• Users Online: 45
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current Articles Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 18

Monitoring the Host Immune Response in Sepsis

1 Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Spain
2 Department of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA

Date of Submission21-Apr-2022
Date of Acceptance07-Sep-2022
Date of Web Publication02-Nov-2022

Correspondence Address:
Dr. Jordi Rello
Passeig Vall d'Hebron, Barcelona 08035
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JTCCM-D-22-00013

Rights and Permissions

Sepsis is a life-threatening condition characterized by immune system dysregulation whose pathophysiology still remains incompletely understood. Better outcomes in patients with sepsis have not been reached despite guidelines updates, development of rapid diagnostic tests, and proper hemodynamic and antimicrobial management. Blood cultures are time-consuming and may delay important therapeutic decisions. Nonculture-based techniques overcome some limitations seen with culture-based techniques with early phenotypic identification of resistance remaining as the cornerstone of optimal diagnosis. A new paradigm has started adjusting preemptive therapy for cytomegalovirus (CMV) infection among kidney transplant patients based on monitoring the host immune response. In this review from a PubMed literature search in adults with sepsis or septic shock, we identified newer tests and highlight some advances in monitoring the host immune response for personalized adjunctive therapy. Monitoring the individual host immune response at the bedside is an unmet clinical need to guide immunomodulatory therapy. The coronavirus disease 2019 pandemic has led to a further understanding of the complex immunopathology of sepsis and opened new avenues for mitigating immune dysregulation. In this review, we discuss current evidence regarding the immune response to sepsis along with challenges and directions for future research.

Keywords: Adjuvant therapy, immunoparalysis, microbiome, personalized medicine, phenotypes

How to cite this article:
Rello J, Watkins RR. Monitoring the Host Immune Response in Sepsis. J Transl Crit Care Med 2022;4:18

How to cite this URL:
Rello J, Watkins RR. Monitoring the Host Immune Response in Sepsis. J Transl Crit Care Med [serial online] 2022 [cited 2023 Mar 31];4:18. Available from: http://www.tccmjournal.com/text.asp?2022/4/1/18/360344

Sepsis is a life-threatening condition characterized by immune system dysregulation whose pathophysiology still remains incompletely understood. Even with progress based on clinical practice guidelines, sepsis remains a leading worldwide cause of mortality and morbidity.[1] Proper volume infusion, early strategies to correct plasma lactate, newer broad-spectrum antibiotics, use of steroids, and immunomodulatory therapy have not been associated with significant improvement of outcomes in patients with septic shock. Progress has been made in nonculture-based techniques, which overcome some limitations seen with culture-based techniques. However, early phenotypic identification of resistance remains a cornerstone of optimal diagnosis. The poor progress with improving outcomes in sepsis is in contrast with other diseases, such as melanoma or breast cancer,[2],[3] where personalized management with immunomodulatory drugs has become standard of care. Monitoring the individual host immune response at the bedside is an unmet clinical need to guide immunomodulatory therapy in sepsis. In this opinion paper, we review current evidence related to the early host immune response to sepsis. In this review from a PubMed literature search in adults with sepsis or septic shock, we identified newer tests and highlighted some advances in monitoring the host immune response for personalized adjunctive therapy. A comprehensive literature search (April 1, 2017 − March 31, 2022) was conducted in PubMed for English-language studies monitoring the immune response for precision medicine in adults with sepsis. Challenges and directions for future research are also discussed.

Novel methods for monitoring and treating sepsis are urgently needed. Precision medicine, which involves rapidly identifying altered biology within an individual and using the findings to guide treatment, is one such approach. The benefits of precision medicine have been actualized in other fields, including oncology, asthma, and chronic obstructive pulmonary disease.[4] However, the complicated pathophysiology of sepsis with its rapidly changing molecular landscape requires therapeutic decisions to be made within hours. Blood cultures are the standard of care for identifying pathogens and their antimicrobial susceptibility. Unfortunately, blood cultures are limited by slow turn-around times and low yield of viable microorganisms. A core problem is a need for broad-spectrum antibiotics in critically ill patients to “get it right the first time” followed by antibiotic de-escalation. Unfortunately, mortality rates for sepsis remain unacceptable high. An example is the 25%−35% mortality rate among ventilated patients with pneumococcal sepsis, which is similar to influenza pneumonia, in spite of effective beta-lactam and macrolide combination therapy for severe Streptococcus pneumoniae sepsis. Therefore, the potential for a new paradigm shift in sepsis monitoring and therapy through precision medicine principles similar to those implemented in oncology has been recognized and should be a priority for further research.[5] The paradigm shift, like in most oncology trials, should focus on an updated design focusing on superiority outcomes instead that in noninferiority.

We recently conducted a comprehensive literature search that evaluated the impact of precision medicine on adults with sepsis, and it has been reported elsewhere.[6] The focus was rapid microbiological approaches in bacterial sepsis, metabolomics, proteomics, and strategies to optimize empirical antimicrobial therapy. Consideration of genetic signatures which could predict which patients with sepsis or acute respiratory distress syndrome (ARDS) would have different responses were also addressed, being an initial signal to stratify the patients in phenotypes and endotypes which would present different responses to steroids or immunomodulatory therapies. Sepsis host response is dynamic and the immune response is evolving. For the purposes of bedside management, this article has focused on the early response. Monitoring methods and findings may be different in the long-term follow-up of a specific patient.

The most recent consensus on sepsis defined it as the recognition that the patients' immune system becomes dysregulated in response to an infection, leading to a subsequent clinical deterioration due to an aberrant immune activation.[7] This principle has already inspired personalized preemptive cytomegalovirus (CMV) therapy among kidney transplant patients based on early cellular immunologic monitoring. Indeed, recent advances using CMV cell-mediated immune assays have been used for delineating preemptive anti-CMV strategies,[8] reducing side effects and costs due to different therapeutic personalized prescriptions.

Moreover, a 23-mRNA response test (IntelliSept test, Cytovale, San Francisco, USA) has been described to predict bacterial infections in patients with suspected sepsis.[9] Another novel rapid diagnostic platform is InSep™ (Inflammatix, Inc., Burlingame, USA). Using a 29-mRNA panel, this set determines the likelihood of bacterial infection compared to viral infection, and the risk of physiologic decompensation.[10] The investigators also showed the biological plausibility of the final chosen 29-mRNA set, and a follow-up prospective clinical study is underway.

The respiratory and gut microbiome play an active role in modulating the host immune response to infection.[11] Different outcomes have been reported in children and infants with respiratory syncytial viral (RSV) bronchiolitis depending on the concomitant nasal or oropharyngeal flora. Outcomes were different if Staphylocccus aureus, Haemophilus influenzae, S. Pneumoniae, or other organisms, were colonizers. This interaction between the RSV and bacterial host microbiota illustrates the complexity between genetic-mediated host immunologic reaction, organism virulence, and accompanying microbiota, with many opportunities for intervention with immunomodulatory agents or probiotics under early monitoring.[12]

The early stages of sepsis are characterized by a wide array of cytokines and mediators produced by the host immune response. Identifying how these factors lead to immune dysfunction could have important diagnostic and therapeutic implications. In a pilot study, Beltrán-García et al. measured cytokines, immune modulators, and other endothelial mediators in patients admitted to a single intensive care unit in Spain with community-onset sepsis (n = 10) or septic shock (n = 15), along with noninfected control patients (n = 5).[13] They found that the innate immune system attempts to counteract infection, likely through neutrophils. The adaptive immune system is not fully activated, and immunosuppressive responses and pro-coagulation signals are active in patients with septic shock. Furthermore, the highest levels of interleukin (IL)-6 and pyroptosis-related cytokines (IL-18 and IL-1α) were found with septic shock, which correlated with D-dimer levels. Endothelial function is likely affected during septic shock, which was demonstrated by the overexpression of adhesion molecules s-ICAM1 and E-Selectin. While influenza infection induces the characteristic innate response in both severe and mild ill patients, severe respiratory failure is characterized by early production of T-helper 1 (Th1) and Th17 cytokines, which are associated with cell-mediated immunity.[14] IL-l2p70, IL-15, and IL-6 represent a hallmark of high severity,[15],[16] whereas PaO2 and IL-8 had a significant inverse relation. Further investigation to elucidate when these cytokines and mediators are beneficial or detrimental is warranted. Thus, monitoring changes in the clinical signatures of immune cells is promising from a precision medicine standpoint as it represents a way to detect an individual's risk of immunosuppression, predict prognosis, and suggest a new therapeutic pathway to control the immune dysregulation present in sepsis.

The coronavirus disease 2019 pandemic has led to a more nuanced understanding of the immunopathology of sepsis.[17],[18],[19],[20],[21] In severe cases, there is an overabundance of circulating immature monocytes, neutrophils, and myeloid progenitors that produce excessive amounts of inflammatory substances leading to vascular permeability and organ damage.[22] In contrast, macrophages that ordinarily reside in the lungs and play an important role in tissue homeostasis and repair are often depleted.[23] Several risk factors for progressing to severe disease and sepsis have been identified, including age > 65 years, male sex, racial minorities, diabetes, hypertension, obesity, and chronic kidney disease.[24] Finally, the observation that when anti-inflammatory agents are used too early or late in the course of illness, there is a trend toward harm underscores the importance of determining where an individual patient is in the continuum of sepsis.[25],[26]

In summary, these results may anticipate an era, in which physicians implement a strategy of monitoring patients with sepsis or risk of septic shock at the bedside in a personalized way and guide the decision to start immunomodulatory therapies. Increasing the current application of immunoassay methods has advantages and disadvantages that need to be balanced. This theranostic approach for sepsis should become a core management paradigm in the future. Indeed, early identification of hyperinflammation (high ferritin) and immunoparalysis (low HLA-DR) is already possible and the combination of both is associated with high mortality rates.[27],[28] The development of techniques able to monitor the cellular host response as an early diagnostic test for patients at risk of septic shock is another urgent unmet clinical need. These monitoring tests should stratify patients based on their immune response in a personalized way. Whereas sepsis is characterized by an aberrant immune response, a research gap exists on this issue and should be a priority for further investigation. In our opinion, fast bedside identification is imperative that differentiates patients with only infection from those at risk for developing ARDS and septic shock. The diversity in specific host response immune dysregulations should be monitored and considered in the design of personalized advances in sepsis therapy.

Financial support and sponsorship

None declared.

Conflicts of interest

There are no conflicts of interest.

  References Top

Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a global health priority – A WHO resolution. N Engl J Med 2017;377:414-7.  Back to cited text no. 1
Loibl S, Poortmans P, Morrow M, Denkert C, Curigliano G. Breast cancer. Lancet 2021;397:1750-69.  Back to cited text no. 2
Waks AG, Winer EP. Breast cancer treatment: A review. JAMA 2019;321:288-300.  Back to cited text no. 3
Shah FA, Meyer NJ, Angus DC, Awdish R, Azoulay É, Calfee CS, et al.. A research agenda for precision medicine in sepsis and acute respiratory distress syndrome: An official American Thoracic Society Research Statement. Am J Respir Crit Care Med 2021;204:891-901.  Back to cited text no. 4
Rello J, van Engelen TS, Alp E, Calandra T, Cattoir V, Kern WV, et al. Towards precision medicine in sepsis: A position paper from the European Society of Clinical Microbiology and infectious diseases. Clin Microbiol Infect 2018;24:1264-72.  Back to cited text no. 5
Watkins RR, Bonomo RA, Rello J. Managing sepsis in the era of precision medicine: Challenges and opportunities. Expert Rev Anti Infect Ther 2022;20:871-80.  Back to cited text no. 6
Evans L, Rhodes A, Alhazzani W, Antonelli M, Coopersmith CM, French C, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Crit Care Med 2021;49:e1063-143.  Back to cited text no. 7
Manuel O, Avery RK. Update on cytomegalovirus in transplant recipients: New agents, prophylaxis, and cell-mediated immunity. Curr Opin Infect Dis 2021;34:307-13.  Back to cited text no. 8
Crawford K, DeWitt A, Brierre S, Caffery T, Jagneaux T, Thomas C, et al. Rapid biophysical analysis of host immune cell variations associated with sepsis. Am J Respir Crit Care Med 2018;198:280-2.  Back to cited text no. 9
He YD, Wohlford EM, Uhle F, Buturovic L, Liesenfeld O, Sweeney TE. The optimization and biological significance of a 29-host-immune-mRNA panel for the diagnosis of acute infections and sepsis. J Pers Med 2021;11:735.  Back to cited text no. 10
Rello J, Schrenzel J, Tejo AM. New insights into pneumonia in patients on prolonged mechanical ventilation: Need for a new paradigm addressing dysbiosis. J Bras Pneumol 2021;47:e20210198.  Back to cited text no. 11
Luna PN, Hasegawa K, Ajami NJ, Espinola JA, Henke DM, Petrosino JF, et al.. The association between anterior nares and nasopharyngeal microbiota in infants hospitalized for bronchiolitis. Microbiome 2018;6:2.  Back to cited text no. 12
Beltrán-García J, Osca-Verdegal R, Jávega B, Herrera G, O'Connor JE, García-López E, et al. Characterization of early peripheral immune responses in patients with sepsis and septic shock. Biomedicines 2022;10:525.  Back to cited text no. 13
Bermejo-Martin JF, Ortiz de Lejarazu R, Pumarola T, Rello J, Almansa R, Ramírez P, et al. Th1 and Th17 hypercytokinemia as early host response signature in severe pandemic influenza. Crit Care 2009;13:R201.  Back to cited text no. 14
Bermejo-Martin JF, Martin-Loeches I, Rello J, Antón A, Almansa R, Xu L, et al. Host adaptive immunity deficiency in severe pandemic influenza. Crit Care 2010;14:R167.  Back to cited text no. 15
Paquette SG, Banner D, Zhao Z, Fang Y, Huang SS, Leόn AJ, et al. Interleukin-6 is a potential biomarker for severe pandemic H1N1 influenza A infection. PLoS One 2012;7:e38214.  Back to cited text no. 16
Barrasa H, Rello J, Tejada S, Martín A, Balziskueta G, Vinuesa C, et al. SARS-CoV-2 in Spanish Intensive Care Units: Early experience with 15-day survival in Vitoria. Anaesth Crit Care Pain Med 2020;39:553-61.  Back to cited text no. 17
Martinez-Reviejo R, Tejada S, Cipriano A, Karakoc HN, Manuel O, Rello J. Solid organ transplantation from donors with recent or current SARS-CoV-2 infection: A systematic review. Anaesth Crit Care Pain Med 2022;41:101098.  Back to cited text no. 18
Frat JP, Thille AW, Arrivé F, Lujan M, Rello J. What is the most adequate non-invasive oxygen support for acute hypoxaemic respiratory failure due to COVID-19? Anaesth Crit Care Pain Med 2021;40:100909.  Back to cited text no. 19
Rello J, James A, Reyes LF. Post-acute COVID-19 syndrome (PACS): A public health emergency. Anaesth Crit Care Pain Med 2021;40:100882.  Back to cited text no. 20
Martinez-Reviejo R, Tejada S, Adebanjo GAR, Chello C, Machado MC, Parisella FR, et al.. Varicella-Zoster virus reactivation following severe acute respiratory syndrome coronavirus 2 vaccination or infection: New insights. Eur J Intern Med 2022;104:73-9.  Back to cited text no. 21
Schulte-Schrepping J, Reusch N, Paclik D, Baßler K, Schlickeiser S, Zhang B, et al.. Severe COVID-19 is marked by a dysregulated myeloid cell compartment. Cell 2020;182:1419-40.e23.  Back to cited text no. 22
Delorey TM, Ziegler CG, Heimberg G, Normand R, Yang Y, Segerstolpe Å, et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature 2021;595:107-13.  Back to cited text no. 23
Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al.. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430-6.  Back to cited text no. 24
Merad M, Blish CA, Sallusto F, Iwasaki A. The immunology and immunopathology of COVID-19. Science 2022;375:1122-7.  Back to cited text no. 25
Rello J, Belliato M, Dimopoulos MA, Giamarellos-Bourboulis EJ, Jaksic V, Martin-Loeches I, et al. Update in COVID-19 in the Intensive Care Unit from the 2020 HELLENIC Athens International Symposium. Anaesth Crit Care Pain Med 2020;39:723-30.  Back to cited text no. 26
Valenzuela-Méndez B, Valenzuela-Sánchez F, Rodríguez-Gutiérrez JF, Bohollo-de-Austria R, Estella Á, Martínez-García P, et al. Plasma levels of mid-regional proadrenomedullin accurately identify H1N1pdm09 influenza virus patients with risk of intensive care admission and mortality in the emergency department. J Pers Med 2022;12:84.  Back to cited text no. 27
Valenzuela-Méndez B, Valenzuela-Sánchez F, Rodríguez-Gutiérrez JF, Bohollo-de-Austria R, Estella Á, Martínez-García P, et al. Host response dysregulations amongst adults hospitalized by influenza A H1N1 virus pneumonia: A prospective multicenter cohort study. Eur J Intern Med 2022 Oct;104:89-97. doi: 10.1016/j.ejim.2022.07.010. Epub ahead of print.  Back to cited text no. 28


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article

 Article Access Statistics
    PDF Downloaded157    
    Comments [Add]    

Recommend this journal