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Association of Baseline Inflammation With Effectiveness of Nutritional Support Among Patients With Disease-Related Malnutrition: A Secondary Analysis of a Randomized Clinical Trial
Open accessAbstract
Importance: Inflammation is a key driver of malnutrition during illness and is often accompanied by metabolic effects, including insulin resistance and reduction of appetite. However, it still remains unclear if inflammation influences the response to nutritional support among patients with disease-related malnutrition. Objective: To examine whether patients' baseline inflammatory status is associated with the effect of nutritional support on 30-day mortality. Design, Setting, and Participants: This is a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized clinical trial conducted in 8 Swiss hospitals from April 2014 to February 2018. A total of 1950 participants who had C-reactive protein measurements at the time of admission were included in this secondary analysis. Data analysis was conducted between June and July 2019. Interventions: Hospitalized patients at risk for malnutrition were randomly assigned to receive protocol-guided individualized nutritional support to reach protein and energy goals (intervention group) or standard hospital food (control group). Main Outcomes and Measures: The primary end point was 30-day mortality. Based on C-reactive protein levels at admission, patients were stratified into groups with low, moderate, or high inflammation (<10 mg/L, 10-100 mg/L, and >100 mg/L, respectively). Results: A total of 1950 patients (median [interquartile range] age, 75 [65-83] years; 1025 [52.6%] men) were included; 533 (27.3%) had low levels of inflammation, 894 (45.9%) had moderate levels of inflammation, and 523 (26.8%) had high levels of inflammation. Compared with the control group, patients receiving nutritional support showed a significant reduction in 30-day mortality, regardless of C-reactive protein level (adjusted odds ratio, 0.61; 95% CI, 0.43-0.86; P = .005). In the subgroup of patients with high inflammation, there was no beneficial effect of nutritional support (adjusted odds ratio, 1.32; 95% CI, 0.70-2.50; P = .39), providing evidence that inflammation has a significant modifying association (P for interaction = .005). Conclusions and Relevance: Based on this secondary analysis of a multicenter randomized trial, a patient's admission inflammatory status was associated with their response to nutritional support. If validated in future clinical trials, nutritional support may need to be individualized based on a patient's initial presentation and markers of inflammation. These results may also help to explain some of the heterogeneity in treatment effects of nutrition seen in previous critical care trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02517476.
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“An RCT in non-ICU patients suggests that nutritional intervention, including both macro- and micronutrients, may improve outcomes [85].”
From Gastrointestinal function and nutritional interventions in septic shock (2025) · cites this paper as [85]
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“A secondary analysis of the multicentre randomized-controlled EFFORT trial suggested that patients with CRP levels of !100 mg/l no longer responded to nutritional therapy, while patients with lower levels had a significant mortality benefit from nutritional support [147] (Level of evidence: 1þþ).”
From ESPEN guideline on nutritional support for polymorbid medical inpatients (2023) · cites this paper as [147]
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“Markers of inflammation (i.e.C-reactive protein [CRP]) have been shown to correlate with disease-related anorexia, reduced food intake and muscle catabolism, and at the same predict lack of response to nutritional treatment [147,190,191].”
From ESPEN guideline on nutritional support for polymorbid medical inpatients (2023) · cites this paper as [147]
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“A secondary analysis of the multicentre randomized-controlled EFFORT trial suggested that patients with CRP levels of 100 mg/l no longer responded to nutritional therapy, while patients with lower levels had a significant mortality benefit from nutritional support [147] (Level of evidence: 1þþ).”
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Wunderle, C., Stumpf, F., & Schuetz, P. (2024) · Journal of Parenteral and Enteral Nutrition · doi:10.1002/jpen.2534 · Cited by 65
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“regard of nutritional support interventions, and also aim to identify predictors for treatment response e or non-response to further increase the efficacy of this intervention [30,31].”
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“…therapy and that nutritional support alone is inadequate to prevent muscle loss during severe, sustained, or repeated bouts of inflammation [34, 35], which emphasizes the importance of considering the double burden of inflammation and malnutrition in disease assessment, intervention, and…”
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“[26] Hospitalized patients with severe inflammatory responses (defined as CRP > 100 mg/L) did not demonstrate a strong, measurable response to nutrition support in a large randomized controlled trial.[27] Among our representative United States population, a lower albumin was associated with a greater CRP in old adults.”
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“of nutrition and exercise, suggesting the potential role of anti-inflammation in multimodal interventions.(41) In a randomized phase III trial of treatment for cachexia in patients”
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“CRP was extracted from the electronic patient chart for assessing inflammatory status [43] in 4 categories: < 10, 10–100, > 100 mg/L, and missing.”
BackgroundMethodResultInfluentialEffect of Whey Proteins on Malnutrition and Extubating Time of Critically Ill COVID-19 Patients
Scarcella, M., Scarpellini, E., Ascani, A., Commissari, R., Scorcella, C., Zanetti, M., Parisi, A., Monti, R., Milić, N., Donati, A., et al. (2022) · Nutrients · doi:10.3390/nu14030437 · Cited by 16
“Moreover, the higher is the Nutritional Risk Score (NRS), the higher is the incidence of acquired healthcare associated infections and the mortality risk index [3,5].”
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Wunderle, C., Haller, L., Laager, R., Bernasconi, L., Neyer, P. J., Stumpf, F., Tribolet, P., Stanga, Z. G., Müeller, B., & Schüetz, P. (2024) · Nutrients · doi:10.3390/nu16162608 · Cited by 16
“However, while the EFFORT focused on an individualized nutritional strategy to reach individual nutritional targets, certain groups of malnourished patients may benefit from more specific, personalized nutritional interventions [11].”
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Association of Malnutrition with Risk of Acute Kidney Injury: A Systematic Review and Meta-Analysis
Xiang, X., Zhu, X., & Zhang, L. (2023) · International journal of clinical practice · doi:10.1155/2023/9910718 · Cited by 15
Relationship of Inflammatory Parameters and Nutritional Status in Cancer Patients
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Malnutrition and sarcopenia worsen short- and long-term outcomes in internal medicine inpatients
Carretero‐Gómez, J., Fernández, T. F. G., Ríos, A. S. V., Palacios, M. R. P., García, G. M. G., Carrasco, C. G., Requena, J. M. R., Recio, J. M. F., López-Alegría, L. N., Pijierro-Amador, A., et al. (2023) · Postgraduate Medical Journal · doi:10.1093/postmj/qgad006 · Cited by 18
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“Inflammation is associated with decreasing albumin synthesis and increasing catabolism [20].”
Tanaka, K., Kimura, H., Ejiri, H., Saito, H., Watanabe, K., Kazama, S., Shimabukuro, M., Asahi, K., Watanabe, T., & Kazama, J. J. (2024) · Hypertension Research · doi:10.1038/s41440-024-01716-5 · Cited by 14
Gastrointestinal function and nutritional interventions in septic shock
Bachmann, K. F., Cotoia, A., & Reintam Blaser, A. (2025) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000001302 · Cited by 13
Peng, L., Tang, J.-F., Zhang, N., Zhang, Z., Wang, D.-Q., & He, Y. (2025) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1518822 · Cited by 13
Madini, N., Vincenti, A., Beretta, A., Santero, S., Viroli, G., & Cena, H. (2024) · Nutrients · doi:10.3390/nu16234141 · Cited by 17
“The EFFORT Study, in fact, revealed that dietary supplementation is less effective in those with severe inflammation (CRP > 100 mg/dl) compared to individuals with CRP concentrations ≤ 100 mg/L, independently of infection and illness severity [142].”
Thompson, J., McGovern, J., Roxburgh, C., Edwards, J., Dolan, R., & McMillan, D. C. (2024) · Critical reviews in oncology/hematology · doi:10.1016/j.critrevonc.2024.104378 · Cited by 13
Qian, Y.-Z., Qian, X., Shen, M., Vu, A., & Seres, D. (2022) · Nutrition in clinical practice · doi:10.1002/ncp.10815 · Cited by 13
Zengin, A., Karataş, M., Çanga, Y., Durmuş, G., Güzelburç, Ö., Durak, F., & Emre, A. (2021) · Anatolian journal of cardiology · doi:10.5152/anatoljcardiol.2021.190 · Cited by 13
“Inflammation induces metabolic turnover, muscle catabolism, and decreased serum albumin levels (16).”
BackgroundMeulemans, A., Matthys, C., Vangoitsenhoven, R., Sabino, J., der Schueren, B. V., Maertens, P., Pans, C., Stijnen, P., & Bruyneel, L. (2021) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqab135 · Cited by 13
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Association of GNRI, NLR, and FT3 with the Clinical Prognosis of Older Patients with Heart Failure
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Self-citationThe role of prehabilitation in HNSCC patients treated with chemoradiotherapy
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Self-citationRitz, J., Wunderle, C., Stumpf, F., Laager, R., Tribolet, P., Neyer, P. J., Bernasconi, L., Stanga, Z. G., Müeller, B., & Schüetz, P. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1335242 · Cited by 10
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“In non-critically ill patients, a large RCT showed benefit by enhanced nutritional support, although this benefit was not observed in patients with severe inflammation [33, 34].”
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“In addition, inflammation induces insulin resistance, decreases appetite, and hinders the absorption of nutrients, ultimately leading to weight loss 27–29 .”
Early Feeding in Critical Care - Where Are We Now?
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Malnutrition: muscle wasting, inflammation, RDW, and their relation with adverse outcomes.
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“Furthermore, nutritional support did not influence C reactive protein levels during the intervention 17 .”
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“14–16] Thus, both inflammatory and nutritional statuses play pivotal roles in assessing ASCVD development and prognosis.”
Pan, L., Peng, Y., & Jiang, L. (2024) · Journal of Stroke and Cerebrovascular Diseases · doi:10.1016/j.jstrokecerebrovasdis.2024.108165 · Cited by 9
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“This disease has a prevalence between 20 and 50% in hospitalized patients [1,2].”
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“A randomized controlled trial has shown that conventional nutritional support in the presence of inflammation does not improve prognosis [9].”
BackgroundNutritional Support Among Medical Inpatients—Feed the Cold (and Malnourished) and Starve the Febrile
Marik, P. E. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.15707 · Cited by 9
The Global Leadership Initiative on Malnutrition (GLIM)
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“These findings potentially suggest that systemic inflammation may be a target for modulation to preserve muscles, based on the machine learning model [37].”
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“Based on results from a former analysis [17], low CRP was defined as 100 mg/l and high CRP as ≥ 100 mg/l. Based on admission NRS 2002 score, we categorized patients as “moderately mal-nourished” (NRS 2002 score 3 and 4 points), or “severely malnourished” (NRS 2002 score ≥ 5 points).”
BackgroundMethodResultSelf-citationMcGovern, J., Dolan, R., Simmons, C., Daly, L., Ryan, A., Power, D., Fallon, M., Laird, B., & McMillan, D. (2023) · Cancers · doi:10.3390/cancers15133497 · Cited by 6
“The present observations, together with those in clinical trials [6,23,29], favor a framework where the systemic inflammatory response is the dominant factor to be used in patients with good performance status to predict the likely outcome.”
ResultYe, S., Xiang, G., Liu, Z., Li, W.-D., Tang, T., Qian, A.-M., Li, X.-Q., & Sun, L.-L. (2023) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2023.1129255 · Cited by 6
“Additionally, nutritional status partly reflects the development of inflammation (31–33), which promotes cytokine production and muscle catabolism, suppresses appetite, and lowers the albumin concentration (34).”
BackgroundGressies, C., & Schüetz, P. (2022) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000894 · Cited by 8
Self-citation
Metadata
- Authors
- Merker, M., Felder, M., Gueissaz, L., Bolliger, R., Tribolet, P., Kägi-Braun, N., Gomes, F., Hoess, C., Pavlicek, V., Bilz, S., Sigrist, S., Brändle, M., Henzen, C., Thomann, R., Rutishauser, J., Aujesky, D., Rodondi, N., Donzé, J., Stanga, Z., Mueller, B., & Schuetz, P.
- Affiliations
- University of Basel (CH)
- Bern University of Applied Sciences (CH)
- Internal Medicine, Kantonsspital Muensterlingen, Muensterlingen, Switzerland
- New York Academy of Sciences (US)
- Kantonsspital Münsterlingen (CH)
- Kantonsspital St. Gallen (CH)
- Luzerner Kantonsspital (CH)
- Internal Medicine, Kantonsspital Solothurn, Solothurn, Switzerland
- Kantonsspital Baselland (CH)
- University of Bern (CH)
- Medical University Department, University of Basel, Kantonsspital Aarau, Aarau, Switzerland
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2020-03-10
- Volume
- 3
- Issue
- 3
- Pages
- e200663
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC7064875
- OpenAlex
- W3011737478
- Cited by
- 262
- References
- 31
- Citations by year
- 2026: 26 · 2025: 71 · 2024: 56 · 2023: 46 · 2022: 35 · 2021: 21 · 2020: 5
- FWCI
- 16.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ARBOR - Bern University of Applied Sciences Repository (submittedVersion, other-oa)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- BFH: ARBOR
- Open Access CRIS of the University of Bern
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (150531)
- Forschungsrat des Kantonsspitals Aarau (1410.000.044, 1410.000.058)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Clinical Nutrition and Gastroenterology
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Health Sciences › Medicine › Nephrology › Dialysis and Renal Disease Management
- Keywords
- disease-related malnutrition, inflammation, C-reactive protein, nutritional support, 30-day mortality, frailty, insulin resistance, appetite, older adults, hospital food service, functional outcome, length of hospital stay, hospital readmission
- MeSH terms
- Aged, Aged, 80 and over, C-Reactive Protein, Female, Hospitalization, Humans, Inflammation, Male, Middle Aged, Cohort Studies, Survival Rate, Treatment Outcome, Nutritional Support, Malnutrition
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