|
 
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| REVIEW ARTICLE |
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| Year : 2022 | Volume
: 4
| Issue : 1 | Page : 18 |
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Monitoring the Host Immune Response in Sepsis
Jordi Rello1, Richard R Watkins2
1 Department of Medicine, Universitat Internacional de Catalunya, Barcelona, Spain
2 Department of Medicine, Northeast Ohio Medical University, Rootstown, Ohio, USA
| Date of Submission | 21-Apr-2022 |
| Date of Acceptance | 07-Sep-2022 |
| Date of Web Publication | 02-Nov-2022 |
Correspondence Address:
Dr. Jordi Rello
Passeig Vall d'Hebron, Barcelona 08035
Spain
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/JTCCM-D-22-00013
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 |
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.
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