Interferon-gamma replacement as salvage therapy in chronic pulmonary aspergillosis: impact on bacterial exacerbations and hospital admissions

Edward Monk*1,2, Chris Kosmidis1,2,3, Chris Harris2, Rainer Doffinger4, Gemma Hayes5, David W. Denning2,1,3

Author address: 

1 Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, United Kingdom, 2 National Aspergillosis Centre, Manchester, United Kingdom, 3 University of Manchester, Manchester, United Kingdom, 4 Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, United Kingdom, 5 University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, United Kingdom

Abstract: 

Background: Chronic pulmonary aspergillosis (CPA) is characterised by persistent Aspergillus infection, often complicated by recurrent bacterial superinfection. The exact immune deficits in CPA are not characterised but poor production of interferon gamma (IFNγ) is common. The immune response to fungal infection has been shown to employ IFNγ and thus supplemental subcutaneous replacement may confer therapeutic benefit as salvage therapy in CPA patients with impaired IFNγ production.

Materials/methods: Retrospective analysis of patients prescribed IFNγ as salvage therapy for CPA refractory to antifungals was conducted. The rates of lower respiratory tract infection (LRTI) and hospital admission within the 12 months before and after IFNγ therapy initiation were compared (Wilcoxon matched-pairs signed-rank test).

Results: Forty-one patients received IFNγ; 36 were available for follow-up. Twenty patients received IFNγ for >12 months, eight stopped treatment due to early side effects (<6 months) and eight died within 12 months of initiating treatment. Of the 20 patients receiving IFNγ >12 months, nine were female. The median age was 58.5 years (IQR 53-65 years).  Pre-existing comorbid respiratory disease was common (bronchiectasis 30%, COPD 25%, previous pneumothorax 20%, fibrosis secondary to connective tissue disease 20% and previous tuberculosis 15%). Eight of the 20 patients had a significant smoking history and three were active smokers.  Fifteen (75%) were on concomitant antifungal therapy and five (25%) were on long-term azithromycin. Of the 19 patients investigated by cytokine assay, 17 (89%) had significantly reduced production of IFNγ. Reduction in IL-17 (58%), IL-12 (32%), TNFα (16%), IL-6 (5%) and IL-10 (5%) were observed less commonly. In those treated for >12 months, the mean number of LRTIs requiring antimicrobials reduced from 3.1 to 1.4 episodes/year (p=0.006). A significant reduction in the mean number of hospital admissions/year was also observed (0.8 to 0.3, p=0.04). No significant changes were seen in individuals treated with IFNγ for <6 months.

Conclusions: In CPA refractory to antifungals alone, 12 months of salvage IFNγ therapy significantly reduced the frequency of LRTI requiring antimicrobial therapy and hospital admission. Almost all patients had impaired IFNγ production. Prospective data are needed to further evaluate the role of IFNγ as adjunctive therapy in CPA.

2019

Poster: 

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abstract No: 

P2274

Full conference title: 

European Congress of Clinical Microbiology & Infectious Diseases 2019
    • ECCMID 29th (2019)