Fungal infections in COPDFungal infections in COPD
Wouter Meersseman, MD,PhDWouter Meersseman, MD,PhDDepartment of General Internal Medicine andDepartment of General Internal Medicine and
Intensive Care MedicineIntensive Care MedicineUniversity Hospital GasthuisbergUniversity Hospital Gasthuisberg
Leuven, Belgium.Leuven, Belgium.
Scope of the problemScope of the problemWhat do we know?What do we know? Aspergillosis well known disease in hematological Aspergillosis well known disease in hematological
and solid organ transplant patientsand solid organ transplant patients
Specific diagnostic tests available in Specific diagnostic tests available in
hematological patientshematological patients
Where do we fail in our knowledge?Where do we fail in our knowledge? Prevalence in COPD patients and other less Prevalence in COPD patients and other less
immunocompromised patientsimmunocompromised patients
Disease presentations in COPD patientsDisease presentations in COPD patients
Treatment options in COPD patientsTreatment options in COPD patients
Interaction of Interaction of AspergillusAspergillus with the with the hosthost
A unique microbial-host interactionA unique microbial-host interaction
Immune dysfunction
Frequency
of a
sperg
illosis
Immune hyperactivity
Frequency
of
asp
erg
illosi
s
Acute IA
Subacute IA
Tracheobronchitis AspergillomaChronic cavitaryChronic fibrosing
ABPAAllergic sinusitis
. www.aspergillus.man.ac.uk
Normal immune function
Types of disease in COPDTypes of disease in COPD
AspergillomaAspergilloma
Chronic pulmonary aspergillosisChronic pulmonary aspergillosis1.1. chronic cavitary aspergillosischronic cavitary aspergillosis
2.2. chronic fibrocavitary aspergillosischronic fibrocavitary aspergillosis
3.3. chronic necrotizing aspergillosischronic necrotizing aspergillosis
Subacute pulmonary invasive aspergillosisSubacute pulmonary invasive aspergillosis
1. Aspergilloma1. Aspergilloma = conglomeration within a pre-existing pulmonary cavity of = conglomeration within a pre-existing pulmonary cavity of
hyphae, mucus and cellular debrishyphae, mucus and cellular debris
1. Aspergilloma1. AspergillomaBenign, asymptomatic colonization , IPA rarely developsBenign, asymptomatic colonization , IPA rarely develops
Occurs in 10% of patients with pre-existing cavities (bullae, TBC)Occurs in 10% of patients with pre-existing cavities (bullae, TBC)
1. Aspergilloma1. AspergillomaPrecipitins: > 95% sensitivityPrecipitins: > 95% sensitivity
Fatal asphyxiation due to massive hemoptysis may occurFatal asphyxiation due to massive hemoptysis may occur
Poor prognostic signs:Poor prognostic signs:
- severity of underlying lung disease- severity of underlying lung disease- increasing size and number of cavities- increasing size and number of cavities- immunosuppression- immunosuppression- increasing IgG titers- increasing IgG titers- sarcoidosis- sarcoidosis- HIV- HIV
2. Chronic fibrocavitary 2. Chronic fibrocavitary aspergillosis: case 1aspergillosis: case 1
45-old smoker with COPD, stage III45-old smoker with COPD, stage IIIOn fluticasone and atropine inhalersOn fluticasone and atropine inhalersRight upper lesion in 2001Right upper lesion in 2001Underwent lobectomy Underwent lobectomy Histology: 2-cm cavity with necrotic Histology: 2-cm cavity with necrotic contents, pleural and parenchymal fibrosiscontents, pleural and parenchymal fibrosisNo signs of malignancyNo signs of malignancyCultures for Cultures for Mycobacterium Mycobacterium and and Aspergillus Aspergillus negativenegative
2. Chronic fibrocavitary 2. Chronic fibrocavitary aspergillosis: case 1 aspergillosis: case 1
Postoperatively (2001- 2003): never Postoperatively (2001- 2003): never admitted with an exacerbationadmitted with an exacerbationTreated twice with short course systemic Treated twice with short course systemic steroidssteroids2003-2005: intermittent hemoptysis, mild 2003-2005: intermittent hemoptysis, mild fatigue and some weight loss, no feverfatigue and some weight loss, no feverLab results: mild to absent inflammationLab results: mild to absent inflammationCT scan of the thoraxCT scan of the thorax
2. Chronic fibrocavitary 2. Chronic fibrocavitary aspergillosis: case 1 aspergillosis: case 1
Bronchoscopy: no lesions, cultures yield Bronchoscopy: no lesions, cultures yield Aspergillus fumigatus, Aspergillus fumigatus, galactomannan OI 5 in galactomannan OI 5 in BAL, < 0.1 in serumBAL, < 0.1 in serum
Aspergillus precipitins 3 +Aspergillus precipitins 3 +
Fine needle aspiration and transbronchial Fine needle aspiration and transbronchial biopsy: hyphae without parenchymal reactionbiopsy: hyphae without parenchymal reaction
2. Chronic fibrocavitary 2. Chronic fibrocavitary aspergillosisaspergillosis
Affects middle-aged personsAffects middle-aged personsOnly mildly immunosuppressed (COPD, Only mildly immunosuppressed (COPD, alcoholism, diabetes)alcoholism, diabetes)Indolent progressive courseIndolent progressive courseChronic cough, hemoptysis, weight loss and Chronic cough, hemoptysis, weight loss and fatiguefatigueNo invasion in tissue or occasionally non-No invasion in tissue or occasionally non-angioinvasive hyphae in tissueangioinvasive hyphae in tissueMany different radiological features (cavitary, Many different radiological features (cavitary, fibrosing and necrotizing)fibrosing and necrotizing)
Chronic cavitary aspergillosis in a patient with old TBC
Chronic cavitary aspergillosis in a patient with old TBC
Chronic fibrosing aspergillosis in a COPD patient
Fibrocavitary aspergillosis postpneumonectomy for chronic aspergillosis
Chronic fibrocavitary Chronic fibrocavitary aspergillosis: treatment optionsaspergillosis: treatment optionsStop inhaled corticosteroids?Stop inhaled corticosteroids?
Systemic antifungals? Which ones? How Systemic antifungals? Which ones? How long? long?
Intracavitary instillation of antifungals?Intracavitary instillation of antifungals?
Interferon-gamma?Interferon-gamma?
Surgery?Surgery?
Combination of all the above treatments?Combination of all the above treatments?
Denning DW. Chronic cavitary and fibrosing aspergillosis. Clin Infect Dis 2003:37, S265
Vertigo trial: treatment of chronic Vertigo trial: treatment of chronic aspergillosis with voriconazoleaspergillosis with voriconazole
41 patients with chronic pneumonia and 41 patients with chronic pneumonia and AspergillusAspergillus spp. in airway sample spp. in airway sampleUnderlying lung disease: Underlying lung disease:
- - COPD (n=18) COPD (n=18)
- prior tuberculosis (n=11)- prior tuberculosis (n=11)- bronchiectasis (n=6) - bronchiectasis (n=6) - pneumothorax (n=5), - pneumothorax (n=5), - lung cancer (n=3)- lung cancer (n=3)- sarcoidosis (n=3)- sarcoidosis (n=3)- postradiotherapy (n=2)- postradiotherapy (n=2)
Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009
Vertigo trial: treatment of chronic Vertigo trial: treatment of chronic aspergillosis with voriconazoleaspergillosis with voriconazole
Underlying risk factors: Underlying risk factors: - - corticosteroids inhaled (n=12), systemic (n=6) corticosteroids inhaled (n=12), systemic (n=6)
- alcoholic abuse (n=4)- alcoholic abuse (n=4)- diabetes (n=2)- diabetes (n=2)- other (n=11)- other (n=11)- none identified (n=12)- none identified (n=12)
Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009
Vertigo trial: treatment of chronic Vertigo trial: treatment of chronic aspergillosis with voriconazoleaspergillosis with voriconazole
Voriconazole oral routeVoriconazole oral routeTwo doses of 400 mg 12 hours apart Two doses of 400 mg 12 hours apart followed by maintenance doses of 200 mg followed by maintenance doses of 200 mg twice dailytwice dailyAt least 6 months duration, to be continued At least 6 months duration, to be continued 3 months after the best achievable response3 months after the best achievable responseMaximum duration of treatment could not Maximum duration of treatment could not exceed 12 monthsexceed 12 months
Cadranel J, et al. Phase II trial of voriconazole for treatment of chronic pulmonary aspergillosis. ATS May 2009
COPD (n=33)
Systemic disease (n=14)
Liver cirrhosis
(n=3)
Solid organ transplants
(n=9)
Other (n=8)
All (n=67)
Age, yrs (mean) 69 60 55 51 73 65
SAPS II (mean) 49 50 64 47 66 52
Predicted mortality, % 43 44 71 40 73 48
Observed mortality, % 85 93 100 100 100 91
Length of stay (days) 23 18 13 22 14 21
Culture positive,* 31/33 10/14 1/3 6/9 8/8 56/67
Asperg Ag** Positive* 12/25 7/11 0/0 4/9 4/6 27/51
Autopsy positive* 12/19 6/9 3/3 3/6 3/4 27/41
Meersseman et al. Invasive aspergillosis in critically ill patients without malignancy. AJRCCM 2004
Proven and probable IPA without malignancy in ICU (’00-’03)
23 pts, 16 proven, 7 probable (repeated isolation)23 pts, 16 proven, 7 probable (repeated isolation)recent steroid treatment, or intensification of steroid treatmentrecent steroid treatment, or intensification of steroid treatment
severe bronchospasm (12/23)severe bronchospasm (12/23)
all required mechanical ventilationall required mechanical ventilation
diagnosis classified as diagnosis classified as confirmed confirmed
positive lung tissue biopsy and/or autopsypositive lung tissue biopsy and/or autopsy probable probable
repeated isolation of Aspergillus from the airways with repeated isolation of Aspergillus from the airways with consistent clinical and radiological findingsconsistent 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?
Clinical characteristics of IPA in COPDClinical characteristics of IPA in COPD
Total number of patientsTotal number of patientsAge yrs (mean)Age yrs (mean)Steroid treatmentSteroid treatment
At admissionAt admission In hospitalIn hospital
NANA
5656
65,565,5
43434949
55
Clinical signsClinical signs Antibiotic resistant pneumoniaAntibiotic resistant pneumonia Dyspnoea exacerbationDyspnoea exacerbation Wheezing increaseWheezing increase Fever > 38° CFever > 38° C HaemoptysisHaemoptysis Tracheobronchitis (bronchoscopy)Tracheobronchitis (bronchoscopy)
53 53 556652523131
556 6
Bulpa et al. IPA in patients with COPD. Eur Resp J 2007; 30: 782
Clinical characteristicsClinical characteristicsDuration between symptoms and Duration between symptoms and diagnosis daysdiagnosis daysVentilationVentilation
InvasiveInvasive
NoninvasiveNoninvasive
NoneNone
NANA
OutcomeOutcome
DeathDeath
SurvivalSurvival
12,512,5
4343
11
1010
22
53 (95)53 (95)
3 (5)3 (5)
Bulpa et al. IPA in patients with COPD. Eur Resp J 2007; 30: 782
Why frequent in ICU? Why such a Why frequent in ICU? Why such a high mortality?high mortality?
Most severe exacerbations end up in ICUMost severe exacerbations end up in ICU
Steroids are given for a lot of reasonsSteroids are given for a lot of reasons
We don’t think of aspergillosisWe don’t think of aspergillosis
Poor sensitivity of culturePoor sensitivity of culture
We don’t know what to do with a positive We don’t know what to do with a positive culture or direct examinationculture or direct examination
Radiology doesn’t help usRadiology doesn’t help us
Meersseman W, Lagrou K, Maertens J. Invasive aspergillosis in ICU. Clin Infect Dis ‘07
Significance of culture positivitySignificance of culture positivity
IA diagnosed in 45/477 patients with “underlying IA diagnosed in 45/477 patients with “underlying pulmonary disease and positive culture”pulmonary disease and positive culture”Positive predictive value lower than in Positive predictive value lower than in haematology patients (around 40%)haematology patients (around 40%)Colonisation vs true disease ???Colonisation vs true disease ???
Temporary passage ?Temporary passage ?Long-term benign carriage ?Long-term benign carriage ?
Perfect JR, et al. Clin Infect Dis 2001; 3:1824-1833. Perfect JR, et al. Clin Infect Dis 2001; 3:1824-1833.
• Halo sign: only applicable to neutropenic patients
• Radiology in ICU “clouded” by atelectasis, pleural effusions, ARDS
• Necrotizing, cavitating lesions: not specific
Balloy et al. Differences in patterns of infection and inflammation. Infect Immun 2005; 73:494
Corticosteroids vs neutropenia: a different lung disease
As a consequence …As a consequence …
Inflammatory reaction: Inflammatory reaction:
- leads to encapsulation of the process- leads to encapsulation of the process- prevents at least partially invasion of- prevents at least partially invasion of hyphae in the blood (minor hyphae in the blood (minor coagulation necrosis) coagulation necrosis)- prevents leakage of antigens in blood- prevents leakage of antigens in blood- probably makes antigen markers in - probably makes antigen markers in blood less suitable for diagnosisblood less suitable for diagnosis
COPD (n=33)
Systemic disease (n=14)
Liver cirrhosis
(n=3)
Solid organ transplants
(n=9)
Other (n=8)
All (n=67)
Age, yrs (mean) 69 60 55 51 73 65
SAPS II (mean) 49 50 64 47 66 52
Predicted mortality, % 43 44 71 40 73 48
Observed mortality, % 85 93 100 100 100 91
Length of stay (days) 23 18 13 22 14 21
Culture positive,* 31/33 10/14 1/3 6/9 8/8 56/67
Asperg Ag** Positive* 12/25 7/11 0/0 4/9 4/6 27/51
Autopsy positive* 12/19 6/9 3/3 3/6 3/4 27/41
Meersseman et al. Invasive aspergillosis in critically ill patients without malignancy. AJRCCM 2004
Proven and probable IPA without malignancy in ICU (’00-’03)
Meersseman et al. Galactomannan in BAL in ICU. AJRCCM Jan 2008
Performance GM in serum and BALPerformance GM in serum and BAL
SummarySummary
Three disease entities in COPDThree disease entities in COPD- aspergilloma- aspergilloma- chronic aspergillosis- chronic aspergillosis- subacute invasive aspergillosis- subacute invasive aspergillosis
Controversial topic: no clear guidelinesControversial topic: no clear guidelinesStudies warranted inStudies warranted in
- chronic aspergillosis: benefits of - chronic aspergillosis: benefits of longterm triazole therapy longterm triazole therapy- subacute IPA: pre-emptive approach - subacute IPA: pre-emptive approach
based based on galactomannan in BAL on galactomannan in BAL