Σπύρος Α Παπίρης MD, PhD, FCCP Καθηγητής Ιατρικής ΕΚΠΑ Β Πανεπιστημιακή Πνευμονολογική Κλινική «Αττικόν» ΓΠΝ Νοσοκομείο

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1 Σπύρος Α Παπίρης MD, PhD, FCCP Καθηγητής Ιατρικής ΕΚΠΑ Β Πανεπιστημιακή Πνευμονολογική Κλινική «Αττικόν» ΓΠΝ Νοσοκομείο

2 Ασθενής 56 ετών, καπνίστρια 30 πακέτα/έτη 1985 Lungs tbc 4 drugs Ρευματοειδής αρθρίτιδα από διετίας υπό αγωγή με: πρεδνιζολόνη μεθοτρεξάτη RITUXIMAB (06/ η δόση 12/ η δόση) Υποθυρεοειδισμός Οστεοπόρωση Αναφερόμενη δύσπνοια προσπαθείας προοδευτικά επιδεινούμενη, 3 ημέρες μετά από την χορήγηση του rituximab, χωρίς πυρετό, χωρίς βήχα

3 17/01/2014

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8 ΟΠΙΣΘΙΟΣ ΑΡ. ΚΑΤΩ

9 ΟΠΙΣΘΙΟΣ ΔΕ. ΚΑΤΩ

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11 Hb: 12.6 (από 13.3 προ μηνός) Quantiferon (-) ANA, ANCA, AGBM (-) Έναρξη αγωγής με ENDOXAN 1gr iv, 1gr methyprednisolone x3 iv & αύξηση της δόσης των κορτικοστεροειδων (25mg prednisolone/die) και διακοπή της μεθοτρεξάτης Bactrimel 960mg x3/week

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17 Hb: /02/2014

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20 AH is a rare but potentially life-threatening condition that can have numerous causes, including autoimmune diseases, infections, drug toxicities, coagulopathies, malignancies and cardiovascular disorders. Clinical worsening may occur within days, and lead to acute respiratory failure or damage to extrathoracic organs such as the kidney, if AH is part of a multisystemic disorder.

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26 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 endstage fibrotic.

27 Admission to the intensive care unit is required in up to 50% of cases. Average mortality is 20 30%, and may reach 50 60% in some conditions. Prompt therapy may be life-saving and preserve organ function, especially in disorders of immune origin. Rapidly and accurately identifying the cause of AH is therefore a key issue.

28 The terms AH, diffuse AH and intrapulmonary hemorrhage are considered synonymous. AH designates bleeding from the pulmonary microcirculation (pulmonary arterioles, alveolar capillaries and pulmonary venules) as a result of microvascular damage leading to blood leakage into the alveolar spaces. AH is a diffuse phenomenon simultaneously affecting multiple areas in both lungs. Bleeding is usually documented indirectly by BAL.

29 BAL is the gold standard method for diagnosing AH.

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31 Dd/ Localized bleeding bronchial circulation bronchiectasis, infection and tumours. Haemorrhage of bronchial origin almost always manifests with haemoptysis. As the volume of the tracheobronchial tree is only 150 ml, even small amounts of blood may cause asphyxia by airway obstruction, although it is usually not sufficient to produce anaemia. In contrast, AH occurs distally in the alveolar spaces and haemoptysis is not always present despite significant blood loss, which may cause severe anaemia.

32 ACUTE OR SUBACUTE AH OCCULT CHRONIC AH Overt AH is defined by the presence of macroscopically haemorrhagic, either pink or red, BAL fluid, which classically becomes increasingly red on successive aliquots. BAL cytology shows numerous red blood cells and haemosiderin-laden alveolar macrophages when AH lasts for > 3 days. Haemosiderin-laden macrophages may be absent in AH of < 3 days duration. Chronic occult AH is defined by the presence of haemosiderinladen macrophages representing 20 30% of the macrophage BAL population, or by a Golde score > 100 with or without red blood cells.

33 Subacute AH can be diagnosed if hemosiderin-laden macrophages represent > 20 30% of the total macrophage count, or with a Golde score > 100, with or without red blood cells. The Golde score is a semi quantitative assessment of hemosiderinladen macrophages, which evaluates both the percentage of macrophages containing haemosiderin and the intensity of staining on a scale between 0 and 4. The result of this score may vary between 0 and 400.

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

35 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

36 One must especially remember that alveolar siderophages are present in cardiac left ventricular failure with chronic pulmonary edema (siderophages were even called cardiac cells at the beginning of the 20th century). 20% of immunocompromised pts Therefore, we consider that the diagnostic value of siderophages in BAL is limited for the diagnosis of DAH (vasculitis).

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39 Patterns I.a Acute pneumonitis/ild I.b Subacute pneumonitis/ild I.d Organizing pneumonia (OP/BOOP) (see also Iu, XVc) I.g Pulmonary fibrosis I.l Diffuse alveolar damage (DAD) I.x Upper lobe fibrosis II.a Noncardiac pulmonary edema (NCPE) II.b ARDS III.a Diffuse alveolar hemorrhage IV.a Bronchoconstriction, bronchospasm, asthma V.a Pleural effusion V.c Pleural thickening and/or fibrosis V.f Pneumothorax V.p Pleuroparenchymal fibroelastosis X.f Anaphylaxis XI.p Chest deformity: platythorax XII.f Cardiomyopathy XII.g Acute coronary syndrome, myocardial infarction XV.a Path: Cellular ILD (NSIP-c pattern) (see also Ia, Ib) XV.h Path: Pulmonary fibrosis (NSIP-f pattern) (see also Ig) XV.i Path: Pneumocyte atypia - A reactive epithelium XV.ap Path: Pleuroparenchymal fibrosis/fibroelastosis XVII.b Opportunistic pulmonary infections XVII.e Pneumocystis jiroveci pneumonia XVII.q Viral pneumonia

40 immune origin 19 42% not immune in 58 81%

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42 ARDS is a form of acute diffuse lung injury occurring in patients with a predisposing risk factor. Lung injury is characterized by inflammation leading to increased endothelial and epithelial permeability and loss of aerated lung tissue resulting in hypoxemia and bilateral radiographic opacities on chest radiography. Additional physiological derangements include increased venous admixture and physiological dead space along with decreased respiratory system compliance. The corresponding pathological findings are lung edema, inflammation, hyaline membranes, and alveolar hemorrhage (i.e., diffuse alveolar damage)

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44 1) chest x-ray - multiple confluent alveolar shadows 2) acute Ht 3) hemorrhagic fluid on BAL, especially if it gets more bloody from the first to the last sample 4) DLCO??????? In 50% of pts, alveolar haemorrhage leads to severe respiratory failure, requiring mechanical ventilation.

45 DLCO has no practical interest for the diagnosis of acute AH and should no longer be performed for this purpose

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49 Sat: 95% (FiO2 21%) Hb: 9,90

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55 INR: 7,04

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

67 Anti glomerular basement membrane autoantibodies (Anti-GBM abs) Goodpasture s syndrome Antineutrophil cytoplasmic autoantibodies (ANCAs) ANCA positive systemic vasculitis (WG, MPA, C-Ss) Granular Ig deposits and complement SLE (Autoimmune rheumatic disorders)

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77 Απύρετος SpO2: 99 % σε FiO2: 21 % (PO2: 95mmHg, PCO2: 39mmHg) Ήπιοι υποτρίζοντες ΑΡ κορυφής μόνο WBC: (87%N) CRP: 160 TKE: 110 Creatinine: 0,8mg/dl AST/ALT: 18/20 Mantoux: 0 mm, Quantiferon: (-)

78 Αρθραλγίες γονάτων Εμπύρετο έως 38,2 WBC: Θρομβοκυττάρωση (PLTs: ) Creatinine: Γενική ούρων / ίζημα ούρων: λίγα δύσμορφα ερυθρά, πρωτεϊνουρία Εξαιρετική 24ωρη διούρηση, χωρίς μεταβολική οξέωση panca-canca εν αναμονή αποτελεσμάτων...

79 1 gr Solumedrol IV για 4 ημέρες και 500mg IV για 2 ημέρες 1 gr Endoxan IV Ετέθη σε προφύλαξη για P.jirovecii με TMP/SMX Τηλέφωνο από το εργαστήριο λίγες ώρες μετά την έναρξη της αγωγής... < ισχυροί τίτλοι PR3 και canca (+)>

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81 «Ανεπαρκές υλικό..» Μετά από Νεφρολογική εκτίμηση τίθεται σε αυστηρό ισοζύγιο και ρύθμιση ηλεκτρολυτών αίματος, λόγω οιδημάτων ανα σάρκα Χρειάστηκε να λάβει δύο δόσεις sodium bicarbonate IV λόγω μεταβολικής οξέωσης Ετέθη σε εβδομαδιαία χορήγηση ερυθροποιητίνης

82 «Λεμφοιστιοκυτταρική, κοκκιωματώδης φλεγμονώδης διήθηση και περιοχές με γεωγραφικού τύπου νέκρωση, συμβατή με ν. Wegener» Παρά την αγωγή.. Ο ασθενής συνεχίζει να αυξάνει την κρεατινίνη ( ), εμφανίζει πτώση αιματοκρίτη ( ), και πτώση της PO 2 : 70 mmhg σε 21%... Επείγουσα CT θώρακος χωρίς IV contrast λόγω νεφρικής ανεπάρκειας..

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89 ...Και αποφασίζεται η 2 η δόση Endoxan IV (750mg) και 2 δόσεις Solumedrol 1 gr, 15 ημέρες μετά την 1 η έγχυση. Ο ασθενής βελτιώνεται αναπνευστικά και απεικονιστικά..

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91 Η κρεατινίνη συνεχίζει την ανοδική πορεία Έως και 6.3 Οπότε και αποφασίζεται να λάβει άλλη μία ώση Endoxan 1 gr και να υποβληθεί σε 7 συνεδρίες πλασμαφαίρεσης. Πριν την τελευταία συνεδρία, ο ασθενής παρουσιάζει εκ νέου λευκοκυττάρωση και αύξηση CRP, χωρίς πυρετό. Αντιμετωπίστηκε ως λοίμωξη σχετιζόμενη με Κεντρικό Φλεβικό Καθετήρα, με αφαίρεση του καθετήρα και δαπτομυκίνη/μεροπενέμη για 14 ημέρες, ενώ αργότερα η καλλιέργεια του άκρου καθετήρα ανέπτυξε πολυανθεκτικό Staph. epidermidis

92 Έκτοτε ο ασθενής παρουσίαζε σταδιακή βελτίωση των δεικτών φλεγμονής και της νεφρικής λειτουργίας (κρεατινίνη ) καθώς και αύξηση του αιματοκρίτη. Σε επανέλεγχο ιζήματος ούρων, ΔΕΝ υπήρχαν δύσμορφα ερυθρά.

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94 Η κρεατινίνη συνέχισε να μειώνεται σταδιακά χωρίς άλλη παρέμβαση, έως και 2.2 που ήταν και η τιμή εξόδου του ασθενούς. Σε επανέλεγχο σε εξωτερική βάση, τα canca/pr3 ήταν αρνητικά, το ίζημα ούρων αρνητικό και η κρεατινίνη 1.7 Χωρίς αυξημένους δείκτες φλεγμονής, αρθραλγίες ή πυρετό.

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97 Medrol 16mg, 1 x 1 Bactrimel forte, 2 tabs / εβδομάδα Pulses Endoxan κάθε ημέρες

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99 Anti-GBM disease (linear deposition of IgG) Autoimmune rheumatic disorders glomerulonephritis (granular deposition of immunoglobulin and complement)

100 Type IV collagen and other structural proteins form basement membranes Six genetically distinct chains are arranged into three triple helical protomers.

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

102 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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107 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 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.

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109 Wegener s granulomatosis Microscopic polyangiitis Churg-Strauss syndrome Other vasculitis (rare) Drugs (Propylthiouracil, D-penicillamine, Hydralazine, Allopurinol, Sulfasalazine) Scleroderma

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114 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. Of the patients with Churg Strauss syndrome, 35 70% have positive MPO ANCA, while only 10% have C ANCA.

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116 Systemic lupus erythematosus Scleroderma (ANCA?) Polymyositis Rheumatoid arthritis Mixed collagen vascular disease

117 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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121 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 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 skin (in 50 percent)

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123 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

124 Remission induction phase Immediate support of pulmonary and renal function according to severity: 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

125 Mantainance phase Prevent and treat opportunistic infections: TMP/SMX for PCP and SA Sustain remission: Use less toxic cytotoxic drugs (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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130 Idiopathic pulmonary haemosiderosis Long-standing disease may be associated with the development of interstitial fibrosis and restrictive ventilatory defect

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144 Ασθενής 44 ετών, πρώην καπνιστής 10 πακέτα/έτη (διακοπή πριν δέκα έτη) Έκθεση σε σκόνη πυρήνα για καύση μούχλιασμένου Δύσπνοια προσπαθείας προοδευτικά επιδεινούμενη από διμήνου

145 Λήψη αντιμικροβιακής αγωγής 17/12/2013

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156 8/02/2014 Ξηρός βήχας Αναπνευστική ανεπάρκεια Έναρξη πιπερακιλλίνης ταζομπακτάμης, αζιθρομυκίνης και βανκομυκίνης

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161 Έναρξη αγωγής με ώσεις κορτιζόνης x3 σταδιακή μείωση έως 64mg μεθυλπρεδνιζολόνης

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166 6MWT: χωρίς αποκορεσμό στην άσκηση Συνολική απόσταση: 555m

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170 AFOP

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175 Idiopathic CTDs Lymphoma, AML Bacterial infections, viruses (H1N1, RSCV, corona virus) Drug exposure (e.g. amiodarone, abacavir, decitabine, statins exposure to inhalative agents (e.g. coal, tungsten mining, construction, zoological work, hairspray) Diabetes, immunosuppression, alcoholism SCTransplantation

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180 ILDs οδηγίες 1&2 HP LAM IPF pathogenesis IPF treatment protocols PAP P-Rs & Ahs Serology in ILDs AFOP Sleeping in IPF A 1 -ATT deficiency Drugs Lung Toxicity Sarcoidosis BOOP-COP Bronchiolitis CTDs and the LUNG Digital Clubbing Pulmonary Vasculitis LCs granulomatosis CPFE

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