Highlights
- Hospitalized infections across diverse body systems are linked to increased 2-year psychiatric and neurologic morbidity, especially in adults.
- Infectious encephalitides confer the highest relative risks and are leading contributors to multiple neuropsychiatric outcomes.
- Age-stratified analysis shows children have increased relative risks but lower absolute risks compared to adults for post-infectious disorders.
- Systemic inflammation, immune dysregulation, and infection-specific pathophysiology underpin the neurological sequelae, suggesting targets for early intervention.
Background
Infections remain a common clinical challenge globally and are increasingly recognized as precipitating or exacerbating psychiatric and neurologic disorders in the postacute phase. While specific infections such as SARS-CoV-2 and viral encephalitis have been extensively studied, the broader question of whether post-infectious neuropsychiatric risks generalize across infections affecting multiple body systems, and how these risks vary by age, remains incompletely understood. Mapping these risks is critical for early identification, risk stratification, and intervention to preserve brain health.
Key Content
Comprehensive Risk Mapping from Large-Scale Multicohort Studies
Taquet et al. (2026) conducted a landmark retrospective multicohort study leveraging the TriNetX US Collaborative Network database, encompassing over one million propensity score–matched patient pairs hospitalized with infections across 10 body systems from 2014 to 2018. This study evaluated 14 psychiatric and neurologic disorders diagnosed 1 month to 2 years post-hospitalization, using metrics such as the ratio of restricted mean time lost (RMTL) and absolute risk differences.
Key findings included that infections universally increase the risk of most psychiatric and neurologic sequelae compared to non-infectious hospitalizations and the general population. Infectious encephalitides posed the highest relative risks (e.g., median RMTL ratio 6.54 for encephalitis after cardiac infections, P < 2.0 × 10⁻¹¹) and ranked top among risk factors for 7 of 14 disorders evaluated. Cognitive deficits showed the largest absolute risk difference, notably 12.37% higher following cardiac infections.
Age-dependent analyses revealed that although pediatric patients also face elevated relative risks, absolute risk differences are significantly lower than in adults, emphasizing the magnitude of postinfectious neuropsychiatric burden in mature populations. Importantly, the risk patterns demonstrated infection specificity, as non-encephalitic infections conferred unique disorder associations.
Insights from COVID-19 and Viral Infection Studies
Longitudinal prospective studies on COVID-19 provide mechanistic and clinical insights into infection-related neurocognitive decline. For instance, Taquet et al. (2026) and related investigations found that COVID-19 severity, autoimmune comorbidities, and elevated neutrophil-to-lymphocyte ratio (NLR) were significant predictors of cognitive deterioration over 2 years in long COVID patients, with vitamin D deficiency also implicated as a modifiable factor.
Epidemiological data from Denmark (2025) further characterize post-COVID sequelae emphasizing the compounded risk in older adults with existing comorbidities, correlating with increased thromboembolic and pulmonary complications along with infections, underscoring systemic inflammation and immune dysregulation as underlying drivers.
Neurologic Complications and Surgical Contexts
The risk of postoperative neurological complications following infections or in postinfectious states is exemplified by studies on spinal surgery and tuberculosis-related kyphosis. Elevated inflammatory markers (e.g., CRP), structural spinal cord compression, and higher osteotomy grades correlate with increased postoperative neurological deficits, highlighting the interplay between infectious pathology and neurological outcomes.
Similarly, sepsis-associated encephalopathy (SAE) research employing early microcirculation perfusion indicators combined with neuroelectrophysiological monitoring has achieved high predictive accuracy (AUC 0.92) for SAE occurrence and prognosis, potentially enabling early risk stratification and targeted critical care management.
Neurological Outcomes in Immunocompromised Populations
Among persons living with HIV, despite effective antiretroviral therapy, increased accumulation of cerebral white matter hyperintensities (WMHs) has been observed over 2 years compared with HIV-negative controls, independent of vascular comorbidities. These white matter changes correlate with cognitive impairment and reflect persistent brain vulnerability early in infection.
Furthermore, new-onset seizures in HIV-positive adults have a significant risk of progressing to epilepsy within 2 years, particularly in those with prior CNS injury, indicating a need for integrated neurological epilepsy care within HIV treatment paradigms.
Expert Commentary
The breadth and methodological rigor of Taquet et al.’s mapping of psychiatric and neurologic risks after infections across body systems and age groups provide a crucial evidence base underscoring infections as major risk factors for brain health. Their use of large-scale real-world data, including propensity matching and network meta-analyses, enhances validity and generalizability.
The pronounced role of infectious encephalitides in elevating neuropsychiatric risk likely reflects direct neuroinvasion, neuroinflammation, and resultant neuronal injury. For systemic infections without CNS invasion, immune-mediated effects, systemic inflammation, and microvascular alterations may drive neuropsychiatric sequelae.
Age-related differences underscore developmental and immunological maturity as modifiers of vulnerability, with adults exhibiting higher absolute risks. These findings call for age-specific monitoring and intervention strategies.
Integration with COVID-19 research shows consistent risk factors such as inflammation, autoimmune comorbidities, and micronutrient deficiencies contributing to neurocognitive decline, suggesting translational potential of anti-inflammatory and immunomodulatory strategies.
Clinically, heightened awareness of infection-related neuropsychiatric risks should inform postdischarge monitoring protocols, interdisciplinary collaboration between infectious disease, neurology, and psychiatry, and the development of predictive tools combining clinical, laboratory, and imaging biomarkers.
Remaining challenges include delineating causal mechanisms, identifying protective factors, and evaluating preventive and therapeutic interventions tailored to infection type, patient demographics, and comorbidities.
Conclusion
The reviewed evidence collectively establishes that hospitalization with infections markedly elevates 2-year risks of psychiatric and neurologic disorders across body systems and ages, with infectious encephalitides posing the greatest hazard. Age stratification reveals differential vulnerability requiring tailored approaches. Emerging mechanistic insights from inflammatory markers, neuroimaging, and neurophysiology support multimodal risk stratification.
Future research should prioritize longitudinal, multicenter prospective studies integrating molecular, immunologic, and imaging biomarkers with clinical phenotyping to refine risk prediction and guide personalized interventions. Clinicians should incorporate infection history into neuropsychiatric risk assessments to improve outcomes and brain health preservation.
References
- Taquet M, Oliver P, Mezher A, et al. Mapping 2-Year Psychiatric and Neurologic Risks After Infections Across Body Systems and Age Groups. JAMA Psychiatry. 2026; PMID: 42455558.
- Garcia JL, et al. Clinical and Inflammatory Predictors of Neurocognitive Decline in Long COVID: A Two-Year Longitudinal Study with Propensity Score Matching. Medicina (Kaunas). 2026;62(6):1180. PMID: 42356192.
- Christensen H, et al. Risk of Sequelae Following COVID-19 Infection: A Nationwide Study Focusing on Risk Factors and Long-Term Impacts. J Clin Med. 2025;14(22):7950. PMID: 41302986.
- Wang Y, et al. Study on Predictive Value of Early Microcirculation Perfusion Indicators Combined with Neuroelectrophysiological Monitoring for Sepsis-Associated Encephalopathy. Front Neurol. 2025;16:1692473. PMID: 41426991.
- Kong G, et al. Greater Accumulation of Brain White Matter Hyperintensities in People Diagnosed and Treated During Acute HIV Compared With People Without HIV. Neurology. 2025;104(10):e213591. PMID: 40327828.
