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Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Infectious Diseases".

Deadline for manuscript submissions: 20 November 2026 | Viewed by 3267

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Dr. Yuki Otsuka

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Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
Interests: general medicine; long COVID; fatigue; biomarkers; medically unexplained symptoms; multidisciplinary care

Special Issue Information

Dear Colleagues,

Long COVID has emerged as a significant global health challenge, affecting a substantial proportion of individuals following acute SARS-CoV-2 infection. Patients frequently experience persistent and heterogeneous symptoms, including fatigue, dyspnea, cognitive impairment, autonomic disturbances, and psychological distress. Among these manifestations, fatigue is consistently reported as one of the most prevalent and disabling symptoms, affecting approximately 40–60% of patients in observational cohorts. Despite its high prevalence and profound impact on daily functioning and quality of life, fatigue remains difficult to quantify and manage, often overlapping with medically unexplained symptoms and conditions such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Unified and evidence-based management strategies for long COVID remain insufficient. Clinicians and patients alike face considerable uncertainty regarding optimal therapeutic approaches, which may include pharmacological interventions, structured rehabilitation programs, pacing strategies, integrative medicine, and other supportive or complementary modalities. While rehabilitation is widely regarded as an essential component of care, excessive or poorly individualized exercise may exacerbate symptoms in certain patients, underscoring the importance of balanced and patient-centered management. Meanwhile, advances in immunology, endocrinology, autonomic function assessment, biomarker discovery, and digital health technologies are expanding opportunities to better understand and treat persistent post-COVID conditions.

As a general physician in Japan who was involved in establishing a COVID-19 aftercare clinic in the university hospital and has been engaged in the clinical management and research of long COVID, I recognize the urgent need to consolidate emerging knowledge and practical experience in this field.

This Special Issue aims to present and disseminate the most recent advances in the clinical management of long COVID, with particular attention to fatigue and other persistent multisystem symptoms. We consider contributions addressing therapeutic strategies, emerging evidence, and ongoing clinical challenges in both research and practice.

Topics of interest for publication include, but are not limited to, the following:

Clinical management strategies for long COVID;
Assessment and treatment of fatigue;
Pharmacological interventions;
Rehabilitation models and pacing strategies;
Integrative medicine and traditional therapies;
Biomarker research and pathophysiological mechanisms;
Autonomic dysfunction and endocrine involvement;
Digital health and AI-supported interventions;
Multidisciplinary and patient-centered care approaches.

Dr. Yuki Otsuka
Guest Editor

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Keywords

long COVID
post-COVID condition
fatigue
clinical management
rehabilitation
therapeutic innovation
integrative medicine
biomarkers

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Published Papers (5 papers)

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15 pages, 818 KB

Open AccessArticle

Evolutionary Predictors of Post-COVID Syndrome

by Maria Luisa Asensio Tomás, Philip Erick Wikman-Jorgensen, Jose Antonio Quesada-Rico, José Miguel Seguí-Ripoll, Vicente Gil-Guillén and Vicente Giner-Galvañ

J. Clin. Med. 2026, 15(14), 5550; https://doi.org/10.3390/jcm15145550 - 15 Jul 2026

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Abstract

Objectives: To analyze evolutionary predictors of post-COVID syndrome (PCS). Methods: This Cohort study was conducted from April 2021 to December 2023. PCS persistence was defined as a score of ≥2 points on the post-COVID-19 Functional Status (PCFS) scale (range 0–4, where higher scores indicate more limitations). Symptom clusters were identified using correspondence analysis. The association between PCS persistence and symptoms and symptom clusters were assessed using multivariable analysis, considering both the acute infection period and the baseline PCS visit variables. Results: The 112 included patients showed a mean of 6.1 symptoms (standard deviation [SD] 3.2), most commonly dyspnea (67.9%), asthenia (67.0%), fatigue (57.1%), and myalgia (49.1%). Regarding baseline functional status, 59.8% scored 2 points on the PCFS; 40.2%, 3 points; and 2.6%, 4 points. Moreover, 68.7% had depression and 83.0%, anxiety. Two symptom clusters emerged: anxiety + depression + severe PCFS, and palpitations + hyporexia + dyspnea. At a mean of 12.1 months (SD 9.2), the persistence rate was 33.9% (cumulative persistence time 20 months [SD 11.9]). Persistence was significantly associated with the absence of rhinitis (odds ratio [OR] 3.67, 95% confidence interval [CI] 1.28–10.52) during acute infection, and the presence of fatigue (OR 4.88, 95% CI 1.77–13.44) and depression (moderate: OR 4.28, 95% CI 1.05–17.44; severe: OR 10.31, 95% CI 2.60–40.90) at the baseline visit. The model multivariable demonstrated a good fit (likelihood ratio test 30.1, p < 0.001) and predictive capacity (area under the receiver operating curve 0.804). The anxiety + depression + severe PCFS cluster was significantly associated with persistence (OR 3.26, 95% CI 1.21–8.76; p = 0.012). Conclusions: A third of patients with PCS still experience significant functional impairment 20 months after onset. Persistence is associated with the absence of rhinitis during acute infection and with severe anxiety, depression, and functional impairment measured by the PCFS on detection of PCS. Full article

(This article belongs to the Special Issue Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations)

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19 pages, 2016 KB

Open AccessArticle

Allergic Status, Long COVID, and Post-Restriction Respiratory Outcomes in Children: A Single-Center Questionnaire-Based Study

by Giulia Brindisi, Alessandra Gori, Elia Pignataro, Giorgio Colletti, Sonia Iavarone, Alberto Spalice, Caterina Anania and Anna Maria Zicari

J. Clin. Med. 2026, 15(10), 3982; https://doi.org/10.3390/jcm15103982 - 21 May 2026

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Background: The relationship between allergic status, SARS-CoV-2 infection, Long COVID, and post-restriction respiratory outcomes in children remains incompletely understood. This study aimed to explore the associations between allergic status and Long COVID, as well as between SARS-CoV-2 vaccination and post-restriction changes in allergic rhinitis (AR), asthma, and upper respiratory infections, in a pediatric tertiary-care cohort. Methods: We conducted a single-center, questionnaire-based observational study involving children aged 0–16 years, who were followed at the Pediatric Allergy Clinic of Umberto I Hospital in Rome. Parents completed an email-based questionnaire addressing SARS-CoV-2 infection, vaccination, persistent post-infectious symptoms, allergic diseases, and respiratory infections following restrictions. Analyses of Long COVID were limited to children with confirmed SARS-CoV-2 infection. Results: A total of 214 questionnaires were analyzed. Allergic status was not significantly associated with SARS-CoV-2 infection in the overall cohort. Among infected children, allergic status was independently associated with higher odds of Long COVID (adjusted OR 3.12, 95% CI 1.20–8.09; p = 0.019). Severe acute infection was also strongly associated with Long COVID (adjusted OR 6.84, 95% CI 2.72–17.21; p < 0.001). Complete vaccination was associated with lower odds of SARS-CoV-2 infection in the overall sample (adjusted OR 0.20, 95% CI 0.09–0.46; p < 0.001) but was not independently associated with Long COVID among infected children. After the removal of COVID-19 restrictions, 90.1% of allergic children reported worsening AR and 52.0% reported worsening asthma, with no significant association with SARS-CoV-2 infection or Long COVID. Group A Streptocossus (GAS) pharyngitis was reported in 50.0% and viral pharyngitis in 10.7% of the cohort, with no significant differences between allergic and non-allergic children. Conclusions: In this single-center, questionnaire-based pediatric cohort, allergic status was correlated with increased likelihood of Long COVID among children with confirmed SARS-CoV-2 infection; however, it was not associated with a higher risk of infection itself. Complete vaccination was linked to a reduced risk of infection, whereas no independent correlation with Long COVID was identified. Post-restriction exacerbation of allergic respiratory symptoms was prevalent, while the incidence of bacterial and viral pharyngitis did not vary significantly according to allergic status. Full article

(This article belongs to the Special Issue Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations)

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20 pages, 949 KB

Open AccessArticle

Symptom Trajectories and Long-Term Sequelae of COVID-19: A Matched Case–Control Study with Population-Based Controls

by Sebastian Sołomacha, Maciej Alimowski, Anna Moniuszko-Malinowska, Łukasz Kiszkiel, Piotr Laskowski, Marlena Dubatówka, Paweł Sowa and Karol Kamiński

J. Clin. Med. 2026, 15(10), 3707; https://doi.org/10.3390/jcm15103707 - 12 May 2026

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Abstract

Background/Objectives: Post-COVID-19 condition involves heterogeneous, multisystem symptoms with uncertain recovery. We characterized symptom trajectories from hospitalization to approximately 4 weeks and to 6–8 months and compared the 6–8-month symptom burden with season-matched controls, accounting for serology-identified, previously unrecognized infections. Methods: An individually pair-matched case–control study of adults with RT-PCR–confirmed SARS-CoV-2 and population controls from the Bialystok PLUS cohort, matched on age, sex and a two-month visit window, was performed. All participants underwent anti-nucleocapsid serology. Hospitalized cases were reassessed at approximately 4 weeks and 6–8 months. Cross-sectional outcomes used non-parametric tests and multivariable regression; longitudinal change used paired tests and generalized estimating equations. Results: We included 402 adults (201 post-COVID-19; 201 controls). In hospitalized cases, respiratory symptoms declined rapidly by approximately 4 weeks and remained low at 6–8 months; smell/taste recovered more slowly; fatigue improved modestly; anxiety changed minimally. At 6–8 months, total symptom counts were higher in post-COVID-19 than in controls (median 4 vs. 2), with serology-positive controls intermediate (median 3). Excess burden was concentrated in non-respiratory domains (fatigue, neurocognitive, cardiovascular, and dermatologic), whereas respiratory differences were not significant. In the multivariable model, female sex remained an independent predictor of higher multisystem burden, whereas age, body mass index, hospitalization, and acute biomarker severity were not associated. Conclusions: Six to eight months after symptomatic COVID-19, multisystem symptom burden remains substantial relative to season-matched controls, despite substantial resolution of respiratory complaints. Serology-based identification of previously unrecognized infections indicates an intermediate burden and can guide targeted follow-up. Full article

(This article belongs to the Special Issue Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations)

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13 pages, 1370 KB

Open AccessArticle

Exploratory Analysis of Serum IGF-I Levels and Symptom Trajectories in Long COVID During the Omicron Period

by Atsuhito Suyama, Yuki Otsuka, Yasuhiro Nakano, Kazuki Tokumasu, Yasue Sakurada, Yui Matsuda, Hiroyuki Honda, Yoshiaki Soejima, Toru Hasegawa, Ryosuke Takase, Daisuke Omura, Kohei Oguni, Keigo Ueda and Fumio Otsuka

J. Clin. Med. 2026, 15(10), 3702; https://doi.org/10.3390/jcm15103702 - 11 May 2026

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Abstract

Background: Although several risk factors have been reported for long COVID (LC), reliable biomarkers for this illness remain lacking. Insulin-like growth factor (IGF)-I, a major mediator of growth hormones, plays an important role in metabolism, neuroprotection, and systemic homeostasis, and therefore may be useful in predicting the severity and prognosis of LC. Methods: This study included patients who visited a specialized clinic for long COVID between 2022 and 2025 during the Omicron period and had serum IGF-I measurements taken. IGF-I levels were expressed as age- and sex-adjusted standard deviation scores (IGF-I SD), and patients were classified into low (SD < −1.0), normal (−1.0 ≤ SD < 1.0), and high (SD ≥ 1.0) groups. Clinical characteristics, patient-reported outcomes, laboratory data, and follow-up duration were analyzed. Results: A total of 811 patients were included (median 42 years; 52.5% female). Compared with the normal group, the low-IGF-I group exhibited higher fatigue (FAS: 37.0 vs. 34.0; p < 0.05) and depressive (SDS: 50.0 vs. 49.0; p < 0.05) status. Multivariable linear regression analyses identified lower IGF-I SD as independently associated with higher scores of both FAS and SDS. IGF-I SD values showed negative correlations with ferritin (ρ = −0.125, p < 0.05) and TSH (ρ = −0.202, p < 0.01) and positive correlations with albumin (ρ = 0.227, p < 0.01) and FT4 (ρ = 0.165, p < 0.01). Among the 237 patients who completed follow-up, the median duration from the initial visit to recovery tended to be longer in the low-IGF-I group (221 days) compared with the normal (191 days) and high (109 days) groups, although these differences were not statistically significant overall. In patients aged < 50 years, the low-IGF-I group showed a relatively longer follow-up duration (p < 0.05). Furthermore, the low-IGF-I group had a longer time to recovery compared to the high-IGF-I group (p < 0.05), and this difference was more pronounced in patients under 50 years of age, with significant differences observed among the three IGF-I groups. Conclusions: Lower IGF-I levels in LC may be associated with greater fatigue and depressive symptoms and longer recovery time, particularly in younger patients. Further studies are needed to clarify the clinical significance of these findings. Full article

(This article belongs to the Special Issue Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations)

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8 pages, 210 KB

Open AccessCommentary

Beyond Fatigue: The Fatigue Assessment Scale as a Potential Indicator of Long COVID Severity

by Giulia Del Duca, Marta Franco, Lorenzo Talamanca, Andrea Antinori and Marta Camici

J. Clin. Med. 2026, 15(15), 5878; https://doi.org/10.3390/jcm15155878 - 28 Jul 2026

Viewed by 491

Abstract

Patient-reported outcomes (PROs) are often regarded in clinical practice as less reliable than biomarkers because they are patient-dependent and not objectively measurable in the same way as circulating molecules or imaging findings. This view may be reductive. Biomarkers are frequently considered reliable because they are easily quantifiable, yet biological meaning does not depend solely on measurement. In precision and personalized medicine, the absolute level of a circulating hormone, cytokine, or metabolite is often insufficient unless interpreted in relation to how a given patient, at a given time, responds to that molecular signal. If biomarkers are considered less absolute and more context-dependent, the relevance of PROs becomes clearer. Standardized PROs capture the subjective impact of disease on the patient system in a reproducible and clinically interpretable manner. This is particularly relevant in Long COVID, where no validated diagnostic biomarker is currently available, and severity stratification cannot rely exclusively on objective biological measures. Among available tools, the Fatigue Assessment Scale (FAS) may be particularly useful for quantifying the fatigue burden in Long COVID, including both physical and mental components. Moreover, FAS scores have been shown to correlate with the number of symptoms reported by patients, suggesting that this scale may help stratify patients not only according to fatigue severity but also according to overall symptom burden. Greater standardization of clinical characterization through instruments such as the FAS may improve comparability across cohorts and facilitate interpretation of data from different clinical trials. Full article

(This article belongs to the Special Issue Integrated Management of Long COVID: Fatigue, Emerging Evidence, and Therapeutic Innovations)

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