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Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.

Name: Αlpha¹ Rigor Record — Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.
Item: Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.
Rating: 96
Author: Αlpha¹

Giamarellos-Bourboulis EJ, Kotsaki A, Kotsamidi I, Efthymiou A, Koutsoukou V, Ehler J, Paridou A, Frantzeskaki F, Müller MCA, Pickkers P, Meylan S, Nikolopoulos I, Lupse M, Gavala A, Vlachogianni G, Solomonidi N, Alevizou A, Kondili E, Antoniadou E, Nakou M, Markou N, Hatziagelaki E, Prekates A, Komnos A, Bakkerus L, Slim MA, Dalekos GN, Karapanagiotou A, Ktena S, De Pascale G, Koulouras V, Psarrakis C, Massa E, Dakou K, Pazvanti C, Ioakeimidou A, Tsangaris I, Antonakos N, Vlaar APJ, Anisoglou S, Calandra T, Papaioannou V, Myrianthefs P, Patrani M, Alamanos I, Antonelli M, van der Meer JWM, van der Poll T, Wiersinga WJ, Ntaganou M, Gkeka E, Bauer M, Mouloudi E, Netea MG, ImmunoSep Study Group

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Αlpha¹ Rigor Review — 3.25★ (Adequate), 0 critical, 3 high issues for “Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.”

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Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · August 15, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

3.25 / 5

Adequate — real issues to address

Interventional Study

Critical

High-priority

How this rating was calculated▸

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
No data or code availability links were detected to verify.

Problems surfaced5 types

Numerical inconsistencies1

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Overstated conclusions3

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed
Conclusions only partially backed by the presented evidenceAssessed

Reporting gaps1

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

This Αlpha¹ Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted randomized clinical trial with rigorous design, clear reporting of ethics, and transparent statistical analysis. The main weakness is the vague data sharing statement, which lacks a concrete access mechanism. Minor copyedit issues and a small internal discrepancy in a secondary endpoint count do not undermine the overall robustness.

Both reviewers classified the study as interventional, and this was adopted. The evaluation covered all eight dimensions; non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification covered only a subset of tests (those with test statistics and df or effect estimates with CIs); exact p-values and threshold-only p-values were not machine-verified. The integrity check flagged a minor internal contradiction in a secondary endpoint count (51 vs 52 patients), which is noted but does not affect the primary endpoint.

10 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

Recomputed 10 tests: 10 consistent, 0 inconsistent; 10 via agent-written checks.

1 integrity concern flagged (0 high).

Reporting

Eight Dimensions7 pass · 1 warn

The introduction cites prior RCTs that failed due to heterogeneity, and references recent data on immune stratification using ferritin and HLA-DR. The rationale for targeting macrophage activation-like syndrome and immunoparalysis is well-supported by prior studies. Limitations of prior work are implicitly addressed by the precision design, though not explicitly detailed.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study clearly establishes its scientific premise by citing prior work on sepsis heterogeneity and the need for precision immunotherapy, and it explains how the current study addresses limitations of previous trials.

Evidence

direct quote[Introduction, paragraph 1]

“Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain.”

paraphrase[Introduction, paragraph 1]

“As such, a precision approach to immunotherapy in sepsis may be necessary, relying on rapid, accurate classification of the immune dysregulation using biomarkers.”

paraphrase[Discussion, paragraph 2]

“First, precision immunotherapy for severe infections has been increasingly considered since the COVID-19 pandemic: a strategy of anakinra treatment guided by soluble urokinase plasminogen activator receptor concentrations as a biomarker of lung hyperinflammation has been registered by the European Medicines Agency and for Emergency Use Authorization by the US Food and Drug Administration for treatment of patients with COVID-19 with pneumonia.”

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise by citing prior research on sepsis heterogeneity and immunotherapy, and provides a logical rationale for the precision approach.

Evidence

paraphrase[Introduction, paragraph 1]

“Many randomized clinical trials (RCTs) studied immunotherapies but failed to demonstrate an improvement in outcome. This is likely related to the heterogeneity of immune dysregulation, which varies from hyperinflammation to immunosuppression.”

paraphrase[Introduction, paragraph 2]

“Recent data suggest that patients with sepsis with shock can be classified by using blood ferritin concentrations and the expression of the human leukocyte antigen (HLA) DR on monocytes into 3 strata of immune activation.”

paraphrase[Introduction]

“The paper does not explicitly discuss limitations of prior research, but the precision approach is presented as a solution to the heterogeneity problem.”

Randomization was computer-generated with 1:1 allocation, and blinding was double-blind with unblinded pharmacists. A priori sample size calculation was provided. Inclusion/exclusion criteria were pre-specified. Outlier handling is addressed through the analysis population and missing data imputation. Controls are the placebo group. Independent replication is not applicable for a single pivotal trial.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study design is robust, detailing randomization, blinding, inclusion/exclusion criteria, and a power analysis. It is a well-conducted clinical trial.

Evidence

paraphrase[Methods, Randomization and Allocation, paragraph 1]

“Enrolled patients were randomized 1:1 into groups: (1) intervention strategy: standard care and precision immunotherapy, and (2) control strategy: standard care and placebo immunotherapy, using separate randomization per study site with the aid of a computer-generated sequencing ( Figure 1 ).”

paraphrase[Methods, Randomization and Allocation, paragraph 3]

“Except for the unblinded pharmacists, the investigators, attending physicians, nursing personnel, and participants remained blinded to the assigned intervention.”

paraphrase[Methods, Sample Size Calculation, paragraph 1]

“The study was powered for the primary end point anticipated to be attained in 40% in the intervention group and in 20% in the control group. At the significance level of 5% and a power of 90%, the calculation yielded 117 patients per trial group. Considering a dropout rate of about 15%, 280 were needed.”

PASSReviewer 2· 95% conf

The trial design is rigorous with clear randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

paraphrase[Methods, Randomization and Allocation]

“Except for the unblinded pharmacists, the investigators, attending physicians, nursing personnel, and participants remained blinded to the assigned intervention.”

paraphrase[Methods, Sample Size Calculation]

“At the significance level of 5% and a power of 90%, the calculation yielded 117 patients per trial group. Considering a dropout rate of about 15%, 280 were needed.”

Sex is reported for both groups, and age is reported as mean (SD). Demographics include race/ethnicity and comorbidities. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing are not applicable for human subjects.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study adequately reports key demographic and health characteristics of the human participants, including age, sex, and comorbidities.

Evidence

direct quote[Abstract, Results]

“mean [SD] age, 70 [13] years; 93 females [33.7%]”

direct quote[Table 1]

“Table 1. Baseline Characteristics of Participants in the ImmunoSep Trial”

direct quote[Table 1]

“Race and ethnicity a African 1 (0.8) 0 Middle Eastern 1 (0.8) 0 White 129 (98.5) 145 (100.0)”

PASSReviewer 2· 95% conf

Sex, age, and demographics are reported; species/strain and housing are not applicable for a human trial.

Evidence

direct quote[Results, Patients]

“276 patients (mean [SD] age,70 [13] years; 93 females [33.7%]) in the primary analysis population”

direct quote[Table 1]

“Race and ethnicity a African 1 (0.8) 0 Middle Eastern 1 (0.8) 0 White 129 (98.5) 145 (100.0)”

The protocol was approved by ethics committees and IRBs, informed consent was obtained, and compliance with GCP, EU Directive, and GDPR is stated. The trial is registered.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study reports explicit ethical approval from named ethics committees and institutional review boards, along with informed consent procedures and adherence to relevant regulations.

Evidence

direct quote[Methods, Trial Design, paragraph 2]

“The study protocol and addenda were approved by the ethics committees and institutional review boards pursuant to country regulations (Supplement 1, eTable 2 in Supplement 2).”

paraphrase[Methods, Trial Design, paragraph 2]

“The study was governed by the international standards for Good Clinical Practice, the Directive 2001/ 20/EC for Clinical trials and the General Data Protection Regulation 679/2016.”

paraphrase[Methods, Participants, paragraph 1]

“Prior to blood sampling and enrollment, written informed consent was provided by study participants or first-degree relatives if patients could not consent.”

PASSReviewer 2· 95% conf

Ethics approval, informed consent, and regulatory compliance are adequately reported.

Evidence

direct quote[Methods, Trial Design]

“The study protocol and addenda were approved by the ethics committees and institutional review boards pursuant to country regulations”

paraphrase[Methods, Participants]

“Prior to blood sampling and enrollment, written informed consent was provided by study participants or first-degree relatives if patients could not consent.”

paraphrase[Methods, Trial Design]

“The study was governed by the international standards for Good Clinical Practice, the Directive 2001/20/EC for Clinical trials and the General Data Protection Regulation 679/2016.”

Anakinra and recombinant human interferon gamma are named with manufacturers and doses. Statistical software (SPSS) is identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a clinical trial without wet-lab assays.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study adequately identifies the investigational products (anakinra and recombinant human interferon gamma) with their manufacturers and dosages, and mentions the software used for statistical analysis.

Evidence

paraphrase[Methods, Randomization and Allocation, paragraph 2]

“In the precision immunotherapy group, the IV injection was 200 mg of anakinra (Kineret, Swedish Orphan BioVitrum) dissolved in 0.9% of normal saline to a final vol- ume of 20 mL for patients with macrophage activation–like syndrome; and the subcutaneous injection was 100 μg of recombinant human interferon gamma (Imukin, Clinigen) to a final volume of 0.5 mL for patients with sepsis-induced immunoparalysis.”

direct quote[Methods, Statistical Analyses, paragraph 3]

“Analysis was conducted using SPSS version 29.0.2.0 (IBM).”

PASSReviewer 2· 95% conf

Investigational products are identified with manufacturer and dose; software is identified.

Evidence

paraphrase[Methods, Randomization and Allocation]

“the IV injection was 200 mg of anakinra (Kineret, Swedish Orphan BioVitrum) dissolved in 0.9% of normal saline to a final volume of 20 mL for patients with macrophage activation–like syndrome; and the subcutaneous injection was 100 μg of recombinant human interferon gamma (Imukin, Clinigen) to a final volume of 0.5 mL for patients with sepsis-induced immunoparalysis.”

direct quote[Methods, Statistical Analyses]

“Analysis was conducted using SPSS version 29.0.2.0 (IBM).”

The primary analysis used Fisher exact test and Mantel-Haenszel for ORs. Exact p-values are reported. Effect sizes with 95% CIs are provided. Data presentation includes per-group n and CIs. Mathematical plausibility is not applicable for large-N continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The statistical analysis is well-described, naming tests, reporting exact p-values, and providing effect sizes with confidence intervals. Data presentation is appropriate for a clinical trial.

Evidence

direct quote[Methods, Statistical Analyses, paragraph 2]

“Comparisons for primary and all secondary end points were calculated by the Fisher exact test; the odds ratios (ORs) and 95% CIs by the Mantel-Haenszel test. A confirmatory model for the primary end point included a stepwise logistic regres- sion for the proportion who achieved at least a 1.4-point de- crease in SOFA score by day 9 as the dependent variable, with the blinded intervention, baseline CCI, SOFA score, and study site as the independent variables. Kaplan-Meier and Cox re- gression analyses reporting hazard ratios (HRs) with 95% CIs were used to illustrate survival. The time to reversal of SIDF was compared by Cox regression analysis. Comparisons of the state of infection by day 15—defined as resolved, intermedi- ate, treatment failure, or superinfection—were conducted by ordinal regression analysis.”

direct quote[Results, Primary End Point, paragraph 1]

“The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002).”

direct quote[Methods, Statistical Analyses, paragraph 3]

“Analysis was conducted using SPSS version 29.0.2.0 (IBM).”

PASSReviewer 2· 95% conf

Statistical tests are named, p-values are exact, effect sizes with CIs are reported, and software is identified.

Evidence

direct quote[Methods, Statistical Analyses]

“Comparisons for primary and all secondary end points were calculated by the Fisher exact test; the odds ratios (ORs) and 95% CIs by the Mantel-Haenszel test.”

paraphrase[Results, Primary End Point]

“46 of 131 patients (35.1%) in the precision immunotherapy group and 26 of 145 patients (17.9%) in the placebo group ( P = .002; Table 2 and Figure 2 A).”

direct quote[Table 2]

“17.2 (6.8 to 27.2) 2.48 (1.42 to 4.32) .002”

The paper states 'Data Sharing Statement: See Supplement 4.' This is vague and does not specify a concrete access route. For a clinical trial, managed access is acceptable, but the statement lacks details on mechanism or conditions. No code sharing is mentioned.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 70% conf

A data availability statement is present, but it refers to a supplement which is not provided, making the actual access mechanism unclear. No code sharing is mentioned.

Evidence

direct quote[ARTICLE INFORMATION, Data Sharing Statement]

“Data Sharing Statement: See Supplement 4.”

absence[N/A]

Not found in paper

WARNReviewer 2· 80% conf

A data sharing statement is present but vague; no repository deposit or accession numbers are provided.

Evidence

direct quote[End of article]

“Data Sharing Statement: See Supplement 4.”

Trial registration is provided (NCT04990232). CONSORT is followed. All prespecified outcomes are reported. Limitations are discussed. Conclusions are proportional. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The study demonstrates high reporting transparency, including trial registration, adherence to CONSORT guidelines, discussion of limitations, and comprehensive funding/COI statements.

Evidence

direct quote[Abstract, Trial Registration]

“TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04990232”

direct quote[Methods, Trial Design, paragraph 2]

“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.”

paraphrase[Limitations, paragraph 1]

“This trial has several limitations. First, the primary end point of a change in SOFA score is a surrogate outcome, so future adequately powered trials should test these strategies on patient-centered outcomes. Second, the measurement of ferritin and HLA-DR measures may not be feasible across hospitals, and the complexity and assay time could limit scaling and implementation. It is notable that average time from sepsis onset to when the study drug was first administered was 36 to 48 hours. Third, the stability of macrophage activation–like syndrome and sepsis-induced immunoparalysis subtypes over time de- serves further study. Fourth, the study findings are general- izable only to patients with sepsis with pneumonia or bacter- emia, and other etiologies of sepsis were excluded.”

PASSReviewer 2· 95% conf

The trial is registered, follows CONSORT, reports all outcomes, discusses limitations, and provides funding/COI statements.

Evidence

direct quote[Abstract, TRIAL REGISTRATION]

“ClinicalTrials.gov Identifier: NCT04990232”

direct quote[Methods, Trial Design]

“This trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.”

paraphrase[Discussion, Limitations]

15 copyedit issues flagged: mostly consistency, punctuation, grammar.

Checked 22 references by DOI: 22 verified.

Reproducibility

Registered (2 IDs: ClinicalTrials.gov, EudraCT). Reporting guideline cited: CONSORT.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported, with only minor reporting gaps. An informed reader should weigh the vague data sharing statement and the minor internal discrepancy in a secondary endpoint count. These do not warrant a correction but suggest that the data sharing statement should be clarified in any future version or erratum.

1.
HIGHdata code
In the Data Sharing Statement section, replace 'See Supplement 4' with a concrete access route, such as a data access committee or repository, including contact details and conditions for access.
The current statement is vague and does not specify how data can be obtained, which is a reporting gap for a clinical trial.
2.
HIGHdata code
If possible, deposit de-identified aggregate data in a public repository with a DOI or accession number, and mention this in the Data Sharing Statement.
A public repository deposit would strengthen data availability and transparency.
3.
HIGHdata code
If custom analysis code was used, share it in a public repository with a persistent identifier and reference it in the Data Sharing Statement.
Code sharing is not mentioned, and providing it would enhance reproducibility.
4.
MEDIUMreporting
In the Results section for the secondary endpoint '>=1.4-Point decrease of mean SOFA score d 2 to 15', reconcile the discrepancy between the text (51 of 131) and Table 2 (52 of 131).
The internal contradiction, though minor, could confuse readers and should be corrected in an erratum or clarified.
5.
MEDIUMcopyedit
In the Abstract Results, remove the unmatched closing parenthesis after '[33.7%]'.
The extra parenthesis is a punctuation error that should be fixed.
6.
MEDIUMcopyedit
In Methods, Randomization and Allocation, fix the hyphenation error 'vol-ume' to 'volume'.
The hyphenation error is a typographical issue that should be corrected.
7.
MEDIUMcopyedit
In Methods, Statistical Analyses, rephrase 'The primary analysis included all patients randomized, who did not withdraw their consent or requested removal of all data.' to 'The primary analysis included all randomized patients who did not withdraw their consent or request removal of all data.'
The original phrasing is awkward and could be clarified.
8.
MEDIUMcopyedit
In Table 1, remove the duplicate row for 'SOFA score e 10 (7-12) 9 (6-11)'.
The duplicate line is a formatting error that should be removed.
9.
MEDIUMcopyedit
In Table 2 footnote a, replace 'kidney' with 'renal' for consistency with the main text's SOFA score description.
Terminology inconsistency between the table and text should be harmonized.
10.
LOWcopyedit
In Methods, Trial Design, add 'and' before 'the General Data Protection Regulation' for better flow.
The conjunction improves readability.
11.
LOWcopyedit
In Table 1 footnotes, ensure consistent capitalization for sentence fragments (e.g., 'Self-reported', 'Refers', 'The').
Capitalization inconsistencies are minor but should be standardized.
12.
LOWcopyedit
In Table 2 footnote b, improve punctuation by replacing the semicolon after 'blood draws' with a period or comma for clarity.
The current punctuation is awkward and could be clarified.
13.
LOWcopyedit
In Table 3 footnote a, ensure consistent spacing around commas and between graded terms and their definitions.
Inconsistent spacing is a minor formatting issue.

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Precision Immunotherapy to Improve Sepsis Outcomes: The ImmunoSep Randomized Clinical Trial.

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DOI

10.1001/jama.2025.24175

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Issued Aug 15, 2026Engine 7.39.0

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