tetano
Editor, Senior Moderator
Published Date: 2013-05-03 14:32:48
Subject: PRO/AH/EDR> Avian influenza, human (70): China H7N9, severity hypothesis
Archive Number: 20130503.1689393
AVIAN INFLUENZA, HUMAN (70): CHINA H7N9, SEVERITY HYPOTHESIS
************************************************************
A ProMED-mail post
http://www.promedmail.org
ProMED-mail is a program of the
International Society for Infectious Diseases
http://www.isid.org
Date: Thu 2 May 22013
From: Kirk Douglas <kirk.douglas@mycavehill.uwi.edu> [edited]
The recent zoonotic infections with a novel H7N9 virus have brought greater attention to avian influenza research. Viral factors do play a role in disease severity, and undoubtedly in avian influenza this has been previously demonstrated (1). However, with greater focus on viral factors, there has been a lesser focus on host related factors of avian influenza disease severity.
A possible role of circulating bacterial endotoxin or lipopolysaccharide (LPS) in disease severity of avian influenza is postulated here. LPS is comprised of lipid A, core oligosaccharide and O polysaccharide. Gram negative bacteria contain LPS in their cell walls and can release LPS to varying extents based on the characteristics of the O polysaccharide chain. LPS can enter the body via 2 routes: either a) through acute Gram negative bacterial infection; and or b) bacterial LPS translocation from the gut or intestine. Bacterial LPS translocation from the gut does occur and can be triggered by trauma, surgical procedures and intestinal epithelial dysfunction by viral replication. This LPS translocation can lead to endotoxemia and trigger overproduction of cytokines. The presence of circulating endotoxin in the blood has been shown to increase pathogenicity of viral infections including West Nile virus, HIV and dengue virus (2-4). In addition, some diseases have been associated with elevated endotoxin levels including obesity, diabetes and cirrhosis and liver disease (5,6).
Endotoxin in the body is cleared by binding to serum proteins including lipopolysaccharide binding protein (LBP) and bactericidal permeating increasing protein (BPI). LBP is produced in the liver, and one function of the liver is to clear endotoxin from the body. If liver function is impaired, then clearance of endotoxin is also impaired, and observance of elevated endotoxin levels is expected. The clinical influence of antibiotic use on endotoxin levels is not definitive, as it has been shown to both have no effect and also to increase them (7,8).
The hypothesis presented here suggests H7N9-infected patients with pre-existing diseases including those observed in the current outbreak have elevated serum/plasma endotoxin levels which exacerbate the clinical course of influenza virus infection. Higher mortality would be expected in such patients. To date there appears to be no gender bias in mortality, with a similar case fatality rate (22 per cent) in men and women (9). These elevated endotoxin levels result in greater production of TH1 cytokines such as TNF-I+/-, IL-10 and IFN-I3, triggering a systemic inflammatory response, vascular/plasma leakage, pleural effusion and pneumonia often associated with influenza mortality.
Gao et al (2013) documented the initial 3 H7N9 fatal human cases (ages 27, 35 and 87) and found underlying diseases were present, including hepatitis B, chronic obstructive pulmonary disease (COPD) and obesity. In addition, 2 out of the 3 cases had _Acinetobacter baumanii_ (Gram-negative) infections, and all 3 were placed on antibiotic treatments (10). Anecdotal evidence of an association of hepatitis B infection in more of the H7N9 human cases is in circulation but needs to be officially verified. Nonetheless, elevated endotoxin levels in these patients would permit the exacerbation of influenza infection through increased cytokine production, inflammation, plasma leakage and pathology.
Not all pre-existing infections would lead to the pathology observed in the H7N9 deaths, which appears to be specific. The specific lung pathology observed in these deaths is likely attributed to limited types of toxins cleared by the liver. Endotoxin has been implicated in a respiratory disease syndrome in pigs caused by PRRSV [porcine reproductive-respiratory syndrome virus] and PRCV(11). PRRSV and/or PRCV infection lead to sensitization of the lung to endotoxin. The presence of endotoxin (complexed with LBP and LBI) in the lung then leads to greater production of inflammatory cytokines and the pathology observed in this respiratory disease syndrome (12). Van Gucht et al (1993) hypothesized that PRRSV increased the amount of LPS receptor complex in the lungs, leading to LPS sensitisation (13). Chronic hepatitis B infection causes liver impairment and reduced ability to clear toxins from the blood including endotoxin. Hepatitis B is endemic in China, and it is possible that hepatitis B infection and systemic elevated endotoxin levels could be involved in H7N9 human deaths. Pre-existing endotoxin in systemic circulation caused by chronic hepatitis B infection may not be very detrimental initially; however, upon H7N9 lung infection, sensitization of the lung to endotoxin could trigger the worsening of avian influenza and the observed deaths in older cases.
Endotoxin, LBP and CD14 levels can be measured using either plasma or sera collected from patients. An adequate endotoxin testing method, the Limulus amoebocyte lysate (LAL) test, could be employed as it offers superior sensitivity in detecting small variations (nanogram quantities). Future studies should also include controlling for blood factors that could affect the LAL test using dilutions and heat treatments where necessary. Greater understanding of the host-related factors involved in avian influenza disease severity is needed for better patient management and improved outcome.
References:
1. Tschernev DM, Garc?*a-Sastre A. Virulence determinants of pandemic influenza viruses. J Clin Invest. 2011 January 4; 121(1): 6-13.
2. Lustig S, Danenberg HD, Kafri Y, Kobiler D, Ben-Nathan D. Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med. 1992 Sep 1;176(3):707-12.
3. Douek D. HIV disease progression: immune activation, microbes, and a leaky gut. Top HIV Med. 2007 Aug-Sep;15(4):114-7.
4. van de Weg CA, Koraka P, van Gorp EC, Mairuhu AT, Supriatna M, Soemantri A, et al. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J Clin Virol. 2012 Jan;53(1):38-42.
5. Lassenius MI, Pietilinen KH, Kaartinen K, Pussinen PJ, Syrjnen J, Forsblom C, et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care. 2011;34(8):1809-15.
6. Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012 Dec;44(12):1027-31.
7. Prins J. Antibiotic induced release of endotoxin - clinical data and human studies. J Endotox Res. 1996; 3(3):269-73.
8. Holzheimer RG. The significance of endotoxin release in experimental and clinical sepsis in surgical patients--evidence for antibiotic-induced endotoxin release? Infection. 1998 Mar-Apr;26(2):77-84.
9. Arima Y, et al. Human infections with avian influenza A(H7N9) virus in China: preliminary assessments of the age and sex distribution. Western Pacific Surveillance and Response Journal 2013; 4(2). doi:10.5365/wpsar.2013.4.2.005
10. Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013 Apr 11. (Ahead of print)
11. van Gucht S, van Reeth K, Pensaert M. Interaction between porcine reproductive-respiratory syndrome virus and bacterial endotoxin in the lungs of pigs: potentiation of cytokine production and respiratory disease. J Clin Microbiol. 2003;41(3):960-6.
12. Qiao S, Feng L, Bao D, Guo J, Wan B, Xiao Z, et al. Porcine reproductive and respiratory syndrome virus and bacterial endotoxin act in synergy to amplify the inflammatory response of infected macrophages. Vet Microbiol. 2011;149(1-2):213-20.
13. Van Gucht S, Labarque G, Van Reeth K. The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs. Vet Immunol Immunopathol. 2004;102(3):165-78.
--
Kirk Douglas, microbiologist
<kirk.douglas@mycavehill.uwi.edu>
communicated by:
Ryan McGinnis
http://bigstormpicture.com
[The above document has been received by ProMED-mail and is posted on the basis of its intrinsic interest. It is not a referred paper; therefore, interested readers in the 1st instance should address comments directly to the author, and subsequently, if appropriate, to ProMED-mail. - Mod.CP]
http://www.promedmail.org/direct.php?id=20130503.1689393
Subject: PRO/AH/EDR> Avian influenza, human (70): China H7N9, severity hypothesis
Archive Number: 20130503.1689393
AVIAN INFLUENZA, HUMAN (70): CHINA H7N9, SEVERITY HYPOTHESIS
************************************************************
A ProMED-mail post
http://www.promedmail.org
ProMED-mail is a program of the
International Society for Infectious Diseases
http://www.isid.org
Date: Thu 2 May 22013
From: Kirk Douglas <kirk.douglas@mycavehill.uwi.edu> [edited]
The recent zoonotic infections with a novel H7N9 virus have brought greater attention to avian influenza research. Viral factors do play a role in disease severity, and undoubtedly in avian influenza this has been previously demonstrated (1). However, with greater focus on viral factors, there has been a lesser focus on host related factors of avian influenza disease severity.
A possible role of circulating bacterial endotoxin or lipopolysaccharide (LPS) in disease severity of avian influenza is postulated here. LPS is comprised of lipid A, core oligosaccharide and O polysaccharide. Gram negative bacteria contain LPS in their cell walls and can release LPS to varying extents based on the characteristics of the O polysaccharide chain. LPS can enter the body via 2 routes: either a) through acute Gram negative bacterial infection; and or b) bacterial LPS translocation from the gut or intestine. Bacterial LPS translocation from the gut does occur and can be triggered by trauma, surgical procedures and intestinal epithelial dysfunction by viral replication. This LPS translocation can lead to endotoxemia and trigger overproduction of cytokines. The presence of circulating endotoxin in the blood has been shown to increase pathogenicity of viral infections including West Nile virus, HIV and dengue virus (2-4). In addition, some diseases have been associated with elevated endotoxin levels including obesity, diabetes and cirrhosis and liver disease (5,6).
Endotoxin in the body is cleared by binding to serum proteins including lipopolysaccharide binding protein (LBP) and bactericidal permeating increasing protein (BPI). LBP is produced in the liver, and one function of the liver is to clear endotoxin from the body. If liver function is impaired, then clearance of endotoxin is also impaired, and observance of elevated endotoxin levels is expected. The clinical influence of antibiotic use on endotoxin levels is not definitive, as it has been shown to both have no effect and also to increase them (7,8).
The hypothesis presented here suggests H7N9-infected patients with pre-existing diseases including those observed in the current outbreak have elevated serum/plasma endotoxin levels which exacerbate the clinical course of influenza virus infection. Higher mortality would be expected in such patients. To date there appears to be no gender bias in mortality, with a similar case fatality rate (22 per cent) in men and women (9). These elevated endotoxin levels result in greater production of TH1 cytokines such as TNF-I+/-, IL-10 and IFN-I3, triggering a systemic inflammatory response, vascular/plasma leakage, pleural effusion and pneumonia often associated with influenza mortality.
Gao et al (2013) documented the initial 3 H7N9 fatal human cases (ages 27, 35 and 87) and found underlying diseases were present, including hepatitis B, chronic obstructive pulmonary disease (COPD) and obesity. In addition, 2 out of the 3 cases had _Acinetobacter baumanii_ (Gram-negative) infections, and all 3 were placed on antibiotic treatments (10). Anecdotal evidence of an association of hepatitis B infection in more of the H7N9 human cases is in circulation but needs to be officially verified. Nonetheless, elevated endotoxin levels in these patients would permit the exacerbation of influenza infection through increased cytokine production, inflammation, plasma leakage and pathology.
Not all pre-existing infections would lead to the pathology observed in the H7N9 deaths, which appears to be specific. The specific lung pathology observed in these deaths is likely attributed to limited types of toxins cleared by the liver. Endotoxin has been implicated in a respiratory disease syndrome in pigs caused by PRRSV [porcine reproductive-respiratory syndrome virus] and PRCV(11). PRRSV and/or PRCV infection lead to sensitization of the lung to endotoxin. The presence of endotoxin (complexed with LBP and LBI) in the lung then leads to greater production of inflammatory cytokines and the pathology observed in this respiratory disease syndrome (12). Van Gucht et al (1993) hypothesized that PRRSV increased the amount of LPS receptor complex in the lungs, leading to LPS sensitisation (13). Chronic hepatitis B infection causes liver impairment and reduced ability to clear toxins from the blood including endotoxin. Hepatitis B is endemic in China, and it is possible that hepatitis B infection and systemic elevated endotoxin levels could be involved in H7N9 human deaths. Pre-existing endotoxin in systemic circulation caused by chronic hepatitis B infection may not be very detrimental initially; however, upon H7N9 lung infection, sensitization of the lung to endotoxin could trigger the worsening of avian influenza and the observed deaths in older cases.
Endotoxin, LBP and CD14 levels can be measured using either plasma or sera collected from patients. An adequate endotoxin testing method, the Limulus amoebocyte lysate (LAL) test, could be employed as it offers superior sensitivity in detecting small variations (nanogram quantities). Future studies should also include controlling for blood factors that could affect the LAL test using dilutions and heat treatments where necessary. Greater understanding of the host-related factors involved in avian influenza disease severity is needed for better patient management and improved outcome.
References:
1. Tschernev DM, Garc?*a-Sastre A. Virulence determinants of pandemic influenza viruses. J Clin Invest. 2011 January 4; 121(1): 6-13.
2. Lustig S, Danenberg HD, Kafri Y, Kobiler D, Ben-Nathan D. Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med. 1992 Sep 1;176(3):707-12.
3. Douek D. HIV disease progression: immune activation, microbes, and a leaky gut. Top HIV Med. 2007 Aug-Sep;15(4):114-7.
4. van de Weg CA, Koraka P, van Gorp EC, Mairuhu AT, Supriatna M, Soemantri A, et al. Lipopolysaccharide levels are elevated in dengue virus infected patients and correlate with disease severity. J Clin Virol. 2012 Jan;53(1):38-42.
5. Lassenius MI, Pietilinen KH, Kaartinen K, Pussinen PJ, Syrjnen J, Forsblom C, et al. Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation. Diabetes Care. 2011;34(8):1809-15.
6. Jain L, Sharma BC, Sharma P, Srivastava S, Agrawal A, Sarin SK. Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy. Dig Liver Dis. 2012 Dec;44(12):1027-31.
7. Prins J. Antibiotic induced release of endotoxin - clinical data and human studies. J Endotox Res. 1996; 3(3):269-73.
8. Holzheimer RG. The significance of endotoxin release in experimental and clinical sepsis in surgical patients--evidence for antibiotic-induced endotoxin release? Infection. 1998 Mar-Apr;26(2):77-84.
9. Arima Y, et al. Human infections with avian influenza A(H7N9) virus in China: preliminary assessments of the age and sex distribution. Western Pacific Surveillance and Response Journal 2013; 4(2). doi:10.5365/wpsar.2013.4.2.005
10. Gao R, Cao B, Hu Y, Feng Z, Wang D, Hu W, et al. Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013 Apr 11. (Ahead of print)
11. van Gucht S, van Reeth K, Pensaert M. Interaction between porcine reproductive-respiratory syndrome virus and bacterial endotoxin in the lungs of pigs: potentiation of cytokine production and respiratory disease. J Clin Microbiol. 2003;41(3):960-6.
12. Qiao S, Feng L, Bao D, Guo J, Wan B, Xiao Z, et al. Porcine reproductive and respiratory syndrome virus and bacterial endotoxin act in synergy to amplify the inflammatory response of infected macrophages. Vet Microbiol. 2011;149(1-2):213-20.
13. Van Gucht S, Labarque G, Van Reeth K. The combination of PRRS virus and bacterial endotoxin as a model for multifactorial respiratory disease in pigs. Vet Immunol Immunopathol. 2004;102(3):165-78.
--
Kirk Douglas, microbiologist
<kirk.douglas@mycavehill.uwi.edu>
communicated by:
Ryan McGinnis
http://bigstormpicture.com
[The above document has been received by ProMED-mail and is posted on the basis of its intrinsic interest. It is not a referred paper; therefore, interested readers in the 1st instance should address comments directly to the author, and subsequently, if appropriate, to ProMED-mail. - Mod.CP]
http://www.promedmail.org/direct.php?id=20130503.1689393