AH. International Registry \201 gures show that the one- year mortality post-transplantat ion is highest in patients with idiopathic PAH compared with any other indication. Median s urvival post-transplantation for idiopathic PAH is between 4 and 5 years. Chronic thromboembolic pulmonary hypertension (CTEPH) Pathogenesis CTEPH occurs when a clot fails to resolve completely after an acute pulmonary embolic event. The rate of resolution of clots after acute pulmonary embolism varies and is longer in patients with pre-existing cardiopulmonary disease, but nor- mal perfusion should be restored by 4 \200\2236 weeks af ter the acute event. To some extent, the rate of resolution depends Prognosis The prognosis of PAH varies depending on the underlying association or cause. Pro gnosis is most closely linked to indices of cardiac function, especially cardiac index. His torical data in the period prior to the availability of modern targeted therapies suggest a n expected median survival for idiopathic PAH between 2.5 and 4 years, and a 3 year surviva l of about 60%. The prognosis is worse N MORRELL 270 the presence of peripheral disease. Ventilation-perfusion lung scans also usually show mult iple segmental perfusion defects not matched by defects in ventilation, even in distal dise ase. Computed tomography can also reveal the extent of right ventricular hypertrophy and di latation, although this is probably best seen by MRI. Three-dimensional reconstruc- tion of the two-dimensional CT and MR images can help decide whether the distribution of disease i s suitable for PEA. The use of a combination of these techniques means that the more invasi ve traditional pulmonary angiogram can be avoided in most patients. Approximately 60% of ca ses of CTEPH are potentially suitable for surgery. Of the patients who are not suitable for surgical management, many may be suitable for targeted therapy with the new pharmacologica l agents described above. on the initial clot burden or the size of the acute pulmonary embolism. If the clot fails t o resolve, it becomes organized before it can be completely \201 brinolysed. The organize d thrombus is incorporated into the wall of the pulmonary artery, becomes covered by endoth elial cells and forms a false intima. The organized material occludes the vascular lumen, w hich increases pulmonary vascular resistance and leads to pulmonary hypertension. The true prevalence of CTEPH is hard to ascertain, because it is not usually sought in patients who are recovering from acute pulmonary embo- lism (PE), but it almost certainly is underdiagno sed. One well-designed study found that 4% of patients with a history of acute PE had a per sistent elevation of pulmonary arterial pressure after two years. Evidence also shows that those with a higher initial clot burden (massive PE) are more likely to develop CTEPH than those with minor PE. The more widespread use of thrombolysis for acute PE is often assumed to reduce the prevalence of CTEPH, but no data at present support this view. It is of note that some of the classic risk factors for acute deep vein thrombosis (DVT)/PE are not found with increased frequency in the population that develops CTEPH. For example, the factor V Leiden polymorphism, which leads to activated protein C resistance and is found with high p revalence in the population of patients with acute DVT, is not overrepresented in patients with CTEPH. The prevalence of protein C and S de \201 ciency is increased in patients with CTEPH, although these conditions account for a small minority of patients. In addition, so me 10% of patients with CTEPH may have circulating antiphospholipid antibodies. Recent rese arch points to a de \201 ciency in the abil- ity to \201 brinolyse established clots as a predisposing factor. Other important predisposing factors include previous splenectomy an d in \202 ammatory bowel disease. Treatment Pulmonary endarterectomy (PEA) is a surgical procedure during which organized thr ombi are removed from the proximal pulmonary arteries. The procedure is a major operation t hat usually requires the patient to undergo repeated cycles of cardiopulmonary bypass with cerebral cooling. This ensures a bloodless \201 eld of view for the sur- geon, who can th en enter the left and right main pulmo- nary arteries via an arteriotomy. The aim is to ide ntify a dissection plane along the base of the false intima and to dissect distally as far as possible. It is often possible to remove organized material as far distally as segmental pul- monary arteries. With successful clearance of proximal clots, the pulmonary vascular resistance can fall dramati- cally post-operatively, and near normalization of resistance c an be achieved in the long term. Patients are maintained on life-long warfarin and have an inferior vena cava \201 lter sited prior to the operation. Long-term survival is often ex cellent after a successful procedure with marked improvements in exercise capacity, NYHA fu nctional status and quality of life. The operation itself carries some risk, and perioperat ive mortality varies between 7 \200\22320% depending on the experience of the center. There are two main aspects to patient selection for this procedure. Comorbidities are important predictors of perioperative mortality and require careful assessment. A further important c onsideration is the distribution of the disease, as organized clots need to be anatomically acces- sible to the surgeon. If the organized material is predomi- nantly of a distal dist ribution within the pulmonary arter- ies, that is involves subsegmental vessels, there is a high risk that pulmonary vascular resistance will not decrease after the procedure and tha t the patient will be left with signi \201 - cant pulmonary hypertension. Patients with pe rsistent PAH following PEA may bene \201 t from the targeted pharma- cological therapies d etailed above. Clinical presentation Clinically, patients often present with persistent symptoms of dyspno ea after an acute embolic event and despite the recommended period of anticoagulation. Up t o 60% of patients with CTEPH will have a prior documented epi- sode of previous venous thro mboembolism, although some patients may present with gradually worsening dys- pnoea in the absence of acute events. A further important \201 nding may be pulmonary \202 ow murmur s, resulting from turbulent \202 ow across partially obstructed large pulmonary arteries, which may be audible on chest auscultation in up to 30% of patients with CTEPH. Otherwise the clinical presentation is similar to that described above for PAH. Investigation The work-up of patients referred with a suspected diagno- sis of CTEPH requir es a multidisciplinary approach involv- ing surgeons, physicians, and radiologists. Imaging plays a key role in determining whether a patient is suitable for the surgical procedure o f choice, pulmonary endarterectomy (PEA). Computed tomographic pulmonary angiography with m odern multislice scanners is a rapid and non-invasive technique that can provide several im portant pieces of in- formation in the assessment of patients with suspected CTEPH. CT can assess the presence of any associated lung disease or tumors. Most importantly, a computed tomo- graphic pulmonary angiogram gives an accurate assess- ment of the extent of proximal organized clots. Although occlusion of very small arteries cannot be visu- alised directly in the case of predominantly distal disease, the characteristic appearance of \200\230mosa ic perfusion \200\231 suggests Further reading Abenhaim L, Moride Y, Brenot F, et al. Appetite-Suppressant Drugs and the R isk of Primary Pulmonary Hypertension. N Engl J Med 1996; 335(9):609 \200\223616. Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous epoprostenol (pr ostacyclin) with conventional ther- apy for primary pulmonary hypertension. New Engl J Med 1996; 334:296 \200\223301. Bonderman D, Skoro-Sajer N, Jakowitsch J, et al. Predictors of Outcome in Chronic Thromboem bolic Pulmonary Hypertension. Circulation 2007; 115(16):2153 \200\2232158. D \200\230Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991; 115(5):34 3 \200\223349. CHAPTER 12.2 Pulmonary hypertension 271 Pengo V, Lensing AWA, Prins MH, et al. Incidence of Chronic Thromboembolic Pulmonary Hypert ension after Pulmonary Embolism. N Engl J Med 2004; 350(22):2257 \200\2232264. Fedullo PF, Auger WR, Kerr KM, et al. Chronic thrombo embolic pulmonary hypertension. N Eng l J Med 2001; 345(20):1465 \200\2231472. Galie N, Ghofrani HA, Torbicki A, et al. Sildena \201 l Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353(20):2148 -2157. Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on surviv al in primary pulmomary hypertension. New Engl J Med 1992; 327:76 \200\22381. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. Circulation 1958; 18:533 \200\223547. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan Therapy for Pulmonary Arterial Hypertension . N Engl J Med 2002; 346(12):896-903. Heath D, Segel N, Bishop J. Pulmonary veno-occlusive disease. Circulation 1966; 34(2):242 \200\223248. The International PPH Consortium, Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous ger m-line mutations in BMPR2, encod- ing a TGF-b receptor, cause familial primary pulmonary hy per- tension. Nat Genetics 2000; 26:81 \200\22384. Newman JH, Trembath RC, Morse JA, et al. Genetic basis of pulmo- nary arterial hypertension : Current understanding and future directions. Journal of the American College of Cardiolog y 2004; 43(12, Supplement 1):S33 \200\223S39. Wagenvoort C, Wagenvoort N. Primary pulmonary hypertension: a pathological study of vessels in 156 clinically diagnosed cases. Circulation 1970; 42:1163 \200\2231184. Olschewski H, Simonneau G, Galie N, et al. Inhaled Iloprost for Severe Pulmonary Hypertensi on. N Engl J Med 2002; 347(5):322 \200\223329. P SIVASOTHY 272 12.3 Pulmonary vasculitis and hemorrhage Pulmonary vasculitis The pulmonary vasculitides are a heterogeneous group of rare disorders that result from an in \202 ammatory process damaging the vessel wall and consequent impa ired blood \202 ow, ischaemia and tissue necrosis. The clinical manifesta- tion of these vasculitides depends on the site, size, type, and severity of the in \202 ammatory process . Several classi \201 cations of the vasculitides have been de- scribed since the original \201 rst description of vasculitis by Kussmaul and Maier. Classi \201 cation based on v essel size is confounded by the fact the vasculitic process does not re- spect vessel size restrictions. However the classi \201 cation shown in Table 12.3.1 is frequently applied. The American College of Rheumatologist (ACR) and Chapel Hill classi \201 - cations allow f or standardized comparison of vasculitis but do not help make an early diagnosis in an indi vidual patient since there is an overlap of features between disorders. Wegener \200\231s g ranulomatosis (WG), Churg \200\223Strauss syndrome (CSS) and microscopic polyangiitis (MPA) are primary small vessel vasculitides linked by an overlapping clinico- pathological pictu re and are frequently called the anti- neutrophil cytoplasmic antibody (ANCA)-associated sy stemic vasculitides (AASV). shown ANCA vasculitis (alveolar hemorrhage, necrotis- ing pulmonary arteritis and focal seg mental glomerulone- phritis) can be caused by the transfer of anti-murine MPO Ig G from MPO -/- mice that have been immunized with MPO to mice that lack functioning T and B cells (Ra g2 -/-). Table 12.3.1 Classi \201 cation of primary and secondary vasculitides. Primary systemic vasculitis Size of vessel affected Small Medium Large Wegener \200\231s granulomatosis Polyarteritis nodosa Giant cell arteritis Churg \200\223Strauss Kawasaki \200\231s disease Takayasi s artertis Microscopic polyangiitis Beh et \200\231s Henoch \200\223Sch nlein Essential cryoglobinaemia Epidemiology \200 The estimated incidence of primary systemic vasculitides is estimated a t 11 \200\22320/million and the prevalence is 90 \200\223 278/million. Isolated pauci-immune pulmonary capillaritis Secondary vasculitides There is geographic variation with WG being the most common vasculitis in northern Europe a nd MPA the most common vasculitis in northern Spain. Connective tissue disorder Systemic lupus erythematosus Rheumatoid arthritis Longitudinal studies have shown an increasing incidence Systemic sclerosis of vasculitis. Polymyositis Vasculitis is very rare in childhood and frequently presents from young adulthood onwards. Anti-phospholipid syndrome There is a seasonal variation in the presentation of WG with an increased rate in winter in Northern Europe. Immune mediated (Goodpasture \200\231s) In \202 ammatory bowel disease Other systemic disorders Etiology \200 The etiology of vasculitis is unclear. \200 Vasculitides have been associ ated with exposure to silica, quartz, grain, occupational solvents and farming (livestock). Autoimmune liver disease Malignancy (hematological and solid organ) Infections (bacterial, fungal and viral) Drug treatments with propylthiouracil, hydralazine, car- bimazole, D-penicillamine, allopur inol and minocycline have been associated with the development of AASV. \200 Patients wit h A1-antitrypsin ZZ de \201 ciency have a 100- Drugs Sarcoidosis fold increased risk of WG. Polymorphisms of genes linked to proteinase 3 overpro- duction, Fc gamma IIa and III recept ors, and adhesion molecules associated with the interaction of neutrophils and endothelial cells have been associated AASV. These studies are supported by the clinical observation that a pregnant women with active M PO-ANCA positive micro- scopic polyangiitis gave birth to a newborn with pulmonary hemorrha ge and crescentric glomerulonephritis. The newborns blood contained MPO-ANCA Ig G not Ig M. It is presumed that passive transplacental transfer of maternal MPO-ANCA Ig G caused the d isease. Corticosteroids and plasma exchange effectively treated the symptoms. Staphylococcu s aureus chronic nasal carriage is associated with WG and relapse of disease. The bacterium contains a protein that mimics the anti-sense sequence of PR-3 incriminating it in the sus ceptibility for disease. Pathogenesis The pathogenesis of ANCA mediated vasculitis is the best understood. ANCA are auto antibodies, predominantly Ig G antibodies, directed against the cytoplasmic contents o f neutrophil granules. The clinically relevant antibodies are directed against the enzymes proteinase 3 (PR3) and my- eloperoxidase (MPO). In vitro studies have shown that ANCA can a ctivate cytokine primed neutrophils and mac- rophages with consequent oxygen free radical f ormation and lysosomal degranulation. In vivo murine studies have CHAPTER 12.3 Pulmonary vasculitis and hemorrhage 273 General principles in the assessment of a patient with vasculitis Clinical presentation of the vasculitides is variable and care- ful attention needs to be made to the history taking , clinical examination and investigations. Frequently the investigations may point to a vas culitis in the absence of major symptoms. The principle pulmonary vasculitides are reviewed below and recommended investigations listed in Table 12.3.2. Lower respiratory features Approximately 25% of patients will have limited WG with involvem ent of the upper and lower respiratory tract only. Table 12.3.2 Investigations for vasculitis. Full blood count (FBC) looking for neutrophilia , eosinophilia, or drop in hemoglobin together with urea and electrolytes (UE) should be ro utinely done. Mixed cyroglobulinaemia is invariably found with hepatitis C and polyarteriti s nodosa with hepatitis B. Vasculitis is found with infections and blood cultures and HIV ( human immunede \201 ciency virus) test should be carried out if indicated. CXR (chest radi ograph). ANCA (anti-neutophil cytoplasmic antibody) High resolution computed tomogram (HRCT ) Investigations for vasculitis All patients Fig. 12.3.1 Chest radiograph showing bilateral nodular lung changes with cavitation of some of the nodules. Urine dipstick and microscopy CXR Blood FBC, CRP, UE AUTHOR \200\231S TIP Frequently overlooked, all patients should have their urine dipsticked for microscopic haematuria and pro- teinuria if a vasculitis is suspected. Selected tests depending on presentation Blood ANCA (AASV) Blood culture, hepatitis B and C, HIV IgE (CSS), Anti-GBM Lung parenchymal \200 Lung involvement manifests as symptoms include cough, Cryoglobulin, Complement Pulmonary physiology Dynamic test, \202 ow volume loop haemoptysis, dyspnoea or may be silent. Abnormalities on the chest radiograph are noted in more than 70% at some point during their disease history. Bronchoscopy To exclude infection and con \201 rm alveolar hemorrhage. Rarely are mucosal or transbronc hial biopsies useful. Radiological abnormalities include (see Fig. 12.3.1): Biopsy of relevant tissue Nasal, lung, kidney \200 \200 \200 \200 \200 Single or multiple nodules (20 \200\22350%). Cavitation of nodules occur in 66% of cases. P ulmonary in \201 ltrates. Consolidation. Intrathoracic lymphadenopathy (<2%). Rarer \201 ndings include pleural effusions, atelectasis and pleural thickening. Radiology HRCT Neurological Nerve conduction Cardiology Echocardiogram Speci \201 c disorders WG WG is the most common pulmonary vasculitis and classically invol ves the triad of the upper respiratory tract (sinuses, ears, nasopharynx, and oropharynx), lower respiratory tract (trachea, bronchi and lung parenchyma) and kidneys. It is character ized by the histopathological \201 nding of necrotis- ing small vessel vasculitis (arteri oles, capillaries and venules) and granulomatous in \202 ammation. Its peak age of onset i s 30 \200\22350 years. Children and young adolescents are rarely affected. Upper respirator y features \200 Ear, nose and throat symptoms are present in 70% of patients at initial p resentation and will develop in 90% of patients throughout their disease history. Trachea and bronchi \200 Granulomatous involvement of the trachea and bronchi will lead t o stenosis in 10 \200\22330% of patients (see Fig. 12.3.2). Symptoms range from non-speci \201 c, dyspnoea, \200\230wheeze \200\231, stridor and change in voice. Subglottic stenosis invariably occurs in the presence of nasopharyngeal disease. Tracheal stenosis is associated with plateauing of both the inspiratory and expiratory limb s of the \202 ow volume loop. At the time of bronchoscopy up to 74% of trachea lesion are due to mature scar and only 26% are due to acute in \202 ammation. Hearing loss will develop in 15 \200\22325% of patients. \200 The nasopharynx is involved in 60% of patients and presents with epistaxis, nasal septal perforation, persist- ent con gestion, pain, nasal crusting and mucosal ulcers. \200 Saddle nose deformity due vascular necrosis of the Bronchial stenosis has a female preponderance. Renal features \200 Hypertension. \200 A cute renal failure (red cell casts and proteinuria). cartilage occurs in up to 25 % patients with WG. P SIVASOTHY 274 (a) (b) (c) (d) Fig. 12.3.2 Subglottic stenosis in WG. (a) bronchoscopic \201 nding of \201 brous steno sis. (b) CT reconstruction showing stenosis beneath vocal cords; (c) Characteristic plateau ing of inspiratory and expiratory limbs of the \202 ow volume loop. (d) Balloon dilation showing waisting of the balloon at the level of the stenosis. Other organ features: Occular symptoms of visual disturbance, pain, grittiness and dryness occur in 20 \200\22340% of patients with WG. Con- junctivitis, episcleritis and scleritis i s found in 15 \200\22320% of patients. Prop-tosis occurs in 20% of patients. Posterior uvei tis, optic neuritis and retinal hemorrhage are rare but serious complications Cutaneous manifestations include palpable purpura, ulcerative lesions and haemorrhagic lesi ons. Neurological presentations include mononeuritis multiplex and cranial nerve palsies. A bdominal and cardiac presentations have been reported. Intended for research use prior to t he advent of ANCA testing two or more of the four ACR diagnostic criteria a CHAPTER 12.3 Pulmonary vasculitis and hemorrhage 275 listed below have been reported to have an 88% sensitivity and 92% speci \201 city for WG. \200 Nasal or oral in \202 ammation (painful or painless oral asthma and rhinitis. It is named after the two pathologists who described it in 1951. The a nnual incidence is reported at 2 \200\2234/million with a prevalence of 8 \200\22311/millio n. It is dis- cussed in more detail in Chapter 18.2. Three stages in the natural history of CSS have been described 1 A prodromal stage characterized by asthma and allergy ulcers or purulent or bloody nasal discharge). Abnormal chest radiograph showing nodules, \201 xed in \201 l- trates, or cavities. Abnormal urinary sediment (microscopic hematuria with or without red cell casts). which last for years. Granulomatous in \202 ammation on biopsy of an artery or 2 A eosinophilic stage characterized by peripheral blood eosinophilia and organ in \201 lt ration. This may remit and relapse for several years. peri-vascular area. The ACR criteria were proposed prior to the de \201 nition of MPA and poorly differentiate it from WG. 3 A systemic vasculitic phase which may be life threat- ening. MPA MPA is a necrotising vasculitis affecting small vessels (capil- laries, venules, and ar terioles). It is characteristically associ- ated with focal segmental glomerulonephritis. G ranuloma- tous in \202 ammation of the upper respiratory tract, trachea and bronchi are no t a feature. It occurs more commonly in men. Up to 30 \200\22360% of patients frequently ha ve a prodromal ill- ness of fever, weight loss, myalgia and arthralgia that pre- cede the d iagnosis by up to 2 years. Pulmonary features \200 Diffuse alveolar hemorrhage is the mos t frequent pul- ANCA patterns in AASV The AASV are the predominant pulmonary vasculitides and have an overlapping clinical presen tation and associa- tion with ANCA summarized above and in Table 12.3.3. Two main patterns of ANCA staining are found on indirect immune \202 uorescence: cytoplasmic (C-ANCA) and pe rinu- clear (P-ANCA). monary feature occurring in 30% of patients. \200 Its presence is associated with a poor prognosis. \200 Other features include pleurisy, pleural effusions and pulmonary \201 brosis. Radiological features are of patchy alveolar changes on CXR without nodules. Pulmonary \201 brosis develops in up to 11% of patients who have had previous pulmonary h emorrhage and carries a poor prognosis. Renal features \200 Over 90% of patients present with renal involvement. \200 Focal seg mental glomerulonephritis with \201 brinoid necro- sis and crescent formation are classically seen. Features of microscopic haematuria and proteinuria are found. Nephrotic syndrome is uncommon but when present carries a poor prognosis. Gastrointestinal features \200 Gastrointestinal bleeding, abdominal pain, diarrhea and bo wel perforation have been reported in 30 \200\22340% of patients. Gastrointestinal involvement is more common with MPA than WG. Neurological features Mononeuritis multiplex and cerebral vasculitis manifesting as headach e, seizures, infarction or hemorrhage has been reported in up to 30% of patients. Other fea tures Mild ENT symptoms and ocular symptoms are seen with MPA. However the presence of dest ructive nasal disease or proptosis would indicate a diagnosis of WG rather than MPA. Fig. 12.3.3 ANCA staining by immune \202 uoresence. (a) C-ANCA with cytoplasmic staining. (b) P-ANCA with peri-nuclear staining. (See Plate 7.) Churg \200\223Strauss syndrome (CSS) CSS is an allergic granulomatous angiitis characterize d by small vessel vasculitis, extra vascular granuloma and hypereosinophilia. It occurs in patients with a history of Over 90% of C-ANCA is directed against the serine pro- tease PR-3 found in the azurophilic granule. P-ANCA is directed against range of intracellular antigens of which MPO is the mos t common. P SIVASOTHY 276 Table 12.3.3 A comparison of the ANCA associated systemic vasculitides Wegener \200\231s gr anulomatosis (WG). Chug- Strauss Syndrome (CSS) and Microscopic polyanglitis (MPA). Diffuse alveolar hemorrhage (DAH). Frequency of organ involvement (*, **, **, ****). High resoluti on computed tomogram (HRCT). DLCO-diffusing capacity for carbon monoxide. Adapted from Pesc i et al, 2007 Clinical features WG CSS MPA Pulmonary involvement Nodular lung disease Asthma DAH Endo bronchial ulceration ENT involvement Nasal destruction Allergic rhinitis and polyposis Very rare and mild Renal involvement Frequent and severe Rare and mild Frequent and severe Other organ involvement Neurological ** Cardiovascular * Gastrointestinal * Cutaneous * Investigation Radiographic Nodules with or without cavitations In \201 ltrates Ground glass changes, nodules and sten osis. (HRCT) Transient In \201 ltrates Non-cavitatory nodules unusual Ground glass changes (HRCT) In \201 ltrates Ground glass changes (HRCT) Pulmonary physiology Obstructive/restrictive Plateauing of \202 ow volume loop DLCOi DAH Obstructive Obstructive but can be restrictive in patients who go onto develop \201 brosis DLCOi DAH ANCA prevalence Up to 90% Up to 65% Up to 90% Immune \202 uorescence C-ANCA P-ANCA P-ANCA PR-3 predominant MPO predominant MPO predominant Pathological biopsy sites If clinically indicated Nasal Kidney Lung Peripheral nerve Lung Kidney Lung Active generalized disease refers to disease with threat- A positive C-ANCA has up to 90% sensitivity and speci \201 - city for active WG. However f or CSS and with MPA a positive P-ANCA is only indicative of AASV. ened end organ function. Severe disease refers to critical organ dysfunction, e.g. diffuse alveolar hemorrhage or se vere renal failure. \200 Refractory disease is any patient who has failed to enter remiss ion despite appropriate therapy. Approximately 10% of patients will fall into this category . Experimental therapy with intravenous immunoglobulin, rituximab, deoxyspergualin and anti -tumor necrosis factor alpha therapy with in \202 iximab have been shown to be effective i n small clinical trials or case series. AUTHOR \200\231S TIPS \200 The utility of ANCA depends on its application in high risk po pulations to maximize its positive predictive value. A negative ANCA does not exclude a vasculitis. Treatment of AASV Prior to the advent of immunosuppression with corticos- teroids and cyclo phosphamide the 1 year mortality for Wegener \200\231s was over 90%. It was not until the 1 970s with the use of cyclophosphamide was this signi \201 cantly altered. Cyclophosphamide has remained the mainstay of therapy ever since. However because of its toxicity alternati ve treatment strategies have been evaluated either to induced remission or maintain treatme nt. The European Vasculitis Study Group (EUVAS) have proposed a clinical staging sys- tem t o help guide management, Table 12.3.4. \200 Limited disease refers to disease con \201 n ed to the upper Treatment for the different stages are summarized in Table 12.3.4. Once remission has been induced the role of therapy is to maintain disease control on the least level of immunesup- pression required. The azathioprine and methotrexate are the best studied however clinical trials are currently under- way investigating the role of mycophenolate and le \202 unomi de. The duration of maintenance treatment is unclear. Co-trimoxazole alone has been shown t o cause remission in limited disease and when used in generalized disease with cyclophospha mide and corticosteroids reduced the relapse rate. It is thought co-trimoxazole reduces Sta phylo- coccus aureus nasal carriage. Furthermore co-trimoxazole has a role to prevent Pneum ocystis jiroveci infection that carries a signi \201 cant mortality in the immunesuppresse d. airway. Early generalized disease refers to disease without threatened end-organ function. Nodular lung disease falls into this category. CHAPTER 12.3 Pulmonary vasculitis and hemorrhage 277 Table 12.3.4 Treatment of AASV based site and severity of disease. Corticosteroid (CS), Aza thioprine (AZA), Methotrexate (MTX), Cyclophosphamide (CYC), Plasma exchange (PE), intraven ous Ig G (IV IgG), Rituximab (RTX), Deoxyspergualin (DSG), anti-Tumor necrosis factor alpha antagonists (anti-TNFA) and human albumin solution (HAS) Adapted from Pesci et al, 2007 Clinical Class Localized Early systemic Generalized Severe Refractory systemic Constitutional \210\222 + + + + Renal function Creatinine < 120 umol/l Creatinine < 120 umol/l Creatinine < 500 umol/l Creatinine > 500 umol/l Any Threatened vital organ function \210\222 \210\222 \210\222 + + Induction Single agent (CS, AZA, MTx) CYC or MTX +CS CYC+CS CYC+CS+PE Investigational drugs IV IgG, RTX, DSG, anti-TNFA Dosage CS (1mg/kg/day) tapered down to 0.25 mg/kg od by 12 weeks Recommended AZA (1mg/kg/day) MTX (20 \200\22325 mg/week) Oral CYC (1.5 \200\2232mg/kg/day) PE Seven exchanges within \201 rst 2 weeks with 60ml/kg plasma exchanged for 5% HAS Maintenance Once remission for is achieved for 3 to 6 months transition to maintenance treatment with A ZA (1 \200\2232 mg/kg/day) or MTX (20 \200\22325mg/week) should be considered into the alveolar space subsequently occurs giving rise to diffuse alveolar hemorrhage (DAH ). This is a often a \201 nd- ing in AASV. However it needs to differentiated from other causes. Histologically three patterns are seen: \200 Pulmonary capillaritis where there i s alveolar wall in \201 l- tration with in \202 ammatory cells centered on capillary wall s. Monitoring of disease activity and complications Monitoring disease response to treatment t hrows up sev- eral problems for the physician. Worsening symptoms have attributed to \200 Disease relapse: \200 40 \200\22360% of patients with WG will relapse on treatment. 15 \200\22325% of patients wi th CSS will relapse on treatment. \200 Infections (10% of infections occur without leucop enia). \200 Drug toxicity on cyclophosphamide: Bland pulmonary hemorrhage where there is bleeding into the alveolar space without in \202 ammatory changes in the vessels or alveoli. \200 \200 12% of patients will develop cystitis. 8% of patients will develop myelodysplasia. 5% of pa tients will develop solid organ malignancies. Diffuse alveolar damage as found in ARSD where the alveoli are oedematous with a hyaline membrane. The role of ANCA in monitoring for disease relapse remains unclear. Prognosis of AASV \200 Even with optimal medical therapy AASV carries a sig- Clinical features \200 The symptoms of DAH are non-speci \201 c. \200 Dyspnoea, cough and fever are common. \200 Haemoptysis is only present in two-thirds of patients. \200 Patients may have clues in their histories to favor one of ni \201 cant 1 and 5 year mortality. A 1 year survival \201 gure of 80-85% is reported for AASV the diagnoses listed in Tables 12.3.5 and 12.3.6. as a whole. Radiological \201 ndings are of diffuse pulmonary in \201 ltrates At 5 years a survival \201 gure of 67 \200\22378% is reported for WG, 63 \200\22369% is r eported for CSS and 45 \200\22353% for MP. \200 Predictors of disease relapse include a d iagnosis of WG, ENT or pulmonary or gastrointestinal involvement, PR-3 ANCA and carriage of Staphylococcus aureus and ground glass changes on HRCT (Fig. 12.3.4). If a baseline value is available for comparison DAH is associated with a drop in hemoglobin. If patients are well enough to undertake a diffusing capacity for carbon monoxide (DLCO) te st it is elevated. Management of airway stenosis in WG Stenotic airways disease can occur in up to 30% of pati ents. At the time of bronchoscopy only a minority have active endobronchial disease. Manage ment should be to actively treat WG and avoid interventions. If this is not possible a mini mal invasive procedure should be undertaken. These include dilation, corticosteroid injecti ons and conservative laser surgery. Tracheostomy and stenting should be avoided if possible . Bronchoscopic lavage is characterized by lavage return that fails to clear in contrast to e ndobronchial bleeding. Lavage should be sent for culture to exclude infection. Speci \201 c test including urine analysis and serological tests for ANCA, anti-GBM antibo dies, anti-nuclear antibodies, anti-phospholipid antibodies and rheumatoid factor as well a s complement together with creatinine kinase should be considered. Diffuse alveolar hemorrhage Biopsies of the kidneys should be considered if a Damage to the alveolar-capillary basement membrane results in \201 lling of the alveolar spaces with blood. Bleeding pulmonary-renal syndrome is suspected. P SIVASOTHY 278 Epidemiology \200 It is a rare disorder occurring in one in million. \200 It is associa ted with cigarette smoking or exposure to Treatment \200 In severe cases treatment cannot be delayed pending the results of serological or biopsy results. If infection and DAH without capillaritis have been excluded immunesuppres and DAH without capillaritis have with corticosteroid (methylprednisolone 1g/day for 3 \200\2235 days) with cyclophosphamide (2 mg/kg/day). inhaled hydrocarbons. Young men are prone to develop pulmonary hemorrhage. \200 Pulmonary hemorrhage without re nal disease is rare. \200 DAH can occur due to bland hemorrhage as well as In unstable severe disease due to systemic autoimmune pulmonary capillaritis. process plasma exchange should considered. An overlap syndrome of AASV and anti-GBM disease Factor VII concentrate have been used achieve haemos- exists. tasis in severe bleeding. Clinical features \200 In 25 \200\22330% of patients, a prodromal period of \202 u like Prognosis \200 Repeated DAH can result in pulmonary \201 brosis espe- cially in patient s with MP, WG, idiopathic haemosiderosis and mitral stenosis. illness occurs. Pulmonary manifestations: The insidious onset with symptoms lethargy, dyspnoea upon exertion, and, sometimes, dry cou gh. Occasionally acute onset with fever, massive haemo- ptysis and acute respiratory failur e. Obstructive features can also develop post DAH. Anti-glomerular basement antibody disease ( Goodpasture \200\231s syndrome) Renal manifestations: Pathogenesis The role of anti-GBM antibodies in the pathogenicity of Goodpastures syndrome has been shown in vivo studies. Antibodies were passively transferred from humans to mon- k eys who went on to develop glomerulonephritis. The pri- mary antigen was subsequently ident i \201 ed as component of the A3 chain of type IV collagen of basement membranes. Usually presents with an abrupt onset of oliguria or anuria. Rarely, the patient \200\231s renal involvement is more insidi- ous in onset and he or she remains asymptomatic, progress ing slowly until the development of uraemia symptoms Diagnosis \200 Urine analysis. \200 Anti-GBM antibodies. \200 ANCA, up to 32% of pati ents testing positive for Table 12.3.5 Causes of diffuse alveolar hemorrhage with pulmonary capillaritis Primary vasculitis anti-GBM will test positive for ANCA. ANCA associated vasculitis Renal biopsy. Typical features are a crescentric glomeru- lonephritis with immunefluorescen ce microscopy demonstrates a linear deposit along the capillaries. WG Beh ets disease CSS Henoch \200\223Sch nlein purpura Treatment \200 Plasmapheresis with concomitant use of corticosteroids Microscopic polyangiitis Pauci-immune pulmonary capillaritis and cyclophosphamide. Secondary vasculitis Patients should be asked to stop smoking. Prognosis \200 Patients who survive the \201 rst year with near normal Collagen vascular disease Mixed connective tissue disease Rheumatoid arthritis Polymyositis Systemic lupus erythematosus Anti-phospholipid syndrome renal function do well. Relapses are rare and when they do occur may re \202 ect Drug-induced vasculitis relapse of the AASV. Good pastures syndrome Bone marrow transplant Summary \200 Pulmonary involvement in primary systemic vasculitis is common especially in the AASV. Table 12.3.6 Causes of diffuse alveolar hemorrhage without pulmonary capillaritis Management relies on early clinical diagnosis and treat- ment to minimize the morbidity and mortality associ- ated with the disease and its treatment. Inhalation toxins Mitral stenosis Severe coagulopathy Anti-glomerular basement membrane dis ease Infections ARDS Idiopathic pulmonary haemosiderosis Lymphangioleiomyomatosis Tuberous sclerosis Pulmonary capillary haemangiomatosis Pulmonary veno-occlusive disease Neoplasms \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Choice of treatment depends on the clinical severity of disease. Advances current medical therapy is unlikely to result in disease free remission and cure t he disease in the majority of patients. Support groups \200 http://www.vasculitisfoundation.org \200 http://www.vasculitis-uk.o rg.uk CHAPTER 12.3 Pulmonary vasculitis and hemorrhage 279 Further reading Bosch X, Guilabert A, Font J. Antineutrophilic cytoplasmic antibodies. Lancet 2006; 368: 404 \200\223414. Brown K. Pulmonary Vasculitis. Proc Am Thorac Soc 2007; 3:48 \200\22357. Jennette JC, Xiao H, Falk RJ. Pathogenesis of vascular in \202 ammation by anti-neutrophil cytoplasmic antib odies J Am Soc Nephrol 2006; 17: 1235 \200\2231242. Lane SE, Watts RA, Shepstone L, et al. Primary systemic vasculitis: clinical features and m ortality. QJM 2005; 98: 97 \200\223111. Lee AS, Specks U. Papillary capillaritis. Semin Res pir Crit Care 2004; 25:547 \200\223555. Pesci A and Manganelli P. Respiratory system involvement in antineutrophil cytoplasmic-asso ciated systemic vasculitides. Drugs RD 2007; 8:25 \200\22342. Smyth L, Gaskin G, Pusey G. Microscopic polyangittis. Semin Respir Crit Care Med 2004; 25: 523 \200\223533. Watt RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis. A ten year stud y in the United Kingdom. Arthritis and Rheumatism 2000; 43: 414 \200\223419. (a) (b) 12.3.4 Radiographic appearance of diffuse alveolar hemorrhage (a) CXR showing bilateral gro und in \201 ltrates (b) HRCT showing ground glass changes within which areas of consolidat ion are seen. This page intentionally left blank 281 Chapter 13 Lung cancer Chapter contents 13.1 Epidemiology of lung cancer 282 13.2 Symptoms and signs (including SVCO) 284 13.3 Work -up of patients with a suspected diagnosis of lung cancer 288 13.4 Treatment of non-small c ell lung cancer 292 13.5 Treatment of small cell lung cancer 298 13.6 PET-CT 300 13.7 Lung cancer screening 304 13.8 Carcinoid 306 13.9 Benign lung tumors 310 13.10 Transbronchial \201 ne needle aspiration 316 13.11 Interventional bronchoscopy techniques 318 R HUBBARD 282 13.1 Epidemiology of lung cancer Incidence and mortality \200 AUTHOR \200\231S TIPS \200 