The Fungal Conundrum Spr 1

The Fungal Conundrum SpR 1

Matt Dickson Our case

• 77 year old female • Current smoker, 30 pack years • Presents to ambulatory care with cough, right sided pleuritic chest pain

In One Stop Clinic…

• Cough for 2 months • 2kg weight loss • PS 1 • PMH: Mild COPD, Angina, Diverticular disease, Hypertension, previous TIA/strokes, previous left sided carotid endarterectomy • CT…

SCE Question 1

A 77 year old female with a 30 pack year history of smoking presents with a 2 month history of weight loss and dry cough. She has a performance status of 1 and mild COPD. Her CT scan reveals a 16mm spiculated mass in the right upper lobe, with no evidence of hilar/mediastinal lymphadenopathy or metastatic disease. Which of the following statements is most accurate? a) A CT guided lung biopsy would be the next investigation of choice b) A follow-up CT in 3 months is advisable c) A PET CT would be the next investigation of choice d) From the CT findings, in terms of TNM lung cancer staging, she would stage at T1cN0M0 e) Lung nodules located in the lower lobes are more likely to be malignant SCE Question 1

Brock Model

Herder Model

=10.3%

CT Guided Lung Biopsy

Fragments of lung tissue showing mild alveolar dilatation with a moderate chronic inflammatory infiltrate, alveolar macrophages and anthracotic pigment. In areas there is evidence of necrosis and a few fungal hyphae are seen. Stains for AF bacilli are negative. No evidence of malignancy.

Follow-up January

• Re-assured likely benign lesion, fungal in origin • Treatment not necessary at this stage • Follow up in 2 months with repeat CXR

Follow-up March

• Asymptomatic • 1 week of antibiotics • F/U in 2 months

Follow-up May

• Small amounts of white sputum (teaspoon/day) • No fevers/night sweats • Bloods: Eosinophils 0.47, Plts 482, Hb 114 Aspergillus IgG 83.5 (0-40mgA/L) Aspergillus IgE 14.3 (0-0.35kUA/L) Total IgE >2500 (0-99.9) Aspergillus PCR and aspergillus antigen (galactomannan) tests negative • Sputum negative (C&S, fungal, TB) • CT booked SCE question 2

A 77 year old female with mild COPD presents with a 2 month history of cough and weight loss. CT guided biopsy of a 16mm lung nodule reveals necrotic material with fungal hyphae, and no evidence of malignancy. Serological and serum tests can be seen below: Eosinophils 0.5, Plts 482, Hb 114 Aspergillus IgG 83.5 (0-40mgA/L) Aspergillus IgE 14.3 (0-0.35kUA/L) Total IgE >2500 (0-99.9) Aspergillus PCR and aspergillus antigen (galactomannan) tests negative The above blood results would be most in keeping with what? a) ABPA b) Aspergilloma c) Atopic allergy d) Invasive aspergillosis e) Semi-invasive (chronic pulmonary) aspergillosis SCE question 2

• Recognises asthma and CF are predisposing factors • Two obligatory criteria are: – 1) positive immediate (type I) cutaneous hypersensitivity to Aspergillus antigen or elevated IgE levels against A. fumigatus, – 2) elevated total IgE levels >1000 IU·mL−1. • At least two out of three other criteria should be fulfilled: – 1) the presence of precipitating or IgG antibodies against A. fumigatus in serum – 2) radiographic pulmonary opacities consistent with ABPA, – 3) a total eosinophil count >500 cells·μL−1 in steroid naïve patients.

SCE question 3

• A 77 year old female with mild COPD presents with a 2 month history of cough and weight loss. CT guided biopsy of a 16mm lung nodule reveals necrotic material with fungal hyphae, and no evidence of malignancy. She then develops further radiological changes including right upper lobe cavitating consolidation with an “air crescent sign”. You are concerned she may have pulmonary aspergillosis. Her presentation and CT appearances are more in keeping with: a) ABPA b) Chronic fibrosing pulmonary aspergillosis c) Invasive aspergillosis d) Semi invasive (chronic necrotising) aspergillosis e) Simple aspergilloma SCE question 3

• ABPA – hypersensitivity to Aspergillus (IgE and IgG mediated) • Invasive aspergillosis - usually severely immunosuppressed – Days to weeks – Galactomannan + B-d-Glucan can be useful – CT: • Halo of low attenuation surrounding nodular lesion • “Air crescent” sign • Single/multiple nodules, ground glass, consolidation

Nomenclature can be confusing!

Chronic pulmonary aspergillosis: • Middle-aged • More often male • Present with constitutional symptoms (weight loss, malaise, sweats, anorexia) chronic productive cough, breathlessness, chest discomfort and occasionally haemoptysis. • Aspergillus IgG present, supported by Aspergillus in sputum or PCR, or biopsy/aspiration Chronic pulmonary aspergillosis

Can be split into: • Semi invasive/chronic necrotising pulmonary aspergillosis – Weeks rather than months – Nodules, consolidation +/- cavitation • Chronic cavitatory pulmonary aspergillosis – Single/multiple cavities – With/without mycotoma (aspergilloma) – Concomitent pleural fibrosis • Chronic fibrosing pulmonary aspergillosis – End point of CCPA Aspergilloma

• Develop in pre-formed cavity (post TB, sarcoid, pneumonia, treated tumours etc) or with other forms of CPA • Air crescent vs Monod’s sign? • Often asymptomatic • Haemoptysis Bronchoscopy June

• No lesion seen • Hypoxic post bronchoscopy, required admission overnight • BAL from RUL – No malignant cells – Saccharomyces cerevisiae • 6 weeks of fluconazole 200mg OD June August Follow-up August

• Poor appetite • Ongoing weight loss • No new respiratory symptoms • 6 weeks of fluconazole completed • F/U planned in 2 months Significance of Brewer’s yeast?

• Unclear • Acted upon given lack of other culture positivity • Few case reports – severe infection mainly in immunocompromised • Yeasts do not produce hyphae • Bystander or contributor in this case? Aspergillus

• Environmental mould that grows in organic matter • Spores inhaled, normally eliminated from respiratory tract – Intact ciliary clearance – Pulmonary macrophages • Aspergillus fumigatus most common pathogenic species – When spores survive germination leads to hyphae which invade parenchyma – Angioinvasion leads to local dissemination, thrombus formation and tissue infarction – Inflammation and infarction lead to fever, cough, pleuritic pain, SOB Treatments for pulmonary aspergillus disease

• ABPA – Prednisolone (2 weeks, 0.5mg/kg/day, followed by gradual tapering) • 5mg every 6 weeks – Total serum IgE can be a marker of disease activity (check every 2/12) – Itraconazole (200mg BD for ~ 4 months) • Invasive aspergillosis – IV Voriconazole – Liposomal amphotericin B – Minimum 12 weeks of treatment Treatments for pulmonary aspergillus disease

• Chronic pulmonary aspergillosis – Oral voriconazole/itraconazole – Duration varies (6-12 months) – Avoid surgery • Aspergilloma – Surgical resection – IR – Consider azoles if systemically unwell, little evidence of efficacy Potential side effects of antifungals

• Long courses needed • Side effect burden significant – Liver toxicity common – GI side effects – Hair loss – Adrenal insufficiency – Photosensitivity – Neuropathies • Consider how effective they will be (CPA) Prognosis of untreated CPA

• Can be up to 50% mortality over 5 years • Relapse common following cessation of treatment Learning/discussion points

• Was biopsy appropriate (PET negative)? • Was treatment of Saccharomyces appropriate? • Treatment of pulmonary aspergillus syndromes difficult (and confusing!) • What are the next steps? References

1. Kosmidis C, Denning DW The clinical spectrum of pulmonary aspergillosis Thorax 2015;70:270-277. 2. Callister MEJ, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70: ii1–ii54. 3. Panse P, Smith M, Cummings K, et al. The many faces of pulmonary aspergillosis: Imaging findings with pathologic correlation. Radiology of Infectious Diseases 2016; 3 (4): 192- 200