Search Results (85)

Background: SARS-CoV-2, originally described as a respiratory pathogen, has been identified as a multisystem disease with complex and interconnected pathophysiological processes. Methods: The PRISMA framework was used to systematically review the evidence and identify and synthesize it in PubMed, Scopus, and Web of Science databases between January 2020 and May 2025. Of the 1410 screened records, 161 peer-reviewed studies involving more than 2 million patients were included in the analysis. The frequency of organ involvement, important biomarkers, and long-term outcomes were derived, and the quality of the studies was assessed using standardized tools. Results: The quantitative synthesis showed that 78%, 32%, 43%, and 28% of hospitalized patients had pulmonary, cardiovascular, 43% neurological, and 28% renal issues, respectively, with 10–35% showing persistent organ dysfunction at 6 months post-infection. The most common were cytokine storm (IL-6 (Interleukin-6) > 100 pg/mL in 72% of severe cases), endothelial dysfunction (biomarkers elevated in 87% of patients), and microvascular thrombosis (D-dimer > 2000 ng/mL in 46% of patients). Most domains were scored as having moderate-to-high confidence in the quality assessment. Conclusions: COVID-19 has long-term, multi-organ sequelae that require integrated multidisciplinary management. Healthcare systems should be ready to participate in long-term monitoring, rehabilitation, and special therapeutic development. The results offer a strong evidence base for clinical practice and post-pandemic health policy. Full article

Background: COVID-19 has been associated with multisystemic sequelae, including persistent neurocognitive impairment and emerging metabolic alterations. Growing evidence suggests that glial dysfunction and inflammation may play a pivotal role in both cognitive decline and new-onset diabetes following SARS-CoV-2 infection. Objectives: This study aimed to assess the prevalence and characteristics of cognitive impairments in post-COVID-19 patients and to explore their correlation with new-onset diabetes, neuroanatomical changes, and psychological symptoms, with a specific focus on gender differences. Methods: A total of 245 patients (mean age 56.8 ± 12 years), previously diagnosed with COVID-19, were enrolled between April 2021 and August 2023. Participants underwent a comprehensive neuropsychological assessment (MMSE, Rey-Osterrieth Figure, FAB, Hamilton, STAI, IES-R), structured interviews, and, in a subset, brain MRI. Individuals with pre-existing neurological disorders were excluded. Data were analyzed for cognitive performance, neuroimaging abnormalities, and metabolic outcomes, including new-onset diabetes. Results: Cognitive dysfunction was identified in 87% of participants: mild in 47%, moderate in 21.6%, and severe in 10.8%. Glial alterations on MRI were observed in 51%, hippocampal atrophy in 9%, and temporal lobe reduction in 4%. Notably, 12% of patients developed new-onset diabetes post-COVID, of whom 80% exhibited mild to moderate cognitive deficits. Depressive symptoms were present in 80.9%, and anxiety in 93.5%, with significantly higher incidence in female patients. PTSD symptoms correlated with greater cognitive impairment. Ongoing research into the mechanisms underlying these persistent cognitive impairments in subjects with and without types 1 and 2 diabetes. This paper presents the final data of the research published in the previous article referenced in the bibliography. Conclusions: This study highlights a significant association between cognitive decline and new-onset diabetes in post-COVID patients, likely mediated by systemic inflammation and glial dysfunction. Particularly noteworthy are the findings of neuroanatomical alterations, including nonspecific glial signal changes, hippocampal atrophy, and temporal lobe volume reductions, suggesting post-infectious cerebral vulnerability with potential long-term consequences. These results support the need for integrating cognitive screening, brain neuroimaging, and metabolic monitoring into post-COVID care pathways—especially for women and individuals presenting with anxiety or depressive symptoms. An early and interdisciplinary approach is essential to address the neuro-metabolic and cerebral sequelae of long COVID. Full article

Since the start of the COVID-19 pandemic, increasing evidence has shown that SARS-CoV-2 infection can cause long-term symptoms, collectively known as long COVID, and that patients with mild COVID-19 can also be affected by persistent fatigue, cognitive impairment, dyspnea, muscle pain, etc. Recent research has also found multiple organ systems, including the liver, to be significant sites of ongoing injury. This narrative review summarizes current knowledge on organ involvement during and after COVID-19, with particular focus on early and delayed hepatic manifestations and associated risk factors. Pathogenesis appears to be multifactorial, involving direct virus action, the body’s immune-mediated inflammatory response, microvascular damage, drug-induced hepatotoxicity, and, in some cases, reactivation or exacerbation of pre-existing liver conditions. The hepatic clinical manifestations range from asymptomatic elevations of transaminases to cholangiopathy and even fibrosis. These can persist or progress for months after the initial infection with SARS-CoV-2 is resolved, requiring prolonged monitoring and interdisciplinary care, especially in the presence of metabolic disorders, obesity, or hepatitis. Neurological, cardiovascular, and other sequelae are discussed in parallel, with attention paid to common inflammatory and thrombotic pathways. This review concludes that liver dysfunction is of particular interest in long-COVID due to the liver’s central role in metabolism and inflammation. While further research is being conducted into organ-specific and systemic interactions, the available evidence makes a compelling case for extended monitoring and integrated management strategies post infection. Full article

This case report presents a unique constellation of symptoms—including dry eye disease, visual and general asthenia, sleep disturbances, and restless legs syndrome—in a patient with a recent history of coronavirus disease 2019 (COVID-19) infection. While these symptoms have individually been associated with either COVID-19 or long COVID, their concurrent presentation and the simultaneous, positive response across all manifestations to a combined therapeutic regimen have not been previously described in a single case. The patient demonstrated notable improvement in both ocular and systemic symptoms following a six-week treatment with topical tear substitutes and oral administration of melatonin, and a multivitamin supplement including B-complex vitamins, antioxidants, and neuroprotective agents (Colinplus Delta^®, Farmaplus Italia Srl, Via Giovanni Porzio 4, 80143 Napoli, Italy). This response suggests a possible shared pathophysiological mechanism underlying these manifestations, potentially involving post-viral neuroinflammation, immune dysregulation, oxidative stress, or autonomic dysfunction. This case report highlights the need for an increased awareness of the interconnected nature of ocular and neurological symptoms in long COVID and supports further research into non-invasive, multimodal treatment strategies for this emerging clinical spectrum. Full article

The COVID-19 pandemic has revealed the profound and lasting impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the nervous system. Beyond acute infection, SARS-CoV-2 acts as a potent immunomodulatory agent, disrupting immune homeostasis and contributing to persistent inflammation, autoimmunity, and neurodegeneration. Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is characterized by a spectrum of neurological symptoms, including cognitive dysfunction, fatigue, neuropathy, and mood disturbances. These are linked to immune dysregulation involving cytokine imbalance, blood–brain barrier (BBB) disruption, glial activation, and T-cell exhaustion. Key biomarkers such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NFL) correlate with disease severity and chronicity. This narrative review examines the immunopathological mechanisms underpinning the neurological sequelae of long COVID, focusing on neuroinflammation, endothelial dysfunction, and molecular mimicry. We also assess the role of viral variants in shaping neuroimmune outcomes and explore emerging diagnostic and therapeutic strategies, including biomarker-guided and immune-targeted interventions. By delineating how SARS-CoV-2 reshapes neuroimmune interactions, this review aims to support the development of precision-based diagnostics and targeted therapies for long COVID-related neurological dysfunction. Emerging approaches include immune-modulatory agents (e.g., anti-IL-6), neuroprotective drugs, and strategies for repurposing antiviral or anti-inflammatory compounds in neuro-COVID. Given the high prevalence of comorbidities, personalized therapies guided by biomarkers and patient-specific immune profiles may be essential. Advancements in vaccine technologies and targeted biologics may also hold promise for prevention and disease modification. Finally, continued interdisciplinary research is needed to clarify the complex virus–immune–brain axis in long COVID and inform effective clinical management. Full article

Multisystemic inflammatory syndrome in children (MIS-C) is a rare but potentially severe condition that affects multiple organ systems. This study aimed to assess the clinical characteristics and outcomes of patients diagnosed with multisystemic inflammatory syndrome in children (MIS-C) associated with COVID-19. A 12-month prospective study was conducted at the “Grigore Alexandrescu” Clinical Emergency Hospital for Children, Bucharest. This study included children aged 0–18 years who were diagnosed with MIS-C, as defined by the World Health Organization (WHO), the Royal College of Paediatrics and Child Health (RCPCH), and the Centers for Disease Control and Prevention (CDC) criteria. Data on age, gender, clinical and laboratory findings, treatment, and outcomes were analyzed. Follow-up evaluations occurred at one, three, six, nine, and twelve months post-discharge. Among 36 patients (47.3% female, 52.7% male; mean age, 9.9 years), fever and inflammatory syndrome were present in all patients. Other common symptoms included mucocutaneous (63.8%), gastrointestinal (52.7%), cardiac (47.2%), pulmonary (38.8%), and neurological (11.1%) manifestations. At admission, 14/36 were IgM-positive, while 34/36 were IgG-positive. Follow-up revealed sequelae in two patients, including coronary aneurysms and ground-glass pulmonary opacities. Although MIS-C can be severe, most patients had favorable outcomes with proper treatment. Few long-term, organ-specific complications were observed, highlighting the importance of systematic monitoring to ensure full recovery. Full article

Neuropathic pain has emerged as a significant concern for patients dealing with persistent post-COVID-19 symptoms. Small fiber neuropathy (SFN) has been identified as a potential underlying mechanism contributing to long-term pain in these patients. Despite an increasing body of evidence associating post-COVID-19 SFN with immune dysregulation and neuroinflammation, the exact pathophysiology and optimal treatment remains unclear. This review aims to explore the pathophysiology, diagnosis, proposed mechanisms, and treatment of post-COVID-19 SFN. A comprehensive literature review was conducted, examining studies on SFN, as well as SFN in the context of COVID-19, including clinical manifestations, diagnostic criteria, and potential treatment modalities. Evidence was gathered from case studies, observational reports, and clinical trials addressing post-COVID-19 neuropathy and SFN. SFN in long COVID presents a heterogeneous range of sensory and autonomic symptoms. Diagnosis relies on clinical evaluation, quantitative sensory testing, and confirmatory skin biopsy. Proposed mechanisms include autoimmune dysregulation, molecular mimicry, direct viral invasion of neural structures, and inflammatory responses. Pharmacological treatments—such as gabapentin, antidepressants, and corticosteroids—have demonstrated symptom relief, while immunomodulatory therapies show promise in immune-mediated cases. Non-pharmacological strategies warrant further investigation. Post-COVID-19 SFN represents a complex and multifactorial condition requiring a multidisciplinary approach to diagnosis and management. While merging evidence supports immune-mediated pathogenesis, further research is needed to establish definitive mechanisms and optimize targeted therapeutic strategies. Continued investigation into post-COVID-19 SFN will be crucial in addressing the long-term neurological sequelae of SARS-CoV-2 infection. Full article

Endothelial dysfunction plays a central role in COVID-19 pathogenesis, by affecting vascular homeostasis and worsening thromboinflammation. This imbalance may contribute to blood–brain barrier (BBB) disruption, which has been reported in long COVID-19 patients with neurological sequelae. The kallikrein–kinin system (KKS) generates bradykinin (BK), a proinflammatory peptide that induces microvascular leakage via B2R. Under inflammatory conditions, BK is converted to Des-Arg-BK (DABK), which activates B1R, a receptor upregulated in inflamed tissues. DABK is degraded by ACE2, the main SARS-CoV-2 receptor; thus, viral binding and ACE2 downregulation may lead to DABK/B1R imbalance. Here, we investigated these interactions using human brain microvascular endothelial cells (HBMECs), as a model of the BBB. Since endothelial cell lines express low levels of ACE2, HBMECs were modified with an ACE2-carrying pseudovirus. SARS-CoV-2 replication was confirmed by RNA, protein expression, and infectious particles release. Infection upregulated cytokines and endothelial permeability, enhancing viral and leukocyte transmigration. Additionally, viral replication impaired ACE2 function in HBMECs, amplifying the response to DABK, increasing nitric oxide (NO) production, and further disrupting endothelial integrity. Our findings reveal a mechanism by which SARS-CoV-2 impacts the BBB and highlights the ACE2/KKS/B1R axis as a potential contributor to long COVID-19 neurological symptoms. Full article

Background/Objectives: SARS-CoV-2 can affect the central nervous system directly or indirectly. AD shares several similarities with long COVID cognitive impairment on a molecular and imaging level, as well as common risk factors. The objective of this review is to evaluate the incidence of post-acute COVID-19 cognitive impairment. Secondarily, we aim to determine if neuroinflammation in COVID-19 survivors may be associated with the onset of neurological disease, with a focus on Alzheimer’s disease (AD). Methods: literature search up to March 2025 on the prevalence of cognitive deficits in COVID-19 survivors, underlying pathophysiology and associations with neurological disorders. Results: a wide array of neuropsychiatric manifestations is associated with COVID-19; executive function, memory, and attention are the most frequently reported neurocognitive deficits, regardless of COVID-19 severity. There are associations between the risks for cognitive deficits post-infection with the age of the patients and the severity of the disease. Increasing evidence suggests that neurocognitive deficits are associated with the onset of neurological and neuropsychiatric disease in COVID-19 survivors. Conclusions: clinicians caring for COVID-19 survivors should actively investigate neurocognitive sequelae, particularly for patients with increased risk for cognitive deficits. Full article

The coronavirus disease 2019 (COVID-19) pandemic has been linked to long-term neurological effects with multifaceted complications of neurodegenerative diseases. Several studies have found that pathological changes in transactive response DNA-binding protein of 43 kDa (TDP-43) are involved in these cases. This review explores the causal interactions between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and TDP-43 from multiple perspectives. Some viral proteins of SARS-CoV-2 have been shown to induce pathological changes in TDP-43 through its cleavage, aggregation, and mislocalization. SARS-CoV-2 infection can cause liquid−liquid phase separation and stress granule formation, which accelerate the condensation of TDP-43, resulting in host RNA metabolism disruption. TDP-43 has been proposed to interact with SARS-CoV-2 RNA, though its role in viral replication remains to be fully elucidated. This interaction potentially facilitates viral replication, while viral-induced oxidative stress and protease activity accelerate TDP-43 pathology. Evidence from both clinical and experimental studies indicates that SARS-CoV-2 infection may contribute to long-term neurological sequelae, including amyotrophic lateral sclerosis-like and frontotemporal dementia-like features, as well as increased phosphorylated TDP-43 deposition in the central nervous system. Biomarker studies further support the link between TDP-43 dysregulation and neurological complications of long-term effects of COVID-19 (long COVID). In this review, we presented a novel integrative framework of TDP-43 pathology, bridging a gap between SARS-CoV-2 infection and mechanisms of neurodegeneration. These findings underscore the need for further research to clarify the TDP-43-related neurodegeneration underlying SARS-CoV-2 infection and to develop therapeutic strategies aimed at mitigating long-term neurological effects in patients with long COVID. Full article

SARS-CoV-2 infection has resulted in more than 700 million cases and nearly 7 million deaths worldwide. Although vaccination efforts have effectively reduced mortality and transmission rates, a significant proportion of recovered patients—up to 40%—develop long COVID syndrome (LC) or post-acute sequelae of COVID-19 infection (PASC). LC is characterized by the persistence or emergence of new symptoms following initial SARS-CoV-2 infection, affecting the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Despite the broad range of clinical symptoms that have been described, the risk factors and pathogenic mechanisms behind LC remain unclear. This review, the first of a two-part series, is distinguished by the discussion of the role of the SARS-CoV-2 spike protein in the primary mechanisms underlying the pathophysiology of LC. Full article

The mechanism of post-acute sequelae of SARS-CoV-2 (PASC) is unknown. Using optical coherence tomography angiography (OCT-A), we compared retinal foveal avascular zone (FAZ), vessel density (VD), and vessel length density (VLD) in non-hospitalized Neuro-PASC patients with those in healthy controls in an effort to elucidate the mechanism underlying this debilitating condition. Neuro-PASC patients with a positive SARS-CoV-2 test and neurological symptoms lasting ≥6 weeks were included. Those with prior COVID-19 hospitalization were excluded. Subjects underwent OCT-A with segmentation of the full retinal slab into the superficial (SCP) and deep (DCP) capillary plexus. The FAZ was manually delineated on the full slab in ImageJ. An ImageJ macro was used to measure VD and VLD. OCT-A variables were analyzed using linear mixed-effects models with fixed effects for Neuro-PASC, age, and sex, and a random effect for patient to account for measurements from both eyes. The coefficient of Neuro-PASC status was used to determine statistical significance; p-values were adjusted using the Benjamani–Hochberg procedure. Neuro-PASC patients (N = 30; 60 eyes) exhibited a statistically significant (p = 0.005) reduction in DCP VLD compared to healthy controls (N = 44; 80 eyes). The sole reduction in DCP VLD in Neuro-PASC may suggest preferential involvement of the smallest blood vessels. Full article

Background/Objectives: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, chronically relapsing disorder that causes life-threatening thrombotic microangiopathy. Many survivors in clinical remission show evidence of ongoing silent cerebral infarction and neurocognitive deficits. Prospective longitudinal studies of this population are needed to acquire a complete understanding of the mechanism behind this ongoing neurologic injury. We aimed to assess the feasibility of a multicenter prospective study of neuropsychological and cognitive function in iTTP survivors in remission and examine novel biomarkers. Methods: We aimed to enroll 50 iTTP patients across three USTMA consortium sites between 2019 and 2022 in a 24-month longitudinal study. Clinical, cognitive, and biomarker assessments, including ADAMTS13 activity, were performed. Results: Despite the COVID-19 pandemic, we enrolled 38 subjects, and 31 (81.6%) completed closeout evaluations at 24 months. Upon the participants’ enrollment in the study, we confirmed previous findings, including high rates of moderate to severe neurocognitive and psychiatric sequelae (anxiety, 47%; depression, 45%; and headaches, 55%). Changes in cognitive function were measurable and included decreased immediate memory and visuospatial abilities. Over this two-year study, we did not see a significant change in neurocognitive findings. There was no association between cognitive function and ADAMTS13 activity; however, we found that the level of soluble thrombomodulin (CD141) was significantly correlated with cognitive impairment. Conclusions: We conclude that a more extensive study is feasible, and at least 5–10 years may be required to detect trends in neurocognitive function. Soluble thrombomodulin is a promising biomarker for cognitive impairment in survivors of iTTP, and it is worthy of additional study. Full article

Post-acute sequelae of COVID-19 (PASC) are a diverse set of symptoms and syndromes driven by dysfunction of multiple organ systems that can persist for years and negatively impact the quality of life for millions of individuals. We currently lack specific therapeutics for patients with PASC, due in part to an incomplete understanding of its pathogenesis, especially for non-pulmonary sequelae. Here, we discuss three animal models that have been utilized to investigate PASC: non-human primates (NHPs), hamsters, and mice. We focus on neurological, gastrointestinal, and cardiovascular PASC and highlight advances in mechanistic insight that have been made using these animal models, as well as discussing the sequelae that warrant continued and intensive research. Full article

Both postural orthostatic tachycardia syndrome (POTS) and Long COVID are currently viewed as heterogeneous disorders with complex, multi-factorial and multi-systemic pathophysiology. POTS, one of the most common autonomic disorders, is a frequent sequela of SARS-CoV-2 infection. Both POTS and autonomic dysfunction, in general, are major pathophysiologic mechanisms of Long COVID. There is emerging evidence that neuroinflammation of the brainstem may be one of the mechanisms of POTS and Long COVID. This commentary argues that neuroinflammation at the dorsolateral inferior medulla is a possible central nervous system localization for POTS and Long COVID based on the limited scientific literature available to date and the neurologic manifestations of both disorders. Further studies involving advanced neuroimaging techniques and animal models with immunohistochemical brainstem tissue assessments are needed to understand how and why possible neuroinflammation at the dorsolateral inferior medulla may occur in patients with Long COVID, POTS and other disorders involving autonomic dysfunction. Full article