Aetiology

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the presence of the Aspergillus fumigatus species of mould in the lungs. These spore-forming fungi are found ubiquitously in the environment, particularly in organic matter such as soil, mulches, wood chips, grass, dead leaves, and decaying matter (e.g., composts), as well as water-damaged walls/ceilings, damp basements, and other moisture-rich indoor conditions. Most human disease is caused by A fumigatus, although other fungal species associated with allergic bronchopulmonary mycoses have been implicated.[7][17] ​The airborne spores of Aspergillus are 3-5 micrometres in diameter and given their small size they can reach the distal bronchioles and alveoli when inhaled. Repeated inhalation of spores in susceptible individuals can lead to airway colonisation and elicit a complex allergic response resulting in airway inflammation and destruction. Although the spores may germinate and form hyphae that can be detected in mucus-impacted bronchial lumen, tissue invasion - such as that seen in angioinvasive aspergillosis - does not occur.

Pathophysiology

The exact pathogenesis of ABPA is incompletely understood but is known to involve IgE- and IgG-mediated immune responses to Aspergillus antigens in the airways of susceptible individuals.[18]

Susceptible hosts typically have underlying airway pathology such as asthma and cystic fibrosis, and have abnormalities in their innate airway mucosal defence mechanisms including mucus hypersecretion, increased mucus viscosity, and impaired mucociliary clearance of pathogens.[18]

This results in an increased risk for airway colonisation by Aspergillus as well as provides a favourable environment for the germination of spores and growth of hyphae, which exposes a slew of antigenic markers that trigger a robust host immune response.[18]

Normally, the immune response to Aspergillus antigens is initiated by innate immune cells (e.g., macrophages and dendritic cells) and ultimately leads to activation of the adaptive T-helper cell response. In a healthy patient, this cascade primarily activates the Th1 subset of T-helper cells, which release cytokines such as IFN-y and TNF-a and ultimately results in an effective pro-inflammatory response characterised by macrophage and neutrophil recruitment, activation, and phagocytosis.[19]​ On the contrary, in certain patients predisposed to ABPA, exposure to Aspergillus antigens results in a predominantly Th2 response, which is characterised by IL-4 and IL-5-mediated eosinophilic inflammation and production of anti-Aspergillus IgE and IgG antibodies, ultimately resulting in a type 1-3 hypersensitivity reaction against Aspergillus antigens.

This pathological inflammatory response manifests clinically as bronchial hyper-responsiveness, increased sputum production, mucus plugging, and ultimately leads to airway destruction and central bronchiectasis. While it is not entirely understood why some individuals are more susceptible to developing fungal sensitisation or ABPA compared to others, recent studies have identified associations with certain genetic risk factors, including IL-4 receptor polymorphisms, HLA DR2/DR5 genotypes, and certain CFTR mutations.[20][21]​ 

IL-10 promoter polymorphisms and surfactant protein polymorphisms have been noted to be more common in patients with ABPA and may be a host susceptibility factor for ABPA. Further research is needed.

Classification

Spectrum of Aspergillus lung disease[6]

Aspergillus may cause a spectrum of pulmonary disease states, depending on the degree of immune dysfunction of the patient and the nature of the patient-pathogen interaction. These include:

Invasive pulmonary aspergillosis

Characterised by invasion of lung tissue by hyphae, typically affecting patients with immunocompromising conditions (e.g., lung transplant recipients, neutropenic patients undergoing chemotherapy, patients taking chronic corticosteroids, etc.)

Chronic pulmonary aspergillosis (CPA)

Affects patients without obvious immune compromise, but with an underlying lung condition such as COPD or sarcoidosis, prior or concurrent TB or non-tuberculous mycobacterial disease

Subacute invasive pulmonary aspergillosis (SIPA)

Similar to invasive pulmonary aspergillosis, but infection occurs over a period of months

Chronic cavitary pulmonary aspergillosis (CCPA)

Indolent infection occurring in patients who not overtly immunocompromised, usually with progression of symptoms and lesions over time, classically affecting patients with underlying structural lung disease (e.g., prior TB infection, prior lung cancer, bronchiectasis, etc.)

Aspergilloma

Characterised by a well-circumscribed mass composed of a conglomerate of fungal hyphae, mucus, and fibrinous debris that typically forms within pulmonary cavities, and is considered a subtype of CPA

Aspergillus nodules

Typically occur in immunocompetent patients without structural lung abnormalities. Indistinguishable from nodules of other causes, and almost always asymptomatic. Usually diagnosed from biopsies of the lesions done to rule out malignancy.

Allergic and hypersensitivity disorders

Characterised by a pathological immune response resulting in airway (e.g., ABPA, severe asthma with fungal sensitisation) or alveolar (e.g., hypersensitivity pneumonitis secondary to mouldy hay) inflammation

Colonisation

Isolation of Aspergillus from lower respiratory samples without evidence of clinical disease

Allergic and hypersensitivity respiratory disorders associated with Aspergillus species

Diseases among this category

  • Allergic bronchopulmonary aspergillosis

  • Allergic fungal sinusitis

  • Severe asthma with fungal sensitisation

  • Hypersensitivity pneumonitis

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