The research team, led by Shengbo Cai of the Fifth Hospital of Xiamen and including colleagues from Peking University Shenzhen Hospital, reviewed the clinical records of 519 children hospitalized with symptomatic COVID-19 between December 2022 and December 2025. This three-year window allowed the investigators to compare two distinct epidemiological eras: a calendar period in which Omicron BA.5 and its close descendants predominated, and a subsequent post-BA.5 period characterized by later viral variants. The cohort was strikingly young. Infants and toddlers accounted for 345 of the 519 admissions, or 66.4 percent, underscoring that the youngest children continue to bear a disproportionate share of pediatric COVID-19 hospitalizations even years into the pandemic.

When the researchers classified disease severity, they found that 192 patients, or 37.0 percent, had mild disease, 227 patients, or 43.7 percent, had moderate disease, and 100 patients, or 19.3 percent, fell into the severe or critical category. Notably, every child in the cohort improved or achieved clinical recovery, a reassuring outcome that reflects both the inherent resilience of young patients and the quality of supportive care available at the study center. Nevertheless, nearly one in five hospitalized children required classification as severe or critical, a proportion high enough to justify a careful search for early warning signs that could help clinicians triage and monitor admissions.

The comparison between the two calendar periods revealed a consistent pattern of attenuation over time. Children admitted during the post-BA.5 period experienced a lower proportion of severe and critical disease, needed supplemental oxygen less often, spent fewer days in the hospital as measured by the median length of stay, and suffered fewer complications overall. All of these differences reached statistical significance, with P values below 0.05. The picture was not uniformly favorable in the later period, however. Neurological symptoms were actually more frequent during the BA.5-predominant calendar period, while the rate of viral co-detection, meaning the simultaneous presence of other respiratory pathogens alongside SARS-CoV-2, was lower during that same period. These shifting patterns illustrate how the clinical phenotype of pediatric COVID-19 is not static but evolves in tandem with the viral population.

To identify factors independently associated with severe and critical disease, the team turned to multivariable logistic regression, the standard statistical tool for isolating the effect of each candidate predictor while accounting for the others. In the primary analysis, three factors emerged: the presence of neurological symptoms, admission during the BA.5-predominant calendar period, and young age. On its face, this result seemed to suggest that children presenting with seizures, encephalopathy, or other neurological manifestations were at markedly elevated risk of progressing to severe or critical illness, and that infants and toddlers faced greater danger than older children.

But the investigators did not stop there, and it is their methodological rigor that elevates this study above many similar analyses. Recognizing two subtle statistical pitfalls, definitional circularity and quasi-complete separation, they repeated the analysis using Firth penalized regression, a technique that applies a penalty term to stabilize estimates when data are sparse or when a predictor almost perfectly separates the outcome groups. Definitional circularity arises when a symptom is itself part of the definition of severe disease, guaranteeing a spurious association; quasi-complete separation occurs when every patient with a certain feature shares the same outcome, producing extreme and unreliable odds ratios. The sensitivity analysis exposed exactly these problems. The extreme estimate for neurological symptoms was driven by circularity, and the associations involving the calendar periods and age groups proved unstable across different model specifications, fluctuating depending on how the variables were defined and adjusted.

What survived this gauntlet of sensitivity testing were two laboratory parameters: hyponatremia, an abnormally low concentration of sodium in the blood, and an elevated neutrophil count. Unlike the clinical and demographic variables, these two markers remained consistently and independently associated with severe and critical disease in both the primary multivariable regression and the Firth penalized sensitivity analyses. This robustness matters enormously for clinical practice, because a predictor that holds up across statistical approaches is far more likely to be genuine and reproducible than one that appears and disappears depending on model assumptions.

The biological plausibility of both markers lends further weight to the finding. Hyponatremia is a well-recognized complication of respiratory infections in children and can arise through several mechanisms, including the syndrome of inappropriate secretion of antidiuretic hormone, in which excess ADH causes water retention and dilution of serum sodium. Inflammatory cytokines such as interleukin-6, which surge in severe COVID-19, can stimulate ADH release, linking low sodium to the intensity of the host immune response. An elevated neutrophil count, meanwhile, is a classic hallmark of bacterial coinfection, intense systemic inflammation, or tissue damage, all of which correlate with worse outcomes in respiratory viral disease. In this sense, the two surviving predictors may be capturing the same underlying phenomenon: a hyperinflammatory host response that drives both electrolyte disturbance and granulocyte production.

The authors draw a careful and clinically useful distinction in their conclusions. Neurological symptoms, they argue, should be regarded as clinical red flags rather than independent statistical predictors. A child who presents with a seizure or altered consciousness warrants close observation and urgent evaluation regardless of what a regression model says, but the association between such symptoms and severe disease is partly an artifact of how severity is defined. By contrast, routine monitoring of serum sodium levels may be considered a practical addition to the care of hospitalized children with COVID-19, since a falling sodium concentration could serve as an early, objective warning of deterioration. Neutrophil counts are already measured routinely in most hospitals, making both of the validated markers essentially free to track once a child is admitted.

The study has limitations inherent to its design. As a single-center retrospective review conducted at the Fifth Hospital of Xiamen, its findings may not generalize to populations with different demographic profiles, vaccination coverage, or access to care, and retrospective designs cannot exclude residual confounding. The stability of the two laboratory associations across sensitivity analyses, however, gives the results a credibility that many risk-factor studies lack, and the honest reporting of unstable estimates for age, calendar period, and neurological symptoms is a model of statistical transparency. As SARS-CoV-2 continues to mutate and pediatric COVID-19 continues to evolve, studies like this one, which combine large observational cohorts with rigorous sensitivity analysis, will remain essential for helping clinicians distinguish the children who can be safely managed with routine supportive care from those who need intensified monitoring before their condition spirals. For now, the message for pediatricians is refreshingly concrete: watch the sodium, watch the neutrophils, and treat neurological symptoms as urgent warning signs rather than statistical curiosities.

Subject of Research: Risk factors for severe and critical COVID-19 in hospitalized children during the Omicron BA.5-predominant and post-BA.5 periods

Article Title: Severe and critical COVID-19 in children during the Omicron BA.5-predominant and post-BA.5 calendar periods: clinical characteristics and risk factors

Article References: Severe and critical COVID-19 in children during the Omicron BA.5-predominant and post-BA.5 calendar periods: clinical characteristics and risk factors. (n.d.). https://doi.org/10.1186/s12887-026-07751-0

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07751-0

Keywords: COVID-19, children, SARS-CoV-2, Omicron BA.5, hyponatremia, neutrophils, pediatrics, risk factors, neurological symptoms, hospitalization, logistic regression, BMC Pediatrics

Long COVID, also known as post-acute sequelae of COVID-19 or PASC, affects people who continue to experience symptoms weeks or months after the initial infection. Estimates vary across studies, but neurological complaints are among the most frequently reported. Patients describe “brain fog,” difficulties with attention and memory, chronic fatigue, headaches, burning or prickling sensations, muscle and joint pain, and abnormal sensitivity to pressure or temperature. The causes remain uncertain. Proposed explanations include persistent viral material, abnormal immune activation, vascular dysfunction, reactivation of latent viruses, and damage to the nervous system. Autoimmunity—the mistaken targeting of the body’s own proteins by immune defenses—has become one of the leading hypotheses, although no single long-COVID autoantibody has yet been consistently identified.

To test whether antibodies might actively contribute to symptoms, researchers in Belgium recruited 13 adults with long COVID and neurological complaints and compared them with 10 age- and sex-matched individuals without persistent symptoms. The long-COVID participants had been infected with SARS-CoV-2 an average of roughly three years before enrollment. All reported pain, fatigue, and cognitive difficulties, while a substantial proportion met questionnaire-based criteria for neuropathic pain. The participants underwent detailed neuropsychological testing, including assessments of memory, attention, executive function, anxiety, depression, and pain. People with previous neurological or autoimmune disorders were excluded, reducing the possibility that the antibody findings were caused by an unrelated pre-existing disease.

The investigators isolated immunoglobulin G, or IgG, from the participants’ blood using protein G purification. IgG is the most abundant antibody class in human circulation and normally helps identify and neutralize pathogens. In autoimmune disease, however, some IgG molecules can bind to self-antigens and alter the behavior of cells, activate immune receptors, or promote tissue injury. The purified antibodies were injected into female C57BL/6J mice at a dose of 8 milligrams per day for four consecutive days. Each human antibody preparation was administered to a separate group of animals, allowing the researchers to compare the effects of antibodies from long-COVID patients with those from healthy controls. The mice were then monitored for two weeks using behavioral tests designed to measure pain sensitivity, memory, anxiety, depressive-like behavior, and general well-being.

The clearest effect appeared in tests of sensory sensitivity. Mice receiving IgG from long-COVID patients withdrew their paws more rapidly from a radiant heat stimulus in the Hargreaves test, indicating thermal hypersensitivity. They also responded to weaker mechanical stimulation in the Von Frey test, a standard assay for mechanical allodynia—the experience of normally harmless touch as painful. These changes were strongest during the first several days after antibody administration and faded during the following week. A facial-grimace assessment, used as an indirect measure of discomfort in laboratory mice, also showed a temporary increase in abnormal facial expressions on the first day. Not every pain assay produced the same result: the hot-plate test did not reveal a significant difference between the groups, illustrating how distinct experimental measures can capture different aspects of nociception.

Additional experiments strengthened the argument that the pain-like responses were caused by intact IgG rather than by another component of the blood preparation. When the researchers injected serum from which IgG had been removed, the hypersensitivity was largely abolished. The same occurred after the antibodies were treated with papain, an enzyme that cuts IgG molecules into antigen-binding Fab fragments and an Fc fragment. Although the digestion was incomplete, the treated material no longer produced the same behavioral effects as native purified IgG. The result suggests that the structural integrity of the antibody is important for the response, although it does not by itself reveal whether the critical activity depends on antigen binding, Fc-receptor signaling, or a combination of both.

Microscopic analysis provided a possible anatomical explanation. Human IgG from long-COVID patients accumulated in the lumbar dorsal root ganglia, clusters of sensory-neuron cell bodies located outside the spinal cord. These structures are unusually accessible to circulating molecules because they contain fenestrated blood vessels, which are more permeable than the vessels that normally protect the brain. In mice given patient-derived IgG, the human antibodies were detected directly on sensory neurons and overlapped with the neuronal marker NeuN. They did not substantially colocalize with satellite glial cells, the support cells that surround sensory neurons. The antibodies appeared to recognize several neuronal populations, including neurons marked by NF200 and, to a lesser extent, peripherin and calcitonin gene-related peptide. These markers broadly represent large myelinated fibers involved in mechanosensation and proprioception, as well as smaller fibers involved in pain and temperature detection.

The researchers also tested whether the antibodies could bind human nervous tissue. When purified IgG was applied to post-mortem human dorsal root ganglia, samples from long-COVID patients showed more punctate staining on sensory-neuron cell bodies than samples from healthy controls. Antibodies from both groups could bind satellite glial cells, but the neuron-associated pattern was more prominent in the long-COVID preparations. The punctate appearance may reflect antibodies attaching to clusters of membrane proteins, ion channels, or receptors, although the precise target remains unknown. A commercial microarray containing 120 neurological and brain-associated antigens failed to identify a common autoreactivity profile. The result does not rule out autoimmunity: conformational epitopes, which depend on a protein’s three-dimensional structure, can be destroyed or hidden when antigens are immobilized on an array. The study therefore leaves open the possibility that the relevant targets are unusual, intracellular, or structurally dependent proteins.

The absence of central nervous system effects was equally important. Human IgG was not detected in the brain parenchyma or spinal cord, apart from antibody staining in vascular or connective tissues such as the meninges and choroid plexus. Mice that received long-COVID IgG performed similarly to control animals in Barnes-maze and Y-maze tasks assessing spatial memory and working memory. They also showed no meaningful differences in elevated-plus-maze or light-dark-box tests of anxiety, or in the tail-suspension test used to measure depressive-like behavior. Locomotor activity and nest-building behavior were unchanged. Examination of the brain, spinal cord, and dorsal root ganglia found no clear increase in microglia or astrocytes, and gene-expression analyses detected no significant rise in the inflammatory markers Iba1 or Gfap. These observations suggest that the transferred antibodies produced a functional change in sensory signaling without triggering widespread neuroinflammation.

The findings do not establish that all long-COVID pain is autoimmune, nor do they show that antibodies cause brain fog or other cognitive symptoms in patients. The study involved only 13 affected participants, most of them women, and relied on a short-term, high-dose passive-transfer model in female mice. Human antibodies may recognize mouse proteins differently from human proteins, and human IgG does not necessarily interact with mouse immune receptors in the same way it does with human receptors. The researchers also measured behavior for only two weeks, whereas long COVID can persist for years. Nevertheless, the work offers a mechanistic bridge between patient blood samples and pain-related biology: IgG from a carefully selected neurological long-COVID cohort bound sensory neurons and temporarily induced hypersensitivity in animals, while antibody depletion or enzymatic disruption prevented the effect. Identifying the responsible antibody targets will be the next major challenge. Future studies using unbiased antibody profiling, cultured human sensory neurons, electrophysiology, and cell-based assays may determine whether these antibodies alter ion-channel activity, activate neuronal Fc receptors, or interfere with signaling pathways that regulate nociception. If confirmed in larger cohorts, the results could help define an immune-mediated subtype of long-COVID pain and guide treatments aimed at neutralizing or removing pathogenic antibodies.

Subject of Research: The potential role of IgG autoantibodies in neurological long COVID, particularly pain-related sensory dysfunction.

Article Title: Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice

Article References: Mignolet M, Deroux C, Florkin T, et al. “Pathogenic IgG from long COVID patients with neurological sequelae triggers sensitive but not cognitive impairments upon transfer into mice.” Acta Neuropathologica 151, article 50 (2026).

Image Credits: AI Generated

DOI: 10.1007/s00401-026-03019-0

Keywords: Long COVID; SARS-CoV-2; post-acute sequelae of COVID; IgG antibodies; autoimmunity; neuropathic pain; mechanical allodynia; thermal hypersensitivity; dorsal root ganglia; sensory neurons; neuroimmunology; passive antibody transfer

Long COVID affects approximately five percent of the global population, manifesting as a constellation of persistent symptoms—many neurological—lasting months beyond the initial SARS-CoV-2 infection. Until now, the pathophysiological mechanisms underlying these chronic neuropsychiatric symptoms remained poorly understood, hindering therapeutic development. This study marks a pivotal advance by characterizing clear dopaminergic neuronal injury in affected individuals.

Dopamine neurons, crucial for motivation, movement, and cognition, predominantly reside in the striatum, a deep brain region. Using PET imaging with a highly specific marker for vesicular monoamine transporter 2 (VMAT2), the researchers quantified dopamine neuron integrity in long COVID patients versus healthy controls. The findings revealed reduced VMAT2 binding across the striatum’s ventral and dorsal components, correlating tightly with clinical symptom severity. Depletion in the ventral striatum aligned with diminished motivation, while loss in the dorsal putamen corresponded to bradykinesia, and reductions in the caudate putamen mirrored memory deficits.

Dr. Jeffrey Meyer, senior author and senior scientist at CAMH’s Brain Health Imaging Centre, emphasized that this is the strongest evidence to date implicating dopaminergic neurodegeneration in long COVID. Such neuronal loss has been extensively documented in other neurological disorders associated with overlapping symptoms, providing a pathophysiological framework for understanding the enduring neurological impairments reported by long COVID patients.

This research builds decisively on previous findings by the same group demonstrating elevated neuroinflammation within dopaminergic brain regions in long COVID. Inflammation is known to mediate dopamine neuron injury, and this study’s direct evidence of reduced dopamine transporter density offers a mechanistic link tying inflammation to neuronal dysfunction and symptomatology.

The implications for treatment are profound. Current long COVID therapeutic strategies largely neglect the dopaminergic system, focusing instead on inflammation and immune modulation. The CAMH team suggests that repurposing drugs aimed at boosting dopamine neurotransmission—such as dopamine precursors or inhibitors of dopamine metabolism—could represent a rational and promising intervention strategy.

Importantly, the study sets the stage for clinical trials to test dopamine-targeted therapies in long COVID. With collaboration from the University Health Network, trials will soon explore whether enhancing dopamine signaling can alleviate long COVID’s neuropsychiatric sequelae including fatigue, memory impairment, and motivational deficits.

For millions suffering worldwide, these findings offer both validation and hope—affirming that their symptoms have a biological basis and opening new avenues for evidence-based treatments. As research progresses, understanding the dopaminergic basis of long COVID may reshape how this multifaceted syndrome is approached clinically and scientifically.

Subject of Research: People
Article Title: Loss of vesicular monoamine transporter 2 in striatum of long COVID and relationship to neuropsychiatric symptoms
News Publication Date: July 10, 2026
Web References: https://www.thelancet.com/journals/EBIOM/article/PIIS2352-3964(26)00252-5/fulltext
References: DOI: 10.1016/j.ebiom.2026.106339
Keywords: Long COVID, dopamine neurons, striatum, PET imaging, neuroinflammation, neuropsychiatric symptoms