Transcript Aspergillosis - Scottish Respiratory Nurse Forum

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
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
Spores inhaled
Germination
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
Acute invasive (< 4 wks)
Subacute IA (1-3 mo)
ABPA
Severe asthma with
fungal sensitisation
Allergic sinusitis
Aspergilloma
Chronic pulmonary
Aspergillus bronchitis
Frequency of aspergillosis
Frequency of aspergillosis
Aspergillus and aspergillosis
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)
Persistence
without disease colonisation of
the airways or
nose/sinuses
•
•
•
•
Sarcoidosis
COPD
Pneumothorax
Pneumonia, RA, asthma, lung surgery
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
Ohba et al, Resp Med 2012; 106:724
GM test
serum
IgG antibody test IgE antibody test
Precipitins (serum) IgG antibody test
ABPA
Acute invasive
Severe asthma with
fungal sensitisation
GM test Subacute
in BAL and
samples
IA other respiratory
Allergic sinusitis
Immune
compromised
Aspergilloma
Chronic pulmonary
Aspergillus bronchitis
Lung damage
Frequency of aspergillosis
Frequency of aspergillosis
Aspergillus and aspergillosis
Allergy - atopy
.
After Casadevall & Pirofski, Infect Immun 1999;67:3703
Chronic Disease
Chronic
Pulmonary
Aspergillosis (CPA)
(>3 months)
Chronic
Cavitary
Pulmonary
Aspergillosis
Aspergilloma
Of
Lung
(Fungal Ball)
Chronic
Fibrosing
Pulmonary
Aspergillosis
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!
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!
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
• Prevent the emergence of antifungal resistance
• Avoid antifungal toxicity
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
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
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)
Drug Management
Cost
Typical
per day
daily dose
(£)
Agent
Oral
Itraconazole capsules – 1st Line CPA ABPA
Typical
duration
(range)
Typical cost per
course
200mg BID
1.40
365
£512.94
200mg BID
13.33
365
£4,865.45
Line IA
200mg BID
82.83
365
£30,232.95
Voriconazole capsules – Voriconazole capsules –
2nd Line CPA or 1st Line IA
Posaconazole tablets – Intolerance
150mg BID
62.12
365
£22,673.80
400mg BID
112.06
AmBisome*
3mg/kg daily
568.05
21 (14-30)
£11929.05*
AmBisome
150mg 3x wk
1022.49 per week,
£145.66 per day
365
£53,169.48
50 ug 3x/wk
£310.20 wk
12 weeks
£3,722.40
Itraconazole suspension –
Voriconazole capsules –
1st
2nd
Line CPA
Line CPA or
1st
£40,901.90
Intravenous
Subcutaneous
Gamma-interferon
* 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
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
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