Aspergillus Lung Disease Flashcards
What is the life-cycle of aspergillus?
spores inhaled–germination–hyphal elongation and branching–mass of hyphae (plateau phase)–spores inhaled etc
How many species of aspergillus are there?
around 180
What are the main species of aspergillus associated with acute invasive disease?
a. fumigatus; a.flavus; a.niger and a.nidulans
Where are aspergillus spores found?
very common in the environment- widespread and readily inhaled
What are the aspergillus lung diseases mediated by fungus digestive proteolytic enzymes?
invasive aspergillosis; semi-invasive aspergillosis
What are the aspergillus lung diseases mediated by host defense?
atopic allergy; asthma and positive IgG precipitins to aspergillus; ABPA; aspergilloma
What is different about aspergilloma compared to the other spectrums of disease?
exploits an exisiting weakness as grows within a cavity of the lung previously damaged, then secretes toxic and allergic products
What proportion of asthmatics are skin prick positive to aspergillus species?
10%
What are precipitins?
ability for complexes that precipitate to be formed between antigens and antibodies
How has asthma been linked to aspergillus?
high spore coutns correlate with asthma attacks ; mouldy housing associated with worse asthma
What is ABPA?
inflammatory response to aspergillus in the airways which causes damage to bronchial walls-bronchiectasis
Who gets ABPA?
asthmatics and CF pts
What are the clinical features of ABPA?
long standing asthma; recurrent episodes of mucus plugging and expectoration; fever/malaise; poorly controlled asthma that needs repeated oral steroid courses; eosinophilia
What are teh features on CXR of ABPA?
flitting infiltrates; bronchiectasis; mucous impaction(gloved finger shadows)
What are the features of ABPA on CT?
central bronchiectasis with upper lobe predominance
What is the treatment for ABPA?
oral steroids and oral antifungals (itraconazole)
What are hte risk factors for invasive aspergillosis?
chemotherapy; bone marrow supression; advanced HIV; immune suppression; anti-TNF
What happens in invasive aspergillosis?
aspergillus hyphae invade the tissue
What are the clinical features of invasive aspergillosis?
fever; chest pain; cough; haemoptysis; dyspnoea; pulmonary infiltrates in a neutropenic patietns failing to respond to broad spec abx
Where can invasive aspergillosis spread?
sinuses and brain; endocarditis; eyes; skin
What is galactomannan?
exoantigen of aspergillus
How many sputum specimens should be submitted for fungal culture when fungal infection is suspected?
at least 3
What is the rate of IPA in actue leukaemia patients and allogenic BMT patients?
7% and 10-15% respectively
What is the classic lesion in IPA?
wedge-lesion peripherally set against the pleura
What is characteristic sign of IPA on CT?
halo sign
What is the mx of invasive aspergillosis?
IV amphotericin B ; IV itraconazole
What is semi-invasive aspergillosis?
low grade chronic invasion of aspergillus into the airway walls and surroudning lung
Who gets semi-invasive aspergillosis?
mild immunodeficiency- DM; steroid therapy; chronic lung disease; poor nutrition
What are the clinical features of semi-invasive aspergillosis?
middle aged; mild immunosuppression; pre-existing chronci lung disease; fever; productive cough; patchy cxr changes
What is seen on CT with semi-invasive aspergillosis?
“tree in bud” and reas of consolidation, cavities
What other name is aspergilloma given?
mycetoma
What is aspergilloma?
ball of fungal hypae wtihin a cavity in pre-damaged lung
What are the clinical features of aspergilloma?
asymptomatic; haemoptysis; fever; malaise
What is seen at higher levels with aspergilloma compared with other aspergillus lung disease?
IgG precipitins
Which fungal infections do type 1 responses promote clearance of?
Histoplasma capsulatum; cryptococcus neoformans
Which fungal infections does IL-17A production from Th17 cells promote the clearance of? How?
blastomyces dermatitidis and coccidiodes –recruitment of neutrophils
What does CLR dectin-2 respond to?
mannan stimulation; glycoprotein of blastomyces dermatitidis
What is the function of MelLec?
sensing of melanin on pathogens such as Aspergillus
What fungal infection do Th2 responses protect against?
Pneumocystic jiroveci
What non-immune cell type are important in the clearance of Pneumocystis infection?
lung epithelial cells
What is the role of LECs against pneumocystis?
directly respond upon binding of pneumocystis by activating NFkB; expression of CCL2; recruitment of Th17
What happens when there is neutralisation of IL17A or IL23 (Th17 promoting cytokine) in pneumocystis?
significant increase in lung fungal burden
What is the common cycle of dimorphic fungi?
spore is the infectious particle and upon entry to the lung undergo a phase-transition to the yeast phase to mediate disease
What happens to mice deficient in IFNy signalling in response to H.capsulatum infection?
very susceptible and die after just over a week of infection
What happens with neutralisation of TNFa upon re-challenge of H.capsulatum?
the mice no longer have protective immunity as recall of anti-H.capsulatum T cells does not occur and the mcie die
What is the effect of Th2 response in H.capsulatum infection?
increases lung fungal burden and mortality even with normal IFNy and TNFa responses- actively promotes progression of the infection
What is a major determinant in driving type 2 immunity in response to H.capsulatum?
CCR2 signalling- homozygous mutants have no defects in IFNy production, but very high IL-4 and increased significant mortality
What happens when there is ablation of TNFa signalling early in C.neoformans infection?
increased skewing towards a Th2 response- defective maturation of DCs?
What happens to mice deficient in the IFNy receptor with C.neoformans?
impaired clearance; increased dissemination and increased mortality– decreased fungicidal activity in macropahges
What is a saprophyte?
organism which gets its energy from dead or decaying organic matter
What cell type is particularly important in clearing A.fumigatus?
neutrophils
What shows that non-type 2 cytokines help drive allergic responses following fungal exposure?
robust eosinophil recruitment; arterial remodelling and collagen deposition around airways associated with allergic airway inflam and ABPA is associated with Th1 and Th17 repsonses as well as Th2, IL-17A is needed for full eosinophil recruitment at hte peak of inflammation
Give an example of the conflicting roles of Th2 responses in C.neoformans infection?
absence of IL-4 is associated with improved control of C.neoformans lung burden later in the infection but show inreased pathogen burder early in infection
What is the effect of eosinophils in Aspergillus infection?
associated with allergic airway inflam following repeated exposure but defects in eosinophil activity are assocaited with impaired clearance, exhibit contact-independent killing aspergillus
Waht is the classic RF for IA?
neutropenia
What is the most common RF for IA in the non-neutropenic host?
corticosteroid use
What is different about the course of infection of IA in neutrpenic vs non-neutropenic patietns?
angioinvasion is not a common feature in non-neutropenic patients
What is the antifungal agent of choice for IA?
voriconazole
Which patients does chronic pulmonary aspergillosis affect?
patients with some form of underlying respiratroy pathology that results in the formation of an air-filled cavity or bulla
What is the most common predispoing factor for CPA worldwide?
previously treated TB
What does haemoptysis in chronic pulmonary aspergillosis suggest a diagnosis of?
aspergilloma
What is the critical diagnosis test for CPA?
aspergillus specific IgG (or precipitans) supported by aspergillus in sputum culture or PCR or biopsy
What is chornic cavitary pulmonary aspergillosis?
slowly evolving, single or multiple lung cavities usually with thick walls and with or wihout aspergilloma and concomitant pleural fibrosis
Who gets CCPA?
patietns who are not overtly immunocompromised but subtle defects eg in mannose-binding lectin; surfatant have been linked to the pathogenesis
What happens with some cases of CCPA, especially if not treated?
develop extensive unilateral pulmonary fibrosis- chronic fibrosing pulmonary aspergillosis
What are aspergillomas?
rounded conglomerates of fungal hyphae, fibrin, mucus and cellular debris that arise in pulmonary cavities as a late manifestation of CPA
What is first line in treatment of CPA?
itraconazole
Why is there thoguht to be a better response to antifungals in SAIA than CCPA?
the more invasive nature of SAIA makes the fungal organisms more readily exposed to antifungals vs in CCPA where fungi are present within cavity walls where antifungals may not be able to penetrate
What is thought to be the mechanism of asthma exacerbation with aspergillus?
defective clearance of spores in asthma and CF allows germination of conidia to hyphae which then induce the production of proinflammatory cytokines responsible for devleopment of symptoms
What is sensitisation and lung damage with fungus other than aspergillus called?
allergic bronchopulmonary mycosis
