title: Low titers of serum antibodies inhibiting hemagglutination predict fatal fulminant influenza A(H1N1) 2009 infection.
abstract: BACKGROUND
  The biology of fatal pandemic influenza infection remains undefined.
  
  
  OBJECTIVE
  To characterize the virologic and immune parameters associated with severity or death in patients who required mechanical ventilation for A(H1N1) 2009 pneumonia of various degrees of severity during the two waves of the 2009-2011 pandemic in Paris, France.
  
  
  METHODS
  This multicenter study included 34 unvaccinated patients with very severe or fatal confirmed influenza A(H1N1) infections. It analyzed plasma A(H1N1) 2009 reverse-transcriptase polymerase chain reaction, hemagglutinin 222G viral mutation, and humoral and cellular immune responses to the virus, assessed in hemagglutination inhibition (HI), microneutralization, ELISA, lymphoproliferative, ELISpot IFN-γ, and cytokine and chemokine assays.
  
  
  RESULTS
  The patients' median age was 35 years. Influenza A(H1N1) 2009 viremia was detected in 4 of 34 cases, and a 222G hemagglutinin mutation in 7 of 17 cases, all of them with sequential organ failure assessment greater than or equal to 8. HI antibodies were detectable in 19 of 26 survivors and undetectable in all six fatal fulminant cases. ELISA and microneutralization titers were concordant. B-cell immunophenotyping and plasma levels of immunoglobulin classes did not differ between patients who survived and died. After immune complex dissociation, influenza ELISA serology became strongly positive in the bronchoalveolar lavage of the two fatal cases tested. H1N1-specific T-cell responses in lymphoproliferative and IFN-γ assays were detectable in survivors' peripheral blood, and lymphoproliferative assays were negative in the three fatal cases tested. Plasma levels of IL-6 and IL-10 were high in fatal cases and correlated with severity. Finally, a negative HI serology 4 days after the onset of influenza symptoms predicted death from fulminant influenza (P = 0.04).
  
  
  CONCLUSIONS
  Early negative A(H1N1) 2009 HI serology can predict death from influenza. This negative serology in fatal cases in young adults reflects the trapping of anti-H1N1 antibodies in immune complexes in the lungs, associated with poor specific helper T-cell response. Clinical trial registered with www.clinicaltrials.gov (NCT 01089400).
authors.affiliation: 1 Laboratory of Immunity and Infection, UPMC Univ Paris 06, UMR-S945, Paris, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Guihot
authors.forename: Charles-Edouard
authors.initials: CE
authors.lastname: Luyt
authors.forename: Antoine
authors.initials: A
authors.lastname: Parrot
authors.forename: Dominique
authors.initials: D
authors.lastname: Rousset
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Cavaillon
authors.forename: David
authors.initials: D
authors.lastname: Boutolleau
authors.forename: Catherine
authors.initials: C
authors.lastname: Fitting
authors.forename: Priya
authors.initials: P
authors.lastname: Pajanirassa
authors.forename: Alain
authors.initials: A
authors.lastname: Mallet
authors.forename: Muriel
authors.initials: M
authors.lastname: Fartoukh
authors.forename: Henri
authors.initials: H
authors.lastname: Agut
authors.forename: Lucile
authors.initials: L
authors.lastname: Musset
authors.forename: Rima
authors.initials: R
authors.lastname: Zoorob
authors.forename: Amos
authors.initials: A
authors.lastname: Kirilovksy
authors.forename: Béhazine
authors.initials: B
authors.lastname: Combadière
authors.forename: Sylvie
authors.initials: S
authors.lastname: van der Werf
authors.forename: Brigitte
authors.initials: B
authors.lastname: Autran
authors.forename: Guislaine
authors.initials: G
authors.lastname: Carcelain
mesh_terms: D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D005260:Female; D005602:France; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000097:blood / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000097:blood / Q000150:complications / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality; D016753:Interleukin-10 / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011024:Pneumonia, Viral / Q000175:diagnosis / Q000276:immunology* / Q000401:mortality / Q000821:virology; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012124:Respiratory Care Units; D012307:Risk Factors; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015415:Biomarkers; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D015850:Interleukin-6; D016753:Interleukin-10