Symptom pathogenesis during acute influenza: Interleukin‐6 and Other cytokine responses

Abstract

In experimental human influenza infection initiated by nasal inoculation, the magnitude of viral replication, fever, and symptoms correlate with nasopharyngeal lavage fluid levels of various cytokines. Our aim was to assess these relationships in patients with naturally occurring acute influenza. Patients with culture-positive influenza illness of less than 36 hr of duration were studied. Nasopharyngeal washing were collected at enrollment and on Day 2, 4, 6 and 8 for quantitative virus isolation and IL-6, TNF-alpha, INF-alpha, INF-gamma and IL-10 determinations. Blood samples collected at entry and on Day 2 and 6 were processed to assess plasma cytokines and circulating influenza RNA. Patients received either oseltamivir or placebo for 5 days. We assessed the correlation between nasopharyngeal lavage fluid or blood levels of cytokines before treatment and viral titers, symptom severity and fever. Sixteen adult subjects (median age of 22 years) were studied. In this small group of patients no significant differences between placebo and oseltamivir patients were found in viral replication or measures of cytokines. Thus the data for all 16 subjects were pooled for analysis. At entry, influenza A viruses were cultured from nasopharyngeal washes at a median titer of 4.8 log(10)TCID(50)/ml of wash. Viral titers correlated positively with symptom score (P = 0.006) and temperature values (P < 0.001). Viral titers, fever and symptoms were highest at enrollment and fell in parallel during the subsequent days. RT-PCR assays failed to detect influenza RNA in the white blood cells from any patient. We observed a significant release, in both nasopharyngeal lavage fluid and in plasma, of IL-6, TNF-alpha, INF-alpha, INF-gamma and IL-10. At entry high IL-6 levels were detected in the nasopharyngeal lavage fluid (median 10.3 pg/ml) and plasma (median 5.1 pg/ml) of all patients. We found a positive correlation between plasma IL-6 levels and both symptom scores and temperature values (P < 0.05), as well as a positive correlation between nasopharyngeal lavage fluid levels of IL-6 and TNF-alpha and temperature (P < 0.05). We did not find significant associations between symptoms, fever and levels of INF-alpha, INF-gamma or IL-10. The magnitude of early decrease in viral titers correlated with initial levels of INF-gamma in nasopharyngeal lavage fluid (P < 0.05). Significant production of IL-6, TNF-alpha, INF-alpha, INF-gamma and IL-10 occurs in response to community acquired influenza A illness. As in experimental influenza, symptoms and fever in natural acute influenza correlate with the release of IL-6.

Distinct KIR/HLA compound genotypes affect the kinetics of human antiviral natural killer cell responses

“…However, it should be noted that NK cells are abundant in inflamed and noninflamed human lymph nodes (71,72) and thus may exert a rapid antiviral effect. Fast-replicating viruses such as IAV reach significant viral titers within 24 h of infection (73); human NK cells respond within 24 h to IAV (47); and IFN-γ levels in nasopharyngeal lavage fluid correlate significantly to IAV titers, clinical symptoms, oral temperature, and nasal discharge (74). In addition to its anti-…”

Interleukin 12 is a primary cytokine responding to influenza virus infection in the respiratory tract of mice

“…In the influenza infection cytokines are produced locally and systemically and their production is important in promoting host-immune defense to alleviate symptoms especially in the early stage of infection (Hayden et al, 1998;Kaiser et al, 2001;Cheung et al, 2002;Van Reeth, 2002). In a murine model, cytokines such as IL-12 and IL-18 as Th1 immune-response mediators, IFN-γ as a Th1 cytokine, IL-4 and IL-10 as Th2 cytokines, IL-1α, IL-1β, IL-6, and TNF-α as inflammatory cytokines, and IFN-α, -β have been shown to be produced in the respiratory tract during infection (Hennet et al, 1992;Kurokawa et al, 1996aKurokawa et al, ,b, 2002Tsurita et al, 2001;Liu et al, 2004).…”

“…IL-12 is a strong inducer of IFN-γ and is important in the development of Th1 cells followed by the generation of cell-mediated immunity contributing to the elimination of influenza virus (Monteiro et al, 1998). IL-18, a novel cytokine with potent IFN-γ-inducing activity, plays an important role in NK cell activity and the Th1-mediated immune response in collaboration with IL-12 (Kaiser et al, 2001;Tsurita et al, 2001;NeffLaFord et al, 2003;Liu et al, 2004). Kaiser et al (2001) reported that the magnitude of the early decrease in viral titers correlated with initial levels of IFN-γ in nasopharyngeal lavage fluid of human volunteers.…”

“…IL-18, a novel cytokine with potent IFN-γ-inducing activity, plays an important role in NK cell activity and the Th1-mediated immune response in collaboration with IL-12 (Kaiser et al, 2001;Tsurita et al, 2001;NeffLaFord et al, 2003;Liu et al, 2004). Kaiser et al (2001) reported that the magnitude of the early decrease in viral titers correlated with initial levels of IFN-γ in nasopharyngeal lavage fluid of human volunteers. IFN-γ is suggested to be the critical cytokine in the cytokine cascade due to the influenza infection as well as to be responsible for viral clearance in humans.…”

Influenza Virus Infection Causes Global Respiratory Tract B Cell Response Modulation via Innate Immune Signals

“…Such rapid induction of humoral responses is not only consistent with a local protective role for Abs during a primary infection, it also indicates that local B cell responses are initiated during the acute innate cytokine response. Cytokines induced rapidly to the virus in the respiratory tract include type I IFN, IL-1, IL-6, and TNF-␣ (13,14). The potential role and the effects such innate immune stimuli might have on B cell responsiveness to subsequent encounter with Ag and/or Th cells has received little attention in the past.…”