IL-6;

How does older people’s immune system place them at high risk of sepsis and death?

FA Manian MD, MPH, , , , , , , , , , , , , , , , , , , , , , , , Leave a comment

Increased risk of sepsis and death from infectious causes among the elderly is a well-known phenomenon—particularly as witnessed in the Covid-19 era— and is in part due to 2 major age-related alterations of their immune system: 1. Defective T and B cell functions in response to acute infections; and 2. Once infection sets in, inadequate control of sepsis-induced pro-inflammatory response and its attendant procoagulant state. Interestingly, the essential elements of the innate immunity (eg, neutrophils, dendritic cells, complements) are generally spared from the effects of aging.1,2

Increased susceptibility of the elderly to acute infections is in part caused by poorer T helper cell function and suboptimal B cell humoral response to neoantigens. Despite this, serum levels of pro-inflammatory cytokines such as IL-1, IL-6,TNF-alpha, and IFN-gamma are intact.  In fact, production of IL-6 and its duration of response is actually increased in the elderly.1,2

Poor control of the inflammatory state due to sepsis in older patients may be related to the difficulty in clearing a pathogen or dysfunction in the signaling by counter-regulatory cytokines, such as IL-10.2 Either way, unchecked inflammatory response is deleterious to the patient and is associated with increased risk of thrombosis and thromboembolism, multiorgan system failure, septic shock and death. 

Bonus Pearl: Did you know that even in the absence of infection, older people are more prone to thrombosis and thromboembolism , in part related to elevated plasma levels of fibrinogen, as well as factor VII, VIII, and IX, among others?2,3  

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 References

  1. Ticinesi A, Lauretani F, Nouvenne A, et al. C-reactive protein (CRP) measurement in geriatric patients hospitalized for acute infection. Eur J Intern Med 2017;37:7-12. https://pubmed.ncbi.nlm.nih.gov/27594414/
  2. Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis 2005;41: (Suppl 7) S504-12. https://pubmed.ncbi.nlm.nih.gov/16237654/
  3. Mari D, Coppola R, Provenzano R. Hemostasis factors and aging. Experimental Gerontology 2008;43:66-73. https://www.sciencedirect.com/science/article/abs/pii/S0531556507001404?via%3Dihub

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

How does older people’s immune system place them at high risk of sepsis and death?

Can my patient develop “anemia of chronic disease” acutely while hospitalized?

FA Manian MD, MPH, , , , , , , , Leave a comment

“Anemia of chronic disease” is better termed anemia of inflammation (AI) which may occur in acute as well as chronic inflammatory states. 1 As such, the view that anemia in the critically ill patients is simply caused by excess phlebotomy is inaccurate. 2 The CRIT study demonstrated that AI in critically ill patients develops even within 30 days, often despite blood transfusions. 3

In addition to the usual causes of AI (eg autoimmune disorders), AI can occur during bacterial, viral or yeast infections and sepsis 4,5.

Recent studies implicate both iron sequestration and impaired erythropoiesis as causes of AI. 1 Inflammation stimulates hepatic production of iron-regulatory peptide, hepcidin, which decreases delivery of iron from macrophages to developing erythrocytes.  Inflammation also causes production of pro-inflammatory cytokine, IL-6, which suppresses erythropoiesis.

Couple of cool studies using injection of heat-killed Brucella abortus in mice as a model of AI, showed dramatic hemoglobin drop by 7 days.6,7. In addition, not only were iron restriction from increase in hepcidin and transient erythropoiesis demonstrated, erythrocyte lifespan was also shortened in these experiments. AI is truly a multifactorial process.

 

References 

  1. Frankel PG. Anemia of inflammation: A review. Med Clin N Ame 2017;101:285-96. https://www.ncbi.nlm.nih.gov/pubmed/28189171
  2. Corwin HL, Krantz SB. Anemia of the critically ill: “Acute” anemia of chronic disease. Crit Care Med 2000;28:3098-99. https://www.ncbi.nlm.nih.gov/pubmed/10966311
  3. Corwin HL, Gettinger A, Pearl RG, et al. The CRIT study: anemia and blood transfusion in the critically ill-current clinical practice in the United states. Crit Care Med 2004;32:39-52. https://www.ncbi.nlm.nih.gov/pubmed/14707558
  4. Gabriel A, Kozek S, Chiari A, et al. High-dose recombinant human erythropoietin stimulates reticulocyte production in patients with multiple organ dysfunction syndrome. J Trauma:Injury, Infection, and Critical Care 1998;44:361-67. https://www.ncbi.nlm.nih.gov/pubmed/9498512
  5. Roy CN. Anemia of inflammation. Hematology Am Soc Hematol Educ Program. 2010;2010:276-80. doi: 10.1182/asheducation-2010.1.276. https://www.ncbi.nlm.nih.gov/pubmed/21239806
  6. Kim A, Fung E, Parikh SG, et al. A mouse model of anemia of inflammation: complex pathogenesis with partial dependence on hepcidin. Blood 2014;123:1129-36. https://www.ncbi.nlm.nih.gov/pubmed/24357728
  7. Gardenghi S, Renaud TM, Meloni A, et al. Distinct roles for hepcidin and interleukin-6 in the recovery from anemia in mice injected with heat-killed Brucella abortus. Blood 2014;123:1137-45. https://www.ncbi.nlm.nih.gov/pubmed/24357729

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Can my patient develop “anemia of chronic disease” acutely while hospitalized?

My patient with cirrhosis and suspected infection has a normal serum C-reactive protein (CRP). Does cirrhosis affect CRP response to infection?

FA Manian MD, MPH, , , , , , , , Leave a comment

CRP is primarily synthesized by the liver mainly as a response to IL-6 production in inflammatory states1.  Lower CRP production may then be expected in cirrhotic patients with significant infections and several studies support this view2. 

In a particularly convincing study involving E. coli-infected patients with bacteremia, the median CRP level in cirrhotic patients was about 40% that of non-cirrhotic patients (62 mg/L vs 146 mg/L)3.  In another study involving bacteremic patients with or without liver dysfunction, median CRP level was about 60% that of  patients with preserved liver function (81 mg/L vs 139 mg/L)4. 

Some investigators have reported a cut-off CRP value of 9.2 mg/L as a possible screening test for bacterial infections in patients with cirrhosis with a sensitivity and specificity of 88% (AUROC 0.93)5.

Collectively, these data suggest that although CRP response may be diminished in patients with advanced liver disease and acute infection, its synthesis is still maintained.

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 References

  1. Pieri G, Agarwal B, Burroughs AK. C-reactive protein and bacterial infection in cirrhosis. Ann Gastroenterol 2014;27:113-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3982625/pdf/AnnGastroenterol-27-113.pdf
  2. Ha YE, Kang C-I, Joo E-J, et al. Usefulness of C-reactive protein for evaluating clinical outcomes in cirrhotic patients with bacteremia. Korean J Intern Med 2011;26:195-200. http://pubmedcentralcanada.ca/pmcc/articles/PMC3110852/pdf/kjim-26-195.pdf
  3. Park WB1, Lee KD, Lee CS et al. Production of C-reactive protein in Escherichia coli-infected patients with liver dysfunction due to liver cirrhosis. Diagn Microbiol Infect Dis. 2005 Apr;51(4):227-30. https://www.ncbi.nlm.nih.gov/pubmed/15808312
  4. Mackenzie I, Woodhouse J. C-reactive protein concentrations during bacteraemia: a comparison between patients with and without liver dysfunction. Intensive Care Med 2006;32:1344-51. https://www.ncbi.nlm.nih.gov/pubmed/16799774
  5. Papp M, Vitalis Z, Altorjay I, et al. Acute phase proteins in the diagnosis and prediction of cirrhosis associated bacterial infection. Liver Int 2011;603-11. https://www.ncbi.nlm.nih.gov/pubmed/22145664

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Massachusetts General Hospital, Harvard Catalyst, Harvard University, its affiliate academic healthcare centers, or its contributors. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

My patient with cirrhosis and suspected infection has a normal serum C-reactive protein (CRP). Does cirrhosis affect CRP response to infection?