Understanding Aspergillus: a driver of COPD exacerbations and mortality

Aspergillus spp. are abundant environmental and residential fungal pathogens associated with negative outcomes in patients suffering from chronic respiratory diseases. Individuals with COPD are particularly vulnerable to Aspergillus infection. In this context, Professor David Denning evaluates the clinical spectrum of aspergillosis in COPD, emphasising that timely and accurate diagnosis is essential for managing the associated burden of exacerbations and mortality.

Chronic obstructive pulmonary disease (COPD) is a significant clinical and public health problem and very burdensome for those affected. One of the underrated drivers of ill health and death in COPD is the airborne and colonising fungus Aspergillus fumigatus (A. fumigatus).¹

Human exposure to Aspergillus is common, and some of the inhaled species will be A. fumigatus. In most people, airway macrophages and epithelial cells kill most, if not all, of these spores before they can germinate. The protein coat of Aspergillus spores elicits no discernible immune response; the immune system starts to take notice and respond only if the spores swell and then germinate.

However, the airways are not typical in those with COPD and Aspergillus spores can persist for longer, leading to germination. This fungal persistence results from compromised epithelial cells and probably inhaled or systemic corticosteroid use, which further impairs cell activity.² Mucus in the airway prevents phagocytes from reaching all spores, thereby aiding Aspergillus surviving and growing in the airways in those with COPD and severe asthma.

The consequences of this shift in the relationship between inhaled Aspergillus and COPD lungs can be profound:

• COPD sputum is more likely to yield a positive culture of A. fumigatus, which may or may not signify parenchymal disease but drives exacerbations
• Exposure to higher levels of A. fumigatus from the environment is directly linked to COPD exacerbations
• A. fumigatus and other Aspergillus spp. can cause invasive and chronic pulmonary aspergillosis and Aspergillus bronchitis, especially in those with concomitant bronchiectasis.

What are the types of aspergillosis?

• Invasive aspergillosis

The first extensive study documenting invasive aspergillosis in hospitalised COPD patients was conducted in Madrid.³ Between 2000 and 2007, 53 out of 239 (22%) patients with a positive Aspergillus culture (A. fumigatus 83%) were found to have invasive aspergillosis, and 72% died. Most of the patients were taking corticosteroids upon admission.

This was followed by a case-control study from Guangzhou of 30 COPD patients with invasive aspergillosis in which progressive infiltrates, systemic corticosteroids, comorbidity and increased antibiotic use were remarkable.⁴ COPD patients had 43% mortality compared with 11% in the control group. In both studies, bacterial pathogens were frequently found in sputum, and fever was usually absent.

• Chronic pulmonary aspergillosis (aspergilloma)

COPD is the most common underlying diagnosis observed in patients with chronic pulmonary aspergillosis (CPA) in developed countries. Tuberculosis and non-tuberculous mycobacterial infection are the leading causes in other regions. However, CPA is a rare complication of COPD, considering the number of patients with COPD worldwide.¹

CPA typically manifests radiologically as upper lobe cavitation accompanied by pleural thickening. A fungal ball (aspergilloma) is seen in less than 40% of patients and is better visualised on CT scans. More commonly, a cavity has an irregular interior surface, indicating fungal growth. The key diagnostic test for CPA is Aspergillus IgG (precipitins), which has a sensitivity of 80–92%.

A less common finding is one or more Aspergillus nodules. In COPD patients, a new nodule sparks consideration of malignancy.

In a Danish study assessing chest CT scans in patients with potential malignancy, 16 of 992 patients (1.6%) had an Aspergillus nodule.⁵

Clearly, the prognosis and management of carcinoma of the lung or Aspergillus nodule are quite different. If resected, antifungal therapy both before and during surgery reduces the risk of relapse, whereas administration after surgery does not.⁶

• Aspergillus bronchitis and bronchiectasis

Most cases of Aspergillus bronchitis occur in patients with established bronchiectasis, cystic fibrosis or follow lung transplantation.⁷

Defined as two or more positive respiratory cultures or positive Aspergillus polymerase chain reaction (PCR) tests in a symptomatic patient without evidence of other forms of aspergillosis, affected individuals are typically highly symptomatic.

Excess sputum and mucus, along with mucous obstruction, are common and often accompanied by mild haemoptysis, significant breathlessness, chronic cough and concurrent bacterial bronchitis. The response to antifungal therapy, typically administered for four months, is encouraging. Unfortunately, relapses are relatively common.

Aspergillus driving COPD exacerbations

Many factors drive COPD exacerbations. These include:

• Inspiration of many live A. fumigatus spores⁸
• Inspiration of hyphal fragments coated in allergens, which elicit an immune response in the lung⁹ and manifest as an exacerbation
• Higher levels of airway A. fumigatus colonisation.¹⁰

A recent study from Singapore and Vancouver found a direct relationship between environmental A. fumigatus and exacerbation frequency, as well as for one of the major allergenic proteins of A. fumigatus.⁸

Sputum fungal cultures may or may not be positive, but a history of recent potential fungal exposure, such as damp housing conditions or a dusty environment, may provide clues for future avoidance strategies. It is not known if antifungal therapy would reduce exacerbation frequency, but it is likely to be beneficial in colonised patients. Corticosteroids given to suppress exacerbations may be key drivers of the development of invasive or chronic pulmonary aspergillosis.

Suspecting aspergillosis in COPD patients

A history of mould and damp exposure should alert clinicians to the possibility of aspergillosis in patients with COPD. Corticosteroid dose and duration both independently increase the risk of invasive aspergillosis.

Three tools help identify the patients with aspergillosis:

1. New or progressive infiltrates on chest X-ray
2. At least one (preferably two) sputum fungal cultures using a high-volume culture technique
3. Aspergillus IgG antibody testing.

Detecting Aspergillus antigen (galactomannan) in serum may be helpful in severely ill patients who are being considered for intensive care support. If bronchoscopy is not contraindicated, it is very helpful in diagnosing Aspergillus bronchitis and for collecting samples for direct microscopy, fungal culture, Aspergillus PCR and Aspergillus antigen, as well as testing for other pathogens.

Managing suspected Aspergillus colonisation in COPD

In patients experiencing a COPD exacerbation, minimising residential exposure to mould, treating Aspergillus colonisation with an oral antifungal (in the author’s opinion) and giving only short courses of systemic corticosteroids are appropriate.

In those with possible invasive aspergillosis, immediate antifungal therapy with voriconazole, posaconazole or isavuconazole is indicated. Stopping corticosteroids is important as the risk of death increases by 250% if continued,¹¹ and full supportive care is necessary.

The usual steps in those with CPA are referral to a specialist with expertise in this challenging condition, treatment of concurrent bacterial infection, immunisation against Pneumococcus (preferably with Prevenar), avoidance of corticosteroids, addressing haemoptysis and giving antifungal therapy.

Conclusion

With an estimated 200–500 million patients with COPD globally, over 50 million admissions to hospital¹² and multiple forms of aspergillosis, emergency, general medical and respiratory consultants will see these patients in various guises. Aspergillosis tends to be clinically ‘quiet’, and, unless appropriate diagnostics are sought, it can be entirely overlooked.

Judicious use of corticosteroids and modern azole antifungal therapy has the potential to really reduce mortality and morbidity in COPD.

Author

Professor David Denning FRCP FRCPath FMedSci

Principal investigator, Manchester Fungal Infection Group, University of Manchester, UK

References

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