Background: Organ and hematopoietic stem cell transplant (HSCT) recipients are predisposed to complications of influenza infection and as such may constitute an important source of influenza genetic and phenotypic diversity. We hypothesized that some mutations in the influenza genome may confer virulence advantages despite not being associated with antiviral resistance. We performed a detailed genetic analysis of influenza virus isolated from these patients and correlated it with clinical outcomes.

Methods: Transplant recipients with influenza A virus (IAV) infection were enrolled in multiple centers from 2011-15. Viral RNA was extracted from diagnostic nasopharyngeal swabs and next generation sequencing was performed using the Illumina MiSeq platform for all 8 influenza genes and splice variants. Raw sequences were subjected to quality scoring, alignment and variant calling relative to prototypical vaccine strains of H1N1 (A/California/7/2009) and H3N2 (A/Texas/50/2012). Statistical significance was set at p<0.01.

Results: We enrolled 82 patients with lab-confirmed IAV; the median age was 56 years. Types of transplant included kidney (24%), lung (17%), liver (13%), heart (10%), other (4%), and HSCT (28%). 63% of patients received the influenza vaccine in the same season they were infected. Oseltamivir was given to 94% of patients. Pneumonia occurred in 10/82 (12%) and death occurred in 5/82 (6%) patients. In H1N1-infected patients (43/82, 52%), development of pneumonia (6/43; 14%) was associated with mutations in nucleoprotein (NP) [V425I, p=0.0066], neuraminidase (NA) [N386K, p=0.0066], non-structural protein 1 (NS1) [E55K, p=0.0013; K131E, p=0.0013], matrix protein 2 (M2) [R12K, p=0.01] and NS2 [N29S, p=0.0013] genes. We also identified 3 mutations associated with protection from pneumonia: A22T in NP [p=0.01], V113I in polymerase basic protein 1 (PB1) [p=0.0021] and R34Q in the NS2 gene [p=0.002]. These mutations occurred in 32-37% patients. In H3N2-infected patients (39/82, 48%), there was a trend to development of pneumonia (4/39; 10%) associated with the T587A mutation in the PB1 gene [p=0.012].

Conclusion: These results suggest that prevalent mutations in IAV (not associated with antiviral resistance) may be associated with influenza-related complications in transplant patients. Validation of selected mutations is being performed in a larger transplant cohort.

CITATION INFORMATION: Ferreira V, Humar A, Cordero E, Blumberg E, Husain S, Kalpoe J, Multicenter Influenza Group M, Kumar D. Mutations in Influenza A Virus and Clinical Implications in Transplant Recipients. Am J Transplant. 2017;17 (suppl 3).

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