This page intentionally left blank S BOURKE 148 7.8 Extrinsic allergic alveolitis Epidemiology The most common types of extrinsic allergic alveolitis (EAA) are bird fancier \200\231s lung from a pet bird in the home or the sport of pigeon racing, farmer \200\231s lung due to fungi in moldy hay or straw and various types of humidi \201 er lung due to fu ngi or bacteria in water aerosols in the home or workplace. A recent international study sh owed that 61% of cases of EAA were due to birds, 21% to farming and 12% to various fungi en countered in the home or workplace. In 1.5% of cases the source of the antigen was not iden ti \201 ed In the UK one million homes have a pet bird, 2% of the population work in agric ulture and there are approxi- mately 85,000 registered pigeon fanciers. Only a small %age o f those exposed to an antigen of EAA develop the dis- ease. It is estimated that 3.4% of bu dgie fanciers, 8% of pigeon fanciers and 4.5% of farmers develop EAA but the prevalence var ies according to the circumstances of antigen exposure. In Japan summer-type EAA is the mos t common type and is due to fungal molds in the home. Work- related EAA accounts for about 6% of occupational lung disease with approximately 500 cases reported to the UK surveillanc e scheme over a decade, mainly involving work- ers in agriculture, foresting and \201 shi ng. As work practices change, some classic causes of EAA have faded but new syndromes emerg e. Thus mushroom worker \200\231s lung and cork worker \200\231s lung are less common nowad ays but metal working \202 uid EAA is now an important cause of EAA in workers in car man ufacturing plants from contamination of \202 uid used to cool and lubricate metal. Classi \201 cation and course EAA is a complex dynamic disease which varies in its pre- se ntation and clinical course (Fig. 7.8.1). Traditionally it is classi \201 ed into acute, s ubacute and chronic forms, but patients don \200\231t always \201 t neatly into this clas si \201 cation and different patterns emerge over time and depend on the population studie d. \200 Sensitisation is the development of antibody and cellular responses as part of an antigen-processing mechanism, but only a few sensitized individuals progress to develop EA A. Acute EAA presents as fever, malaise, cough and dys- pnoea 4 \200\2238 hours after antigen exposure, resolving within 48 hours. This is common amongst pigeon fanciers who have high i ntensity exposure to 100 \200\223200 racing pigeons. Many have acute mild stable symptoms w hich they manage themselves in the community without medical attention. More severe acute E AA presents to hospital with alveolitis and hypoxaemia, which usually resolve quickly, but may recur on further antigen exposure. \200 Chronic EAA presents insidiously with progres sive dys- pnoea and \201 brosis. This pattern is more common where there is low-grade pro tracted antigen exposure, such as occurs when pet birds are kept in the home. Subacute EAA is characterized by progressive dyspnoea and alveolitis with some acute sympto ms after antigen exposure. Acute or recurrent EAA does not usually progress to chronic \201 brotic EAA and the outco me is usually good with only mild residual impairment of lung function. However, a small pr oportion of patients with EAA develop progressive \201 brosis \200\223 even after stoppi ng antigen exposure \200\223 which behaves like IPF. Chronic bronchitis, airways obstructi on, and emphysema may occur as part of the spectrum of EAA. Factors in \202 uencing the on set and progression of EAA AUTHOR \200\231S TIP Focus on the work, home and recreational environment. Fig. 7.8.1 EAA. CHAPTER 7.8 Extrinsic allergic alveolitis 149 are poorly understood but include the circumstances of antigen exposure and individual susc eptibility in terms of human leucocyte antigen (HLA) type, cytokine gene poly- morphisms an d T-regulatory cell function. Investigation and diagnosis Because EAA is so diverse and dynamic no single test is diagnos tic, investigations should be adapted to the clinical circumstances, and the diagnosis is e stablished from a combination of features and exclusion of alternative diagnoses. \200 Su spicion of an association between symptoms and con- tact with a provoking antigen is the \201 rst step in diagnosis. Table 7.8.1 Diagnosing extrinsic allergic alveolitis 1 Identify a provoking antigen 2 Demonstrate an immune response 3 Relate symptoms to antige n exposure 4 Measure impairment of lung function 5 De \201 ne the radiographic abnormaliti es 6 Consider the need for lung biopsy and lavage 7 Consider an antigen challenge study 8 E xclude alternative diagnoses Fig. 7.8.2 Acute EAA showing airway centered nodules and ground glass shadowing with areas of hyperlucency. Demonstration of an antibody or cellular response to the antigen is essential, but not suf \201 cient for diagnosis since many asymptomatic exposed subjects show similar immune resp onses. At least 85% of patients with farm- er \200\231s lung or bird fancier \200\231s lung have antibodies to the provoking antigen. Dif \201 culties in detecting an antibody respo nse may occur when the precise antigen is unknown or if exposure has now ceased although th e patient has developed chronic disease. Antibody-nega- tive EAA is unusual and the diagnos is then requires persuasive evidence from other tests. Lymphocyte stim- ulation tests may c on \201 rm the immune nature of the disease but these assays are not widely available and are not well validated since many of the antigens of EAA can provoke non-speci \201 c immu ne stimulation. Lung function tests typically show reduced lung volumes, impaired gas transfer and hypoxaemia. The chest radiograph usually shows diffuse parenchymal in \201 ltrates but is normal in 20 % of cases of acute EAA. HRCT is more sensitive and is probably always abnormal in active E AA. In acute EAA there is often a characteris- tic appearance of diffuse airway centered mi cronodules with patchy ground-glass shadowing and areas of hyper- lucency on expiration due to bronchiolotis and air-trap- ping (Fig. 7.8.2). Fig. 7.8.3 Chronic EAA showing reticularious, secondary bronchial dilatation and honeycombi ng. granulomas. Granulomas are most characteristic but are present in only 66% of cases. In chr onic \201 brotic EAA surgical biopsy may show the histological patterns of UIP, NSIP or C OP. The prognosis is worse for patients with UIP but there can be considerable dif \201 cu lty in determining whether this histopathological pattern has arisen from EAA or from IPF. In chronic EAA the HRCT appearances may be similar to IPF with reticulation, secondary bron chial dilatation and honeycombing (Fig. 7.8.3). BAL typically shows a lymphocytosis with a predomi- nance of CD8 T-cells, but a neutrophil alveolitis occurs after antigen exposure and also in chronic \201 brotic EAA. Furthermore asymptomatic exposed subjects may also have lymphocytosis so that it re \202 ects a cellu lar immune response rather than disease. BAL also helps to exclude infection. Laboratory-based antigen challenge tests can be helpful in the context of research, particu larly where new anti- gens are identi \201 ed but for most forms of EAA there is a lack of standardized antigens and it can be dif \201 cult to differentiate EAA from other reactio ns such as inhala- tion fevers or organic dust toxic syndrome. A natural challenge may be h elpful in clinical practice whereby the clinical features are monitored when the patient is removed from and then re-exposed to the suspect envi- ronment in the workplace or home. The histopathology of EAA is distinctive but not pathog- nomonic and diagnosis requires com patible clinical fea- tures. In acute EAA transbronchial biopsy may provide supporting evid ence of lymphocytic in \202 ammation, foamy macrophages, giant cells with cholesterol clef ts and S BOURKE 150 Patients \200\231 FAQ: do I have to give up my work/birds? Answer. stopping exposure is the safest advice, and is essential if you have severe or progressive EAA. If EAA has been mil d and stable you may choose to continue expo- sure using respiratory protection and antigen avoidance but you should have medical supervision to ensure that progressive lung damage i sn \200\231t developing. AUTHOR \200\231S TIP In most cases a diagnosis of EAA can be made from a combination of cli nical features and non-invasive tests without the need for lung biopsy or bronchoalveolar l avage. Treatment \200 Avoidance of further contact with the provoking antigen Further reading Bourke SJ, Banham SW, Carter R, et al. Longitudinal course of extrinsic all ergic alveolitis in pigeon breeders. Thorax 1989; 44: 415 \200\223418. is the main treatment of EAA. Some patients have had mild stable symptoms for several years but have not consulted doctor s because they fear that their livelihood is at stake in the case of farmers or that their commitment to their sport will not be appreci- ated in the case of pigeon fanciers. They ma y be reluctant to stop antigen exposure. Several long-term studies show a favorable outcome in such patients despite con- tinued antigen exposure, indicating the complexity of the ho st \200\223antigen interaction in EAA. Pigeon fanciers can be encouraged to spend less time in the loft, to avoid activi- ties where there is a high level of antigen, such as \200 \230scrap- ing out \200\231, and to wear a loft coat and hat that are removed on leaving th e loft so as to avoid continuing contact with antigen carried on clothing or hair. Farmers can use silage rather than hay for foddering animals and adopt modern practices with drying systems which reduce the moisture and mold content of hay. Bourke SJ, Dalphin JC, Boyd G, et al. Hypersensitivity pneumonitis: current concepts. Eur Respir J 2001: 18(Suppl 32): 81s \200\22392s. Cormier Y, Brown M, Worthy S, et al. High resolution computed tomographic characteristics i n acute farmer \200\231s lung and in its fol- low-up. Eur Respir J 2000; 16: 55 \200\22360. Dawkins P, Robertson A, Robertson W et al. An outbreak of extrinsic alvoelitis at a car eng ine plant. Occup Med 2006; 56: 559 \200\223565. Erkinjuntti-Pekkanen R, Kokkarinen J, Tukiainen HO, et al. Longterm outcome of pulmonary fu nction in farmer \200\231s lung: a 14 year follow- up with matched controls. Eur Respir J 1 997; 10: 2046 \200\2232050. Fink JN, Ortega HG, Reynolds HY et al. Needs and opportunities for research in hypersensiti vity pneumonitis. Am J Respir Crit Care Med 2005; 171: 792 \200\223798. Kokkarinen JS, Tukianen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer \200\231s lung. Am Rev Respir Dis 1992; 145: 3 \200\2235. Respiratory protection masks have been shown to improve symptoms and prevent a reaction to antigen challenge. Lacasse Y, Selman M, Costabel U et al. Clinical diagnsosis of hyper- sensitivity pneumoniti s. Am J Respir Crit Care Med 2003; 168: 952 \200\223958. McDonald JC, Chen Y, Zeveld et al. Incidence by occupation and industry of acute work-relat ed respiratory diseases in the UK, 1992 \200\2232001. Occup Environ Med 2005; 62: 836 \200 \223842. In acute severe EAA prednisolone 40 mg/day, tapering over 8 weeks to zero, hastens the rate of recovery of lung function but does not alter the longterm outcome. \200 In chronic \201 brotic EAA further antigen contact is not advisable. Many of these patients improve on predniso- lone particularly when biopsy shows a NSIP or COP pattern. Patients with a UIP p attern respond poorly to steroids and they are usually treated in the same way as patients with IPF. Ohtani Y, Saiki S, Kitaichi M et al. Chronic bird fancier \200\231s lung: his- topathologic al and clinical correlation. An application of the 2002 ATS/ERS consensus classi \201 cati on of the idiopathic interstitial pneumonias. Thorax 2005; 60: 665 \200\223671. Management of occupational EAA involves management of both the individual and the affected industry in order to reduce the risk to other workers. AUTHOR \200\231S TIP Be sympathetic to the commitment of farmers to their livelihood and of pigeon fanciers to their sport. Give sen- sible advice based on a knowledge of the natural history of the different forms and patterns of EAA. Some patients will opt to continue the ir work or hobby in much the same way that not all sportsmen stop playing sports when injur ed! This page intentionally left blank S MUKHERJEE & M SPITERI 152 7.9 Sarcoidosis Sarcoidosis is a chronic multisystem disorder of unknown etiology character ized by formation of granulomata within affected organs and consequent distortion of their normal architecture. Typically, these are non-caseating epithelioid granulomata involving o rganized collections of activated macrophages and T lymphocytes. Pulmonary involvement is m ost common followed by eyes, lymph nodes, skin and liver. Presentations \200 Asymptomatic: (10 \200\22320%); discovered during routine CXR screening. Acute: (20 \200\22340%); develops over 1 \200\2232 weeks with fever, malaise, polyarthralgi a, anorexia, cough, chest discom- fort, occasionally night sweats and weight loss. Fig. 7.9.2 Conjunctival sarcoid nodules. (See Plate 2.) Lofgrens syndrome: acute onset with erythema nodo- sum, polyarthritis and bilateral hilar l ymphadenopathy on CXR. Upper respiratory tract: involvement of nasal mucosa, Heerfordt syndrome: acute onset fever, parotid enlarge- larynx, epiglottis. ment, anterior uveitis and facial nerve palsy. Liver: granulomatous hepatitis, asymptomatic elevation of liver enzymes, hepatomegaly, intr ahepatic cholestasis; portal hypertension is rare. Insidiuous onset: (40 \200\22370%); this group tends to develop chronic sarcoidosis with gr adual \201 brotic remodeling of involved organs with eventual irreversible damage. Heart: restrictive cardiomyopathy, pericarditis, arrhyth- mias, conduction defects includin g complete heart block, sudden cardiac death, congestive cardiac failure, cor pulmonale. Organ involvement \200 Lungs: 90% have abnormal \201 ndings at some point during the co urse of the disease. Around 50% develop perma- nent abnormalities including background pare nchymal scarring and/or persistent mediastinal lymphadenopathy. 5 \200\22315% exhibit progr essive disease with interstitial \201 bro- sis, large airways involvement and/or pleural effusion (1 \200\2235%); pneumothorax is rare. Musculoskeletal: polyarthritis, myopathy and myositis, bone lesions and dactylitis (Fig. 7.9.3). Lymph nodes: lymphadenopathy (paratracheal, hilar, mediastinal commonest). Skin: erythema nodosum, plaques, maculopapular erup- tions (Fig. 7.9.1), subcutaneous nodul es, lupus pernio, in \201 ltration of new/existent scars and keloid formation. Fig. 7.9.3 Extensive hand digit distortion with bone cyst formation and associated dactylit is in sarcoidosis. (See Plate 3.) Nervous system: unilateral facial nerve palsy, multiple cra- nial nerve palsies, space-occu pying lesion, aseptic meningi- tis, hypothalamic \200\223pituitary axis involvement, seizur es, cerebellar ataxia, spinal cord involvement, peripheral neu- ropathy; presentations can mimic multiple sclerosis. Hematology: peripheral lymphopaenia and splenomeg- aly, occasionally eosinophilia; bone mar row in \201 ltration can cause anemia, neutropaenia and thrombocytopae- nia at presentatio n. Fig. 7.9.1 Typical sarcoid cutaneous lesions on nape of neck. (See Plate 1.) Eye: anterior and posterior uveitis with secondary com- plications of glaucoma and cataract and blindness, retinopathy, conjunctival nodules (Fig. 7.9.2), optic nerve involvement, pa pilloedema, keratoconjunctivitis sicca. Endocrine and metabolic: diabetes insipidus secondary to involvement of hypothalamic \200 \223pituitary axis, hypopitu- itarism, hypoadrenalism, hypercalcaemia (secondary CHAPTER 7.9 Sarcoidosis 153 to overproduction of 1 \200\22325 dihydrocholecalciferol by acti-vated macrophages) with ne phrocalcinosis and nephrolithiasis. Hypercalciuria can occur in the absence of hypercalcaem ia. Other abnormalities include nodular infiltrates and con-glomerate masses especially in a mi d and upper zone bilateral distribution; rarely cavitating lesions, pleural effu- sions and atelectasis. Exocrine glands: enlarged parotid and lacrimal glands. HRCT scan of chest Upper lobe pre-dominance; parenchymal granulomatous load may be re \202 ected as small nodules in peribronchovas- cular distribution (subpleural, septal and \201 ssural) produc- ing a characteristic \200\230beading \200\231 appearance and scattere d patches of ground glass opacities or large conglomerate masses occasionally with presence of air - bronchograms. Etiology \200 Cause is unknown. \200 Various infectious and non-infectious agents impli cated but no speci \201 c agent identi \201 ed. There is heightened cellular response to unidenti \201 ed antigens in individuals genetically predisposed. ECG Arrhythmias, bundle branch block pattern in some patients. Epidemiology \200 Usually manifest in the 20 \200\22340 year age group. \200 More usual in temperate than in tropical climates. \200 Prevalence rates dif \201 cult to establis h as disease is often asymptomatic; UK incidence is 10 \200\22320 in 100,000 popula- tion; frequency is higher in Ireland. Pulmonary function tests Can be entirely normal despite widespread radiographic abnormaliti es, or may show signi \201 cant physiological dysfunc- tion with clear lung \201 elds. T he classical abnormality in estab- lished pulmonary sarcoidosis is a restrictive defect wit h reduced lung volumes and diffusion capacity. Occasionally there may be air \202 ow obstr uction; in patients who have a history of asthma, air \202 ow patterns may become \201 x ed. More prevalent and chronic in black population, who have higher risk of non-pulmonary manifestations. Differential diagnosis Hilar lymphadenopathy Tuberculosis, lymphoma, infectious mononucleos is, leukemia, bronchogenic carcinoma, metastases, enlarged pulmonary arteries. BAL May be helpful adjunct to diagnosis; many patients with \200\230active \200\231 sarcoi dosis show lavage lymphocytosis (Fig. 7.9.4); as \201 brosis develops, an increase in neu trophils occurs. Hilar lymphadenopathy with pulmonary in \201 ltrates Tuberculosis, pneumoconiosis, lymphan gitis carcinomatosa, idiopathic pulmonary haemosiderosis, pulmonary eosino- philia, alveola r cell carcinoma, histiocytosis X. Diffuse pulmonary in \201 ltration Previous lists + chronic beryllium disease, idiopathic inter- stitial pneumonias, rheumatoid lung, Sjogren \200\231s disease, extrinsic allergic a lveolitis. Non-caseating granulomata Tuberculosis and other mycobacterial infections, leprosy, syphili s, cat-scratch disease, berylliosis, hypersensitivity pneumonitis, foreign body reactions, lymphoma, carcinoma, primary biliary cirrhosis, Crohn \200\231s disease, hypogammaglob- uli naemia, granulomatous vasculitis, parasitic and fungal infections. Fig. 7.9.4 A cytospin of sarcoid bronchoalveolar lavage showing lymphocytosis; a classical rosette pattern of lymphocytes in close proximity to alveolar macrophages is also seen. Symptoms \200 Asymtompatic. \200 Dyspnoea: commonly on exertion. \200 Cough: usually non-productive. \200 Chest discomfort: intermittent sharp pains. \200 Fatigue, malaise, weight loss, fever. \200 Symptoms of other organ involvement and complications. Histology Commonly performed on lymph nodes, lung tissue, skin, liver; classical well forme d tightly knit non-caseating granu- lomata (Fig. 7.9.5). Special situations may call for th e following: gallium-67 scans (often positive in sarcoidosis); radioactive 201Tl (taken up by sarcoid tissue and by ischaemic myocardium); MRI may be particularly useful in unusual o r dif \201 cult diagnostic circum-stances such as neurosarcoidosis; opthalmological assess -ment should include slit lamp examination and if necessary \202 uorescein angiography in patients with associ- ated ocular symptoms. Investigations Blood tests Hematology: lymphopaenia, mild eosinophilia, raised ESR. Biochem istry: raised serum angiotensin converting enzyme in 2/3 of acute patients, hypercalcaemia, hypercal- ciuria (may have normal serum calcium), hypergammaglob- ulinaemia, other abnorma lities secondary to different organ involvement. Course of disease The clinical expression, natural history and prognosis of sarcoidosis are highly variable with a tendency to wax and wane, either spontaneously or in response to th erapy. Chest radiograph 90% have abnormal chest radiographs; classic patterns are shown in radiolo gical clinical staging. S MUKHERJEE & M SPITERI 154 Currently held view is that patients with stage I disease do not require treatment with ora l steroids. Patients with Stage II and Stage III may bene \201 t from steroid treatment an d show radiological improvement (Fig. 7.9.7). Fig. 7.9.5 Histological appearances of tightly knit, well formed granulomata formation. (Se e Plate 4.) Fig. 7.9.7 CXRs of same patient at presentation with predominant mid-zone peripheral inters titial shadowing, which in this case has resolved following steroid treatment. Spontaneous remissions: 70% patients within 1 year of pre- sentation; the course is chronic or progressive in the rest. Incidence of clinically signi \201 cant extrapulmonary involv e- ment increases with disease progression and can be in \202 u- enced by background ethni city. Death (1 \200\2235%) is rare; when it occurs is typically secondary to respiratory fa ilure, myocardial or central nervous sys- tem involvement. There is little documented evidence that treatment with oral steroids has a bene \201 cial effect on lung function; in practice resolution of radiological granulomatous load is asso ciated with lung function improvement. There is limited evidence that oral steroids can alt er clini- cal progression or that early treatment alters disease out- come. Clinically, ste roids may be helpful in controlling sympto- matic manifestations of extrapulmonary sarcoido sis. Inhaled steroids (with less systemic side effects) may be used in endobronchial sarcoi dosis and bronchial hyperre- sponsiveness manifested by chronic troublesome cough although there are no published randomized trials. Radiological clinical staging Stage 0: normal chest (5 \200\22310%). Stage I: bilateral hil ar lymphadenopathy (50%) (Fig. 7.9.6). Stage II: bilateral hilar lymphadenopathy and pulmon ary in \201 ltrates; paratracheal nodes may be enlarged (25%). Stage III: parenchymal in \201 ltrates only (15%). Stage IV: established pulmonary \201 brosis with parenchymal rem odeling and lung volume loss, especially in upper lobes. Criteria for steroid use in sarcoidosis Following consensus recommendations from the Americ an Thoracic Society, European Respiratory Society and World Association of Sarcoidosis and Other Granulomatous Disorders: \200 Progressive symptomatic pulmonary disease. \200 Asy mptomatic pulmonary disease with persistent in \201 l- Treatment Pulmonary sarcoidosis is usually benign and can resolve within 1 year of presenta tion. Corticosteroids There is so far limited data on the role of corticosteroids in the manageme nt of sarcoidosis. trates or progressive loss of lung function. Cardiac disease. \200 Neurological disease. Suggested steroid dosage Prednisolone 30 mg daily for 4 weeks; reduced by 5 mg every month to 15 mg daily if patient improves; reduced by 2.5 mg every 1 \200\2232 months to 10 mg dai ly if patient stable; reduced gradually, aiming to stop after completing 12 months of conti nuous treatment if sarcoid activity in remission. Methylprednisolone can be used in neurosa rcoidosis and other cases of complicated extrapulmonary sarcoidosis. Contraindications: unc ontrolled hypertension, diabetes mellitus, infection, severe osteoporosis. Relapses: treate d by increased dose; patients with objec- tive evidence of 2 or more relapses may need long -term low dose prednisolone alone or in combination with other agents. Fig. 7.9.6 A CXR showing the presence of bilateral hilar lymphadenopathy (sarcoid stage I ) . CHAPTER 7.9 Sarcoidosis 155 if no change in symptoms or decline in lung function, CXR should be repeated within 6 month s. Immunosuppressants and immunomodulatory agents used in sarcoidosis: \200 Methotrexate. \200 Chloroquine and hydroxychloroquine. \200 Azathioprine. \200 In \202 iximab. \200 Thalidomide. \200 Le \202 unomide. Methotrexate, hydroxychloroquine and azathiopri ne are currently the preferred agents in pulmonary sarcoidosis. Methotrexate and azathiopri ne can be used as steroid sparing agents. Methotrexate can be particularly useful in troubl esome uveitis; recently proposed to be \201 rst-choice immunosuppressant in steroid resis tant neurosarcoidosis. Le \202 unomide is an analog of methotrexate, effective in sar- coi dosis with less pulmonary toxicity than methotrexate. Antimalarial drugs chloroquine and hy droxychloroquine (less oculotoxicity than chloroquine) are more effective in skin and mucos al disease. Thalidomide might be particularly suitable for lupus pernio. In \202 iximab is a chimeric monoclonal antibody against solu- ble and membrane bound TNF- and recently pr oved effective in refractory sarcoidosis. Where possible repeat HRCT scan within 18 months. \200 Referral to subspecialists if dise ase progression or new organ involvement. Multidisciplinary approach. AUTHOR \200\231S TIPS \200 Serum ACE levels are elevated in 2/3 patients with sarcoidosis. 5% patients have false \200\223positive tests seen in a variety of conditions including as bestosis, silicosis, berylliosis, fungal infections, granulomatous hepatitis, hypersensitiv - ity pneumonitis, leprosy, lymphoma and tuberculosis. AUTHOR \200\231S TIPS \200 For young patients presenting with hilar/mediastinal lymphaden opathy, it is important that lymphoma and TB is excluded by mediastinoscopy and biopsy; if a biopsy is not performed at presentation, to follow these patients in their \201 rst yea r; then if clinical picture changes \206\222 early alert for biopsy. Endobronchial biopsies can provide diagnosis in 40% patients especially when there is cha racteristic visible cobblestone appearance. Key points in sarcoidosis \200 Spontaneous remission in 2/3 of patients. \200 Acute on set and Stage I disease have best prognosis. \200 Serum ACE level is more useful for trea tment follow-up AUTHOR \200\231S TIPS \200 Because of sarcoid centrilobular distribution, unlike IIPs; TB Bs have a high diagnostic yield in pulmonary sarcoid- osis ( 4 biopsies are necessary for s tage II disease). \200 TBB is also useful in diagnosing other granulomatous disease, meta static disease, infections, pulmonary alveo- lar proteinosis and eosinophilic pneumonias. than diagnosis. Often disparity between physiological and radiological parameters. There is still limited evidence on \200\230when to treat \200\231. \200 Some patients wi th repeated relapses may need long term steroids. Endobronchial biopsies can provide diagnosis in 40% patients especially when there is cha racteristic visible cobblestone appearence. Recommended clinical evaluation in sarcoidosis \200 Thorough history taking with emphasis on occupational and environmental exposure. Physical examination with emphasis on lungs, liver, eye, Further reading Costabel U, Hunninghake GW. ATS/ERS/WASOG statement on skin and heart. Pulmonary function tests: spirometry and diffusing sarcoidosis. Eur Respir J 1999; 14: 735 \200\223737. capacity as a minimum. Grutters JC, van den Bosch JMM. Corticosteroid treatment in HRCT lung scan to document extent of parenchymal sarcoidosis. Eur Respir J 2006; 28: 627 \200\223636. and nodal involvement and guide need for biopsy. Newman LS, Rose CS, Maier LA. Sarcoidosis. N Eng J Med 1997; Histological con \201 rmation essential if diagnosis not clear cut or if clinical conditio n progresses; biopsy (usually lymph nodes, lungs, skin, liver or target affected organ), sp ecial stain and culture to exclude TB, fungi and other infectious agents. 336: 1224 \200\2231234. Paramothayan NS, Lasserson TJ, Jones PW. Corticosteroids for pul- monary sarcoidosis (revie w). Cochrane database of systematic reviews 2005. Paramothayan NS, Lasserson TJ, Walters EH. Immunosuppressive (and cytotoxic therapy for pul monary sarcoidosis (review)). Cochrane database of systematic reviews 2005. Ophthalmologic evaluation especially with slit-lamp. \200 Full biochemical evaluation inc luding serum calcium and 24-hour urinary calcium. Relevant tests as clinically appropriate to exclude other extrapulmonary disease. Follow-up \200 Especially in the \201 rst 2 years from presentation. \200 Close monit oring for resolution or progression of dis- ease and for new organ development. 3 \200\2234-monthly checks with blood/urine tests and l ung function. A MILLAR 156 7.10 Pulmonary manifestations of connective tissue disorders Connective tissue disorders (C TDs) by de \201 nition can affect any organ system including the lung. This chapter deals mainly with speci \201 c lung complications but it is criti- cal to remember lung problems that are not CTD speci \201 c but may be more common in these subjects e.g. infection, CO PD, bronchiectasis. Presentation Patients typically present with breathlessness and/or cough. Greater awareness of the pulmonary complications of CTD in the rheumatology \201 eld has led to an increas e in presentation of asymptomatic patients with clinical \201 ndings e.g. basal crepitati ons. Investigations \200 FBC and differential. Anemia, neutropenia or lympho- penia can b e key issues in breathlessness or infection. \200 Physiology. Lung volumes and gas transf er are essential. 6MWT and exercise oximetry both for monitoring change and particularly in cases of disproportionate breathlessness. In cases where any clinical suggestion of muscle weakness, then lying and standing VC and inspiratory and expiratory mouth pressures should be undertaken. AUTHOR \200\231S TIP CTD patients can have COPD, bronchiectasis, commu- nity acquired pneum onia, ischaemic heard disease, and heart failure: consider but do not assume a speci \201 c CTD- related diagnosis in a breathless patient. Non-CTD speci \201 c diagnosis \200 Smoking related lung disease. Some CTD conditions su ch as rheumatoid disease can lead to signi \201 cant physical limitation and discomfort. S moking is common in these patients and COPD may present late due to physical inactivity. A typical presentation is following joint replacement when the cardiorespiratory system sud- denly becomes the limiting factor. Radiology. CXR may be normal. HRCT and diaphragm screening may be useful. ECG and echocardiography. Evidence of right heart abnormalities on ECG should be promptly f ollowed with echocardiography. Evidence of pulmonary hyper- tension should be followed up p romptly as described in Chapter 12.2. Infection. Many forms of CTD lead to relative immuno- compromise either due to the conditio n itself e.g lym- phopenia in SLE (systemic lupus erythematosus) or therapies used. If ther apies are overtly cytotoxic this will be obvious but small doses of steroids in an elderly patients can be overlooked as a cause of either recur- rent or opportunistic infection. Tre atments are described in Chapter 9.1. HRCT and histological \201 ndings in CTD-associated ILD \200 The histological entities of the ATS/ERS classi \201 cation for IIP can all be associated with the connective tissue diseases. The prevalence of individual histological patterns differs Bronchiectasis. This may occur in many forms of CTD at least in part related factors descri bed above. It is par- ticularly a problem in RA and Sjogren \200\231s disease. Treat- ment is described in Chapter 10.2 with the additional recognition of potential relative immunoco mpromise. \200 Pleural effusion. This is most commonly associated with rheumatoid disease . It may resolve with systemic treat- ment but may be an isolated presentation. Speci \201 c treat- ment is discussed in Chapter 14.8. strikingly between CTD and non-CTD related IIP. AUTHOR \200\231S TIP The range of HRCT appearances from ground glass to reticular does not translate into corresponding differ- ences in outcome in SSc and is unproven in other CTDs. \200 In the only large study of lung histology in SSc, there was a high prevalence of NS IP (62/80, 75%) and a very low prevalence of UIP (6/80, 8%).The HRCT features of lung disea se in SSc can range from predominant ground-glass attenuation to a predominant reticular pa ttern and are broadly similar to the range seen in idiopathic NSIP. Coarse reticulation and honeycombing are more unusual. \200 Overall outcome differs little between UIP and NSIP in SSc, even after adjustment for baseline disease severity \200 UIP in SSc has a better outcome than IPF, perhaps re \202 ect- ing a lower profusion of \201 broblastic foci in UIP in CTD in general or earlier diagnosis of the lung disease. CTD: speci \201 c diagnosis CTDs differ in the frequency with which speci \201 c lung com plications occur. Certain common principles apply in terms of investigation and diagnosis, especially where ILD is concerned. \200 Many of the principles described in other chapter s for the general management of the ILD also apply to con- nective tissue disease associate d ILD in particular relat- ing to lymphocytic interstitial pneumonia (Chapter 7.6) and obli terative bronchiolitis (Chapter 7.7) NSIP is the predominant histological diagnosis in CTDs, Rheumatoid arthritis is the commonest of the CTDs to be associated with ILD, but data on tr eatment are limited. \200 Systemic sclerosis (SSc) is much less prevalent than rheumatoid arthritis but is more commonly complicated by ILD and the evidence base is much more exten sive. \200 Not all the recent advances in understanding of the natural history of the IIP s can be extrapolated to their CTD-associated counterparts. with the possible exception of RA, HRCT re \202 ects this to some extent but there tend to be particular HRCT pro \201 les a ssociated with speci \201 c CTD. \200 Other than for SSc, data on treatment outcomes in rela- tion to HRCT pattern have yet to emerge in suitably large series. CHAPTER 7.10 Pulmonary manifestations of connective tissue disorders 157 Management principles No formal placebo-controlled trial has been performed in lung disease in CTD current management is based on anecdotal and inconclusive retrospective data. The d eci- sion to treat must be largely based on the likelihood, in individual patients, that th e risk of therapy (drug toxicity) will be outweighed by the bene \201 t (protection agains t pro- gression of disease). Apart from a minority of patients with predominantly HRCT in \202 ammatory appearances, therapy is aimed at slowing or preventing progression, rather th an in the hope of a striking short term response. Early lung involvement in PM/DM is an imp ortant exception to this rule (see below) Treatment issues, including the question of which patients to treat and the selection of therapeutic agent, have been most widely explored i n SSc, perhaps because IIP is most prevalent in that disease. In SSc, the threshold for int roduc- ing treatment is reduced when: \200 The duration of systemic disease is short (<4 years), indicating a higher risk of progression of lung disease \200 Disease is severe, a s judged by pulmonary function tests and the extent of \201 brosis on HRCT. TLCO provides a stronger prediction of mortality and correlates better with the extent of disease on HRC T than other lung function variables. Other immunosuppressive agents such as azothiaprine have been used but data are limited. Treatment in RA \200 There is an extreme paucity of data for the management of IIP in RA. IIP in RA may result from the disease itself or as a consequence of its treatment e.g. meth otrexate (MTX)- induced pneumonitis, the two sometimes being indistin- guishable. A smoking history of >25 pack years increases risk. Current treatment recommendations are based on anecdote. Oral prednisolone 0.5mg/kg/day for 1 \200\2233 months, weaned to 10mg/day or 20mg/alternate days if there is improvement. Immunosuppressant treatment such as cyclophospha- mide, azathioprine, D-penicillamine, MTX and cyclospo- rin-A have been used in cases of treatment failure or progression. Anti-tumor necrosis factor (TNF)-alpha therapy has been reported to induce both both bene \201 t and exacer- bation of RA-associated IIP. Cyclophosphamide can also be useful for the treatment of MTX-induced pneumonitis, which has not responded to the usual management of MTX withdrawal, oxygen therapy and/or corticoster oids. There is evidence of recent deterioration, as judged by symptomatic worsening and/or, a dec line in serial pul- monary function tests. Ongoing deterioration in treated patients is mor e predictive of mortality than any clinical feature at presentation. Cryptogenic organizing pneumonia (COP) in RA is highly likely to respond to corticosteroids. Treatment in PM/DM \200 Acute fulminant disease may require high-dose IV meth- HRCT appearances are strongly suggestive of predomi- nantly in \202 ammatory disease (seen in a minority of cases) \200 BAL remains contentious, with opposing views that a BAL neu trophilia identi \201 es greater risk of progression or merely greater disease severity at the time of sampling. \200 In the absence of a strong evidence base, these broad ylprednisolone (1.0g daily for 3 days) Less severe disease oral prednisolone 0.75 \200\2231.0mg/kg per day (or equivalent) followed by gradual weaning. In patients with a suboptimal response or adverse effects from corticosteroids, considerati on should be given to second-line therapies with either immunosup- pressant or cytotoxic ag ents as described for RA. considerations may be applied to other CTD. Treatment in SSC \200 Outcome in the IIP of SSc is substantially better than outcome in I PF, after adjustment for baseline disease severity. Complete remission as judged by serial HRCT is rare. Even with aggressive therapy, severe interstitial \201 brosis remains a maj or poor prognostic feature. Prognosis is good with early treatment. Short-term improvement is seen in greater than 90%. Patients with elevated CK levels have a 3-fold better response. In the longer term, respon se rates are resolution occurs in >70% and is re \202 ected in long term survival. High dose corticosteroid should not be used as it is CTD- associated pulmonary hypertension Pulmonary hypertension had been most intensively stu d- ied in SSc where its relationship to the underlying CTD as a lone pulmonary vasculopathy has been recognized. This has led to clear cut investigation (including annual echocardiog raphy) and treatment pathways as described in Chapter 12.2. The advances in understanding o f PHT in SSc cannot necessarily be extrapolated to other CTDs. The presence of pulmonary hy pertension in other CTDs, often in the presence of other pulmonary pathology, e.g. COPD, II P is not well characterized. Conventional treatment of asso- ciated lung pathology and corr ection of hypoxaemia must be undertaken as initial steps and may correct \200\230simple \200\231 hypoxaemic pulmonary vasoconstriction. Further investi- gation and management can be considered as described in Chapter 12.2. associated with renal crises.