Chronic Pulmonary Aspergillosis Dr. Iain Page

Intended Learning Outcomes To recognise and diagnose cases of chronic pulmonary aspergillosis (CPA) To be aware of the global burden of CPA To be able to identify individuals at risk for CPA

Chronic pulmonary Aspergillosis Chronic pulmonary aspergillosis (CPA) is a chronic progressive and destructive parenchymal lung infection in non-immunocompromised or subtly immunocompromised patients Occurs almost exclusively (90%) in patients with current or previous underlying lung disease or immune deficit Radiological presentation with formation of new cavities or expansion of the existing ones +/- fungal ball or nodule Prominent respiratory and systemic symptoms occurring over months (>3 months) Denning et al. Clin Infect Dis. 2003; 37(s3), pp.S265-S280. Schweer et al Mycoses, 2014. 57:257–270

Clinical presentation Respiratory Constitutional Productive cough Breathlessness Chest pain Haemoptysis Weight loss Malaise Poor appetite Sweats Swinging fevers (+/-) None of these symptoms are pathognomonic for CPA Jhun et al. Med. Mycol. 2013, 51, 811–817. Patterson et al . Chest 2014, 146, 1358–1368

Radiological Phenotypes of CPA CPA includes several disease manifestations, including (i) Aspergillus nodules , (ii) simple (surgical) aspergilloma, (iii) chronic cavitary pulmonary aspergillosis, and (iv) chronic fibrosing pulmonary aspergillosis Aspergillus Nodule Simple Aspergilloma Chronic Cavitary Pulmonary Aspergillosis Chronic Fibrosing Pulmonary Aspergillosis

Risk factors for CPA Condition Frequency Tuberculosis 17-80% COPD±Emphysema 30-50% Non-tuberculous mycobacterial infection <20% Pneumothorax or bullous lung disease 9-20% Allergic bronchopulmonary aspergillosis 12-18% Pulmonary fibrocystic sarcoidosis 9-17% Lung irradiation ~5% Rheumatoid arthritis 2-4% Ankylosing spondylitis <5% None 2-10% Smith et al Eur Resp J 2011;37: 865 Denning & Chakrabarti Lancet infect dis. 2017. S1473-3099(17)30309-2.

~3 million CPA cases globally; 1.2 million cases following TB 0.32-5.70/100,000 1.38/100,000 31/100,000 15.9/100,000 22.4/100,000 78/100,000 24/100,000 6.2/100,000 Denning et al Bull WHO 2011; 89:864-72

CPA complicates 3-12% of sarcoidosis 37% 24% ~72,000 CPA cases complicating sarcoidosis globally Denning et al . Eur Respir J. 2013 Mar;41(3):621-6.

Innate and adaptive immune defects in CPA Innate immune defects CD56: 43% Adaptive immune defects CD19: 43% CD8: 32% CD4: 17% Bongomin et al. J. Fungi 2017, 3, 26

CPA is a spectrum of disease entities that have considerable overlap and variation in severity Single/simple aspergilloma Subacute Invasive aspergillosis (SAIA) or chronic necrotizing pulmonary aspergillosis (CNPA) Aspergillus nodule(s) Chronic cavitary pulmonary aspergillosis (CCPA) A duration of disease longer than three months distinguishes CPA from acute and subacute invasive pulmonary aspergillosis Chronic fibrosing pulmonary aspergillosis (CFPA) Denning et al. Eur Respir J 2016;47:45-68

A single (simple) aspergilloma Single (simple) pulmonary aspergilloma is a single fungal ball in a single pulmonary cavity Serological or microbiological evidence implicating Aspergillus spp No radiological progression over months of observation Very few, if any persistent pulmonary or systemic symptoms Can be complicated by sudden, potentially fatal haemoptysis Kosmidis and Denning. Thorax. 2015; 70: 270-277. Denning et al. Eur Respir J 2016;47:45-68

Chronic cavitary pulmonary aspergillosis Formation or expansion of existing cavities (usually multiple) is characteristic Cavities may or may not contain an aspergilloma (fungal ball) Aspergilloma may or may not disappear Associated with high mortality (50-85% at 5 years) Causes of death include severe haemoptysis and respiratory failure Most cases are likely to be associated with an underlying defect in innate immunity Remove some details Kosmidis and Denning. Thorax. 2015; 70: 270-277. Denning et al. Eur Respir J 2016;47:45-68

Chronic fibrosing pulmonary aspergillosis Extensive fibrosis with fibrotic destruction of at least two lobes of lung complicating CCPA Associated with major loss of lung function CFPA can represent an end result of untreated CCPA One or more aspergillomas may be present Serological or microbiological evidence implicating Aspergillus spp. is required for diagnosis Kosmidis et al. Infect Dis (Lond). 2017;49 (4):296-301

Sub-acute invasive pulmonary aspergillosis (chronic necrotising pulmonary aspergillosis) Tissue biopsy demonstrates hyphal invasion of lung parenchyma Detectable Aspergillus antigen in blood and respiratory samples Detectable Aspergillus antibody in blood More rapid development of symptoms (i.e., weeks as opposed to months) Radiological pattern of nodules, consolidation with or without a solitary cavity with thin walls Clinical and radiological features are similar to CCPA but is more rapid in progression The computed tomography scan shows a dual cavity with moderately thick walls, an external irregular edge and some material within the cavity on an almost normal lung background. L: left side; R: right side. Denning et al. Eur Respir J 2016;47:45-68

Sub-acute invasive pulmonary aspergillosis (chronic necrotising pulmonary aspergillosis) SAIA occurs in mildly immunocompromised or very debilitated patients Risk factors includes: Diabetes mellitus Malnutrition Alcoholism Advanced age Prolonged corticosteroid administration or other modest immunocompromising agents, Chronic obstructive lung disease, Connective tissue disorders Radiation therapy Non-tuberculous mycobacterial (NTM) infection or HIV infection The computed tomography scan shows a dual cavity with moderately thick walls, an external irregular edge and some material within the cavity on an almost normal lung background. L: left side; R: right side. Denning et al. Eur Respir J 2016;47:45-68

Aspergillus nodules Aspergillus nodules occur in immunocompetent hosts May be single or multiple, with or without cavitation Patients are usually asymptomatic or have minor pulmonary symptoms Aspergillus IgG titre may be raised Natural history is poorly described, but progression to CCPA can occur Muldoon et al. BMC Pulm Med. 2016; 18;16(1):123.

The clinical spectrum of pulmonary aspergillosis Pathological features and characteristics of various forms of pulmonary aspergillosis. CGD, chronic granulomatous disease; CPA, chronic pulmonary aspergillosis; GVHD, graft versus host disease; HSCT, haematopoietic stem cell transplant; IPA: invasive pulmonary aspergillosis. Kosmidis and Denning. Thorax. 2015; 70: 270-277.

Diagnostic criteria Criteria ESCMID/ERS/ECMM IDSA 1 One or more cavities with or without a fungal ball present or nodules on thoracic imaging All present for ≥3 month Three month of chronic pulmonary symptoms or chronic illness or progressive radiographic abnormalities, with cavitation, pleural thickening, pericavitary infiltrates, and sometimes a fungus ball 2 Direct evidence of Aspergillus infection or an immunological response to Aspergillus spp. Aspergillus IgG antibody elevated or other microbiological data 3 Exclusion of alternative diagnosis No or minimal immunocompromise, usually with one or more underlying pulmonary disorders Denning et al. Eur Respir J. 2016;47:45–68. Patterson et al. Clin Infect Dis. 2016;63:e1–e60..

Functional antibody testing Laboratory diagnosis Immunology /Serology Mycological (Sputum) Aspergillus PCR Culture + Sensitivity Microscopy Immune biomarkers Functional antibody testing Aspergillus IgG Precipitins

Laboratory diagnosis Aspergillus specific IgG Aspergillus precipitin “Gold standard” for CPA diagnosis Positive in ~95% of the cases Positive predictive value ~100% Used in combination with other tests to confirm diagnosis of CPA Used for monitoring treatment response Aspergillus precipitin Low sensitivity Qualitative Culture of Aspergillus ~50% positivity Cannot distinguish contamination, colonisation or infection High volume fungal culture more sensitive Useful in monitoring for resistance Galactomannan Unclear utility in the diagnosis of CPA Aspergillus PCR Higher sensitivity than conventional culture No much data in CPA patients Useful in identification of antifungal resistance Signal strength correlates with treatment success or failure Page et al. Med. Mycol. 2015, 53, 417–439. Fayemiwo et al. J Microbiol Methods. 2017;140:32-39 Hope et al. Med. Mycol. 2005, 43, S207–S238.

Summary CPA occurs in patients with underlying lung diseases such as previous tuberculosis, atypical mycobacteria, COPD, sarcoidosis or lung cancer The clinical presentation and radiological features OF CPA overlap substantially with the underlying diseases themselves Aspergilloma are only present in a minority of CPA cases Aspergillus-specific IgG measurement is therefore key to diagnosis The predicted global prevalence is around 3 million cases, mostly secondary to tuberculosis At present most of these cases go undiagnosed

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