Significance A unique avian-origin H7N9 influenza virus caused 134 human infections with 44 deaths. The host factors contributing to moderate vs. severe disease are not clear. Here, we show that H7N9 severity was associated with a higher level of cytokines/chemokines. We demonstrate that the cytokines in the infected lung were 100- to 1,000-fold higher than those in the plasma. Furthermore, we found that the IFN-induced transmembrane protein-3 (IFITM3) C/C genotype was associated with severe clinical outcome, as reflected by reduced time in seeking medical aid; more rapid progression to acute respiratory distress syndrome; and higher viral load, cytokine/chemokine levels, and mortality rate. Overall, our data suggest that the IFITM3 genotype is a primary driver of the observed differences in clinical outcome after H7N9 infection.

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Background Diagnostics to identify tuberculosis infection are limited. We aimed to assess the diagnostic accuracy and safety of the novel ESAT6-CFP10 (EC) skin test for tuberculosis infection in Chinese adults. Methods We conducted two randomized, parallel-group clinical trials in healthy participants and tuberculosis patients. All participants were tested with the T-SPOT.TB test, then received EC skin test and tuberculin skin test (TST). The diameter of skin indurations and/or redness at injection sites were measured at different time periods. A Bacillus Calmette Guerin (BCG) model was also established to assess the diagnosis of tuberculosis infection using EC skin test. Results In total, 777 healthy participants and 96 tuberculosis patients were allocated to receive the EC skin test at 1.0μg/0.1ml or 0.5μg/0.1ml. The area under the curve was 0.95 (95% CI, 0.91–0.97) from the EC skin test at a dose of 1.0μg/0.1ml at 24–72 hours. Compared to the T-SPOT.TB test, the EC skin test demonstrated similar sensitivity (87.5, 95% CI 77.8–97.2 versus 86.5, 95% CI 79.5–93.4) and specificity (98.9, 95% CI 96.0–99.9 versus 96.1, 95% CI 93.5–97.8). Among BCG vaccinated participants, the EC skin test had high consistency with the T-SPOT.TB test (96.3, 95% CI, 92.0–100.0). No serious adverse events related to the EC skin test were observed. Conclusions The EC skin test demonstrated both high specificity and sensitivity at a dose of 1.0μg/0.1ml, comparable to the T-SPOT.TB test. The diagnostic accuracy of the EC skin test was not impacted by BCG vaccination.

Specific changes in immune repertoires at genetic level responding to the lethal H7N9 virus are still poorly understood. We performed deep sequencing on the T and B cells from patients recently infected with H7N9 to explore the correlation between clinical outcomes and immune repertoire alterations. T and B cell repertoires display highly dynamic yet distinct clonotype alterations. During infection, T cell beta chain repertoire continues to contract while the diversity of immunoglobulin heavy chain repertoire recovers. Patient recovery is correlated to the diversity of T cell and B cell repertoires in different ways – higher B cell diversity and lower T cell diversity are found in survivors. The sequences clonally related to known antibodies with binding affinity to H7 hemagglutinin could be identified from survivors. These findings suggest that utilizing deep sequencing may improve prognostication during influenza infection and could help in development of antibody discovery methodologies for the treatment of virus infection.