Cytokine response patterns in severe pandemic 2009 H1N1 and seasonal influenza among hospitalized adults.
BACKGROUND
Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis.


METHODS
Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed.


RESULTS
63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course.


CONCLUSIONS
A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis.
Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Special Administrative Region, People's Republic of China. leelsn@cuhk.edu.hk
Nelson
N
Lee
Chun Kwok
CK
Wong
Paul K S
PK
Chan
Martin C W
MC
Chan
Rity Y K
RY
Wong
Samantha W M
SW
Lun
Karry L K
KL
Ngai
Grace C Y
GC
Lui
Bonnie C K
BC
Wong
Sharon K W
SK
Lee
Kin Wing
KW
Choi
David S C
DS
Hui
D000328:Adult; D018925:Chemokines / Q000096:biosynthesis / Q000097:blood; D002681:China / Q000453:epidemiology; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood*; D005260:Female; D006760:Hospitalization / Q000706:statistics & numerical data*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007251:Influenza, Human / Q000097:blood* / Q000453:epidemiology* / Q000276:immunology / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D058873:Pandemics / Q000706:statistics & numerical data*; D012621:Seasons
D018925:Chemokines; D016207:Cytokines