Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes


Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood1,2,3,4,5,6,7,8,9,10. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex–mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition—a marker of complement activation mediated by immune complexes—was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.

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Figure 1: Histopathology and virus titers in 2009 H1N1 disease.
Figure 2: Inflammation in influenza A 2009 H1N1 disease.
Figure 3: Lymphopenia in influenza A 2009 H1N1 disease.
Figure 4: Immune complex–mediated disease in 2009 H1N1 influenza infection.


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Funded by the Fundacion INFANT 2008 Fundraising Campaign and AI-054952 (F.P.P.), the Thrasher Research Fund Early Career Award and Fogarty International Center International Clinical Research Fellows Program at Vanderbilt (R24 TW007988) (G.A.M. and J.P.B.), US Department of Defense grant HDTRA1-08-10-BRCWMD-BAA and US National Institutes of Health grant P01 AI058113 (J.E.C. Jr.). Doctoral awards from the Consejo Nacional de Investigaciones Cientıficas y Técnicas, Argentina (A.C.M. and J.P.B.).

Author information

F.P.P., G.A.M., K.M.E., J.D.C., J.E.C. Jr., J.V.W., A.C.M., J.P.B. and M.F.L. designed the project. A.C.M., J.P.B., M.F.L., J.Z.H., B.M., L.D., K.P.W., J.V.W., G.A.M. and F.P.P. performed experiments. J.C.K., J.K., J.B., C.R., Le. A., L.D., R.L., V.S., E.B., Li. A., G.C., J.F., L.S., J.J., M.E., J.E.C. Jr. and J.V.W. developed or provided key reagents or contributed samples. F.P.P. supervised the project. A.C.M., J.P.B., M.F.L., K.M.E., J.D.C., G.A.M. and F.P.P. wrote the paper.

Correspondence to Guillermina A Melendi or Fernando P Polack.

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Monsalvo, A., Batalle, J., Lopez, M. et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nat Med 17, 195–199 (2011).

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