Systemic Inflammatory Response Syndrome (SIRS)SIRCSSNCT02887274
Application of Stimulated Immune Response Change to Predict Outcome of Patient With Severe Sepsis
An observational study of Systemic Inflammatory Response Syndrome (SIRS) and Sepsis, run by Chang Gung Memorial Hospital at 1 site in Taiwan.
Trial summary
Persistence of a marked compensatory anti-inflammatory innate immune response after an insult is termed immunoparalysis. There is no biomarker available to determine the immune status of patient. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis
- How many people
- 300 participants
- Where
- 1 siteTaiwan
- Study dates
- Jul 2013to Dec 2018
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: The study will be conducted at Kaohsiung Chang Gung Memorial Hospital. All adult patients presenting with sepsis or severe sepsis will be enrolled on admission to medical intensive units (total 34 beds). Sepsis and severe sepsis are defined as American College of Chest Physicians/Society of Critical Care Medicine consensus criteria for sepsis syndromes.
Who may be able to join
- Severe sepsis
- Septic shock
Who cannot join
- Patients are < 18 yrs
- Patients are immunocompromised (treatment with corticosteroids >1 mg/kg equivalent prednisone)
- Bone marrow or organ transplant recipients,
- Leucopenia [white blood cells count< 109/L] or neutropenia [polymorphonuclear granulocyte count <0.5 109/L]
- Hematologic malignancy
Trial locations and contacts
1 site in 1 country.
Taiwan1 site, 1 recruiting
- Recruiting
Chang Gung Memorial Hospital
Kaohsiung City
Cheryl Huang, Bachelor, 886 077317123 ext. 2639, cheryl60286@gmail.com
About this study
Persistence of a marked compensatory anti-inflammatory innate immune response after an insult is termed immunoparalysis. There is no biomarker available to determine the immune status of patient. Thus, the need for early and definite diagnosis of immune status of patient with sepsis, as well as the identification of patients at risk of evolving with severe organ dysfunctions, is crucial.
Most important of all, speed is the key to survival. Therefore, it of crucial importance to identify which patient characteristic determines the poor prognosis. Early intervention can improve the prognosis. Investigators foresee an urgent need to identify predictors for mortality in severe sepsis, including clinical factors or immune status. Recently, the PIRO model has been proposed as a way of stratifying septic patients according to their Predisposing condition, the severity of Infection, the Response to therapy and the degree of Organ dysfunction. The immune status may be associated with above model. However, there is paucity data addressing this issue. In this study, investigators will also analyze the progression of patient condition during treatment and the associated immune status change. In the future, Investigators hope the determination of immune status may contribute to this model of classification rather than just being used as prognostic markers. Despite the advances in the knowledge of the basic processes that trigger and sustain the systemic inflammatory response in sepsis, the search for a "magic bullet" to treat this syndrome has been frustrating. The incidence of severe sepsis and septic shock still remains quite high, as does its mortality, which has decreased very little over the past decades.
Read the detailed description
Binding of TLRs to epitopes on microorganisms stimulates intracellular signaling, increasing transcription of proinflammatory molecules such as tumor necrosis factor α (TNF-α) and interleukin-1β, as well as antiinflammatory cytokines such as interleukin-10. Macrophage dysfunction, as a component of immune suppression seen during trauma and sepsis, appears to be one of the contributing factors to morbidity and mortality. Critically ill patients demonstrating prolonged, severe reductions in monocyte HLA-DR expression or ex vivo tumor necrosis factor alpha production are at high risk for nosocomial infection and death. Most septic patients have decreasing cytokine levels at the time of treatment, suggesting a transition from a hyperinflammatory to a hypo-inflammatory state. Immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in multiple organ dysfunction syndrome. Whole-blood ex vivo TNF alpha response is a promising marker for monitoring this condition. Investigators call it as "stimulated immune response". Toll-like receptors (TLRs) are a recently described family of immune receptors involved in the recognition of pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide (LPS) is present in the outer membranes of Gram-negative bacteria and has been demonstrated to be responsible for the development of GNB-associated sepsis. Recognition of bacterial LPS by macrophages is a key component of host defense against infection by Gram-negative bacteria. A monocyte which encounters LPS should vigorously produce proinflammatory cytokines regardless of whether or not it has been exposed to LPS in the past. Sepsis induces suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. Whether further ground can be gained by manipulating innate immunity is an important question waiting to be answered. Several strategies to enhance innate immunity have been tried in normal subjects, including using granulocyte colony-stimulating factor to increase the number and activation state of circulating neutrophils, and IFN-γ to enhance macrophage dependent immunity. Investigators will use this characteristic to assess patient's stimulated immune response. In addition, differences in the nature of the initiating agent causing sepsis and the lack of co-morbidities in the animal models probably contribute to some of the differences in animal studies and clinical trials in sepsis. Investigators need to address these important issues and work toward promoting immunologic homeostasis in the ICU. Here investigators performed a systematic study aimed at evaluating
- The diagnostic accuracy of stimulated immune response for predicting mortality;
- Whether trend change in stimulated immune response more useful for above prediction;
- Whether stimulated immune response can predict patients at risk of evolving with severe organ dysfunctions (the presence or development of severe sepsis or progression of organ dysfunctions within a 72-hr time period from biomarker checked along with treatment)
- Conditions
- Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic Shock, Multiple Organ Failure
- Keywords
- Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic shock, Multiple organ failure
- Medical subject headings
- Systemic Inflammatory Response Syndrome, Sepsis, Shock, Septic, Multiple Organ Failure
What is being measured
The primary outcome is the main question the study is designed to answer.
The diagnostic accuracy of stimulated immune response for predicting mortality
Measured: 4 weeks, up to 24 weeks
Secondary outcomes (1)
Whether trend change in stimulated immune response more useful for prediction mortality
Measured: 4 weeks, up to 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Sep 2016 (estimated)
- Study startJul 2013
- Primary completionDec 2018 (estimated)
- Study completionDec 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (10)Papers the sponsor has linked to this study.
- Other trials for Systemic Inflammatory Response Syndrome (SIRS)Studies of the same condition, open and under way.
- More trials run by Chang Gung Memorial HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Chang Gung Memorial Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Wen-Feng Fang, M.D, Principal investigator, Chang Gung Memorial Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02887274
- Sponsor's protocol ID
- CMRPG8B1073
- Acronym
- SIRCSS
- Status last verified
- Aug 2018
- First submitted
- 15 Aug 2016
- Last updated
- 7 Dec 2018
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Undecided
Publications
Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am. 2008 Jun;55(3):647-68, xi. doi: 10.1016/j.pcl.2008.02.009.
PubMed 18501759Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, Carcillo JA. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011 Mar;37(3):525-32. doi: 10.1007/s00134-010-2088-x. Epub 2010 Dec 10.
PubMed 21153402Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant. 1996 Feb;11(2):293-9. doi: 10.1093/oxfordjournals.ndt.a027256.
PubMed 8700363Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care. 2002 Dec;6 Suppl 3(Suppl 3):S1-18. doi: 10.1186/cc1860. Epub 2002 Dec 5.
PubMed 12720570Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008 Dec;29(4):605-16, vii. doi: 10.1016/j.ccm.2008.08.001.
PubMed 18954696Sakr Y, Burgett U, Nacul FE, Reinhart K, Brunkhorst F. Lipopolysaccharide binding protein in a surgical intensive care unit: a marker of sepsis? Crit Care Med. 2008 Jul;36(7):2014-22. doi: 10.1097/CCM.0b013e31817b86e3.
PubMed 18552695Shiramizo SC, Marra AR, Durao MS, Paes AT, Edmond MB, Pavao dos Santos OF. Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle in a hospital setting. PLoS One. 2011;6(11):e26790. doi: 10.1371/journal.pone.0026790. Epub 2011 Nov 3.
PubMed 22073193Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. 2007 Apr;35(4):1105-12. doi: 10.1097/01.CCM.0000259463.33848.3D.
PubMed 17334251Phua J, Koh Y, Du B, Tang YQ, Divatia JV, Tan CC, Gomersall CD, Faruq MO, Shrestha BR, Gia Binh N, Arabi YM, Salahuddin N, Wahyuprajitno B, Tu ML, Wahab AY, Hameed AA, Nishimura M, Procyshyn M, Chan YH; MOSAICS Study Group. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. BMJ. 2011 Jun 13;342:d3245. doi: 10.1136/bmj.d3245.
PubMed 21669950Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. doi: 10.1097/01.CCM.0000050454.01978.3B.
PubMed 12682500
Study at a glance
From the registry record, last updated by the sponsor on 7 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Application of Stimulated Immune Response Change to Predict Outcome of Patient With Severe Sepsis
- ClinicalTrials.gov ID
- NCT02887274
- Acronym / sponsor ID
- SIRCSS / CMRPG8B1073
- Conditions
- Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic Shock, Multiple Organ Failure
- Keywords
- Systemic Inflammatory Response Syndrome (SIRS), Sepsis, Severe Sepsis, Septic shock, Multiple organ failure
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- Chang Gung Memorial HospitalUniversity, hospital or other
- Study start
- Jul 2013 (actual)
- Primary completion
- Dec 2018 (estimated)
- Study completion
- Dec 2018 (estimated)
- First posted
- 2 Sep 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Persistence of a marked compensatory anti-inflammatory innate immune response after an insult is termed immunoparalysis. There is no biomarker available to determine the immune status of patient. Thus, the need for early and definite diagnosis of immune status of patient with sepsis, as well as the identification of patients at risk of evolving with severe organ dysfunctions, is crucial.
Most important of all, speed is the key to survival. Therefore, it of crucial importance to identify which patient characteristic determines the poor prognosis. Early intervention can improve the prognosis. Investigators foresee an urgent need to identify predictors for mortality in severe sepsis, including clinical factors or immune status. Recently, the PIRO model has been proposed as a way of stratifying septic patients according to their Predisposing condition, the severity of Infection, the Response to therapy and the degree of Organ dysfunction. The immune status may be associated with above model. However, there is paucity data addressing this issue. In this study, investigators will also analyze the progression of patient condition during treatment and the associated immune status change. In the future, Investigators hope the determination of immune status may contribute to this model of classification rather than just being used as prognostic markers. Despite the advances in the knowledge of the basic processes that trigger and sustain the systemic inflammatory response in sepsis, the search for a "magic bullet" to treat this syndrome has been frustrating. The incidence of severe sepsis and septic shock still remains quite high, as does its mortality, which has decreased very little over the past decades.
Detailed description
Binding of TLRs to epitopes on microorganisms stimulates intracellular signaling, increasing transcription of proinflammatory molecules such as tumor necrosis factor α (TNF-α) and interleukin-1β, as well as antiinflammatory cytokines such as interleukin-10. Macrophage dysfunction, as a component of immune suppression seen during trauma and sepsis, appears to be one of the contributing factors to morbidity and mortality. Critically ill patients demonstrating prolonged, severe reductions in monocyte HLA-DR expression or ex vivo tumor necrosis factor alpha production are at high risk for nosocomial infection and death. Most septic patients have decreasing cytokine levels at the time of treatment, suggesting a transition from a hyperinflammatory to a hypo-inflammatory state. Immunoparalysis is a potentially reversible risk factor for development of nosocomial infection in multiple organ dysfunction syndrome. Whole-blood ex vivo TNF alpha response is a promising marker for monitoring this condition. Investigators call it as "stimulated immune response". Toll-like receptors (TLRs) are a recently described family of immune receptors involved in the recognition of pathogen-associated molecular patterns (PAMPs). Lipopolysaccharide (LPS) is present in the outer membranes of Gram-negative bacteria and has been demonstrated to be responsible for the development of GNB-associated sepsis. Recognition of bacterial LPS by macrophages is a key component of host defense against infection by Gram-negative bacteria. A monocyte which encounters LPS should vigorously produce proinflammatory cytokines regardless of whether or not it has been exposed to LPS in the past. Sepsis induces suppression of macrophage function as determined by a reduction of pro-inflammatory cytokine production upon re-exposure to lipopolysaccharide (LPS) in vitro. Whether further ground can be gained by manipulating innate immunity is an important question waiting to be answered. Several strategies to enhance innate immunity have been tried in normal subjects, including using granulocyte colony-stimulating factor to increase the number and activation state of circulating neutrophils, and IFN-γ to enhance macrophage dependent immunity. Investigators will use this characteristic to assess patient's stimulated immune response. In addition, differences in the nature of the initiating agent causing sepsis and the lack of co-morbidities in the animal models probably contribute to some of the differences in animal studies and clinical trials in sepsis. Investigators need to address these important issues and work toward promoting immunologic homeostasis in the ICU. Here investigators performed a systematic study aimed at evaluating
- The diagnostic accuracy of stimulated immune response for predicting mortality;
- Whether trend change in stimulated immune response more useful for above prediction;
- Whether stimulated immune response can predict patients at risk of evolving with severe organ dysfunctions (the presence or development of severe sepsis or progression of organ dysfunctions within a 72-hr time period from biomarker checked along with treatment)
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- The study will be conducted at Kaohsiung Chang Gung Memorial Hospital. All adult patients presenting with sepsis or severe sepsis will be enrolled on admission to medical intensive units (total 34 beds). Sepsis and severe sepsis are defined as American College of Chest Physicians/Society of Critical Care Medicine consensus criteria for sepsis syndromes.
Key inclusion criteria (2 listed)
- Severe sepsis
- Septic shock
Key exclusion criteria (5 listed)
- Patients are < 18 yrs
- Patients are immunocompromised (treatment with corticosteroids >1 mg/kg equivalent prednisone)
- Bone marrow or organ transplant recipients,
- Leucopenia [white blood cells count< 109/L] or neutropenia [polymorphonuclear granulocyte count <0.5 109/L]
- Hematologic malignancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
The diagnostic accuracy of stimulated immune response for predicting mortality
Time frame: 4 weeks, up to 24 weeks
1 secondary outcome
Whether trend change in stimulated immune response more useful for prediction mortality
Time frame: 4 weeks, up to 24 weeks
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Dec 2018.
- Results publication: PubMed 18501759Frazier WJ, Hall MW. Immunoparalysis and adverse outcomes from critical illness. Pediatr Clin North Am. 2008 Jun;55(3):647-68, xi. doi: 10.1016/j.pcl.2008.02.009.
- Results publication: PubMed 21153402Hall MW, Knatz NL, Vetterly C, Tomarello S, Wewers MD, Volk HD, Carcillo JA. Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome. Intensive Care Med. 2011 Mar;37(3):525-32. doi: 10.1007/s00134-010-2088-x. Epub 2010 Dec 10.
- Results publication: PubMed 8700363Neveu H, Kleinknecht D, Brivet F, Loirat P, Landais P. Prognostic factors in acute renal failure due to sepsis. Results of a prospective multicentre study. The French Study Group on Acute Renal Failure. Nephrol Dial Transplant. 1996 Feb;11(2):293-9. doi: 10.1093/oxfordjournals.ndt.a027256.
- Results publication: PubMed 12720570Vincent JL, Abraham E, Annane D, Bernard G, Rivers E, Van den Berghe G. Reducing mortality in sepsis: new directions. Crit Care. 2002 Dec;6 Suppl 3(Suppl 3):S1-18. doi: 10.1186/cc1860. Epub 2002 Dec 5.
- Results publication: PubMed 18954696Marshall JC, Charbonney E, Gonzalez PD. The immune system in critical illness. Clin Chest Med. 2008 Dec;29(4):605-16, vii. doi: 10.1016/j.ccm.2008.08.001.
- Results publication: PubMed 18552695Sakr Y, Burgett U, Nacul FE, Reinhart K, Brunkhorst F. Lipopolysaccharide binding protein in a surgical intensive care unit: a marker of sepsis? Crit Care Med. 2008 Jul;36(7):2014-22. doi: 10.1097/CCM.0b013e31817b86e3.
- Results publication: PubMed 22073193Shiramizo SC, Marra AR, Durao MS, Paes AT, Edmond MB, Pavao dos Santos OF. Decreasing mortality in severe sepsis and septic shock patients by implementing a sepsis bundle in a hospital setting. PLoS One. 2011;6(11):e26790. doi: 10.1371/journal.pone.0026790. Epub 2011 Nov 3.
- Results publication: PubMed 17334251Nguyen HB, Corbett SW, Steele R, Banta J, Clark RT, Hayes SR, Edwards J, Cho TW, Wittlake WA. Implementation of a bundle of quality indicators for the early management of severe sepsis and septic shock is associated with decreased mortality. Crit Care Med. 2007 Apr;35(4):1105-12. doi: 10.1097/01.CCM.0000259463.33848.3D.
- Results publication: PubMed 21669950Phua J, Koh Y, Du B, Tang YQ, Divatia JV, Tan CC, Gomersall CD, Faruq MO, Shrestha BR, Gia Binh N, Arabi YM, Salahuddin N, Wahyuprajitno B, Tu ML, Wahab AY, Hameed AA, Nishimura M, Procyshyn M, Chan YH; MOSAICS Study Group. Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study. BMJ. 2011 Jun 13;342:d3245. doi: 10.1136/bmj.d3245.
- Results publication: PubMed 12682500Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003 Apr;31(4):1250-6. doi: 10.1097/01.CCM.0000050454.01978.3B.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wen-Feng Fang, M.D principal investigator
Chang Gung Memorial Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Systemic Inflammatory Response Syndrome (SIRS) and Sepsis, run by Chang Gung Memorial Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 7 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Cheryl Huang, Bachelor (886077317123 ext. 2639, cheryl60286@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The diagnostic accuracy of stimulated immune response for predicting mortality (time frame: 4 weeks, up to 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02887274, which also lists 10 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Dec 2018.