvement on HRCT, or young patient). When re quired, biopsies should be obtained at VATS or thoracotomy; transbron- chial biopsies provi de smaller samples, which rarely give diagnostic infor- mation due to the patchy distributi on of disease. Differential diagnosis \200 Left ventricular failure (a common clinical misdiagnosis in IPF, and patients are often pre scribed inappropriate diuretics) Asbestosis (may mimic clinically and radiologically; occup ational history and presence of pleural plaques may suggest this diagnosis) Connective tiss ue disease (may mimic clinically and radiologically, and precede extrapulmonary manifestati ons of disease) Chronic hypersensitivity pneumonitis (suggested by typically upper/ mid-zon e predominance, micronodules, ground glass, areas of reduced attenuation) Drug-induced lung disease. 264 CHAPTER 30 Idiopathic interstitial pneumonias IPF: management 1 Treatment choices are hindered by a lack of large well-conducted placebo- controlled trials. There is currently no evidence that any drug treatment improves surviva l or quality of life. Drugs should not be used routinely, but may be considered in a closel y observed trial of therapy. They may be of bene \201 t in patients with other IIPs misdia gnosed as IPF. Drug treatments include: \200 Oral corticosteroids Prior to the reclassi \201 cation of IIPs, studies suggested that cor ticosteroids may improve lung function (in around 20 \200\22330% of patients) and symptoms (in around 50%). However, these studies probably included patients with conditions other th an IPF that are associated with a better treatment response and prognosis (e.g. NSIP). Sign i \201 cant side-effects may affect at least a fourth of patients (e.g. hyperglycaemia nec essitating insulin, osteoporosis, myopathy, peptic ulcer disease, cataracts, raised intraoc ular pressure, psychosis). Consider routine septrin prophylaxis (960 mg 3 times/week) again st PCP Azathioprine in combination with prednisolone may improve survival compared with pre dnisolone alone; again this may re \202 ect studies undertaken on individuals with IIPs ot her than IPF. Side-effects appear to be uncommon. Use of azathioprine alone has not been in vestigated Cyclophosphamide does not appear to improve survival and side- effects are commo n Colchicine appears to have a comparable effect to prednisolone and may be better tolerate d Penicillamine and ciclosporin have not been studied in detail. Management protocol The following recommendations are adapted from the BTS guidelines. In a ll cases they should be considered in the context of the individual patient \200\231s clini cal condition, comorbidity, and wishes, particularly in view of the often unpredictable dis ease course, unknown ef \201 cacy of treatment, and high frequency of serious side-effects . Initial assessment and decision to treat On presentation, all patients should have full c linical assessment, pulmonary function tests, and HRCT chest. In general, decisions regardi ng treatment are based on severity and rate of progression of symptoms, changes in pulmonar y function, and HRCT appearance. Predominant ground-glass appearance on HRCT suggests an II P other than IPF, and may be associated with steroid responsiveness \200\224consider lung b iopsy prior to starting treatment. Predominantly reticular patterns are usually less steroi d-responsive. Indications for trial of treatment \200 \200 Severe or rapidly progressive symptoms Predominantly ground-glass appearance on HRCT (consi der biopsy) Consider in the context of a reticular pattern on HRCT if lung func- tion signi \201 cantly impaired or patient requests treatment. IPF: MANAGEMENT 1 265 If mild/moderate symptoms or a long history, and without predominant ground glass on HRCT ( i.e. a reticular/mixed pattern), consider withholding treatment and follow-up within 3 mont hs. If stable on follow-up, review 3-monthly for at least 1 year and regularly thereafter; consider trial of treatment if lung function deteriorates or symptoms worsen. Monitoring Di sease progression and response to treatment are best assessed by serial measurements of VC and TLCO; document them at each clinic attendance. Changes in VC or TLCO of 10 \200\22315% or more are considered signi \201 cant in terms of assessing treatment response or disease progression. Changes in symptoms such as exercise tolerance and cough frequency/severity m ay also be useful. Recommended treatment Oral prednisolone (0.5 mg/kg) is the mainstay of t reatment. Consider IV methylprednisolone in very ill patients. Reassess lung function after 1 month (some recommend treating for a longer period before response to therapy is formerl y assessed, e.g. 3 \200\2236 months): \200 Improvement (increase in VC or TLCO by 10 \200\22315% or more) or stable: slowly reduce pre dnisolone dose (e.g. reduce by 5 mg weekly to 20 mg and review \200\224if no worse, reduce by 5 mg a month to mainte- nance dose of 10 mg and continue at 10 mg for 1 year, and consid er further reduction after this). Consider combination treatment with azathioprine (regimen s vary; an example is initial daily dose of 50 mg for 4 weeks, then increase by 50 mg each week to maximum of 2 \200\2233 mg/kg, although do not exceed 150 mg daily; check WCC weekly until established on maximum dose for 2 weeks, then check WCC and LFTs every 6 \200\2238 w eeks). Azathioprine is used less frequently in patients with a predominantly ground-glass H RCT appearance, who may be treated with prednisolone alone Deterioration (decrease in VC or TLCO by 10 \200\22315% or more): quickly reduce prednisolone dose (e.g. reduce by 10 mg we ekly to 10 mg daily, and more slowly after this). Supportive treatment (see below). Conside r lung transplant referral. Patients who are unable to tolerate treatment \200 \200 Consider trial of azathioprine alone if prednisolone is not tolerated Colchicine may be tri ed as an alternative to prednisolone alone. Further information British Thoracic Society. BTS guidelines on the diagnosis, assessment a nd treatment of diffuse parenchymal lung disease in adults. Thorax 1999; 54 (suppl. 1): S1 \200\22330 266 CHAPTER 30 Idiopathic interstitial pneumonias IPF: management 2 Supportive treatment Consider use of home oxygen if very limited by breat hlessness and in respiratory failure. Use of oxygen during exer- cise may improve exercise tolerance. Encourage pulmonary rehabilitation program, if no contraindications. Cough may b e troublesome; consider oral codeine. Opioids are frequently required for palliation of sev ere breathlessness. Lung transplantation Patients with IPF are often referred for consid- e ration of transplantation too late and most die whilst on the waiting list (which is around 12 months in the UK). Single lung transplant in IPF leads to an 80% survival at 1 year and 55% at 3 years. Guidelines recommend referral of all suitable patients with histological o r radiographic evidence of UIP, irrespective of vital capacity and without delaying for tri als of treat- ment. These are not widely applied in the UK, and, in practice, referral is o ften considered following failure of \201 rst-line treatment in symptomatic patients aged <65 years, with TLCO <40% predicted, fall in FVC \211 10% over 6 months, oxygen desaturat ion <88% on 6-min walk, and/or honeycombing on HRCT. Causes of acute deterioration in patients with previously stable IPF \200 Accelerated decline of IPF \200\224an important cause of death in even mild \200\223moderat e, apparently stable IPF; mechanism poorly understood; biopsy often shows diffuse alveolar damage Pneumothorax \200\224collapsed lung is often relatively resistant to re-expansion, m aking treatment dif \201 cult Infection (especially if immunocompromised), e.g. PCP Pulmon ary embolism Acute deterioration may also occur post-operatively following major surgery, e .g. cardiac or orthopedic \200\224the reasons behind this are unclear. \200 \200 Prognosis is variable: some decline rapidly, others remain stable or decline slowly over ye ars. Several studies have demonstrated a median survival of 2.5 \200\2233.5 years, although prognosis is dif \201 cult to predict for indi- vidual patients. One study has shown oxyg en desaturation <88% during 6-min walk, whilst breathing air is associated with 35% 4-year survival (compared with 69% in patients who do not desaturate below this level). More exten sive \201 broblastic foci on lung biopsy have also been shown to correlate with shorter s urvival. Death is commonly due to respiratory failure and/or infection. Risk of developing lung cancer is increased. Future developments Therapeutic agents currently under evaluation include: \200 Pirfenidone (anti \201 brotic, inhibits collagen synthesis and reduces \201 broblast pro liferation). No improvement in primary end-point (desaturation during 6-min walk) compared with placebo, although possible bene \201 t in secondary end-points (vital capacity and pr evention of acute exacerbation of IPF). IPF: MANAGEMENT 2 267 Interferon G-1b (anti \201 brotic, inhibits \201 broblast proliferation and down-regulat es transforming growth factor B). A large study of IPF patients unresponsive to corticoster oids showed no difference from placebo in disease progression or functional deterioration, and a trend towards improved survival with interferon G-1b (particularly in the mild-to-mod erate disease group with FVC>62% predicted). A further larger study (INSPIRE) is ongoing. A nticoagulation A placebo-controlled study suggested a possible survival bene \201 t from a nticoagulation in addition to prednisolone, particularly following acute exacerbations of I PF, but the study was small, open label, and with differential drop-out between groups; fur ther studies needed Oral co-trimoxazole as a disease-modifying agent; pilot studies have be en promising Oral N-acetylcysteine (an antioxidant, increases lung glutathione levels) at a high dose (600 mg tds) in combination with prednisolone and aza- thioprine appears to conf er a small improvement in lung function when compared with prednisolone and azathioprine al one (no effect on mortality). The combination of prednisolone and azathioprine has not in i tself been compared with placebo, however-they may be more toxic, and so this \200\230trip le combination \200\231 cannot be recommended at present Bosentan (endothelin receptor 1 an tagonist). Studies are ongoing Etanercept (TNF-A blockade). Studies are ongoing Imatinib (P DGF receptor antagonist and c-Abl tyrosine kinase inhibitor). Studies are ongoing Sirolimus (or rapamycin, a macrolide and immunosuppressant). Studies are ongoing. \200 \200 268 CHAPTER 30 Idiopathic interstitial pneumonias Non-speci \201 c interstitial pneumonia (NSIP) De \201 nition The term NSIP is a descript ion of a histological pattern rather than a speci \201 c clinical entity. This form of IIP is poorly understood, and may be subject to further reclassi \201 cation in the near futu re. Patients with NSIP on lung biopsy have a generally better prognosis and greater respons e to steroids when compared with patients with IPF. NSIP may be idiopathic or occur in asso ciation with other systemic conditions, most notably connective tissue diseases. Epidemiolo gy Typically affects younger patients than IPF, with age of onset 40 \200\22350 years. May rarely affect children. Causes/associations \200 \200 Idiopathic Connective tissue disease (NSIP may be the \201 rst manifestation of disease) Hypersensitivity pneumonitis Drugs Infection Immunode \201 ciency (including HIV, post bon e marrow transplant, chemotherapy) \200 \200 \200 Clinical features There are few speci \201 c clinical features that help distinguish NSIP from other IIPs. Described features include: \200 \200 \200 Breathlessness, cough Weight loss is common Onset gradual or subacute, typical symptom dura tion before diagnosis varies 0.5 \200\2233 years Crackles at lung bases, later more extensi ve Clubbing in a small proportion of patients \200 Investigations \200 HRCT frequently shows diffuse symmetrical ground-glass change, with or without reticulation and traction bronchiectasis. The con \202 uent and homogeneous appearance contrasts with the patchy heterogeneous distribution seen in IPF. Honeycombing is rare PFTs typically rest rictive pattern, but impaired gas transfer in only 50%. Desaturation on exertion is common BAL lymphocytosis common Lung biopsy Investigations to exclude underlying disease (see abov e) \200 \200 Histology Variable, ranging from a predominantly \200\230cellular \200\231 pattern (mild \200\223moderate interstitial in \202 ammation, no \201 brosis) to a \200\230 \201 bro tic \200\231 pattern (interstitial \201 brosis, more homogeneous appearance than in UIP a nd lack of \201 broblastic foci or honeycombing, lung architecture may be relatively pres erved). NSIP may be subclassi \201 ed based on the relative proportions NON-SPECIFIC INTERSTITIAL PNEUMONIA 269 of in \202 ammation and \201 brosis: NSIP 1 (primarily in \202 ammation), NSIP 2 (in \202 ammation and \201 brosis), and NSIP 3 (primarily \201 brosis). Features of both NS IP and UIP are sometimes seen on biopsies from the same indi- vidual \200\224in such cases, the diagnosis is considered to be IPF (indicating a poor prognosis). Diagnosis Clinical an d HRCT features are non-speci \201 c and surgical lung biopsy is required for diagnosis. C onsider the presence of associated diseases (see list above). Management Treatment is with corticosteroids (see p 265 for example of protocol). Additional immunosuppressive treatment s may be considered in patients who fail to respond to corticosteroids alone (see p 265). P rognosis Variable. Most patients improve or remain stable on treat- ment. \200\230Cellular \200\231 pattern on biopsy is associated with a good prognosis. Disease progression to dea th occurs, but is unusual. 270 CHAPTER 30 Idiopathic interstitial pneumonias Cryptogenic organizing pneumonia (COP) (formerly bronchiolitis obliterans organizing pneumo nia, BOOP) De \201 nition Cryptogenic organizing pneumonia (COP) is a disease of unknown cause charac terized by \200\230plugging \200\231 of alveolar spaces with granula- tion tissue that may also extend up into the bronchioles. In addition to the \200\230cryptogenic \200\231 form , organizing pneumonia may also occur in the context of other diseases (see below). Use of the name BOOP is no longer recom- mended, as it erroneously suggests a primarily airways di sease and is easily confused with bronchiolitis obliterans, a distinct disease entity. Epid emiology More common in non-smokers. Mean age of onset 55 years, although can affect any ag e. Males = females. Causes of organizing pneumonia \200 \200 Cryptogenic (COP) Organizing pneumonia secondary to: \200 \200 \200 Infection (including pneumonia, lung abscess, bronchiectasis) Drug reaction or radiotherapy Connective tissue disease (particularly myositis, rheumatoid arthritis, Sj gren \200\231s ) Diffuse alveolar damage Hypersensitivity pneumonitis Eosinophilic pneumonia In \202 amma tory bowel disease Post bone marrow transplant Lung malignancy or airways obstruction Pulmo nary infarction. \200 \200 \200 \200 \200 \200 Clinical features \200 Typically short (<3 months) history of breathlessness and dry cough, often with malaise, fe vers, weight loss, and myalgia. Often presents as a \200\230slow to resolve chest infectio n \200\231, frequently after several courses of antibiotics Breathlessness is usually mild, although a minority of patients experi- ence severe breathlessness, and rapid onset of res piratory failure and sometimes death Examination may be normal or reveal crackles. Clubbing is absent. Investigations \200 \200 Blood tests Raised CRP and ESR, neutrophilia PFTs Mild \200\223moderate restrictive pattern is typical, although mild airways obstruction may also be seen in smokers. Mild hypoxaemia is common CXR classically shows patchy consolidation, sometimes with nodular shadowing. Ma y present as a solitary mass on CXR CRYPTOGENIC ORGANIZING PNEUMONIA 271 HRCT Areas of consolidation with air bronchograms, sometimes with associated ground glass o r small nodules. Often basal, subpleural, and peribronchial. May migrate spontaneously. Ret iculation may suggest poor response to treatment. Less common appearance is as a solitary m ass that may cavitate and that is often mistaken radiologically for a lung cancer. Septal t hickening may occur TBB often con \201 rms diagnosis, but there is concern that the relati vely small samples may not effectively exclude associated diseases. Usually adequate in pat ients with typical clinical and HRCT features who are subsequently followed up closely. Sur gical lung biopsy (at VATS) is otherwise required BAL if performed, shows lymphocytosis, ne utrophilia, and eosinophilia. Histology Alveolar spaces \200\230plugged \200\231 with gran ulation tissue ( \201 brin, collagen- containing \201 broblasts, often with in \202 amm atory cells), sometimes with exten- sion up into the bronchiolar lumen. Patchy. Lack of arc hitectural distortion. Examine for evidence of underlying cause, e.g. infection, vasculitis . Diagnosis Usually made on the basis of clinical and HRCT features and transbronchial biop sy. Surgical lung biopsy may be required in atypical cases or if an underlying disease is s uspected. Remember that the histo- logical \201 nding of \200\230organizing pneumonia \200\231 is non-speci \201 c, and search for secondary causes (see list above). Lung cance rs may be surrounded by patches of organizing pneumonia, and biopsy of these areas in patie nts with a solitary lung mass may give misleading results. Differential diagnosis \200 Infective consolidation \200 Connective tissue disease, vas culitis \200 Lymphoma, alveolar cell carcinoma \200 Lung cancer (when COP presents as l ung mass). Management Steroids are the mainstay of treatment. Optimal dose and duration unknown. Typic al initial dose of oral prednisolone is 0.75 mg/kg daily. Slowly taper the dose over a peri od of several months (see p 264, for example). Additional treatment with azathioprine or cy clophosphamide may be considered in patients with minimal response to steroids; intra venou s pulses of cyclophosphamide may be tried in addition to steroid treatment in critically il l patients. Prognosis Generally good. Most patients respond to steroids, and improve within a week of starting treatment. Consider alternative diagnosis (e.g. lymphoma) if no improve ment on steroid doses >25 mg/day. Relapse is com- mon on reduction of steroid dose, and tre atment courses of 6 \200\22312 months are usually required. A minority improve spontaneousl y. Lack of steroid response and progressive respiratory failure and death are rare, but wel l- documented. Further information Cordier J-F Organizing pneumonia. Thorax 2000; 55: 318 \200\22328 272 CHAPTER 30 Idiopathic interstitial pneumonias Acute interstitial pneumonia (AIP) De \201 nition Rapidly progressive form of interstitial pneumonia charac- terized histologically by diffuse alveolar damage. May be considered as an idiopathic form of ARDS. Formerly known as Hamman \200\223Rich syndrome. Epidemiology Po orly described. Mean age of onset is 50, but may occur at any age. Patients often previousl y healthy. Clinical features \200 Often preceded by \200\230viral \200\231-type illness, with systemic symptoms, e.g. fevers , tiredness, myalgia, arthralgia Rapid onset (over days) of breathlessness; usually present s <3 weeks after symptom onset Widespread crackles on examination. Investigations \200 CXR Bilateral diffuse airspace shadowing with air bronchograms, progressing to widespread r eticulation and ground glass; often spares costophrenic angles, heart borders, and hila HRC T Bilateral diffuse ground glass and patchy airspace consolidation in early stages; later t raction bronchiectasis, cystic change, reticulation PFTs Restrictive, reduced gas transfer. Often profound hypoxia and respiratory failure BAL Increased total cells, red blood cells, and haemosiderin. Non-diagnostic, but may be useful in excluding infection Lung biopsy req uired for diagnosis. Transbronchial biopsy may be diagnostic; the risk of pneumothorax is h igher in mechanically ventilated patients (about 10%), although serious complications are r are. Surgical lung biopsy is otherwise required. Histology Diffuse alveolar damage: hyaline membranes, oedema, intersti- tial in \202 ammat ion, and alveolar septal thickening, progressing to organizing \201 brosis and sometimes honeycombing. Diagnosis based on lung biopsy and exclusion of causes of ARDS. Differential diagnosis \200 ARDS (ARDS is of known cause, whereas AIP is idiopathic; often otherwise indistinguishable on clinical and histological grounds) Accelerated decline of IPF (with diffuse alveolar dam age on biopsy) Connective tissue disease (causing diffuse alveolar damage) Diffuse infectio n (community-acquired pneumonia, PCP, CMV) Drug-induced pneumonitis Acute hypersensitivity pneumonitis Acute eosinophilic pneumonia Cardiogenic pulmonary oedema Pulmonary hemorrhage/ vasculitis. \200 \200 \200 \200 \200 \200 \200 