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. Fig. 7.4.1 65-year-old man with DIP. (a) At the level of the lower pole of hila there are p atchy areas of ground glass opaci \201 cation (arrowed). (b) Lower down at the lung base t he ground glass spaci \201 cation is much more extensive. CHAPTER 7.4 Desquamative interstitial pneumonia 139 Treatment and prognosis of DIP \200 There are no controlled studies on which to make evid ence-based recommendations on treatment. All cur- rent smokers should receive smoking cessa tion advice. \200 In patients with only mild functional impairment, smok- ing cessation a lone will often lead to resolution of DIP. \200 In those with more signi \201 cant impai rment, there should be a low threshold for introducing a trial of cortico- steroid therapy since treatment is associated with improvement, if not complete resolution, in up to 75% an d stability in a further 10%. Further reading Akira M, Yamamoto S, Hara H, et al. Serial computed tomographic evaluation in desquamative interstitial pneumonia.Thorax 1997; 52(4): 333 \200\223337. Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual an d desquamative inter-stitial pneumonia. N Engl J Med 1978; 298: 801 \200\223809. Hartman TE, Tazelaar HD, Swensen SJ, et al. Cigarette smok-ing: CT and pathologic findings of associated pulmonary diseases. Radiographics 1997; 17: 377 \200\223390. Nicholson AG, Colby TV, du Bois RM, et al. The prognostic signi \201 - cance of the histol ogic pattern of interstitial pneu-monia in patients presenting with the clinical entity of cryptogenic \201 bros- ing alveolitis. Am J Respir Crit Care Med 2000; 162: 2213 \200\223 2217. Tubbs RR, Benjamin SP, Reich NE, et al. Desquamative interstitial pneumonitis. Cellul ar phase of \201 bros-ing alveolitis. Chest 1977; 72: 159 \200\223165. The dose and duration of corticosteroid therapy should be tailored to the individual; predn isolone initially at 0.5 \200\2230.75 mg/kg/day for 4 \200\2238 weeks with dose reduction t hereafter depending on clinical response is a reasonable regimen. Relapse is not uncommon, sometimes occur- ring many months or years after resolution. Higher cortico steroid doses a re justi \201 ed in the occasional patient with severe disease. Other immunomodulatory the rapies have been used with varied success. Wells AU, Nicholson AG, Hansell DM. Challenges in pulmonary fibrosis 4: Smoking-induced dif fuse interstitial lung diseases. Thorax 2007; 62(10): 904 \200\223910. DIP is associated with overall good outcome, far better than is associated with IPF or \201 brotic NSIP. However, death due to lung \201 brosis and progressive respiratory fail ure is reported in DIP. AUTHOR \200\231S TIP Smoking cessation is the critical therapeutic interven- tion, but unle ss the disease is mild, treatment with corti- costeroids is also recommended. A WELLS 140 7.5 Acute interstitial pneumonia Introduction Acute interstitial pneumonia (AIP) is a rapid ly progressive form of diffuse lung disease, \201 rst described by Hamman and Rich over 5 0 years ago. AIP is characterized by a histological pattern of diffuse alveolar damage (DAD ), indistinguishable from appearances in the acute respiratory distress syndrome (ARDS) and best conceptualized as the idiopathic form of that disorder. There is no gender predi- lec tion and the age range is wide, peaking in the sixth decade. Although the etiology is uncer tain, there is indi- rect evidence to suggest that lung injury results from viral infection or other toxic insults in some cases. However, histological appearances are similar in som e patients with autoimmune disease or acute exacerbations of IPF, prompt- ing the hypothesi s that AIP represents a fulminant variant of IIPs that more typically present as chronic \201 brotic disease. Ground-glass is indicative of early proliferative diffuse alveolar damage when the airways are normal, whereas the presence of bronchiectasis is a cardinal feature of advanced prolif erative or \201 brotic diffuse alveolar damage. \200 Other frequent CT \201 ndings in clude nodular opacities, interlobular septal thickening and, especially, consolida- tion, w hich is present in over two-thirds of cases, often in a sub-pleural distribution. Septal thickening on CT is believed to represent limited alveolar collapse when located wit hin areas of ground- glass. Honeycombing is not a cardinal feature of AIP and should prompt suspicion of an acute exacerbation of underlying IPF. Outcome is linked to the morphologic extent of disease, with more extensive ground-glass or consolidation linked to a higher mortality, especially in patients with prominent traction bronchiectasis. Presentation \200 In typical cases, dyspnoea progresses inexorably over days to weeks, of ten in association with distressing cough. Diagnosis For de \201 nitive diagnosis, a typical clinical and CT presenta- tion should be associated with the absence of an overt cause and the presence of DAD at a diagnostic surg ical biopsy. However, disease is often too extensive at presen- tation to allow a biopsy to be performed and in many cases, BAL to exclude underlying infection with con \201 dence m ay not be realistic. In reality, the diagnosis is often based on clinical and CT features a nd the differential diagnosis can be subdivided into other forms of diffuse lung disease (c onsidered below) and heart failure, infection or drug- induced lung disease. The combinatio n of extensive ground-glass attenuation and traction bronchiectasis on CT is strongly indic ative of AIP. However, it should not be forgotten that both infection and drug toxicity may result in DAD. Furthermore, even when it is clear that heart fail- ure is not the primary problem, the possibility of superven- ing heart failure due to hypoxia should be kept in mi nd. In some cases, there is no obvious prodrome but more commonly, the illness begins with symp toms suggestive of viral infection, including fever, myalgia and malaise. \200 The clinic al \201 ndings at presentation do not distinguish between AIP and ARDS of known cause. In spiratory crackles are usual but clubbing has not been reported. \200 Pulmonary function data have yet to be reported (due to the rapidly progressive nature of the presentation). \200 In most cases, there is the highly non-speci \201 c \201 nding of a neutrophilia at BAL. High resolution CT Prognosis The average survival rate is probably less than 20%, based upon a reported range of 10 \200\22350%, but with advances in intensive care practice this may be an underestimat e. In approximately half of survivors, pulmonary function is either normal or stable but im paired in the long term. In the remaining cases, there is slow progression of underlying pu l- monary \201 brosis with recurrent acute respiratory failure in occasional patients. Th is has caused some to argue that AIP is sometimes an initial presentation of IPF, whether d e novo or in a setting of hitherto unsuspected chronic disease. Management AUTHOR \200\231S TIP Because AIP is a rare disease, there are no controlled treatment data and it is not known whether therapeutic intervention is bene \201 cial. It is usual to giv e high doses of corticosteroids (e.g. IV methyl prednisolone) and IV cyclophosphamide is oc casionally employed. Because dis- ease stabilizes or resolves in half of survivors, an aggr es- sive initial approach is warranted, including the use of mechanical ventilation in pati ents without major co-mor- bidity. In this regard, AIP should be distinguished from acute e xacerbations of IPF, a disorder in which admission to the intensive care unit is virtually never appropriate Fig. 7.5.1 CT scan of patient with AIP showing widespread ground glass shadowing with some consolidative changes typically in a sub-pleural distribution (Courtesy of Dr Fergus Gleeso n). On CT, ground-glass attenuation is almost always the most prominent abnormality and tends t o be extensive, although often patchy, and variably associated with ana- tomical distortion and traction bronchiectasis. CHAPTER 7.5 Acute interstitial pneumonia 141 Other diffuse lung diseases with an AIP presentation Acute exacerbations of IPF It is incre asingly recognized at least 10% of IPF patients develop a precipitous course, in which an e pisode of acute deterioration follows a period of relative stability. The term \200\230acu te exacerbation of IPF \200\231 is currently reserved for episodes in which the etiology is uncertain. Major variations in case de \201 nitions between clinical series have prompted a recent consensus statement in which it is recommended that diagnostic criteria should in clude: \200 a previous or concurrent diagnosis of IPF; \200 unexplained worsening or de velopment of dyspnoea Acute exacerbations of NSIP A clinical and CT presentation of acute exacerbation, indis- ti nguishable from that seen in IPF, is increasingly recognized in patients with idiopathic NS IP, and also in the setting of connective tissue disease. Although total numbers of reporte d cases are low, the treated outcome tends to be good, even when disease is extensive, exce pt in rheuma- toid arthritis (in which an underlying histological pattern of usual intersti tial pneumonia is more likely). Underlying NSIP, which is, itself, characterized by promine nt ground- glass, tends to be more dif \201 cult than IPF to detect on CT, in the setting of an acute exacerbation. Pending further data, it appears reasonable to adopt a more aggre ssive management algorithm for acute exacerbations in known NSIP than in IPF, including mec hanical ventilation in carefully selected cases. over 30 days; bilateral ground-glass abnormalities and/or consolida- tion superimposed on a background re ticular or honey- comb pattern compatible with IPF on CT; Fulminant cryptogenic organizing pneumonia (COP) Very infrequently, COP is devastatingly se vere at presenta- tion and may progress to death, in the absence of overt pulmonary \201 brosis. Fulminant COP has been described in a small series and number of case reports and h as a variable but often good treated outcome. This clinical presentation with a picture res embling ARDS may be indistinguishable from AIP, clinically and on CT. However, the combinat ion of traction bronchiectasis, interlobular septal thickening and intralobular reticular a bnormalities tends to be more prominent on CT in AIP. In this life- threatening disorder, t he outcome may be critically depen- dent on ventilatory support and aggressive therapy with IV corticosteroids. no evidence of pulmonary infection, based on endotra- cheal aspirate or BAL; exclusion of alternative disorders including left heart failure, pulmonary embolism and ide nti \201 able causes of lung injury. The risk of an acute exacerbation does not, in general, appear to be linked to underlying d isease severity in IPF (as judged by the severity of lung function impairment). How- ever, disease severity may be important in episodes devel- oping after diagnostic surgical lung b iopsy, which is believed to be a precipitating factor in some cases. This may explain a pos t-operative mortality of 15% in group of IPF patients with average gas transfer levels of a pproximately 30% of predicted. Hypoxia is usual, and early respiratory failure is common. T here are no diagnostic laboratory \201 ndings, with the typi- cal BAL neutrophilia also e xpected in AIP. Diffuse ground- glass is generally present on chest radiography and is prom inent on CT, with or without consolidation. The key diagnostic CT feature, not seen in AIP, is the presence of typical IPF \201 ndings (predominantly bibasal sub-pleural reticular abnormalities or honeycombing). DAD in combi- nation with usual interstitial pneumonia is a lmost always found at surgical biopsy, although organizing pneumonia is occasionally seen i n the absence of DAD. The history of recent deterioration and presence of exten- sive groun d-glass on HRCT in a setting of known IPF usually makes the diagnosis obvious. However, hea rt failure, oppor- tunistic infection and drug-induced lung disease may all result in exten sive ground-glass on CT in a setting of IPF and may all bene \201 t from correct managemen t. In typical disease, characterized by hypoxia and extensive ground-glass on CT, in-hospit al mortality is 80 \200\22390% despite treatment. As in AIP, high dose corticosteroid thera py tends to be instituted, in the absence of controlled treatment data. Although non-invasi ve ventilatory support may be useful in selected patients, both as a bridge to transplantat ion and for palliation, invasive ven- tilation is not appropriate, because of the poor outc ome associated with underlying IPF. In the small subset of patients presenting with milder disease, outcomes are more variable, but this may re \202 ect major differences in diagnos tic criteria. When ground-glass on CT is focal and limited, the short term outcome with cor ticosteroid therapy is relatively good. However, it is not clear that this CT picture is a precursor of typical extensive disease and nor is it clear that the better outcome in these patients can be ascribed to treatment. Further reading Akira M, Hamada H, Sakatani M, et al. CT \201 ndings during phase of acce lerated deterioration in patients with idiopathic pulmonary \201 brosis. AJR Am J Roentge nol. 1997; 168: 79 \200\22383. Collard HR. Diseases: other entities of the idiopathic interstitial pneumonias. In Costabel U, du Bois RM, Egan JJ (eds): Diffuse Parenchymal Lung Disease. Cape Town: Karger, 2007; p p. 181 \200\223184. Collard HR, Moore BB, Flaherty KR, et al. Idiopathic Pulmonary Fibrosis Clinical Research N etwork Investigators. Acute exacer- bations of idiopathic pulmonary \201 brosis. Am J Res pir Crit Care Med 2007; 176: 636 \200\223643. Hamman L, Rich AR. Acute diffuse interstitial \201 brosis of the lungs. Bull Johns Hopkins Hosp 1944; 74: 177 \200\223212. Ichikadu K, Suga M, Muller NL, et al. Acute interstitial pneumonia: comparison of hig-resol ution computed tomography \201 ndings between survivors and non-survivors. Am J Respir Cr it Care Med 2002; 165: 1551 \200\2231556. Kondoh Y, Taniguchi H, Kitaichi M, et al. Acute exacerbation of inter- stitial pneumonia fo llowing surgical lung biopsy. Respir Med 2006; 100: 1753 \200\2231759. Nizami IY, Kissner DG, Visscher DW, et al. Idiopathic bronchiolitis obliterans with organiz ing pneumonia. An acute and life-threaten- ing syndrome. Chest 1995; 108: 271 \200\223277. Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than id iopathic pulmonary \201 brosis. Chest 2007; 132: 214 \200\223220. Utz JP, Ryu JH, Douglas WW, et al. High short-term mortality fol- lowing lung biopsy for us ual interstitial pneumonia. Eur Respir J 2001; 17: 175 \200\2239. Vourlekis JS, Brown KK, Cool CD, Y et al. Acute interstitial pneumo- nitis: case series and review of the literature. Medicine 2000; 79: 369 \200\223378. K HARRISON 142 7.6 Lymphoid interstitial pneumonia De \201 nition Lymphoid interstitial pneumonia (LIP) is a rare clinico- pathological entit y \201 rst described by Liebow and Car- rington in 1966. Some cases previously described as LIP have been re-evaluated as non-Hodgkin \200\231s low-grade B cell MALT (mucosa-associ ated lymphoid tissue) lymphoma. LIP is now considered a histological variant of diffuse pul mo- nary lymphoid hyperplasia although its pathogenesis remains unknown. Idiopathic and sec ondary forms of LIP are recognized. Idiopathic LIP is one of seven IIPs in the new ATS/ERS re-classi \201 cation. Epidemiology Incidence and prevalence are unknown. Patients may pre s- ent at any age (mean 48 years). LIP is more common in women with a male: female ratio of 1:2.2. The typical delay between symptom onset and presentation ranges from 1 month to 12 years (mean of 29 months). LIP and HIV infection \200 LIP is seen in 16 \200\22350% of HIV affected children and is an AIDS-de \201 ning illness in the <13 years age group. Can be diagnosed by symptoms and radiographic appearances alone. Usually occurs when the CD4+ T-lymphocyte count is within the normal range. Is rare in adults with HIV (<5%). Investigations Lung function \200 There is a restrictive defect with reduced gas transfer . \200 Airways obstruction has occasionally been reported. \200 Levels of hypoxaemia ar e variable. Serological tests \200 A mild anemia and raised ESR are often present. \200 Over 80% of patients have dysproteinaemias \200\223 most Clinical approach History: key points \200 Breathlessness \200\223 typically progressive over several months. \200 Cough \200\223 usually dry, productive in 20%. \200 Additio nal symptoms \200\223 fever, malaise, weight loss, pleu- commonly polyclonal elevation of IgG and IgM. Hypogammaglobulinaemias ( 20% of all patients) and mono clonal gammopathies (IgG or IgM) ar e less frequent. AUTHOR \200\231S TIP Check serum immune electrophoresis in all patients with LIP. A monoclo nal gammopathy or hypogamma- globulinaemia suggest lymphoproliferative malignancy. ritic pain and arthralgia less common. Symptoms of speci \201 c autoimmune disease or immuno- de \201 ciency states. Examination: key points \200 Basal inspiratory crackles in around 60% of patients; become more prominent as the disease progresses. \200 Finger clubbing is uncommon (10% cases), unless Chest radiography (Fig. 7.6.1) advanced \201 brotic disease is present. \200 Examination may be unremarkable. \200 P eripheral lymphadenopathy and splenomegaly are uncom- mon and suggest an alternate or co-ex isting diagnosis. \200 Features of underlying autoimmune disease or systemic manifestatio ns of immunode \201 ciency in 50% of cases. Causes Underlying associations \200 LIP is associated with underlying collagen vascular d is- eases, particularly Sj grens \200\231 syndrome (approximately 25% of cases) and up to 1% of patients with Sj grens \200\231s syndrome will acquire LIP at some time. Fig. 7.6.1 Typical CXR features of LIP. LIP is also associated with the following conditions: systemic lupus erythematosus, rheumat oid arthritis, per- nicious anemia, autoimmune haemolytic anemia, Hashimoto \200\231s thyro iditis, chronic active hepatitis, primary biliary cirrhosis, myasthenia gravis, common vari able immunode \201 ciency (CVID) \200\223 high incidence of conver- sion to malignancy. Bibasal, reticulonodular opacities, with or without septal lines, are common. There may be nodules merging with patchy, multifocal consolidations which are occasionally transient. In severe disease honeycombing can develop. \200 Pneumothorax is a rare presenting featur e. HRCT thorax (Fig. 7.6.2) \200 Ground glass attenuation with poorly de \201 ned centri - lobular (and often sub-pleural) nodules is common. \200 Thickening of bronchovascular b undles and interlobular Drug-induced LIP may occur with phenytoin and captopril. \200 Rarely associated with bone marrow transplantation, legionella pneumonia and Castleman \200\231s disease. \200 Epstein \200\223Barr viral has been isolated in some cases. \200 Once systemic disease has been excluded, LIP may be termed idiopathic. septa are seen in > 80% cases. Cystic airspace shadowing and lymphadenopathy occur AUTHOR \200\231S TIP Idiopathic LIP is rare. All cases must be thoroughly inves- tigated fo r underlying cause or associations such as col- lagen vascular disease and immunode \201 c iency. in 68% cases. Pleural effusions are rare, except in HIV-related LIP and may represent underlying lymphopr oliferative disease. CHAPTER 7.6 Lymphoid interstitial pneumonia 143 Unproven effect on the natural history of the condition. \200 Optimum dose and duration o f therapy uncertain. \200 Similar treatment regimens as recommended for COP have been utilized: \200 Prednisolone 0.75 \200\2231mg/kg/day for 8 to 12 weeks or until maximum improvements in lun g function/ radiology Subsequent slow dose tapering to 0.25mg/kg/ day for 6 to 12 weeks Most patients with HIV-related LIP treated with cortico- steroids exhibit a good response. Anti-retroviral therapy \200 Symptoms improve with a reduction in viral load and increase in the CD4+ count. Single agent (Zidovudine) and triple therapy with nucle- oside analogs have resulted in cli nico-radiological resolution in some HIV-positive patients. Fig. 7.6.2 Some of the different HRCT changes seen in LIP (images courtesy of Prof David Ha nsell). Thin-walled, perivascular cysts ranging from 1 \200\22330mm in Other treatments \200 There are anecdotal reports of clinical response to other immunosup pressive agents outlined in Prognosis. \200 Case reports on CVID-related LIP have improve d with- cyclosporin (which inhibits CD4 +ve Th2 lymphocyte activation) and IV immunoglobuli n. size are seen in 68 \200\22382% of cases. CT differential diagnosis includes: hypersensitivity pneu- monitis, DIP, NSIP, sarcoidosis and lymphangitis. AUTHOR \200\231S TIP Demonstration of mediastinal or hilar lymphadenopathy necessitates exc lusion of other diagnoses, e.g. lymphoma. Prognosis \200 In a recent observational study of 15 patients the median survival was 11.5 years. Surgical lung biopsy \200 Allows de \201 nitive diagnosis in >90% cases. \200 Procedur e of choice if patient \201 t enough and able to Survival in HIV-positive patients is similar to those without LIP. Prognosis is better in younger patients and those with tolerate intended therapy. non-idiopathic LIP. Histopathology \200 Benign-looking, predominantly T lymphocytes expand Combining \201 ve studies of 52 patients all treated with cor- ticosteroids alone or with additional chlorambucil, cyclo- phosphamide, colchicine, azathioprine or methotrexate: 35% had a dramatic improvement, 15% had some improve ment, 27% remained stable and 23% died (f rom progressive pulmonary \201 brosis, respiratory failure, infec- tion from immunosuppre ssion or transformation to lymphoma). the interstitium and compress alveolar spaces. There are perilymphatic and bronchial lymphoid aggre- gates of polyclonal B cells. There is type II cell hyperplasia and interstitial giant cells. Non-caseating granulomata may be seen. Perivascular and paraseptal amyloid deposition may occur. \200 Pathological \201 ndings must be differentiated from: B-cell lymphoma, follicular bronchiolitis, lymphomatoid granu - lomatosis, hypersensitivity pneumonitis, NSIP, UIP and EBV-associated infections. Malignant transformation Malignant transformation to a low grade B-cell lymphoma occurs in <5% of patients and has a favorable outcome. Lung transplantation Single lung transplantation should be considered in patients who deter iorate despite therapy. Referral criteria are broadly similar to those for patients with UI P. AUTHOR \200\231S TIP In immunocompromised patients, histochemical stains to exclude Pneumoc ystis jirovecii and Epstein \200\223Barr virus must be performed as these conditions mimic LIP. Further reading Cha S-I, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumo- nia: cli nical features, associations and prognosis. Eur Respr J 2006; 28: 364 \200\223369. Management and treatment Overview \200 No formal controlled trials \200 Current therape utic regimens are based on anecdotal Davies CWH, Juniper MC, Gray W, et al. Lymphoid interstitial pneumonitis associated with co mmon variable hypogammaglob- ulinaemia treated with cyclosporin A. Thorax 2000; 55: 88 \200 \22390. Johkoh T, Muller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-s ection CT \201 ndings in 22 patients. Radiology 1999; 212: 567 \200\223572. experience from small case series. Decisions regarding treatment should take into account the patient \200\231s symptoms, phys iological variables, \201 tness and desire for therapy. Nicholson AG, Wotherspoon AC, Diss TC, et al. Reactive pulmo- nary lymphoid disorders. Histopathology 1995; 26: 405 \200\223412. Exclude infections such as Mycobacterium tuberculosis Swigris JJ, Berry GJ, Raf \201 n TA, et al. Lymphoid Interstitial Pneumonia: and fungi before commencing steroid therapy. a narrative review. Chest 2002; 122: 2150 \200\2232164. Corticosteroid monotherapy \200 Corticosteroids are used in >90% of cases J MURCHISON & N HARANI 144 7.7 Cryptogenic organizing pneumonia The terms cryptogenic organizing pneumonia (COP) is pre- ferred to bronchiolitis obliterans organizing pneumonia (BOOP) since the former better re \202 ects the clinico-patho- logic al entity of organizing granulation tissue within the alveo- lar ducts and sacs that someti mes, but not always, extends into the small bronchioles. There are a number of causes of, o r associations with, organizing pneumonia that must be con- sidered before a diagnosis of c ryptogenic OP can be made (Table 7.7.1). common than generally considered. COP occurs with equal frequency in men and women and is p robably more common in smokers than non-smokers. Typical COP Clinical and radiological features Most cases of COP present with symptoms, cli nical signs and chest radiography that are largely indistinguishable from community acquire d pneumonia, a far commoner condition. A diagnosis of COP is often \201 rst considered wh en there is failure to respond to empirical antibiotic therapy. \200 Typical symptoms of COP are dry cough, breathlessness, fatigue and anorexia. Sputum production is uncommon and haemoptysis is rare. AUTHOR \200\231S TIP The presentation of COP is often indistinguishable from community acqu ired pneumonia; failure to respond to antibiotic therapy and migratory CXR changes should a lways raise the possibility of COP. Fever with unilateral/bilateral crackles or clear chest are common examination \201 nding s. Bronchial breathing, even in the presence of radiographic evidence of consolida- tion, i s rarely reported. Table 7.7.1 Is it cryptogenic? Some causes of secondary organizing pneumonia Lung function tests play little or no role in diagnosing or monitoring COP. Airflow obstruc tion is uncom- mon despite the apparent \200\230bronchocentric \200\231 pattern of disease . Infective pneumonia Streptococcus pneumoniae, Mycoplasma pneumoniae, Legionella sp, oppourtunistic organisms, v iruses Blood tests usually reveal mild neutrophilia and raised Radiation Post breast-cancer radiotherapy in \202 ammatory markers (CRP, ESR) Connective tissue disease Rheumatoid arthritis, dermatomyositis/polymyositis, systemic sclerosis, systemic lupus eryt hematosus Chest radiography typically features unilateral or bilat- eral patchy non-segmental consoli dation, without a par- ticular zonal predilection. Presentation with a single area of lobar consolidation is far less common. Migratory or \200\230 \202 itting \200\231 radiograph changes over a period of weeks or months is suggestive of COP (Fig. 7.7.1). Pleural effusio n is rarely visible on CXR. Occasionally COP presents as a solitary lung nodule. Drugs Bleomycin, amiodarone, methotrexate and others In \202 ammatory bowel disease Crohn \200\231s, ulcerative colitis Neoplasms In vicinity of bronchial carcinoma, in association with hematological malignancies. The HRCT scan aids in the distinction of COP from \201 brotic ILDs, in particular IPF, bu t the distinction from other IIPs or from hypersensitivity pneumonitis is less reliable. Th ere are no pathognomic features on HRCT to distinguish COP from infection. Air-space con- s olidation, which is often peripheral and/or peribron- chial, is present on CT in 90% of pat ients with COP (Fig. 7.7.2). Epidemiology The incidence of COP is not known and has not been extensively studied. Whilst often considered a rare condi- tion, most chest physicians will have experience of seeing patients with COP and indeed the condition may be more (a) (b) Fig. 7.7.1 40-year-old female with \201 tting consolidation due to COP. (a) Right lower a nd left upper zone consolidation. (b) Three months later there is consolidation lateral to left heart border, medially at the right base and laterally in the right mid zone. CHAPTER 7.7 Cryptogenic organizing pneumonia 145 Relapses, both on and off treatment are quite common, and may be more common with short-cou rse (3 \200\2236 months) compared to extended-course (12 months) steroid therapy. However r elapses in typical COP are; (i) not associated with increased mortality; (ii) not associate d with progressive lung \201 brosis; and (iii) as responsive to corticosteroids as the in itial presentation. \200 On this basis, a suggested regimen, that may be modi \201 ed to suit the individual case, is oral prednisolone as follows: \200 \200 \200 \200 \200 0.75mg/kg for 4 weeks; 0.5mg/kg for 4 weeks; 20mg daily for 4 weeks; 10mg daily for 6 weeks ; 5mg daily for 6 weeks then stop. Relapses can be treated by re-instigating the regimen either with the initial dose, or with the lowest dose at which the disease was previously controlled. Fig. 7.7.2 HRCT scan of COP. Patchy peripheral consolidation with limited ground glass atte nuation. On occasion, COP can relapse and remit radiologically with few or no associated symptoms an d without a change in therapy. Thus relapses of COP do not always require treatment. Typically the consolidation seen on HRCT is accompanied by diffuse ground-glass opaci \201 cation and there may also be multiple small nodules not necessarily obvious on the plain c hest radiograph. Another common \201 nding is bronchial wall thickening and bronchial dil atation in involved areas. 20 \200\22330% patients are found to have small unilateral or bi lat- eral pleural effusions on CT. Sub-pleural reticulation is seen occasionally. Other manifestations of organizing pneumonia Acute fulminant COP \200 Occasionally COP pr esents with widespread CXR in \201 l- trates and acute respiratory failure, in a syndrome that overlaps with AIP and ARDS. The usual scenario is that such cases are initially misdia gnosed as severe commu- nity acquired pneumonia on the high dependency or intensive care un it, but fail to respond to conventional antibiotic therapy. Making a diagnosis of COP AUTHOR \200\231S TIP The diagnosis of COP is dependent upon integrating clinical, radiologi cal and wherever possible histological evidence. COP should never be diagnosed on the basis of histology alone. BAL plays an important role in excluding infection (noso- comial, antibiotic resistant bact eria or opportunistic organisms) in this setting, but a con \201 dent diagnosis of COP aga in requires transbronchial or preferably surgical lung biopsy. A con \201 dent diagnosis of COP requires integration of clinical, radiographic and histol ogical evidence. Typical COP may be diagnosed with reasonable con \201 dence on clinical a nd radiological grounds alone if infection can be excluded and a subsequent brisk response to corti- costeroids is observed. In general however, lung tissue biopsy should be sought w henever possible before treating COP. The diagnosis of acute fulminant COP is important since there is the prospect of recovery w ith high dose corti- costeroid therapy (e.g. methylprednisolone, 500 \200\2231000mg per day for 3 consecutive days followed by prednisolone 1 \200\2231.5mg/kg/day or equivalent). Post-radiotherapy organizing pneumonia \200 A well-recognized form of OP occurs in associ ation with radiotherapy, particularly tangential \201 eld radiotherapy for breast cancer. Transbronchial lung biopsy may be suf \201 cient to make a histological diagnosis of organ izing pneumonia, but a surgical lung biopsy should be sought if the diagnosis remains uncer tain. Post-radiotherapy OP is different to classic (sporadic) post-radiotherapy pneumonitis in th at it generally occurs later (9 \200\22312 months, as opposed to 1 \200\2232 months followi ng radiotherapy), involves non-radiated areas of lung, and does not progress to lung \201 brosis. The diagnosis of COP should never be made on histo- logical basis alone because the histolo gical pattern of organizing pneumonia can occur in other settings. For example, it is quite common to \201 nd OP in the vicinity of lung cancer. Post-radiotherapy OP is therefore very like the crypto- genic form of the disease and shoul d be treated in the same way.