Pulmonary-Renal Syndromes. Spyros A Papiris MD, FCCP Athens Medical School National and Kapodistrian University of Athens, Greece

Transcription

1 Pulmonary-Renal Syndromes Spyros A Papiris MD, FCCP Athens Medical School National and Kapodistrian University of Athens, Greece

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5 Pulmonary-Renal Syndromes are a combination of Diffuse Alveolar Hemorrhage and Rapidly Progressive Glomerulonephritis

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7 Capillaritis characterized by the infiltration of alveolar septa by neutrophils, several of which are fragmented. There is reactive proliferation of lining type II pneumocytes. Neutrophils are also seen within the alveolar space associated with edema. Other areas of this biopsy specimen showed DAH. Chest 1998

8 Capillaritis associated with marked DAH admixed with fibrin. The alveolar septum is thickened by homogenous material and infiltrating neutrophils. Schwarz MI et al. Chest 1998

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10 Hemosiderin-laden macrophages (darkly stained cells) from bronchoalveolar lavage (Prussian blue staining). Peters S, Afessa B 2005

11 Electron micrograph (original magnification, 510) of lung tissue from patient B showing an alveolar macrophage containing iron which causes cell death by necrosis. Cohen S 2002

12 Scanning electron microscope (original magnification, 3500) showing holes in the membrane of the lung macrophage causing the death of the macrophage. On radiographic microanalysis, the macrophage contains large amounts of iron. Cohen S 2002

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15 Renal lesion is a form of focal, segmental, proliferative glomerulonephritis characterized by fibrinoid necrosis, microvascular thrombi, and crescent formation. Initially the crescents are composed of macrophages, epithelial cells, PMNs and fibrin. Cellular and fibrocellular crescents may become end- stage fibrotic.

16 Diffuse Alveolar Hemorrhage Hemoptysis is the most common clinical manifestation of diffuse alveolar haemorrhage (30-35% 35% of patients have no evidence of hemoptysis) 1) chest roentgenogram showing multiple coalescent alveolar shadows 2) acute decrease of the Ht 3) hemorrhagic fluid on BAL, especially if it gets more bloody from f the first to the last sample 4) an increased or a gradually increasing Kco, provided that these patients can cooperate and undergo pulmonary function tests. Breathlessness, cough and low grade fever may coexist. In 50% of pts, alveolar haemorrhage leads to severe respiratory failure, requiring mechanical ventilation.

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26 Glomerulonephritis = active urinary sediment haematuria,, non nephrotic proteinuria dysmorphic red cells, red-cell casts and other cellular and granular casts, BUN and serum creatinine

27 Lau K, Wyatt R. Adolesc Med 2005

28 Pulmonary-Renal Syndromes Main Pathogenetic Mechanisms Anti glomerular basement membrane autoantibodies (Anti-GBM abs) Goodpasture s syndrome Antineutrophil cytoplasmic autoantibodies (ANCAs) ANCA positive systemic vasculitis Immunocomplexes Autoimmune rheumatic disorders

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31 Immunofluorescence helps to distinguish among anti-gbm disease (linear deposition of IgG), autoimmune rheumatic disorders glomerulonephritis (granular deposition of immunoglobulin and complement) and necrotizing vasculitis (pauci( pauci-immune immune glomerulonephritis).

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33 Type IV collagen and other structural proteins form basement membranes Six genetically distinct chains are arranged into three triple helical protomers. Collagen IV was first isolated by Kefalides from glomerular basement membrane in Kefalides NA. Biochem Biophys Res Commun 1966; 22:26-32.

34 Protomers create networks with other protomers by uniting two NC1 trimers to form an hexamer at the C-terminalC and by uniting four triple helical 7S domains at the N-terminalN terminal.

35 The epitopes for the anti GBM abs are inaccessible unless there is a dissociation of the hexamer,, which may be caused by oxidative stress. These epitopes reside mainly in the a3(iv) NC1 domain. Hudson and coworkers identified the a3(iv) NC1 domain as the Goodpasture autoantigen. Saus J, Wieslander J, Langeveld JP, Quinones S, Hudson BG. J Biol Chem 1988;263:

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37 Goodpasture s syndrome Anti-GBM abs disease 1 in 1 million persons each year. Whites and men are affected more commonly. 2 different age groups: mid 30s and late 50s. With current therapy, survival through the acute phase is more than 90%. However, 2-year 2 survival is less than 50%, and the mortality rate in patients with chronic renal failure is even worse. End-stage renal disease develops in 40% to 70% of patients who have nephritis mediated by anti GBM abs. The syndrome has a genetic component and has been linked to the HLADRBI 1501 region. Recurrence of the syndrome is infrequent, and pulmonary hemorrhage seldom occurs in patients who do not smoke tobacco.

38 Jung C, et al. Chest 2005; 127:1437 Goodpasture syndrome with negative serum anti-gbm antibody and normal renal function. Treatment should consist of corticosteroids, cyclophosphamide, and plasmapheresis.

39 ANCA +ve+ Pulmonary-Renal Syndromes Wegener s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Other vasculitis (rare) Drugs (Propylthiouracil( Propylthiouracil,, D-penicillamineD penicillamine, Hydralazine, Allopurinol, Sulfasalazine) Scleroderma

40 Wegener s granulomatosis Granulomatous inflammation affecting the respiratory tract, and necrotising vasculitis affecting small-sized sized to medium-sized vessels (ie( ie,, capillaries, venules, arterioles, and arteries). Necrotising glomerulonephritis is common. Churg-Strauss syndrome Eosinophil-rich granulomatous inflammation in the respiratory tract, and necrotising vasculitis aff ecting small-sized sized to medium-sized vessels, and associated with asthma and eosinophilia. Microscopic polyangiitis Necrotising vasculitis,, with few or no immune deposits, affecting small vessels (ie( ie,, capillaries, venules,, or arterioles). Necrotising arteritis involving small sized and medium-sized arteries might be present. Necrotising glomerulonephritis is very common. Pulmonary capillaritis frequently arises. Operative definitions of ANCA-associated vasculitis adopted by the Chapel Hill conference consensus on the nomenclature of systemic vasculitis.

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49 C C ANCA are found in more than 85% of patients with generalized Wegener s granulomatosis and in 60% of patients with the limited form of the disease. Approximately 40 80% of patients with microscopic polyangiitis have ANCA, mainly MPO ANCA. Positive MPO ANCA and a negative serological test for hepatitis B are, in general, suggestive of microscopic polyangiitis. Of the patients with Churg Strauss syndrome, 35 70% have positive MPO ANCA, while only 10% have C ANCA.

50 Disorders other than ANCA-associated vasculitis,, in which ANCA have been detected either by indirect immunofluorescence or ELISA Bosch X, et al. 2006

51 Pulmonary-Renal Syndromes in Autoimmune Rheumatic Diseases (immune complexes and/or ANCA mediated) Systemic lupus erythematosus Scleroderma (ANCA?) Polymyositis Rheumatoid arthritis Mixed collagen vascular disease

52 Alveolar hemorrhage occurs in less than 2% of lupus patients. For patients developing the condition, it carries a poor prognosis with reported mortality rates of 70% to 90%. When examined histologically,, the lungs of 13% of these lupus patients show a neutrophilic capillaritis,, and in another 13% of the lupus patients, the pulmonary pathology consists of diffuse alveolar damage. In more than 70% of cases there are few identifiable changes other than alveolar hemorrhage, a finding that has been referred to as bland pulmonary hemorrhage.

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55 Pulmonary-Renal Autoimmune Inflammatory Syndromes Differential Diagnosis

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58 Pulmonary embolism and infarction pulmonary hypertension ARDS intra-alveolar alveolar haemorrhage primary thrombosis of lung vessels, both large and small pulmonary capillaritis Less commonly, a postpartum syndrome and fibrosing alveolitis associated with APS have been described Obviously, many of these manifestations are interrelated and they may occur simultaneously in the same patient

59 CATASTROPHIC ANTIPHOSPHOLIPID SYNDROME thrombotic storm acute and devastating syndrome characterized by multiple simultaneous vascular occlusions throughout the body, often resulting in death clinical involvement of at least three different organ systems over o a period of days or weeks with histopathological evidence of multiple occlusions of large or small vessels acute thrombotic microangiopathy affecting small vessels of multiple organs The kidney is the organ most commonly affected (in 78 percent of patients), followed by the lungs (in 66 percent), the central nervous system (in 56 percent), the heart (in 50 percent), and the t skin (in 50 percent)

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63 Therapeutic Considerations for the Physician For a fulminating disease immediate decisions are mandatory Consult specialists Act in a timely manner as a team Close monitoring of the patient Collect all necessary samples to ensure diagnosis and rule out infection Decide therapeutic options considering also availability Immunosuppression should be administered even if definite diagnosis is pending

64 Principles of Treatment Remission induction phase Immediate support of pulmonary and renal function according to severity: s Oxygen therapy, mechanical ventilation, hemodialysis Under empiric antimicrobial coverage prompt initiation of immunosuppressive treatment to halt further production of autoantibodies and suppress inflammation : high dose pulse corticosteroids for the first 3 days plus pulse cyclophosphamide Remove circulating antibodies: Apheresis, IGs Mantainance phase Prevent and treat opportunistic infections: TMP/SMX for PCP and SA Sustain remission: Use less toxic cytotoxic drugs (azathioprine( azathioprine, mycofenolate mofetil) Renal transplantation for end stage renal disease Monitoring for complications Infection, drug toxicity, disease relapse, a new disease

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