Allergic Bronchopulmonary Aspergillosis: Management - PowerPoint Presentation

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Allergic Bronchopulmonary Aspergillosis: Management

Ritesh

Agarwal,

MD, DM

Professor of Pulmonary Medicine

Postgraduate Institute of Medical Education and Research

Chandigarh, India

Intended aims of this module

To be aware of the different stages of allergic bronchopulmonary aspergillosis (ABPA)

To be familiar with the management goals and treatment approaches for patients with ABPA

To gain an understanding of the roles of glucocorticoids, antifungals and other adjunctive management options in ABPA

Introduction

ABPA occurs in persons with asthma and those with cystic fibrosis ABPA may occur in conjunction with allergic fungal sinusitis (symptoms including chronic sinusitis with purulent sinus drainage) Patients often manifest with uncontrolled asthma, expectoration of mucus plugs, and haemoptysis Recurrent pulmonary infiltrates ( fever) unresponsive to antibacterial therapy suggests ABPA in patients with asthma and cystic fibrosisPatients with asthma and ABPA may have poorly controlled disease and difficulty tapering off oral corticosteroids

Agarwal

et al

.

Clin

Exp

Allergy.

2013; 43:850-873.

Agarwal et al.

Expert Rev Respir Med

. 2016;10:1317-1334.

Diagnostic criteria for ABPA

Predisposing conditionsBronchial asthma, cystic fibrosisObligatory criteria (both should be present)Elevated A. fumigatus-specific IgE (>0.35 kUA/L)Elevated total IgE levels (>1000 IU/mL)Other criteria (at least two of three)Elevated A. fumigatus-specific IgG (>27 mgA/L)Radiographic pulmonary opacities consistent with ABPAEosinophil count >500 cells/µL (may be historical)

Agarwal

et al

.

Clin

Exp

Allergy.

2013; 43:850-873.

Agarwal et al.

Expert Rev Respir Med

. 2016;10:1317-1334.

Stages of ABPA

Stage DefinitionFeatures1 Acute Never diagnosed to have ABPA in the past; presentation with uncontrolled asthma/constitutional symptoms, and meeting the diagnostic criteria of ABPA2  ResponseClinical and/or radiological improvement AND fall in IgE by ≥25% of baseline at eight weeks3  Exacerbation Clinical and/or radiological worsening accompanied by an increase in IgE by ≥50% from the ‘new’ baseline4 Remission Sustained clinicoradiological improvement with IgE levels remaining at or below the ‘new’ baseline (or increase by <50%) for ≥6 months off therapy5a Treatment-dependent ABPATwo or more relapses within six months of stopping treatment OR deterioration in clinical and/or radiological condition and/or immunological worsening on tapering oral steroids/azoles5b Glucocorticoid-dependent asthmaSystemic corticosteroids required for asthma control while the ABPA activity is controlled (as indicated by IgE levels and thoracic imaging)6 Advanced ABPA Presence of complications (cor pulmonale and/or chronic type II respiratory failure) along with presence of extensive bronchiectasis

Agarwal

et al

.

Clin

Exp

Allergy.

2013; 43:850-873.

Management goals

To optimise control of cystic fibrosis and exacerbation of asthmaTo avoid steroid dependencyTo improve airflow through reduction of mucus and obstruction To control bacterial infection (often associated with bronchiectasis)To control severity and exacerbation frequency of ABPA To avoid treatment (steroids and/or antifungal) related adverse eventsTo control emergence of antifungal resistance

Moss

et al

.

Eur

Respir

J

. 2014; 43:1487-1500.

Denning

et al

.

Clin

Transl

Allergy

. 2014; 4:14.

Agarwal

et al

.

Clin

Exp

Allergy.

2013; 43:850-873.

Management approaches

Control of the immune response

Airway hypersensitivity syndrome; IgE mediatedApproachImmunosuppression with oral steroidsReduced inflammation Anti-IgE therapy

Control of airway fungal burden

? More fungus, more airway immune response Approach Antifungal therapy to decrease airway fungal burden Avoiding environmental exposures to fungal organisms

Patterson

et al.

Clin

Infect Dis

. 2016; 63: e1-e60

Moss

et al

.

Eur

Respir

J

. 2014; 43:1487-1500.

Management: Glucocorticoids

Oral glucocorticoids reduce the inflammatory response in acute stage (stage 1) and exacerbations (stage 3) of ABPAMainstay of ABPA management Inhaled steroids are not effective (can control asthma in some patients).Many short and long-term adverse events Relapse is frequent after discontinuation

Greenberger

et al. J Allergy

Clin

Immunol

Pract

. 2014;2:703-708.

Agarwal

et al. Chest

. 2009;135:805-826

Management: Antifungals

Adding oral itraconazole to steroids in patients with recurrent or chronic ABPA may be helpfulThis may allow more rapid resolution of infiltrates and symptoms, facilitating steroid tapering or lowering the required dose of maintenance corticosteroidsRelapse after improvement during antifungal therapy is common; Long-term suppressive therapy may be necessaryTherapeutic azole monitoring is recommended to optimise ABPA control and avoid emergence of resistanceIn CF patients with ABPA, the concomitant use of itraconazole and inhaled steroids may precipitate Cushing’s syndrome

Moreira

et al

.

Clin

Exp

Allergy.

2014; 44:1210-1227.

Stevens

et a

l.

N

Engl

J Med.

2000; 342:756-762.

Management: Antifungals

Indications for itraconazole in ABPARecurrent exacerbationsGlucocorticoid-dependent ABPATransformation to CPAAlternative to steroids in acute-stage ABPA in those at-risk for steroid complications

Itraconazole

solution

is preferred in CF patients because of poor absorption of capsules. Patients who fail itraconazole, or are intolerant to itraconazole, may respond to voriconazole, posaconazole, or inhaled amphotericin B

Chang

et al.

Curr

Allergy Asthma Rep

. 2013;13:152-61.

Agarwal

et al

.

Expert Rev Respir Med

. 2016;10:1317-1334.

Management: Itraconazole vs. Placebo

Higher response in the itraconazole group (46%), compared to the placebo group (19%, P=0.04)

The rate of adverse events was similar in the two groups

Stevens

et al

.

N

Engl

J Med.

2000; 342:756-762.

Management: Itraconazole vs. Prednisolone

Composite response was significantly higher in the prednisolone group compared with the itraconazole group (100% vs 88%; P = .007)The rate of adverse events was higher in the glucocorticoid armPrednisolone was more effective in inducing response than itraconazole in acute-stage ABPA

Agarwal et al. Chest. 2018:S0012-3692(18)30077-1.

Omalizumab

13 patients with chronic ABPA randomized to 4-month treatment with omalizumab (750 mg monthly) or placebo

Exacerbations occurred less frequentlyMean FeNO decreased Basophil sensitivity to A. fumigatus decreased significantly after omalizumab but not after placebo

Voskamp

et al.

J

Allergy

Clin

Immunol

Pract

2015; 3: 192-199

Management: Surgical care

Areas of mucoid impaction in ABPA may have a mass-like appearance and are sometimes resected as an undiagnosed lung mass; however, steroid therapy and oral itraconazole therapy are preferred.

Patients who have associated allergic fungal sinusitis benefit from surgical resection of obstructing nasal polyps and inspissated mucus in addition to corticosteroid therapy.

Nasal washes with amphotericin or itraconazole have also been employed

Allergic fungal sinusitis usually requires endoscopic sinus surgery to improve drainage

Other treatment additions in ABPA

AzithromycinReduces cough and sputum productionNebulized hypertonic salineMay help clears sputum in some patientsVaccination Haemophilus influenzae / Pneumococcal vaccinesPrevents exacerbation

Kellett

et al

.

Respir Med

. 2005; 99:27–31.

Stage-wise management of ABPA

Stage 1: Acute• Prednisolone 4-16 weeks• Total IgE follow-up every 8 weeks for 1 yearStage 2: Response• Management of underlying CF or AsthmaStage 3: Exacerbation• Same management as Stage 1• Prednisolone: daily for 2 weeks, then every other day for 8 weeksTotal serum IgE should be repeated after the initial 8 weeks of corticosteroid therapy, then every 8 weeks for 1 year

Stage 4: Remission• Management of underlying CF or AsthmaStage 5: Corticosteroid-dependent asthmaOral corticosteroids, given indefinitely Stage 6: End-stage fibrosis• Daily oral corticosteroids

An antifungal may be considered as a corticosteroid-sparing agent at any stage from 1 to 5

Agarwal

et al. Expert Rev Respir Med

. 2016;10(12):1317-1334.

Virnig

& Bush.

Curr

Opin

Pulm

Med

.2007;13:67-71.

Greenberger.

J Allergy

Clin

Immunol

. 2002;110:685-692.

Total IgE is a useful test for monitoring treatment response in ABPA

Total IgE declines consistently from baseline to 2 months on therapyAspergillus specific IgE values are variableTotal IgE is a useful test in monitoring treatment responses in ABPA while A. fumigatus specific IgE has limited utility.

Agarwal

et al. Mycoses

. 2016;59(1):1-6.

High-attenuated mucus in ABPA

High-attenuation mucus (HAM) is a characteristic radiologic finding seen in patients with ABPAHAM impaction in ABPA is associated with initial serologic severity and frequent relapses Central bronchiectasis and HAM are independent predictors of recurrent relapses in ABPATherapeutic flexible or rigid bronchoscopy may be required to relieve HAM.

Agarwal

et al

.

PLoS

ONE. 2010;

5(12): e15346.

Summary

The treatment of ABPA is directed at the inflammatory component caused by the hypersensitivity reaction to

Aspergillus fumigatus

Timely diagnosis and treatment can prevent the progression to end-stage ABPA

The underlying asthma or cystic fibrosis (CF) should also be aggressively treated

Corticosteroids are a cornerstone of therapy for exacerbations of ABPA

Antifungal interventions in ABPA improved patient and disease outcomes in both asthma and cystic fibrosis

Antifungals are considered an adjunctive but not primary therapy for APBA

For patients with corticosteroid-dependent ABPA, addition of itraconazole leads to improvement in the condition without added toxicity

END