Aspergillosis Scottish Respiratory Nurses Forum Conference 12-November-2016 Marie Kirwan

The National Aspergillosis Centre (NAC) The UK's National Aspergillus Centre (NAC) opened on May 1st 2009 Mycology Reference Centre Manchester (MRCM) processes samples provides air sampling and mould identification services for domestic and working environments. NAC clinic Friday's - Chest Clinic 0845am Fungal Asthma Clinic (ABPA SAFS) Wednesday's 1.30PM pm - Chest Clinic NAC MDT meeting Thursday's 9am Thoracic MDT meeting every Thursday Specialist Thoracic Radiologists Surgical MDT meeting every three months

NAC Referrals & Outcomes 7 years NAC Referrals & Outcomes Bands = mild moderate severe as per annual report 10% of caseload die per annum. New aspergillosis n=450 CPA n=120. Projections - refer in difficult patients or resistance or patient decision

History of Aspergillus 1729 - 1st discovered and catalogued by an Italian biologist – Pier Angelo Micheli 1815 - 1st known case of infection 1815 in a Jackdaw 1842 – 1st case of human infection in 1842. 1800’s - 19th century occupational hazard amongst wig combers - allergic disease of the lungs.

What is Aspergillus? Aspergillus is a fungus whose spores are ubiquitous in the air we breathe Does not normally cause illness to a healthy individual Aspergillus can cause disease in weakened immune systems, damaged lungs or allergies Aspergillosis is a group of diseases which can result from Aspergillus infection and includes Invasive Aspergillosis (IA) Allergic Broncho Pulmonary Aspergillosis (ABPA) Chronic Pulmonary Aspergillosis (CPA) Aspergilloma Some asthma patients with very severe asthma may also be sensitised to fungi like Aspergillus (SAFS).

Aspergillus Life Cycle Germination Spores inhaled Mass of hyphae Hyphal elongation & branching

Aspergillus Life Cycle Aspergillus fumigatus Aspergillus fumigatus spore forming head (Electron micrograph)

Where is Aspergillus Aspergillus species are found in : Soil Air; spores may be inhaled Water / storage tanks in hospitals etc Food Compost and decaying vegetation Fire proofing materials Bedding, pillows Ventilation and air conditioning systems Computer fans

Aspergillus and aspergillosis Acute invasive (< 4 wks) ABPA Severe asthma with fungal sensitisation Allergic sinusitis Subacute IA (1-3 mo) Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary Aspergillus bronchitis Immune deficit Lung damage Allergy-Atopy . After Casadevall & Pirofski, Infect Immun 1999;67:3703

Aspergillosis in chronic respiratory diseases Airways/nasal exposure to airborne Aspergillus Invasive aspergillosis COPD grade III-IV, +/- steroids ICU - immunoparalysis Chronic aspergillosis (>3 months) TB and NTM (Non-Tuberculous Mycobacterium) Sarcoidosis COPD Pneumothorax Pneumonia, RA, asthma, lung surgery Persistence without disease - colonisation of the airways or nose/sinuses Exposure to individual Aspergillus spores or conidia is almost constant. If eradicated immediately, as is usual in normal people, no disease results. If colonisation occurs, it may be short or long term. The pattern of disease is mostly determined by the host group (see next slide), with probably a component of the inoculum size contributing to invasive disease. However chronic disease if usually seen in patients with apparently normal immune systems. Allergic Allergic bronchopulmonary (ABPA) asthma, CF Extrinsic allergic (broncho) alveolitis (EAA) Severe Asthma with fungal sensitisation (SAFS) Allergic Aspergillus sinusitis (eosinophilic fungal rhinosinusitis)

Prognosis: Comparison of CPA and Aspergillus colonization Abstract Background Not easy to distinguish CPA from colonization when Aspergillus species are isolated from respiratory samples. Methods We retrospectively reviewed the medical records of 110 patients with Aspergillus species isolation from respiratory samples, to analyze and compare the differences between CPA and colonization of the Aspergillus species. Ohba et al, Resp Med 2012; 106:724

Aspergillus and aspergillosis GM test serum IgG antibody test Precipitins (serum) IgE antibody test IgG antibody test Acute invasive ABPA Severe asthma with fungal sensitisation Allergic sinusitis GM test in BAL and other respiratory samples Subacute IA Frequency of aspergillosis Frequency of aspergillosis Aspergilloma Chronic pulmonary Aspergillus bronchitis Immune compromised Lung damage Allergy - atopy . After Casadevall & Pirofski, Infect Immun 1999;67:3703

Pulmonary Aspergillosis Chronic Disease Chronic Pulmonary Aspergillosis (CPA) (>3 months) Cavitary Pulmonary Aspergillosis Aspergilloma Of Lung (Fungal Ball) Fibrosing

Chronic Pulmonary Aspergillosis CPA CPA occurs in various forms: Simple Aspergilloma (Fungal Ball) Chronic Cavitary Pulmonary Aspergillosis (CCPA) +/- Chronic Fibrosing Pulmonary Aspergillosis (CFPA) +/- CPA occurs in immunocompetent patients unlike invasive aspergillosis Morbidity is significant - both systemic and respiratory symptoms Haemoptysis Weight loss Profound fatigue Severe shortness of breath Life-threatening haemoptysis common. Progressive pulmonary fibrosis and loss of lung function common CPA has a case fatality rate of 20–33% in the short-term and of 50% over a span of 5 years!

Denning DW et al, Clin Infect Dis 2003; 37:S265 Signs and Symptoms Denning DW et al, Clin Infect Dis 2003; 37:S265

Who gets Aspergillosis? Aspergillosis affects respiratory & immuno-compromised patients: - Chronic Respiratory Disease Cystic fibrosis Chronic Obstructive Pulmonary Disease (COPD) Asthma (ABPA - SAFS) Invasive Aspergillosis Leukaemia Chemotherapy patients HIV or AIDS Steroids Transplant patients Chronic Granulomatous Disease (CGD) and others……………………

Chest CT scan with HALO sign (Invasive Disease - Leukaemia)

Chronic Pulmonary Aspergillosis CPA Aspergilloma Chest X-ray

Aspergilloma – Fungal Ball CPA fungal ball is a later stage development

Allergic Broncho Pulmonary Aspergillosis (ABPA) Allergy to the spores of Aspergillus moulds Predominantly affects patients with Asthma CF Bronchiectasis

Presentation of ABPA Shortness of breath Coughing and wheezing Pulmonary infiltrates that do not respond to antibiotics in asthmatic and CF patients Cough up plugs of brown coloured mucous Presence of Aspergillus sensitisation- antibodies serum Total IgE >1000ku/l, Asp IgE >0.4kua/l, pos skin prick test (ideally both tests) Can lead to permanent lung damage if left untreated! THINK – uncontrollable asthma symptoms in the context of fully compliant medications & optimised medical therapies Consider – ABPA. Do the tests

Diagnosis of Aspergillosis Investigations: Aspergillus IgG (precipitins) and titre (titre falls with therapy and rises with relapse or resistance development) Inflammatory markers, CRP, Plasma Viscosity Total IgE (Allergic disease) Aspergillus specific IgE (RAST) Sputum – MCS & Fungal sensitivities X-ray CT scan History MRC – Medical Research Council Dyspnoea Score

Objectives of antifungal therapy (CPA) Very ill patients: Save their lives with (usually) IV and then oral therapy Quite ill patients: Improve quality of life by minimising symptoms Prevent further haemoptysis Stop progression of scarring in the lung Prevent the emergence of antifungal resistance Avoid antifungal toxicity Patients with few symptoms Stop (silent) progression of scarring in the lung 24

Oral triazole therapy for Chronic Pulmonary Aspergillosis A lower dose advised in those over 70 years, low weight, significant liver disease and those of NE Asian descent who may be slow metabolisers TDM = therapeutic drug monitoring Could we perhaps merge this with the next slide for a single treatment recommendation? If you think you are ok for time then no need I have moved the therapy slides to be all together. Denning DW et al, Chronic pulmonary aspergillosis – Rationale and clinical guidelines for diagnosis and management. Eur Resp J 2016;47:45

Therapeutic Drug Monitoring (TDM) Itraconazole Levels – random level Voriconazole Levels – trough level Posaconazole Levels – record time of last dose Aim is to keep blood concentration at a therapeutic level Too low can lead to resistance Too high can result in increased side effects MRCM – and other labs

Drug Management Itraconazole is available as 100 mg pink and blue capsules with the brand name brand name Sporanox.® Now generic Important to take Itraconazole capsules whole with food or an acidic drink, like Coca-Cola. Itraconazole available as an oral liquid, brand name Sporanox® in a 150ml bottle, concentration of 10mg/mL. Sugar free cherry flavoured. It is important to take Itraconazole oral liquid on an empty stomach.

Drug Management Voriconazole is available as 50mg or 200mg tablets Vfend® and generic taken at a dose of 200mg twice daily, 12 hours apart. Voriconazole, brand name Vfend® available as an orange flavoured oral liquid of 200mg/5mL. Important to take Voriconazole tablets whole with food or an acidic drink, like Coca-Cola. TDM Drug level to adjust dose (dose range 100-900mg daily – split dose)

Drug Management Posaconazole available as tablets and should be taken at a dose of 400mg once daily with or without food. If patients are not eating a lot of food it should be taken 200mg 4 times daily. Also available as liquid form 400mgs twice daily 12 hourly

Monitoring long term azole therapy LFT abnormalities rare after 6/12 – usually something else Hypertension with itraconazole Fatigue and loss of libido Corticosteroid drug interactions with itraconazole Skin and skin cancer with voriconazole Rare cases of myositis and weakness resistance

Side effects of Azoles Itraconazole GI Intolerance Hepatitis Peripheral neuropathy (17%) 3-18mths after start of drug Fluid retention Rash Hypertension Cardiac Failure Headache Tremor Insomnia

Side effects of Azoles Voriconazole Photosensitivity – even trivial light Visual Disturbance Peripheral neuropathy (9%) Poor concentration Abnormal thinking Headache Dry painful lips Abnormal LFTs Dry eyes Tightening feeling of the skin

Side effects of Azoles Posaconazole GI Intolerance Peripheral Neuropathy (1%) Rash Headache Sleep disturbance Anorexia Abnormal LFTs Arrhythmias & palpitations Generally well tolerated

IV Antifungals Invasive or resistant disease Ambisone- 3 weeks course can cause renal impairment. Patients usually have IV saline for an hour prior to the Ambisone. Ambisone is run over 2 hours or longer if patients are having discomfort or there is evidence of renal deterioration Micafungin- 4 week course can cause hepatitis (there has been 2 patients where it caused low sodium)

Typical duration (range) Typical cost per course Drug Management Agent Typical daily dose Cost per day (£) Typical duration (range) Typical cost per course Oral Itraconazole capsules – 1st Line CPA ABPA 200mg BID 1.40 365 £512.94 Itraconazole suspension – 1st Line CPA 13.33 £4,865.45 Voriconazole capsules – 2nd Line CPA or 1st Line IA 82.83 £30,232.95 Voriconazole capsules – Voriconazole capsules – 2nd Line CPA or 1st Line IA 150mg BID 62.12 £22,673.80 Posaconazole tablets – Intolerance 400mg BID 112.06   £40,901.90 Intravenous AmBisome* 3mg/kg daily 568.05 21 (14-30) £11929.05* AmBisome 150mg 3x wk 1022.49 per week, £145.66 per day £53,169.48 Subcutaneous Gamma-interferon 50 ug 3x/wk £310.20 wk 12 weeks £3,722.40 * based on 70kg person for 21 day course. Ambisome cost per 50mg vial = £113.61

Long Term Management Blood tests Serial Aspergillus IgG (precipitins) and titre Inflammatory markers, CRP, Plasma Viscosity Total IgE (Fungal Asthma) Aspergillus specific IgE (RAST) (Fungal Asthma) Sputum Microscopy Sputum – sensitivities Asp PCR Radiology X-ray CT scan History – crucial for assessment for toxicity MRC – Medical Research Council Dyspnoea Score St Georges Respiratory Questionnaire Research Avoidance to known sources of Aspergillus spores

How to avoid Aspergillus Pulmonary infections can be prevented by avoiding sources of Aspergillus spores: Smoking Bedside humidifiers Animal stables Hay Mulch Rotten plants, Compost piles, Wood & bark chips Construction sites

Denning DW et al, Chronic pulmonary aspergillosis – Rationale and clinical guidelines for diagnosis and management. Eur Resp J 2016;47:45-68.

7,104 young adults in 13 countries (11 Europe) Questionnaires, sensitisation to Alternaria and Cladosporium, assessment of homes, asthma evaluation (metacholine challenge). New onset asthma the key output (n=355) Follow up 8.7 (5.9-11.7) years. Risk ratio for new asthma = 1.46 (water damage) and 1.3 (indoor moulds). Correlation with water damage and mould in the house Norback D, Occup Environ Med 2013;70:325-31.

Damp Homes National Aspergillosis Centre (NAC) & Institute for Specialist Surveyors and Engineers (ISSE) http://nacpatients.org.uk/damp_general Dr Graham Atherton 2016

Asthma and fungus Interactions Fungal and damp exposure at home increases the risk of asthma Dampness and fungus at home increase asthma exacerbations Thunderstorm asthma Some occupational asthma linked to fungal exposures [Link between fungi and extrinsic allergic alveolitis] Fungal sensitisation linked to severe asthma Antifungal therapy reduces asthma severity in most patients with ABPA and SAFS

What should I do? Identify source of water and stop it Occasionally it is a leak from plumbing, roof, guttering Usually it is excessive humidity caused by a combination of: Normal daily living (cooking, washing, breathing!) Poor house design and lack of ventilation If neither of these options is true seek further advice (Environmental Health Officer or www.isse.org.uk ) Dr Graham Atherton 2016

Over 1M pages read monthly in >125 countries www.aspergillus.org.uk 18 years Over 1M pages read monthly in >125 countries Supported by the Fungal Infection Trust – 25 year anniversary 2016 New section on drug interactions which you can search very quickly + app for iphones and android (search antifungal interaction) 691 interactions were rated as minor, 919 moderate and 381 severe,   = 2216 recorded interactions 43

GAFFI Global Action Fund for Fungal Infection VISION is to reduce illness and death associated with fungal diseases worldwide - a “hidden crisis”. MISSION is to improve the health of patients suffering from serious fungal infections through better patient care, improved access to o diagnostics and treatment, and by provision of educational resources to health professionals. WHY GAFFI? Fungal Infections are neglected diseases worldwide Globally, > 300 million people of all ages estimated to suffer from a serious fungal infection every year Of these, over 1.66 million people are estimated to die In comparison, deaths from malaria and tuberculosis are 600,000 and 1,540,000 respectively

On behalf of the National Aspergillosis Centre Team Thank You