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Open research questions in Long-Term Effects of COVID-19

72 unresolved questions extracted from the limitations and future-work sections of 554 Long-Term Effects of COVID-19 papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Future research should investigate links between new onset PI/SAD and POTS, the role of COVID in triggering dysautonomia, and whether IVIg can be systematically evaluated as a therapeutic option.

    Post COVID-19 Rise in Postural Orthostatic Tachycardia Syndrome and Antibody Deficiency: Exploring Immunoglobulin Therapy for Symptom Management 2309853 · 2026 · DOI

  • While olfactory training (OT) is the current gold standard for rehabilitation, the additive role of systemic corticosteroids remains controversial, particularly for patients presenting late.

    Comparative efficacy of olfactory training versus combination therapy with oral corticosteroids in COVID-19 associated post-viral olfactory dysfunction · 2026 · DOI

  • This instrument does not capture lower respiratory symptoms (dyspnea, pneumonia) or chemosensory dysfunction (anosmia/ageusia) characteristic of COVID-19, and its performance for discriminating COVID-19 severity has not been established.

    Association between COVID-19 infection experience and physical activity levels in post-recovery college students · 2026 · DOI

  • While more prospective data are needed, these findings moti- vate further research on the post-COVID-19 condition, with impaired cognitive function as a key feature, and highlight the need for monitoring of individuals experi- encing severe acute COVID-19 illness.

    Acute COVID-19 severity and impaired cognitive function up to 32 months after diagnosis: an observational study · 2026 · DOI

  • Introduction Long COVID is known to be associated with prolonged multiple organ symptoms and decreased health-related quality of life (HRQoL), but the pathogenesis and relationship between immune, inflammatory, and metabolic biomarkers and HRQoL remains poorly understood.

    Long COVID and health-related quality of life: a systematic review of immune, inflammatory, and metabolic markers · 2026 · DOI

  • Strengths and limitations of this studyO_LIRECOVER-ENERGIZE is a large, multicenter, randomized controlled platform trial that stratifies participants by PEM status, separately evaluating cardiopulmonary rehabilitation in those without significant PEM and structured activity pacing in those with PEM, while mitigating the risk of exertional harm.

    Rationale and Design of RECOVER-ENERGIZE: A Platform Clinical Trial of Interventions for Exercise Intolerance With and Without Post-exertional Malaise in Long COVID · 2026 · DOI

  • Multimorbidity, the co-occurrence of multiple long-term conditions, represents a major challenge for ageing populations, yet its genetic architecture and relationship to long COVID remain unclear, despite shared epidemiological risk factors.

    Exploring the genetic architecture of multimorbidity and its impact on long COVID risk · 2026 · DOI

  • Abstract Introduction Although tobacco use disorder (TUD) and long COVID (LC) have been associated to neuropsychiatric disturbances, it remains unclear how tobacco dependence affects the recovery of clinical, cognitive, and biological processes over time.

    Divergent Long-Term Recovery After Long COVID in Tobacco Use Disorder and Healthy Controls: A Longitudinal Study · 2026 · DOI

  • The small sample size limits statistical power, increases the risk of overfitting in high-dimensional analyses, and may inflate effect size estimates. Accordingly, this pilot integrative analysis should be con- sidered exploratory and hypothesis-generating. In addition, differences in matching and sample selection strategies between transcriptomic and metabolomic analyses, driven by biospecimen availability and quality constraints, resulted in differences in sex distribution across Frontiers in Cellular and Infection Microbiology 15 frontiersin.org Espı´n et al. 10.3389/fcimb.2026.1808564 analytical platforms. Although age and sex were balanced between LC cases and controls within each analysis, these design differences may introduce heterogeneity between platforms and represent an additional study limitation. Serum metabolomic profiles may also be influenced by covariates such as diet, fasting status, circadian variation, medication use, and physical activity. Because previously biobanked samples were used, detailed metadata for several of these variables were not available. Although age, sex, BMI, and sampling time were balanced between groups, residual metabolic confounding cannot be excluded. Cross- cohort validation was further limited by substantial methodological and clinical heterogeneity across publicly available LC datasets, likely contributing to reduced statistical replication. Therefore, the identified immune–metabolic signatures should be interpreted cautiously as candidate biomarkers requiring validation in larger, better-matched independent cohorts.

    Pilot longitudinal integrated transcriptomic–metabolomic study reveals immune and metabolic signatures in non-hospitalized healthcare workers with long COVID · 2026 · DOI

  • This pilot study was conducted at two study sites with a short observation period and a small sample size, which may limit generalizability and underrepresent certain social groups (e.g., minorities, low education levels). As this pilot study focused on feasibility and adherence, no control group was included. Consequently, conclusions regarding added benefit over standard pPCS care are limited, despite encour- aging descriptive findings. Intermittent smartwatch data transmission and the inability to evaluate heart rate vari- ability limited the full potential of wearable-based monitor- ing in this pilot study setting. Nevertheless, HRV remains a key parameter in pediatric PCS, and the technical chal- lenges encountered provide important insights for refining future telemonitoring concepts. Licensing of the telemoni- toring components from the age of 12 years limits the sci- entific significance in younger patients. Telemonitoring also risks reinforcing the digital divide, excluding those without access to or financial means for devices or stable internet. The project was only feasible through research funding, as telemonitoring for PCS or ME/CFS is currently not reim- bursed in Germany. Contributing factors include low eco- nomic incentives for pediatric care [50], complex design requirements, and higher legal and ethical hurdles.

    Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study · 2026 · DOI

  • Telemonitoring is a valuable tool for managing pPCS, how- ever, supporting severely ill patients, especially in ME/ CFS care, requires further development, including extended monitoring periods considering the longer disease course, adapted PROMs, and medication tracking. Device and parameter selection should mirror specific symptom clus- ters (e.g., spirometry for respiratory symptoms, blood pres- sure and medication tracking for POTS, alongside standard HR, HRV, and PROMs). Future studies should assess smart- watch wear time to evaluate adherence and user behavior. We are already implementing these insights in two follow- up projects Telemonitoring for Youth ME/CFS (TYME) [80] and Pediatric Network for Care and Clinical Research on Page 11 of 15 76 Post-Acute Sequelae of COVID-19 (Long COVID), similar Post-Acute Infection Syndromes, and ME/CFS (PEDNET- LC) (AP 4.3 TELE-LC) [81]. Broader use of digital parameters may support the iden- tification of digital biomarkers and more personalized treat- ment strategies. Moreover, the potential of telemonitoring data to support biomarker research and personalized treat- ment or exercise-management strategies remains to be fur- ther investigated in future studies. Despite telemonitoring’s considerable potential for improving pPCS and ME/CFS care, high-quality evidence on these diseases and general pediatric telemedicine remains limited. Larger studies with extended follow-up, compare groups, quality of life assess- ment, and cost-effectiveness analyses are needed to support its integration into standard care and pediatric reimburse- ment frameworks. For patients severely affected by PEM, telemonitoring emerges as ethically essential to avoid further deteriora- tion triggered by in-person visits by reducing the necessity of such visits through remote alternatives and prioritize in-person visits only when specifically indicated. Future guidelines should prioritize its inclusion to support safe, continuous care.

    Feasibility, Adherence, Acceptance and Usability of a Multimodal Telemonitoring for Pediatric Post-COVID Syndrome: A Bicentric Pilot Study · 2026 · DOI

  • Limitations include the cross-sectional design (precluding causal inference); absence of a pre-COVID psychological baseline and a non-COVID control group; possible underrepresentation of informally tested individuals; social desirability bias in telephonic self-reporting; confounding by differential time since infection across waves; and restriction to the urban area of a single city in Jharkhand. Findings may not generalize to rural or tribal populations in the region.

    Prevalence and Severity of Depression, Anxiety, and Stress Among COVID-19 Survivors in Urban Hazaribagh, Jharkhand: A Community-Based Cross-Sectional Study · 2026 · DOI

  • investigated in future studies. In view of the current data, it is crucial infection or PCS undergo comprehensive cardiac diagnostic evaluation and follow-up to identify and treat potential complications at an early stage. Future studies should focus on understanding the mechanisms of altered cardiac function and morphology in order to develop appropriate intervention strategies.

    Cardiovascular phenotyping of children and adolescents with post-COVID syndrome (PCS) at initial diagnosis - a prospective observational single-center study · 2026 · DOI

  • The contribution of both traditional and less typical factors, particularly pain syndrome, to the course of ischemic stroke on the background of coronavirus disease 2019 (COVID-19) remains insufficiently studied, especially in the context of fatal outcomes.

    Comprehensive assessment of pain syndrome and other clinical factors in the development of adverse outcomes in patients with stroke and concomitant COVID-19 · 2025 · DOI

  • The detection of SARS-CoV-2 viral antigen in brain autopsy samples is highly controversial. Although we are currently still trying to generate EM to assess evidence for direct viral infection in substantia nigra neurons, those studies are technically extremely challenging given the low number of DA neurons and difficulties in sample availability and quality. In addition, due to the biosafety requirements of COVID-19 autopsy samples, we are not capable of performing extensive analysis, such as scRNA-seq, on autopsy samples of COVID-19 patients. The co-staining of the TH neuron marker and SARS-N viral antigen was initially conducted on an autopsy sample, but further validation with a larger sample size is necessary to confirm these findings and to rule out technical challenges such as senescence-related lipofuscin expression that could interfere with reliable SARS-N detection. Furthermore, our study represents the first detailed, quantitative pathological analysis of midbrain DA neurons in severe COVID-19 patients and is limited to the cohort 2 of patients presented here, representing the first wave of COVID-19 cases. Additional analyses using independent and more recent cohorts of patients are needed to further validate the inflammatory and degenerative phenotypes observed. Finally, by focusing on cellular senescence in 72-h infection model, Figure 7. Inflammatory, senescence, and DA neuron degenerative phenotypes were detected in autopsy substantia nigra samples of COVID- 19 patients (A–D) Heatmap of chemokine/cytokine (A), inflammation-associated genes (B), senescence-associated genes (C), and SASP associated genes (D) in the autopsy substantia nigra sections of COVID-19 patients versus non-COVID-19 patients (cohort 1: N = 6 COVID-19 patients; N = 3 non-COVID-19 patients). (E) Heatmap of viral transcripts in autopsy substantia nigra sections of COVID-19 patients (cohort 1: N = 6 COVID-19 patients; N = 3 non-COVID-19 patients). (F) Representative confocal images (left) and quantification (right) of p-aSyn in the autopsy substantia nigra sections of COVID-19 patients versus non-COVID-19 patients (cohort 1: N = 2 COVID-19 patients; N = 3 non-COVID-19 patients). Scale bars, 50 mm. (G) Representative images of TH-immunoreactivity (gray) in the substantia nigra (cohort 2). Scale bars, 200 mm. Data were presented as mean ± SD. p values were calculated by unpaired two-tailed Student’s t test. (H) Graphs illustrating quantification of neuromelanin-containing neurons, TH-immunoreactive neurons, and threads (cohort 2). p values were calculated by a Kruskal-Wallis test. *p < 0.05, **p < 0.01, and ***p < 0.001. n.s., no significant. See also Figure S7 and Tables S1, S2, S3, and S4.

    SARS-CoV-2 infection causes dopaminergic neuron senescence · 2024 · DOI

  • Introduction: While there is sufficient information about acute COVID-19, which can cause a multisystemic and fatal disease, post-COVID syndrome and risk factors for this condition remain poorly known.

    Analysis of post-COVID symptoms and predisposing factors for chronic post-COVID syndrome · 2023 · DOI

  • The information obtained is based on a review of electronic records with retrospective technique, obtained from different specialist physicians, where precision may vary between different professionals.

    Clinical Complications in Patients with SARS-CoV-2 in a Secondary Care Hospital in Tijuana, Mexico · 2022 · DOI

  • The statistics suggest that alterations of the chemosensory function are strongly correlated with COVID-19, although the exact pathophysiologic mechanism is not well established.

    How COVID-19 brought smell disorders in the spotlight · 2021 · DOI

  • Rehabilitation management of lung transplant recipients with Covid-19 has not been studied and therefore it is crucial to investigate the effects of early evaluation and treatment of impairments exhibited by these patients, as they will likely require acute and long-term rehabilitation.

    Acute Rehabilitation in a Lung Transplant Recipient Infected with Covid-19: Case Report · 2021 · DOI

  • However, there is a lack of evidence on salivary consistency and flow of COVID-19 patients, the increased salivation reported by our patients might cause AC as the salivary enzymes can irritate the skin of the mouth corners leading to maceration and digestion.

    Angular cheilitis of COVID‐19 patients: A case‐series and literature review · 2020 · DOI

  • Although the pathophysiology of the virus and the epidemiology of its impact are only just being unraveled, clinical characteristics, and outcomes specifically among patients with primary psychiatric disorders who are hospitalized with COVID-19 remain unclear and unreported.

    Clinical characteristics, hospital course, and outcomes among COVID-19 positive patients with mental illness in a community hospital in New York City · 2020 · DOI

  • 9%) LC], highlighting that symptom emergence is not limited to the early post-infection period.

    Longitudinal trajectories of long COVID among hospitalized patients with omicron infection in Changzhi, China · 2026 · DOI

  • These findings prompt further research into optimal strategies to reduce the impact of ILI in MHS settings and the general population.

    Assessing the relationship between body mass index and influenza-like illness risk and symptom severity among military health system beneficiaries vaccinated against influenza: a pooled prospective cohort study from a randomized trial · 2026 · DOI

  • The population (n = 56) was limited to the par‑ ticipants who attended the second postinfec‑ tion visit at our center.

    D-dimer changes and associations in Long COVID: a prospective observational study · 2026 · DOI

  • Change correlations between 30s-STS repetitions and the anchors were insufficient for anchor-based MID calculation.

    Measurement properties of the 30-second sit-to-stand test in post COVID-19 condition: Results from the PYCNOVID randomised controlled trial · 2026 · DOI

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72 open questions have been extracted from the limitations and future-work passages of 554 Long-Term Effects of COVID-19 papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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