Tumor necrosis factor-alpha;

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?

When should I consider steroids in my patient with alcoholic hepatitis?

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

The short answer is not very often! In the treatment of alcoholic hepatitis (AH), steroids are reserved for a narrow group of patients only, with a 2018 meta-analysis finding a reduction in short-term mortality (average 36%) at 28 days but not at 6 months.1

The most studied scoring system to help clinicians decide whether a patient should get steroids is the Maddrey’s Discriminant Function (MDF), which is based on the prothrombin and total bilirubin. A score of ≥32 indicates severe disease and potential response to steroids, while a score <32 indicates mild to moderate disease, for which the risk of steroids (e.g. infection, worsening ulcer disease/bleeding, and glucose intolerance) may outweigh any potential benefit.

However, even with a score ≥32, the likelihood of patient adherence to 28 days of steroid therapy, risk of infection and other steroid-related complications should be carefully considered in individual patients. It’s also important to note that a 2008 meta-analysis showed that patients with a very high MDF score of >54 actually had higher mortality rates with steroid therapy, possibly related to the lack of response in very advanced disease as well as high infection risk.2

Many clinicians also use the Lille’s score to help determine whether a patient is a responder after 7 days of initial therapy. A score >0.45 (calculated based on bilirubin levels at day 0 and 7 and other initial labs and age) indicates poor response and that steroids may be stopped due to its risks.3

Based on the result of a small retrospective study, Glasgow Alcoholic Hepatitis (GAH) score has also been suggested as a means of further defining patients with a MDF ≥32 who may potentially benefit from steroids (ie, score ≥9).4

Bonus pearl: Did you know that pentoxifylline, a tumor necrosis factor (TNF), has generally not been found to be effective in the treatment of AH?5,6

Contributed by Tom Wang, MD, Mass General Hospital, Boston, MA.

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References

  1. Louvet A, et al. “Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or Placebo—a meta-analysis of individual data from controlled trials.” Gastroenterology 2018; 155: 458-468. https://www.sciencedirect.com/science/article/abs/pii/S0016508518344950
  2. Rambaldi A, et al. “Systematic review: glucocorticosteroids for alcoholic hepatitis–a Cochrane Hepato‐Biliary Group systematic review with meta‐analyses and trial sequential analyses of randomized clinical trials.” Alimentary pharmacology & therapeutics 2008; 27: 1167-1178. https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2036.2008.03685.x
  3. Louvet A, et al. “The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.” Hepatology 2007; 45: 1348-1354. https://www.ncbi.nlm.nih.gov/pubmed/17518367
  4. Forrest EH, et al. “Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.” Gut 2005; 54: 1174-1179. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774903/
  5. Thursz MR, et al. “Prednisolone or pentoxifylline for alcoholic hepatitis.” N Engl J Med 2015; 372: 1619-1628. https://www.nejm.org/doi/full/10.1056/NEJMoa1412278
  6. Parker R. “Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis.” Alimentary Pharm Therapeutics 2018; 37: 845-854. https://onlinelibrary.wiley.com/doi/10.1111/apt.12279

 

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!

When should I consider steroids in my patient with alcoholic hepatitis?

My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

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

The weight of the evidence to date suggests that immunosuppressive therapy, including steroids, other oral immunosuppressants and anti-tumor-necrosis factor (TNF) agents, may negatively impact IGRA results.1

In some ways the finding of false-negative IGRA in the setting of immunosuppression is intuitive since many immunosuppressive agents are potent inhibitors of T cells and interferon-gamma response. 1,2 Despite this, the initial reports have been somewhat conflicting which makes a 2016 meta-analysis of the effect of immunosuppressive therapy on IGRA results in patient with autoimmune diseases (eg, rheumatoid arthritis, lupus, inflammatory bowel disease) particularly timely. 1

This meta-analysis found a significantly lower positive IGRA results among patients on immunosuppressive therapy ( O.R. 0.66, 95% C.I. 0.53-0.83). Breakdown by IGRA test showed a significant association between QuantiFERON-TB Gold In-Tube and lower positive results and a trend toward the same with T-SPOT though the latter did not reach statistical significance with fewer evaluable studies (O.R. 0.81, 95% C.I 0.6-1.1).   Breakdown by type of immunosuppressant showed significantly negative impact of corticossteroids, other oral immunosuppressants, and anti-TNF agents for all. Some studies have reported daily steroid doses as low as 7.5 mg-10 mg may adversely impact T-cell responsiveness in IGRA. 3,4

So, whenever possible, testing for latent TB should be performed before immunosuppressants are initiated.

Bonus Pearl: Did you know that an estimated one-third of the world’s population may have latent TB?

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References

  1. Wong SH, Gao Q, Tsoi KKF, et al. Effect of immunosuppressive therapy on interferon gamma release assay for latent tuberculosis screening in patients with autoimmune diseases: a systematic review and meta-analysis. Thorax 2016;71:64-72. https://thorax.bmj.com/content/thoraxjnl/71/1/64.full.pdf
  2. Sester U, Wilkens H, van Bentum K, et al. Impaired detection of Mycobacterium tuberculosis immunity in patents using high levels of immunosuppressive drugs. Eur Respir J 2009;34:702-10. https://erj.ersjournals.com/content/34/3/702
  3. Kleinert S, Kurzai O, Elias J, et al. Comparison of two interferon-gamma release assays and tuberculin skin test for detecting latent tuberculosis in patients with immune-mediated inflammatory diseases. Ann Rheum Dis 2010;69:782-4. https://ard.bmj.com/content/69/4/782
  4. Ponce de Leon D, Acevedo-Vasquez E, Alvizuri S, et al. Comparison of an interferon-gamma assay with tuberculin skin testing for detection of tuberculosis (TB) infection in patients with rheumatoid arthritis in a TB-endemic population. J Rheumatol 2008;35:776-81. https://www.ncbi.nlm.nih.gov/pubmed/18398944
My patient with rheumatoid arthritis might have been exposed to tuberculosis. Does immunosuppressive therapy affect the results of interferon gamma release assay (IGRA) testing for latent tuberculosis?

My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?

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

Although fever and atelectasis often coexist during the early postop period, there is no evidence that atelectasis causes fever.

A 2011 systematic analysis of 8 published studies found that all but 1 study failed to find a significant association between postop fever and atelectasis.1  A 1988 study reported a significant association between postop fever during the first 48 h and atelectasis on day 4 postop, but not each postop day.2  Even in this study, however, fever as a predictor of atelectasis performed poorly with a sensitivity of 26%, specificity of 75% and accuracy of 43%.

In another study involving postop cardiac surgery patients, despite a fall in the incidence of fever from day 0 to day 2, the incidence of atelectasis based on serial chest X-rays actually  increased. 3

Experimental studies in dogs and cats in the 1960s also support the lack of a causative relationship between atelectasis and fever. 4,5 Although fever was observed within 12 hrs of placement of cotton plugs in the left main bronchus of these animals, almost all animals also developed pneumonia distal to the plug.  Antibiotic treatment was associated with resolution of fever but not atelectasis.

So if it’s not atelectasis, what’s the explanation for early postop fever? The great majority of postop fevers during the first 4 days postop are unlikely to be related to infections. Instead, a more plausible explanation is the inflammatory response to the tissue injury as a result of the surgery itself causing release of cytokines (eg, interleukin-1 and -6 and tumor necrosis factor) associated with fever. 6

References

  1. Mavros MN, Velmahos GC, Falagas ME. Atelectasis as a cause of postoperative fever. Where is the clinical evidence? CHEST 2011;140:418-24. https://www.ncbi.nlm.nih.gov/pubmed/21527508
  2. Roberts J, Barnes W, Pennock M, et al. Diagnostic accuracy of fever as a measure of postoperative pulmonary complications. Heart Lung 1988;17:166-70. https://www.ncbi.nlm.nih.gov/pubmed/3350683
  3. Engoren M. Lack of association between atelectasis and fever. CHEST 1995;107:81-84. https://www.ncbi.nlm.nih.gov/pubmed/7813318
  4. Lansing AM, Jamieson WG. Mechanisms of fever in pulmonary atelectasis. Arch Surg 1963;87:168-174. https://jamanetwork.com/journals/jamasurgery/fullarticle/561080
  5. Jamieson WG, Lansing AM. Bacteriological studies in pulmonary atelectasis. Arch Surg 1963;87:1062-66. https://www.ncbi.nlm.nih.gov/pubmed/14063816
  6. Narayan M, Medinilla SP. Fever in the postoperative patient. Emerg Med Clin Nam 2013;31:1045-58. https://www.ncbi.nlm.nih.gov/pubmed/24176478 

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My postop patient now has fever with atelectasis on her chest X-ray one day after surgery. Does atelectasis cause fever?

My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

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

Hepatic encephalopathy (HE) may be precipitated by a variety of factors including infection, hypovolemia, electrolyte imbalance (eg, hyponatremia, hypokalemia), metabolic alkalosis, sedatives, and of course UGIB. 1-3

Ammonia is often considered to play a central role in the the pathogenesis of HE, particularly when associated with UGIB. The ammoniagenic potential of UGIB is primarily attributed to the presence of hemoglobin protein in the intestinal tract. One-half of the ammoniagenesis originates from amino acid metabolism (mainly glutamine) in the mucosa of the small bowel, while the other half is due to the splitting of urea by the resident bacteria in the colon (eg, Proteus spp., Enterobacteriaceae, and anerobes).1,2

A large protein load in the GI tract, as occurs in UGIB, may result in hyperammonemia in patients with cirrhosis due to the limited capacity of the liver to convert ammonia to urea through the urea cycle as well as by the shunting of blood around hepatic sinusoids. Recent studies, however, also implicate the kidneys as an important source of ammonia in this setting, further compounding HE.3

It’s important to stress that ammonia is not likely to be the only mediator of HE. Enhanced production of cytokines due to infection or other inflammatory states, neurosteroids, endogenous benzodiazepines, and other bacterial byproducts may also play an important role in precipitating HE.2,4-6  So stay tuned!

Bonus pearl: Did you know that proinflammatory cytokines tumor necrosis factor-alpha and inerleukin-6 increase ammonia permeability across central nervous system-derived endothelial cells? 7

 

References

  1. Olde Damink SWM, Jalan R, Deutz NEP, et al. The kidney plays a major role in the hyperammonemia seen after simulated or actual GI bleeding in patients with cirrhosis. Hepatology 2003;37:1277-85.
  2. Frederick RT. Current concepts in the pathophysiology and management of hepatic encephalopathy. Gastroenterol Hepatol 2011;7:222-233.
  3. Tapper EB, Jiang ZG, Patwardhan VR. Refining the ammonia hypothesis: a physiology-driven approach to the treatment of hepatic encephalopathy. Mayo Clin Proc 2015;90:646-58.
  4. Shawcross DL, Davies NA, Williams R, et al. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004;40:247-254.
  5. Shawcross DL, Sharifi Y, Canavan JB, et al. Infection and systemic inflammation, not ammonia, are associated with grade ¾ hepatic encephalopathy, but not mortality in controls. J Hepatol 2011;54:640-49.
  6. Shawcross D, Jalan R. The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.Cell Mol Life Sci 2005;62:2295-2304.
  7. Duchini A, Govindarajan S, Santucci M, et al. Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996;44:474-82.

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My patient with cirrhosis now has an upper gastrointestinal bleed (UGIB) with hepatic encephalopathy (HE). What’s the connection between UGIB and HE?

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

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

The presence of hepatitis B surface antibody (HBsab) in patients who also test positive for core antibody does not necessarily confer full protection against hepatitis B virus (HBV) reactivation during immunosuppression (incidence 4.3%). 1 This is because despite having HBsab and no HB surface antigen,  a small portion of patients continue to have detectable HBV DNA in the serum and are therefore at risk of reactivation during severe immunosuppression. 2

In fact, the American Gastroenterological Association recommends against using anti-HBs status to guide antiviral prophylaxis in anti-HBc-positive patients. 1

Overall, antiviral prophylaxis may reduce the risk of HBV reactivation by 87% (C.I. 70%-94%). Antiviral drugs with a high barrier to resistance (eg, entecavir) are preferred over lamivudine.

Immunosuppressants often requiring HBV prophylaxis include: 1-3

  • B cell-depleting agents (eg, rituximab, ofatumumab)
  • Anthracycline derivatives (eg, doxorubicin, epirubicin)
  • Prednisone (4 weeks or more)
  • Tumor necrosis factor inhibitors (eg, etanercept, adalimumab, certolizumab, infliximab)
  • Other cytokine or integrin inhibitors (eg, abatacept, ustekinumab, natalizumab, vedolizumab)

Traditional immunosuppressive agents such as azathioprine, 6-mercaptopurine and methotrexate are often considered “low-risk” and do not generally require prophylaxis. 1

Fun Fact: Did you know that hepatitis B virus is very old and probably originated in birds when dinosaurs roamed the earth? 4

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References

  1. Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute Guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015;148:215-19. https://www.ncbi.nlm.nih.gov/pubmed/25447850
  2. Gigi E, Georgiou T, Mougiou D, et al. Hepatitis B reactivation in a patient with rheumatoid arthritis with antibodies to hepatitis B surface antigen treated with rituximab. HIPPOKATRIA 2013;17:91-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738290/
  3. Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat 2008;40:36-38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699087/
  4. Suh A, Brosius J, Schmitz J, et al. The genome of a Mesozoic paleovirus reveals the evolution of hepatitis B virus. Nature Communications 2013; Article no. 1791. http://www.nature.com/articles/ncomms2798

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

Does my patient about to undergo immunosuppressive therapy need antiviral prophylaxis even if she tests positive for hepatitis B surface antibody?

What is the association between sepsis and jaundice in patients without biliary obstruction?

FA Manian MD, MPH, , Leave a comment

Up to 20% of cases of jaundice in community hospitals may be due to sepsis and bacterial infections, often occurring within a few days of onset of bacteremia or even before other clinical features of infection become apparent. 1 

Although biliary obstruction as the cause of jaundice is usually suspected, many patients lack extrahepatic cause for their jaundice. Gram-negative bacteria (eg, E. coli) are often the culprit with intraabdominal or urinary tract infection, pneumonia, endocarditis, and meningitis sources also often cited. Hyperbilirubinemia (often 2-10 mg/dl) is commonly associated with elevated alkaline phosphatase and mild aminotransferases elevations, and usually resolves with treatment of infection.1

Although factors such as increased bilirubin load from hemolysis, hepatocellular injury, and drugs (eg, penicillins and cephalosporins) may play a role, cholestasis—likely due to cytokines such as tumor necrosis factor (TNF)α— is the predominant cause. 1  

Interestingly, anti-TNF-α antibodies block reduction in bile flow and bile salt excretion in laboratory animals2. 

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References

  1. Chand N, Sanyal AJ. Sepsis-induced cholestasis. HEPATOLOGY 2007;45: 230-240. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.21480
  2. Whiting J, Green R, Rosenbluth A, Gollan J. Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. HEPATOLOGY 1995;22:1273-1278. https://www.deepdyve.com/lp/wiley/tumor-necrosis-factor-alpha-decreases-hepatocyte-bile-salt-uptake-and-J9rdeMQBpF

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. 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!

What is the association between sepsis and jaundice in patients without biliary obstruction?