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

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