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

2. 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

3. 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

4. History of Aspergillus
st discovered and catalogued by an Italian biologist – Pier Angelo Micheli
st 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.

5. 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).

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

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

8. 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

10. 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

11. 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)

12. 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

13. 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

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

15. 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!

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

17. 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……………………

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

19. Chronic Pulmonary Aspergillosis CPA
Aspergilloma Chest X-ray

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

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

22. 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

23. 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

24. 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

25. 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

26. 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

27. 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.

28. 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 mg daily – split dose)

29. 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

30. 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

31. 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

32. 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

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

34. 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)

35. 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)
£ *
AmBisome
150mg 3x wk
per week, £ per day
£53,169.48
Subcutaneous
Gamma-interferon
50 ug 3x/wk
£ wk
12 weeks
£3,722.40
* based on 70kg person for 21 day course. Ambisome cost per 50mg vial = £113.61

36. 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

37. 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

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

39. 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 ( ) 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:

40. Damp Homes
National Aspergillosis Centre (NAC) & Institute for Specialist Surveyors and Engineers (ISSE)
Dr Graham Atherton 2016

41. 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

42. 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 )
Dr Graham Atherton 2016

43. Over 1M pages read monthly in >125 countries
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

44. 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

45. On behalf of the National Aspergillosis Centre Team Thank You