D’Alessio: The Pathobiology of Sepsis

Today we are very fortunate to welcome Franco Rafael D’Alessio MD, assistant professor of medicine at the Johns Hopkins University School of Medicine with a specialty on critical care medicine. If there is one thing that Dr. D’allasio knows, it is sepsis. In fact over the last several years he has published numerous papers on the immunology of lung disease, focusing on T cell use, macrophage response, and the changes to inflammation that occur with aging. Today he focuses his brilliance to a 45 minute talk that is essential if you ever want to truly understand what sepsis does to your patients!

Clinical Pearls (assisted by Dr. Faith Armstrong)

  • Sepsis is a Spectrum of Illness
    • Ranges from Sepsis to MODS/Death
    • Do not rely on fevers, which the elderly may not develop
  • Epidemiology
    • 750K cases a year with huge economic impact ($25 billion/yr!!)
    • Incidence is increasing due to aging population and increased virulence
  • Mortality is upwards of 50%
    • Most common cause of death in ICU and most common cause of ICU admission
    • Now Gram (+) cases have increased and almost matched the cases of Gram (-) sepsis
    • Cases of Fungal Sepsis are increasing (more immunosuppressed patients)
  • Factors involved in the transition to Sepsis is the interaction btw the host and the pathogen
    • Host:
      • Dysregulated Inflammatory response- Toll Like Receptor (TLR)
      • Coagulation and anticoagulation
      • Immunosuppression and apoptosis
      • Genetic susceptibility
    • Pathogen:
      • Virulence factors (e.g. MRSA PVL)
      • Endotoxins/exotoxins
      • Resistance to antibiotics

Sepsis 1

Robbins & Cotran Pathologic Basis of Disease, 9e (Robbins Pathology)

  • TLR 4 (recognizes LPS which is highly expressed in Gram (-) bacteria)
    • When a TLR is engaged with the bacteria, a biologic cascade is initiated
    • This signals and activates transcription factor NFKB which, when activated, goes inside the nucleus and is a transcription factor for about 150 genes involved in host immune response.
    • Anti-inflammatory pathways are also activated to avoid collateral damage and clear the bacteria (IL-10); this is an important area of research
  • Activation of the Coagulation Cascade (particularity extrinsic factor)
    • DIC with intravascular fibrin deposition is frequently found
    • Fibrinolytic processes inhibited.

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N Engl J Med 2006; 355:1699-1713

  • Future directions:
    • Septic patients may have an enhancement of TLRs, why?
    • Why does early antibiotic therapy save lives– especially within the first hour! (higher mortality if we wait to begin antibiotics)
      • #1: Implementing source control is necessary
    • Further research will be in an individual’s own genetic profile

Suggested Reading

  1. Cinel I, Opal SM. Molecular biology of inflammation and sepsis: a primer. Crit Care Med. 2009 Jan;37(1):291-304. [PubMed Link]
  2. Russell JA. Management of sepsis. N Engl J Med. 2006 Oct 19;355(16):1699-713.[PubMed Link]
  3. Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013 Aug 29;369(9):840-51.[PubMed Link]
About the Author

Jim Lantry

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Just your average critical care doc: Wandering the ED and ICUs for the USAF down in the San Antonio Military Medical Center, traveling the globe to cannulate for ECLS wherever the need arises, and trying to keep up with great minds of today. E: JlantryMD@gmail.com

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