Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy

Aiba, Hideo; Mochizuki, Mika; Kimura, Mitsuaki; Hojo, Hiroatsu

doi:10.1212/wnl.57.2.295

Cited by 142 publications

(88 citation statements)

References 24 publications

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“…Treatment of H5N1-infected ferrets with a potent antagonist of CXCL10 receptor resulted in reduced viral loads in the lungs, improved clinical symptoms, and prolonged survival (42). There have also been elevated levels of IL-6 documented in cerebrospinal fluid and serum/plasma samples associated with influenza virus-induced neurological disorders in children (43,44). As such, the overall contribution of host inflammatory cytokine and chemokine responses to the severity of H5N1 influenza virus pathogenesis in various host species remains to be fully elucidated.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Lowther

Stambas

2015

J Virol

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Highly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/ 1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species. IMPORTANCEHighly pathogenic avian influenza virus infection causes severe morbidity and mortality in both humans and poultry. Widespread antiviral resistance necessitates the need for the development of additional novel therapeutic measures to modulate overactive host immune responses after infection. Disease severity following avian influenza virus infection can be attributed in part to hyperinduction of inflammatory mediators such as cytokines, chemokines, and reactive oxygen species. Our study shows that highly pathogenic avian influenza H5N1 virus and low-pathogenicity avian influenza H7N9 virus (both associated with human fatalities) promote inactivation of FoxO3 and downregulation of the TAM receptor tyrosine kinase, Tyro3, leading to augmentation of the inflammatory cytokine response. Inhibition of influenza-induced reactive oxygen species with apocynin activated FoxO3 and stimulated SOCS1 and SOCS3 proteins, restoring cytokine homeostasis. We conclude that modulation of host immune responses with antioxidant and/or anti-inflammatory agents in combinati...

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Section: Discussionmentioning

confidence: 99%

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Lowther

Stambas

2015

J Virol

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“…During the acute stage of acute encephalopathy, the serum and CSF levels of inflammatory cytokines, such as interleukin-6 and tumor necrosis factor-␣, were markedly elevated. [7][8][9] Several pathologic studies have suggested that vascular injury as a result of endothelial damage by inflammatory cytokines is the pathologic substrate of severe types of acute encephalopathy, such as acute necrotizing encephalopathy. 1,10 Although serum and CSF levels of inflammatory cytokines were not measured, it is possible that hypercytokinemia may contribute to the pathogenesis of diffuse lesions.…”

Section: Discussionmentioning

confidence: 99%

Differences of Clinical Manifestations According to the Patterns of Brain Lesions in Acute Encephalopathy with Reduced Diffusion in the Bilateral Hemispheres

Okumura¹,

Kidokoro²,

Tsuji³

et al. 2009

AJNR Am J Neuroradiol

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“…[3][4][5][6][7] Hypercytokinaemia, therefore, is suggested to have an important role in the pathogenesis of acute encephalopathy and multiple organ dysfunction. 9 From the suspected pathogenesis, anti-inflammatory therapies (methylprednisolone pulse therapy, high dose gamma globulin therapy, and plasma exchange therapy) are proposed for the treatment of the illness.…”

Section: Discussionmentioning

confidence: 99%

Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure

Hosoya

2006

Archives of Disease in Childhood

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Aims: To evaluate the prognostic predictive values of cytochrome c, cytokines, and other laboratory measurements in serum collected during neurological onset in acute encephalopathy with multiple organ failure. Methods: In addition to general laboratory examinations, the concentrations of cytochrome c (apoptosis marker) and cytokines (inflammatory markers) were measured in serum samples collected at the initial phase in 29 patients with acute encephalopathy. The obtained values were evaluated as predictors for the development of severe encephalopathy. Results: Cytochrome c, tumour necrosis factor a (TNF-a), interleukin 6 (IL-6), soluble TNF-receptor 1 (sTNF-R1), and aspartate aminotransferase (AST) concentrations at the initial phase were high and correlated well with patient outcome. High concentrations of serum cytochrome c (.45 ng/ml), sTNF-R1 (.2000 pg/ml), AST (.58 IU/dl), IL-6 (.60 pg/ml), and TNF-a (.15 pg/ml) predicted an unfavourable prognosis (sequelae and death) at 93%, 79%, 82%, 77%, and 60%, respectively. The specificity of those markers was 100%, 89%, 83%, 100%, and 100%, respectively. Conclusions: Serum cytochrome c is the most sensitive and specific predictor for the development of severe encephalopathy at the initial phase. Results suggest that this marker might be used to guide decisions regarding the start of the initial treatment and further intensive care.

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Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy

Abstract: The serum IL-6 level may be the most useful indicator for the diagnosis and the clinical severity of influenza virus-associated encephalopathy.

Cited by 142 publications

References 24 publications

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Inhibition of Reactive Oxygen Species Production Ameliorates Inflammation Induced by Influenza A Viruses via Upregulation of SOCS1 and SOCS3

Differences of Clinical Manifestations According to the Patterns of Brain Lesions in Acute Encephalopathy with Reduced Diffusion in the Bilateral Hemispheres

Prognostic predictive values of serum cytochrome c, cytokines, and other laboratory measurements in acute encephalopathy with multiple organ failure

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