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Fungal infections in COPD Wouter Meersseman, MD,PhD Department of General Internal Medicine and Intensive Care Medicine University Hospital Gasthuisberg.

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Presentation on theme: "Fungal infections in COPD Wouter Meersseman, MD,PhD Department of General Internal Medicine and Intensive Care Medicine University Hospital Gasthuisberg."— Presentation transcript:

1 Fungal infections in COPD Wouter Meersseman, MD,PhD Department of General Internal Medicine and Intensive Care Medicine University Hospital Gasthuisberg Leuven, Belgium.

2 Scope of the problem What do we know? Aspergillosis well known disease in hematological and solid organ transplant patients Aspergillosis well known disease in hematological and solid organ transplant patients Specific diagnostic tests available in hematological patients Specific diagnostic tests available in hematological patients Where do we fail in our knowledge? Prevalence in COPD patients and other less immunocompromised patients Prevalence in COPD patients and other less immunocompromised patients Disease presentations in COPD patients Disease presentations in COPD patients Treatment options in COPD patients Treatment options in COPD patients

3 Interaction of Aspergillus with the host A unique microbial-host interaction Immune dysfunction Frequency of aspergillosis Immune hyperactivity Frequency of aspergillosis Acute IA Subacute IA Tracheobronchitis Aspergilloma Chronic cavitary Chronic fibrosing ABPA Allergic sinusitis. www.aspergillus.man.ac.uk Normal immune function

4 Types of disease in COPD Aspergilloma Chronic pulmonary aspergillosis 1. chronic cavitary aspergillosis 2. chronic fibrocavitary aspergillosis 3. chronic necrotizing aspergillosis Subacute pulmonary invasive aspergillosis

5 1. Aspergilloma = conglomeration within a pre-existing pulmonary cavity of hyphae, mucus and cellular debris = conglomeration within a pre-existing pulmonary cavity of hyphae, mucus and cellular debris

6 1. Aspergilloma Benign, asymptomatic colonization, IPA rarely develops Occurs in 10% of patients with pre-existing cavities (bullae, TBC)

7 1. Aspergilloma Precipitins: > 95% sensitivity Fatal asphyxiation due to massive hemoptysis may occur Poor prognostic signs: - severity of underlying lung disease - increasing size and number of cavities - immunosuppression - increasing IgG titers - sarcoidosis - HIV

8 2. Chronic fibrocavitary aspergillosis: case 1 45-old smoker with COPD, stage III On fluticasone and atropine inhalers Right upper lesion in 2001 Underwent lobectomy Histology: 2-cm cavity with necrotic contents, pleural and parenchymal fibrosis No signs of malignancy Cultures for Mycobacterium and Aspergillus negative

9 2. Chronic fibrocavitary aspergillosis: case 1 Postoperatively (2001- 2003): never admitted with an exacerbation Treated twice with short course systemic steroids 2003-2005: intermittent hemoptysis, mild fatigue and some weight loss, no fever Lab results: mild to absent inflammation CT scan of the thorax

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11 2. Chronic fibrocavitary aspergillosis: case 1 Bronchoscopy: no lesions, cultures yield Aspergillus fumigatus, galactomannan OI 5 in BAL, < 0.1 in serum Aspergillus precipitins 3 + Fine needle aspiration and transbronchial biopsy: hyphae without parenchymal reaction

12 2. Chronic fibrocavitary aspergillosis Affects middle-aged persons Only mildly immunosuppressed (COPD, alcoholism, diabetes) Indolent progressive course Chronic cough, hemoptysis, weight loss and fatigue No invasion in tissue or occasionally non- angioinvasive hyphae in tissue Many different radiological features (cavitary, fibrosing and necrotizing)

13 Chronic cavitary aspergillosis in a patient with old TBC

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15 Chronic fibrosing aspergillosis in a COPD patient

16 Fibrocavitary aspergillosis postpneumonectomy for chronic aspergillosis

17 Chronic fibrocavitary aspergillosis: treatment options Stop inhaled corticosteroids? Systemic antifungals? Which ones? How long? Intracavitary instillation of antifungals? Interferon-gamma?Surgery? Combination of all the above treatments? Denning DW. Chronic cavitary and fibrosing aspergillosis. Clin Infect Dis 2003:37, S265

18 Vertigo trial: treatment of chronic aspergillosis with voriconazole 41 patients with chronic pneumonia and Aspergillus spp. in airway sample Underlying lung disease: - COPD (n=18) - prior tuberculosis (n=11) - bronchiectasis (n=6) - pneumothorax (n=5), - lung cancer (n=3) - sarcoidosis (n=3) - postradiotherapy (n=2) Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009

19 Vertigo trial: treatment of chronic aspergillosis with voriconazole Underlying risk factors: - corticosteroids inhaled (n=12), systemic (n=6) - alcoholic abuse (n=4) - diabetes (n=2) - other (n=11) - none identified (n=12) Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009

20 Vertigo trial: treatment of chronic aspergillosis with voriconazole Voriconazole oral route Two doses of 400 mg 12 hours apart followed by maintenance doses of 200 mg twice daily At least 6 months duration, to be continued 3 months after the best achievable response Maximum duration of treatment could not exceed 12 months Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009

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23 Meersseman et al. Invasive aspergillosis in critically ill patients without malignancy. AJRCCM 2004 Proven and probable IPA without malignancy in ICU (00-03)

24 23 pts, 16 proven, 7 probable (repeated isolation) 23 pts, 16 proven, 7 probable (repeated isolation) recent steroid treatment, or intensification of steroid treatment severe bronchospasm (12/23) all required mechanical ventilation diagnosis classified as confirmed confirmed positive lung tissue biopsy and/or autopsy probable probable repeated isolation of Aspergillus from the airways with consistent clinical and radiological findings mortality 100% mortality 100% * Bulpa P. COPD patients with invasive pulmonary aspergillosis: benefits of intensive care? Intens Care Med 2001; 27: 59-67 COPD patients: benefits of ICU?

25 Clinical characteristics of IPA in COPD Total number of patients Age yrs (mean) Steroid treatment At admission At admission In hospital In hospital NA NA5665,5 43 49 5 Clinical signs Antibiotic resistant pneumonia Antibiotic resistant pneumonia Dyspnoea exacerbation Dyspnoea exacerbation Wheezing increase Wheezing increase Fever > 38° C Fever > 38° C Haemoptysis Haemoptysis Tracheobronchitis (bronchoscopy) Tracheobronchitis (bronchoscopy)53 56 5231 56 Bulpa et al. IPA in patients with COPD. Eur Resp J 2007; 30: 782

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27 Clinical characteristics Duration between symptoms and diagnosis days VentilationInvasiveNoninvasiveNoneNAOutcomeDeathSurvival12,5431102 53 (95) 3 (5) Bulpa et al. IPA in patients with COPD. Eur Resp J 2007; 30: 782

28 Why frequent in ICU? Why such a high mortality? Most severe exacerbations end up in ICU Steroids are given for a lot of reasons We dont think of aspergillosis Poor sensitivity of culture We dont know what to do with a positive culture or direct examination Radiology doesnt help us Meersseman W, Lagrou K, Maertens J. Invasive aspergillosis in ICU. Clin Infect Dis 07

29 Significance of culture positivity IA diagnosed in 45/477 patients with underlying pulmonary disease and positive culture Positive predictive value lower than in haematology patients (around 40%) Colonisation vs true disease ??? Temporary passage ? Long-term benign carriage ? Perfect JR, et al. Clin Infect Dis 2001; 3:1824-1833.

30 Halo sign: only applicable to neutropenic patients Radiology in ICU clouded by atelectasis, pleural effusions, ARDS Necrotizing, cavitating lesions: not specific

31 Balloy et al. Differences in patterns of infection and inflammation. Infect Immun 2005; 73:494 Corticosteroids vs neutropenia: a different lung disease

32 As a consequence … Inflammatory reaction: - leads to encapsulation of the process - prevents at least partially invasion of hyphae in the blood (minor coagulation necrosis) hyphae in the blood (minor coagulation necrosis) - prevents leakage of antigens in blood - probably makes antigen markers in blood less suitable for diagnosis blood less suitable for diagnosis

33 Meersseman et al. Invasive aspergillosis in critically ill patients without malignancy. AJRCCM 2004 Proven and probable IPA without malignancy in ICU (00-03)

34 Meersseman et al. Galactomannan in BAL in ICU. AJRCCM Jan 2008 Performance GM in serum and BAL

35 Summary Three disease entities in COPD - aspergilloma - chronic aspergillosis - subacute invasive aspergillosis Controversial topic: no clear guidelines Studies warranted in - chronic aspergillosis: benefits of longterm triazole therapy - subacute IPA: pre-emptive approach based on galactomannan in BAL


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