*Purpose: In non-transplant patients with severe influenza illness, an increased rate of invasive mould infection (IMI) has been noted possibly due to the local inflammatory environment. This association has not been well studied in transplant patients who are at high risk for complications of both influenza and IMI. We investigated this in a transplant cohort with influenza infection.

*Methods: We performed a single-center, retrospective study in adult solid organ and hematopoietic stem cell (HCT) transplant recipients infected with lab-confirmed influenza during 2014-2019. Patients were followed for outcomes at 90 days after influenza infection. IMI was defined as proven or probable cases according to EORTC/MSG criteria, and was classified as new onset IMI if patients had not been diagnosed with infection or colonization with the same fungal species within 1 year before influenza diagnosis.

*Results: We included 300 transplant patients with influenza in this study. The majority were men (58%) and median age was 56 years (IQR 43-65). Median onset of influenza was 1.8 years after transplant (IQR 0.5-5.3 years). Influenza A was the most common influenza subtype (195/300; 65%). Eighty-seven patients (29%) had lower respiratory tract involvement, 39 (13%) had nosocomial infection, and 285 (95%) received adequate antiviral therapy. In the total cohort, 20 (6.7%) were diagnosed with new-onset IMI within 90 days of influenza diagnosis, with median onset of 10 days (0-90 days). The incidence of new-onset IMI was greatest in lung transplant recipients (14/97; 14.4%), followed by allogeneic HCT (5/66; 7.6%) and heart transplant (1/20; 5%). No kidney (n=57) or liver (n=25) transplant recipient developed IMI. The most common fungal pathogen was Aspergillus spp. (18/20; 90%). In the lung transplant subgroup, antiviral therapy duration less than 5 days (HR 7.1; 95%CI 1.3-39.6) and lower respiratory tract involvement (HR 4.5; 95%CI 1.3-15.6) were associated with IMI. Overall 90-day mortality rate in lung transplant recipients was 7.2% (7/97) and was significantly higher in patients with IMI (21.4% vs. 3.7%; p=0.04 for IMI vs. no IMI respectively). Factors associated with death include intensive care unit admission (HR 44.4; 95%CI 4.7-423.8), lymphopenia; defined by absolute lymphocyte count <=200 cells/mm³ (HR 27.7; 95%CI 4.2-182.9) and new-onset IMI (HR 7.1; 95%CI 1.3-39.6). Among surviving patients, allograft dysfunction, defined by >=20% decline in FEV1 at 90 days was similar in IMI vs. no IMI (27.3% vs. 14.9%; p=0.4). A trend towards greater biopsy confirmed or clinically treated acute rejection was seen in the IMI group (36.4% vs. 14.1%; p=0.058).

*Conclusions: IMI appears to be a frequent complication of influenza only after lung transplant and is associated with greater mortality in that group. Lung transplant patients with severe influenza should receive adequate antiviral treatment and could be considered for targeted antifungal prophylaxis.

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