---
title: "Immunological effects of supervised exercise in adults with long COVID: randomized crossover subst"
id: "pubmed-42665974"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42665974"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42665974/"
doi: "10.14814/phy2.71031"
published_at: "2026-09-01T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Immunological effects of supervised exercise in adults with long COVID: randomized crossover subst
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42665974
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42665974/)
- **DOI:** [10.14814/phy2.71031](https://doi.org/10.14814%2Fphy2.71031)
- **Published At:** 2026-09-01T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- This is a pre-specified exploratory substudy of the EXER-COVID randomized 2 × 2 crossover trial evaluating immunological responses to supervised exercise in adults with **long COVID**. - Intervention: a 6-week supervised, moderate-intensity exercise program delivered twice weekly; comparator was usual care, with participants crossing over after a 3–5 day washout. - Measured outcomes included plasma **cytokines** (IL-1β, IL-6, IL-10, TNF-α, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, IP-10/CXCL10) by multiplex assay and detailed immunophenotyping (20 CD4+ and CD8+ T‑cell subsets and five innate immune populations). - Statistical approach used within-period change scores for treatment-effect estimation and controlled multiple testing with the Benjamini–Hochberg procedure (false discovery rate < 5%). - Five variables reached nominal significance before multiple-testing correction: two CD8+ T‑cell subsets and three cytokines (IL‑1β, IL‑10, and MIP‑1α). After adjustment, none remained statistically significant. - No significant changes were observed in the assessed innate immune cell populations (neutrophils, low‑density neutrophils, monocytes, M2‑like monocytes, NK cells). - No evidence of carryover effects was detected in the crossover design analyses. - Authors conclude that supervised, moderate‑intensity exercise was not associated with significant immunological alterations after correction for multiple comparisons, supporting the short‑term immunological safety of this exercise regimen in **PESE‑negative** adults with long COVID. - Trial registration: ClinicalTrials.gov NCT04797871. Details such as sample size, participant demographics, and exact effect estimates were not reported in the abstract provided.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain. * 2 CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain. * 3 Medical Oncology Department, Hospital Universitario de Navarra, Pamplona, Spain. * 4 Oncobiona Group, Navarrabiomed, Pamplona, Spain. * 5 IdiSNA; Oncoimmunology Group, Pamplona, Spain. * PMID: **42665974** * PMCID: [ PMC13525194 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13525194/) * DOI: [ 10.14814/phy2.71031 ](https://doi.org/10.14814/phy2.71031) Item in Clipboard Randomized Controlled Trial # Immunological effects of supervised exercise in long COVID in adults: A secondary analysis of a randomized crossover trial Nora García-Alonso et al. Physiol Rep. 2026 Sep. Show details Display options Display options Format Abstract PubMed PMID Physiol Rep Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Physiol+Rep%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Physiol+Rep%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42665974/) . 2026 Sep;14(17):e71031. doi: 10.14814/phy2.71031. ### Authors [Nora García-Alonso](https://pubmed.ncbi.nlm.nih.gov/?term=Garc%C3%ADa-Alonso+N&cauthor_id=42665974)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-1 "Instituto de Investigación Sanitaria de Navarra \(IdiSNA\), Navarrabiomed, Hospital Universitario de Navarra \(HUN\), Universidad Pública de Navarra \(UPNA\), Pamplona, Spain."), [Mikel Izquierdo](https://pubmed.ncbi.nlm.nih.gov/?term=Izquierdo+M&cauthor_id=42665974)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-1 "Instituto de Investigación Sanitaria de Navarra \(IdiSNA\), Navarrabiomed, Hospital Universitario de Navarra \(HUN\), Universidad Pública de Navarra \(UPNA\), Pamplona, Spain.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-2 "CIBER of Frailty and Healthy Aging \(CIBERFES\), Instituto de Salud Carlos III, Madrid, Spain."), [Hugo Arasanz](https://pubmed.ncbi.nlm.nih.gov/?term=Arasanz+H&cauthor_id=42665974)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-3 "Medical Oncology Department, Hospital Universitario de Navarra, Pamplona, Spain.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-4 "Oncobiona Group, Navarrabiomed, Pamplona, Spain.")[ 5 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-5 "IdiSNA; Oncoimmunology Group, Pamplona, Spain."), [Robinson Ramírez-Vélez](https://pubmed.ncbi.nlm.nih.gov/?term=Ram%C3%ADrez-V%C3%A9lez+R&cauthor_id=42665974)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-1 "Instituto de Investigación Sanitaria de Navarra \(IdiSNA\), Navarrabiomed, Hospital Universitario de Navarra \(HUN\), Universidad Pública de Navarra \(UPNA\), Pamplona, Spain.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42665974/#short-view-affiliation-2 "CIBER of Frailty and Healthy Aging \(CIBERFES\), Instituto de Salud Carlos III, Madrid, Spain.") ### Affiliations * 1 Instituto de Investigación Sanitaria de Navarra (IdiSNA), Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), Pamplona, Spain. * 2 CIBER of Frailty and Healthy Aging (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain. * 3 Medical Oncology Department, Hospital Universitario de Navarra, Pamplona, Spain. * 4 Oncobiona Group, Navarrabiomed, Pamplona, Spain. * 5 IdiSNA; Oncoimmunology Group, Pamplona, Spain. * PMID: **42665974** * PMCID: [ PMC13525194 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13525194/) * DOI: [ 10.14814/phy2.71031 ](https://doi.org/10.14814/phy2.71031) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Long COVID (post-acute sequelae of SARS-CoV-2 infection) affects approximately 5%-30% of survivors and is characterized by persistent fatigue, dyspnea, exercise intolerance, and cognitive impairment. We evaluated the immunological effects of supervised exercise in adults with long COVID. In this pre-specified exploratory substudy of the EXER-COVID randomized 2 × 2 crossover trial, participants completed a 6-week supervised exercise program (twice weekly) or usual care before crossing over after a 3-5 day washout. Plasma cytokines (IL-1β, IL-6, IL-10, TNF-α, MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4, and IP-10/CXCL10) were measured by multiplex immunoassay. Immunophenotyping included 20 CD4+ and CD8+ T-cell subsets and five innate immune populations. Treatment effects were estimated using within-period change scores, with multiple testing controlled by the Benjamini-Hochberg procedure (false discovery rate < 5%). Five variables reached nominal significance before correction (two CD8+ T-cell subsets and IL-1β, IL-10, and MIP-1α), but none remained significant after adjustment. No changes were observed in innate immune populations, and no evidence of carryover was detected. Supervised exercise was not associated with significant immunological changes after correction for multiple comparisons, supporting the short-term immunological safety of moderate-intensity exercise in PESE-negative adults with long COVID (ClinicalTrials.gov: [NCT04797871](http://clinicaltrials.gov/show/NCT04797871 "See in ClinicalTrials.gov")). **Keywords:** T lymphocytes; cytokines; exercise training; immunophenotyping; long COVID. © 2026 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement The authors declare no conflict of interest. No generative AI tool was used to produce, analyze, or interpret experimental data, perform statistical analyses, or create figures. All AI‐assisted text was reviewed, edited, and approved by the authors. The authors take full responsibility for the accuracy, integrity, and originality of the manuscript content. ## Figures [ ![FIGURE 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/362685e38ab6/PHY2-14-e71031-g002.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/6f9279e8fe8f/PHY2-14-e71031-g002.webp) ** FIGURE 1 ** Effects of Exercise on CD4 … ** FIGURE 1 ** Effects of Exercise on CD4 + T‐Cell Subsets in a 2 × 2… **FIGURE 1** Effects of Exercise on CD4+ T‐Cell Subsets in a 2 × 2 Crossover Trial. Changes in circulating CD4+ T‐cell subsets after exercise and usual care conditions in a randomized 2 × 2 crossover design. Each panel shows the mean change (Δ%) with corresponding variability (error bars) for specific phenotypic subsets: (a) CD4+CD28+CD62L−, (b) CD4+CD28+CD62L−CD57+KLRG1−, (c) CD4+CD28+CD62L−KLRG1+CD57+, (d) CD4+CD28+CD62L−CD57+PD1+, (e) CD4+CD28+CD62L−CD57−PD1+, (f) CD4+CD28+CD62L+, (g) CD4+CD28+CD62L+CD57+KLRG1−, (h) CD4+CD28+CD62L+KLRG1+CD57+, (i) CD4+CD28+CD62L+CD57+PD1+, and (j) CD4+CD28+CD62L+CD57−PD1+. Treatment‐effect _p_ values correspond to the pre‐specified one‐sample z test of within‐participant paired treatment contrasts. _p_ values for period and carryover effects were obtained from linear mixed‐effects models. [ ![FIGURE 2](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/bc7d8b161719/PHY2-14-e71031-g001.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/a0353fdfb972/PHY2-14-e71031-g001.webp) ** FIGURE 2 ** Effects of Exercise on CD8 … ** FIGURE 2 ** Effects of Exercise on CD8 + T‐Cell Subsets in a 2 × 2… **FIGURE 2** Effects of Exercise on CD8+ T‐Cell Subsets in a 2 × 2 Crossover Trial. Changes in circulating CD8+ T‐cell subsets under exercise and usual care conditions. Panels represent mean changes (Δ%) across phenotypes: (a) CD8+CD28+CD62L−, (b) CD8+CD28+CD62L−CD57+KLRG1−, (c) CD8+CD28+CD62L−KLRG1+CD57+, (d) CD8+CD28+CD62L−CD57+PD1+, (e) CD8+CD28+CD62L−CD57−PD1+, (f) CD8+CD28+CD62L+, (g) CD8+CD28+CD62L+CD57+KLRG1−, (h) CD8+CD28+CD62L+KLRG1+CD57+, (i) CD8+CD28+CD62L+CD57+PD1+, and (j) CD8+CD28+CD62L+CD57−PD1+. Treatment‐effect _p_ values correspond to the pre‐specified one‐sample z test of within‐participant paired treatment contrasts. _p_ values for period and carryover effects were obtained from linear mixed‐effects models. [ ![FIGURE 3](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/ba3b520e9309/PHY2-14-e71031-g003.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/ad552981eaa3/PHY2-14-e71031-g003.webp) ** FIGURE 3 ** Effects of Exercise on Innate… ** FIGURE 3 ** Effects of Exercise on Innate Immune Cell Populations. Changes in innate immune cell… **FIGURE 3** Effects of Exercise on Innate Immune Cell Populations. Changes in innate immune cell populations following exercise and usual care conditions. Panels include (a) neutrophils (CD11b+CD66b+CD116+), (b) low‐density neutrophils (LDN; CD11b+CD66b+CD116+CD119−), (c) monocytes, (d) M2‐like monocytes (CD11b+CD116+CD14+CD66b−CD163+), and (e) natural killer (NK) cells. Treatment‐effect _p_ values correspond to the pre‐specified one‐sample z test of within‐participant paired treatment contrasts. _p_ values for period and carryover effects were obtained from linear mixed‐effects models. [ ![FIGURE 4](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/1843f091372a/PHY2-14-e71031-g004.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d21b/13525194/af58967c9072/PHY2-14-e71031-g004.webp) ** FIGURE 4 ** Effects of Exercise on Circulating… ** FIGURE 4 ** Effects of Exercise on Circulating Cytokines. Changes in circulating cytokine concentrations (pg/mL) under… **FIGURE 4** Effects of Exercise on Circulating Cytokines. Changes in circulating cytokine concentrations (pg/mL) under exercise and usual care conditions. Panels show (a) IL‐1β, (b) IL‐10, (c) MIP‐1α/CCL3, (d) IL‐6, (e) TNF‐α, (f) MCP‐1/CCL2, (g) MIP‐1β/CCL4, and (h) IP‐10/CXCL10. Treatment‐effect _p_ values correspond to the pre‐specified one‐sample z test of within‐participant paired treatment contrasts. _p_ values for period and carryover effects were obtained from linear mixed‐effects models. [See this image and copyright information in PMC](https://pubmed.ncbi.nlm.nih.gov/42665974/) ## Similar articles * [ Peripheral blood cytokines during early and post-acute stages of SARS-CoV-2 infection are associated with disease severity and long-term symptoms. ](https://pubmed.ncbi.nlm.nih.gov/42528778/) Mendall C, Li X, Pakanati V, Liu C, Wang T, Morelli D, Korpak A, Baraff A, Isaacs SN, Chang KM, Le E, Holodniy M, Sugimoto JD, Smith NL, Lee JS, Ross JM, Shah JA.Mendall C, et al.Front Immunol. 2026 Jul 15;17:1870109. doi: 10.3389/fimmu.2026.1870109. eCollection 2026.Front Immunol. 2026.PMID: 42528778Free PMC article. * [ Persistent symptoms and clinical findings in adults with post-acute sequelae of COVID-19/post-COVID-19 s
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