Title 

Validation of diagnostic criteria for chronic pulmonary aspergillosis (CPA)

Authors 

Iain D Page1,2 (corresponding), Rosemary Byanyima3, Sharath Hosmane4,, Nathan Onyachi5, Cyprian Opira6, John Opwonya7, Malcolm Richardson1,8, Richard Sawyer4, Anna Sharman4, David Denning1,2

1.	Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, UK.
2.	National Aspergillosis Center, Manchester University Hospitals NHS Foundation Trust, UK.
3.	Kampala Imaging Centre, Kampala, Uganda
4.	Manchester University Hospitals NHS Foundation Trust, UK.
5.	Gulu Regional Referral Hospital, Uganda.
6.	St. Mary’s Hospital, Lacor, Uganda
7.	Department of Tuberculosis and Leprosy Control, Gulu District Health Office, Uganda.
8.	Mycology Reference Centre, Manchester University Hospitals NHS Foundation Trust, UK.

Objectives

Chronic pulmonary aspergillosis (CPA) is a serious condition estimated to afflict millions of people worldwide. Denning et al initially proposed the case definition upon which all subsequent studies have been based in 2003, with guidelines later published by ESCMID in 2016. These definitions are arbitrary in nature. 

In 2015 we completed the first survey of CPA prevalence. We have now analysed the results of that study to see which clinical and radiological features are associated with raised Aspergillus-specific IgG and CPA diagnosis to validate the case definition used and inform future case definitions.

Methods

400 adults with treated tuberculosis were recruited between October 2012 and February 2013. 285 were resurveyed between October 2014 and January 2015. Aspergillus-specific IgG was measured by Siemens Immulite 2000 with results above 20mg/L reported as positive. Clinical assessment and chest X-ray were performed on both occasions. CT thorax was performed in those with suspicion of fungal ball on chest X-ray or raised Aspergillus-specific IgG.

CPA was diagnosed in patients with all of; 1 - cough or haemoptysis for ≥ 1 month, 2 – Either paracavitary fibrosis or fungal ball on CT thorax or progressive cavitation on serial chest X-rays, 3 – Raised Aspergillus-specific IgG, 4 - Absence of positive GeneXpert test for M. tuberculosis.

Results

CPA was diagnosed in 14 (4.9%) of patients with a statistically non-significant trend towards decreased CPA frequency in those with HIV co-infection (3% vs. 6.7%, p=0.177). 

Case definition features cough, haemoptysis, fungal ball and paracavitary fibrosis (on CT thorax) were all associated with CPA. Each was also associated with raised Aspergillus-specific IgG. 

Chest pain was also significantly more common in those with CPA (50% vs. 25%, p=0.043). Chest X-ray cavitation, fungal ball, paracavitary fibrosis and pleural thickening were all significantly more common in those with raised Aspergillus-specific IgG. Cavitation, pleural thickening and destroyed lung on CT thorax were all significantly more common in those with raised Aspergillus-specific IgG and CPA.

Bronchiectasis and nodules were not associated with raised Aspergillus-specific IgG. 

Conclusion

This study provides the first validation of the arbitrary case definitions used in CPA research and clinical practice. The association with raised Aspergillus-specific IgG levels provides validation for the established use of cough, haemoptysis, fungal ball and paracavitary fibrosis in the case definition.

While chest pain and pleural thickening are recognized features of CPA, they do not normally form part of the case definition used in studies. It may now be appropriate to include them in future case definitions.

It has been postulated that raised Aspergillus-specific IgG might simply be due to colonization of bronchiectatic airways, rather than CPA. The absence of any association between bronchiectasis and raised Aspergillus-specific IgG in this treated tuberculosis cohort suggests this is not the case

1 / Validation of diagnostic criteria for chronic pulmonary aspergillosis (CPA)