Persistent Inflammation, Immunosuppression Catabolism Syndrome: History
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An addition to the introduction was undertaken. Further going into detail regarding immunological issues on a cellular basis. Can be seen as possible suggestion.

  • PICS
  • MDSC
  • DAMPs
  • inflammation
  • immunosuppression

1. Introduction

Since its first description by Gentile et al. in 2012 [17], the concept of PICS has been validated and is becoming more and more accepted as the underlying pathophysiology of chronic critical illness (CCI) [18–24]. The paradigm implies that, following the simultaneously triggered pro- and anti-inflammatory responses to a major inflammatory insult (e.g., trauma, burns, sepsis, acute pancreatitis, etc.), the increasing number of acute survivors either proceed to a fairly rapid recovery or a prolonged trajectory partially ending in CCI [18,19]. Clinically speaking, these patients present with a prolonged ICU stay (typically >14 days) under the coexistence of ongoing inflammation and immunosuppression, resulting in persistent catabolism and organ dysfunction [18–20]. Besides an ICU length of stay (LOS) of over 14 days, applied clinical markers defining the diagnosis are as follows: a C-reactive protein (CRP) over 0.15 mg/dL as sign of inflammation; a total lymphocyte count under 0.800 G/L as sign of immunosuppression; and a serum albumin concentration under 3.0 g/dL, a creatinine height index under 80% or a weight loss over 10% as signs of ongoing catabolism [17]. Regarding sepsis patients on surgical ICU, an observational study was able to show that more than half of the acute survivors ended up developing CCI. This was associated with older age, an increased rate of hospital-acquired infections and a six-month survival of merely 63% [25].

A possible suggestion for extending the Introduction:

On a cellular level initial emergency myelopoiesis also inducts a primarily beneficial expansion of so-called myeloid-derived suppressor cells (MDSC) [1,2]. However, a prolonged expansion of these MDSCs promotes the suppression of adaptive immunity and the evolvement of chronic inflammation [3–5]. The concomitant tissue damage of trauma, major surgery or sepsis with the release of damage associate molecular patterns (DAMPs) can amplify the above mentioned [6,7]. Even mere muscle wasting – itself triggered by the ongoing inflammation – has been shown to propagate systemic inflammation through liberation of mitochondria derived DAMPs [8,9]. Monocyte paralysis with reduced phagocytosis and HLA-DR expression as well as a reduced T-cell proliferation with elevated expression of suppressor molecules (e.g. programmed death ligand – 1; PDL-1) are only a few of the known inhibitory results, lastly predisposing for recurrent infections and therefore feeding this viscous cycle [10–13].

  1. Manz, M.G.; Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 2014, 14, 302–14, doi:10.1038/nri3660.
  2. Gabrilovich, D.I.; Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009, 9, 162–174, doi:10.1038/nri2506.
  3. Mathias, B.; Delmas, A.L.; Ozrazgat-Baslanti, T.; Vanzant, E.L.; Szpila, B.E.; Mohr, A.M.; Moore, F.A.; Brakenridge, S.C.; Brumback, B.A.; Moldawer, L.L.; et al. Human Myeloid-derived Suppressor Cells are Associated With Chronic Immune Suppression After Severe Sepsis/Septic Shock. Ann. Surg. 2017, 265, 827–834, doi:10.1097/sla.0000000000001783.
  4. Cuenca, A.G.; Delano, M.J.; Kelly-Scumpia, K.M.; Moreno, C.; Scumpia, P.O.; LaFace, D.M.; Heyworth, P.G.; Efron, P.A.; Moldawer, L.L. A Paradoxical Role for Myeloid-Derived Suppressor Cells in Sepsis and Trauma. Mol. Med. 2010, 17, 281–292, doi:10.2119/molmed.2010.00178.
  5. Loftus, T.J.; Mohr, A.M.; Moldawer, L.L. Dysregulated myelopoiesis and hematopoietic function following acute physiologic insult. Curr. Opin. Hematol. 2018, 25, 37–43, doi:10.1097/moh.0000000000000395.
  6. Yamanouchi, S.; Kudo, D.; Yamada, M.; Miyagawa, N.; Furukawa, H.; Kushimoto, S. Plasma mitochondrial DNA levels in patients with trauma and severe sepsis: time course and the association with clinical status. J. Crit. Care 2013, 28, 1027–31, doi:10.1016/j.jcrc.2013.05.006.
  7. Timmermans, K.; Kox, M.; Scheffer, G.J.; Pickkers, P. Danger in the Intensive Care Unit: Damps in Critically Ill Patients. SHOCK 2016, 45, 108–116, doi:10.1097/shk.0000000000000506.
  8. Picca, A.; Lezza, A.M.S.; Leeuwenburgh, C.; Pesce, V.; Calvani, R.; Bossola, M.; Manes-Gravina, E.; Landi, F.; Bernabei, R.; Marzetti, E. Circulating Mitochondrial DNA at the Crossroads of Mitochondrial Dysfunction and Inflammation During Aging and Muscle Wasting Disorders. Rejuvenation Res. 2018, 21, 350–359, doi:10.1089/rej.2017.1989.
  9. Puthucheary, Z.A.; Rawal, J.; McPhail, M.; Connolly, B.; Ratnayake, G.; Chan, P.; Hopkinson, N.S.; Padhke, R.; Dew, T.; Sidhu, P.S.; et al. Acute Skeletal Muscle Wasting in Critical Illness. JAMA 2013, 310, 1591–1600, doi:10.1001/jama.2013.278481.
  10. Hawkins, R.B.; Raymond, S.L.; Stortz, J.A.; Horiguchi, H.; Brakenridge, S.C.; Gardner, A.; Efron, P.A.; Bihorac, A.; Segal, M.; Moore, F.A.; et al. Chronic Critical Illness and the Persistent Inflammation, Immunosuppression, and Catabolism Syndrome. Front. Immunol. 2018, 9, 1511, doi:10.3389/fimmu.2018.01511.
  11. Stortz, J.A.; Mira, J.C.; Raymond, S.L.; Loftus, T.J.; Ozrazgat-Baslanti, T.; Wang, Z.; Ghita, G.L.; Leeuwenburgh, C.; Segal, M.S.; Bihorac, A.; et al. Benchmarking clinical outcomes and the immunocatabolic phenotype of chronic critical illness after sepsis in surgical intensive care unit patients. J. Trauma Acute Care Surg. 2018, 84, 342–349, doi:10.1097/ta.0000000000001758.
  12. Leijte, G.P.; Rimmelé, T.; Kox, M.; Bruse, N.; Monard, C.; Gossez, M.; Monneret, G.; Pickkers, P.; Venet, F. Monocytic HLA-DR expression kinetics in septic shock patients with different pathogens, sites of infection and adverse outcomes. Crit. Care Lond. Engl. 2020, 24, 110, doi:10.1186/s13054-020-2830-x.
  13. Landelle, C.; Lepape, A.; Voirin, N.; Tognet, E.; Venet, F.; Bohé, J.; Vanhems, P.; Monneret, G. Low monocyte human leukocyte antigen-DR is independently associated with nosocomial infections after septic shock. Intensive Care Med. 2010, 36, 1859–1866, doi:10.1007/s00134-010-1962-x.

 

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This entry is adapted from the peer-reviewed paper 10.3390/jcm9093017

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