Activation of the Cytokine Network and Unfavorable Outcome in Patients with Yellow Fever

Abstract

To study the contribution of inflammatory mediators to the pathogenesis of yellow fever (YF), the serum levels of several cytokines and chemokines were measured in 7 patients with fatal YF (f-YF), 11 patients with nonfatal hemorrhagic YF (nf/h-YF), and 18 patients with nonfatal nonhemorrhagic YF (nf/nh-YF). The levels of interleukin (IL)-6, monocyte chemoattractant protein-1, interferon-inducible protein (IP)-10, tumor necrosis factor- alpha , and IL-1 receptor antagonist (IL-1RA) were all statistically significantly higher in the patients with f-YF than in those with nf/nh-YF. In patients with nf/h-YF, only levels of IP-10 and IL-1RA were significantly elevated. The high levels of pro- and anti-inflammatory cytokines and chemokines in serum from patients with f-YF are reminiscent of those seen in patients with bacterial sepsis. This finding has implications for the understanding of the pathophysiology of YF and the development of therapeutic strategies.

Spectrum of disease outcomes in mice infected with YFV-17D

“…Additionally, YFV-17D RNA was only detected in approximately half of patients with fatal YFV-AVD (Bae et al, 2008;Monath et al, 2013;ter Meulen et al, 2004). Similarly, we found that viral titres at disease onset did not correlate with disease outcome.…”

“…In humans, severe DENV, YFV and YFV-17D-associated viscerotropic disease are potentially mediated by dysregulated secretion of cytokines and chemokines (Bae et al, 2008;Lee et al, 2006b;Monath, 2008;ter Meulen et al, 2004). We found significantly elevated serum levels of IP-10 and MCP-1 in mice with viscerotropic disease as compared with mice with neurotropic disease and mice displaying no clinical signs of disease (Fig.…”

“…Interestingly, a study of WT YFV infections in humans found similar levels of detectable YFV RNA in fatal haemorrhagic and non-fatal haemorrhagic cases (ter Meulen et al, 2004). Additionally, YFV-17D RNA was only detected in approximately half of patients with fatal YFV-AVD (Bae et al, 2008;Monath et al, 2013;ter Meulen et al, 2004).…”

“…Other studies have found that MCP-1 and/or IP-10 levels correlated with disease severity during infection with viruses causing haemorrhagic fever, such as ebolavirus and hantavirus Wauquier et al, 2010), as well as other flavivirus infections. MCP-1 levels were elevated in DENV-infected humans (Lee et al, 2006a;Rathakrishnan et al, 2012), severe YFV and YFV-17D infections in humans (Bae et al, 2008;ter Meulen et al, 2004), YFV-infected IFN-a/b and IFN-a/b/c receptor knockout mice (Meier et al, 2009;Thibodeaux et al, 2012), and in some strains of WNV-infected mice (Kumar et al, 2013). MCP-1 has previously been shown to increase vascular permeability and disrupt tight junctions in endothelial cells, suggesting a potential role in haemorrhagic manifestations and shock syndrome characteristic of fatal YFV and DENV infections (Lee et al, 2006b;Rathakrishnan et al, 2012).…”

“…Approximately 20 % of YFV-infected individuals develop a severe visceral disease involving many organs, particularly the liver. Fatal YFV infection is induced by systemic shock and multi-organ failure, and immunopathology or 'cytokine storm' correlates with disease severity (Monath, 2008;Monath & Barrett, 2003;ter Meulen et al, 2004). Elevated levels of IL-6, IL-1 receptor antagonist, TNF-a, IFN-inducible protein (IP)-10 and monocyte chemotactic protein (MCP)-1 were found in patients with fatal YFV infection (ter Meulen et al, 2004).…”