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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 Narrative Review: Analysis of Supplemental Parenteral Nutrition in Adults at the End of Life
García, F. R., Martínez, R., Camarasa, F., Cerdá, J., Messeguer, F., & López-Viota, M. (2023) · Pharmaceuticals · doi:10.3390/ph17010065 · Cited by 2
“Thus, patients with malnutrition exhibit an increase in inflammatory markers (IL6, CRP, β 2 microglobulin) due to the presence of an inflammatory state that is associated with malnutrition and cachexia [16].”
BackgroundMangelernährung in der Inneren Medizin
Kaegi-Braun, N., Gressies, C., Tribolet, P., Stumpf, F., Keller, B., & Schüetz, P. (2023) · Die Innere Medizin · doi:10.1007/s00108-023-01525-x · Cited by 2
“Während Patient*innen mit starker Entzündung und CRP-Leveln über 100mg/dl keinen Überlebensvorteil durch die Ernährungstherapie hatten, profitierten Patient*innen mit geringerer Entzündung deutlich [34].”
Self-citationNutrition during the acute phase of critical illness: discussions on NUTRIREA-3.
Patel, J. J., Puthucheary, Z., & McClave, S. (2023) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(23)00213-8 · Cited by 1
Aruğaslan, E., Zengin, A., Karataş, M., & Akyuz, S. (2022) · Acta Cardiologica Sinica · doi:10.6515/acs.202201_38(1).20210718a · Cited by 1
Nutritional Assessment, Diagnosis, and Treatment in Geriatrics
Holst, M., & Beck, A. M. (2021) · Perspectives in nursing management and care for older adults · doi:10.1007/978-3-030-63892-4_3 · Cited by 3
Asensio, L. E., López, P. P., Izaola-Jáuregui, O., Cebriá, Á., González, M. P. B., Hoyos, E. G., Gutiérrez, J. G., Primo, D., Saavedra-Vasquez, M. A., Godoy, E. J., et al. (2026) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2026.501928
Nutrition Clinical Framework, Mortality, and Length of Stay Among Older Inpatients With Malnutrition
Ishida, Y., Maeda, K., Motegi, M., Sato, Y., Sugiura, M., & Mori, N. (2026) · JAMA Network Open · doi:10.1001/jamanetworkopen.2026.33637
Wen, Z., Wang, S.-B., Li, Y., Tu, X., Zhang, Q.-B., & Qing, Y.-F. (2026) · Medicine · doi:10.1097/md.0000000000050312
“[9] Malnutrition in RA may result from systemic inflammation, [10] metabolic disturbances, [11] and disuse atrophy related to reduced physical activity.”
Providing appropriate response-contingent phase-specific nutrition therapy in critical illness
McClave, S. A., Martindale, R. G., & Patel, J. J. (2026) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000001419
Zhu, Z., Zha, T., Luo, Y.-H., Chen, Y., Xu, X.-M., Mao, X.-Y., Xia, S.-L., Chu, M., Liu, Y., & Niu, H.-C. (2026) · Journal of clinical neuroscience · doi:10.1016/j.jocn.2026.112066
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Self-citationHALP score: A powerful and promising index for predicting prognosis among hypertension adults
Deng, M., Wu, Q., Liu, D.-L., & Zhou, X.-H. (2026) · Medicine · doi:10.1097/md.0000000000049880
“A secondary analysis conducted on a multicenter trial demonstrated that nutritional support did not improve 30-day mortality in hospitalized patients at nutritional risk who had high inflammatory levels at admission, [49] which may explain this.”
Mashambo, A. E., Solanki, M. V., Makakala, M. C., Ngimba, C., & Ng’wanasayi, M. (2026) · Cureus · doi:10.7759/cureus.110623
Seres, D. S. (2026) · Nutrition in clinical practice · doi:10.1002/ncp.70128
“6 They also found that removing the disease ‐ related components of the NRS strengthened its predictive value.”
Souza, V. R., Trida, V. C., Mazzoni, B. P., Gandolfo, A. S., de Carvalho, W., Delgado, A., & Zamberlan, P. (2026) · Revista Paulista de Pediatria · doi:10.1590/1984-0462/2026/44/2025246
“27-30 Elevated CRP has been associated with prolonged inflammation, poor nutritional tolerance, and extended hospital stays.”
Linking Inflammation to Reduced Food Intake in Advanced Cancer: A Prospective Observational Study
Bye, A., Balstad, T. R., Raaness, I., Solheim, T. S., Habberstad, R. H., Klepstad, P., Løhre, E. T., Dajani, O. F., Kaasa, S., Aass, N., et al. (2026) · Current Oncology · doi:10.3390/curroncol33040209 · Cited by 1
“Merker et al. [27] examined whether inflammatory status influenced the effectiveness of nutritional support on mortality and found no significant benefit among patients with high inflammation (CRP > 100 mg/L).”
Yu, C., Zhu, L., Xiong, F., Wang, T., Zhou, W., Bao, H., & Cheng, X. (2026) · BMC Public Health · doi:10.1186/s12889-026-26400-w
Matsui, R., Nunobe, S., Ri, M., Makuuchi, R., Irino, T., Hayami, M., Ohashi, M., & Sano, T. (2026) · Surgery Today · doi:10.1007/s00595-025-03164-1
Prognostic importance of nutritional status in patients with atrial fibrillation
Özmen, M. M., Aydemir, S., Altınkaya, O., Aydın, S., Özkoç, M., & Aydınyılmaz, F. (2026) · BMC Cardiovascular Disorders · doi:10.1186/s12872-026-05504-6
Yu, C.-L., Yu, C., Ding, C., Bao, H., & Cheng, X. (2025) · BMC Public Health · doi:10.1186/s12889-025-26008-6
Optimising Patient Care: Cutting-Edge Nutritional Strategies in Oncology
Boreham, H. (2025) · EMJ Oncology · doi:10.33590/emjoncol/pwpe6967
Fan, J., Guo, X., Cao, S., Li, R., & Zhan, S. (2025) · Computer Methods and Programs in Biomedicine · doi:10.1016/j.cmpb.2025.109201
Ghalibaf, M. H. E., Kamelnia, E., Behrouz, S., Saberi, R., Kioumarsi, Z., & Boskabady, M. (2025) · Nutrition and Dietary Supplements · doi:10.2147/nds.s553742
Amano, K., Imai, K., Toyota, S., Yamauchi, T., Miwa, S., Yuasa, M., Okamoto, S., Inoue, S., Kogure, T., & Morita, T. (2025) · Healthcare · doi:10.3390/healthcare13222959
“These cutoffs were predefined based on a clini-Healthcare cal rationale and previous clinical research [15,19,36,37].”
Gu, W., Yang, F.-Z., Liu, Z.-J., Xu, D., Song, Y., Xu, A.-Y., Ma, X.-N., Peng, Y.-J., & Chen, L.-X. (2025) · Reviews in cardiovascular medicine · doi:10.31083/rcm39500
Arends, J., Dajani, O., Philips, I., Skipworth, R. J. E., Solheim, T., & Laird, B. (2025) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.70069
Morell, C. L., Miranda, M. B., Sánchez, B. L., Molina, J. B., Muñoz, J. T., Novo, C., Novo, M., Luna, V., Portillo, P., & Martínez, D. S. L. (2025) · Nutrición Hospitalaria · doi:10.20960/nh.05684
Understanding the rationale for recent paradigm shifts in critical care nutrition
Miller, K. R., & McClave, S. A. (2025) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000001291
Matsui, R., Nunobe, S., Ri, M., Makuuchi, R., Irino, T., Hayami, M., Ohashi, M., & Sano, T. (2025) · Langenbeck's archives of surgery (Print) · doi:10.1007/s00423-025-03785-7
“Third, the mechanism underlying the increase in prealbumin levels after nutritional intervention remains without immunonutrients in patients with inflammation lev - els 1–10 mg/dL [20].”
A key step toward gaining a deeper understanding of individual responses to protein supplementation.
Schuetz, P. (2025) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2025.05.030
Self-citationNutrition in Internal Medicine
Özçetin, M., & Dizdar, O. S. (2025) · Turkish Journal of Internal Medicine · doi:10.46310/tjim.1571069
Preoperative Parenteral Nutrition Optimization in Acute Care Surgery Patients: Is it Worth the Wait?
Busch, R. A., Katz, J., Stephens, K. R., & Collier, B. R. (2025) · Current Surgery Reports · doi:10.1007/s40137-025-00446-y
“…to reduce the risk of post - operative complications is too broad, and likely should not apply to a large portion of acute care surgery patients, specifically patients with underlying inflammatory processes. function, and impair a patient’s ability to withstand surgi - cal stress [16, 17, 32 ].”
InfluentialMaya, M. R. P., Aminuddin, A., & Taslim, N. A. (2025) · Nutrición clínica y dietética hospitalaria/Nutrición clínica, dietética hospitalaria · doi:10.12873/451maya
Schuetz, P., Haenggi, E., & Wunderle, C. (2024) · Clinical Nutrition · doi:10.1016/j.clnu.2024.02.012
Self-citationEFFORT Protein trial: questions remain - Authors' reply.
Patel, J. J., Lee, Z., Stoppe, C., & Heyland, D. (2023) · The Lancet · doi:10.1016/s0140-6736(23)01253-9
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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