Search Results (1,600)

Background/Objectives: Tick-borne encephalitis (TBE) is the most important tick-borne viral central nervous system (CNS) infection in Europe and Asia. Since the introduction of a vaccine in Austria in the late 1970s, sero-epidemiological studies on the true incidence of tick-borne encephalitis virus (TBEV) infection in the population have been difficult, because it was not possible to distinguish between vaccine- and infection-induced antibodies. The goal of our study has been to analyze the sero-epidemiology of TBEV infections, vaccination protection rate, and manifestation index of the disease in the region of interest. Methods: Applying a newly developed anti-TBEV-NS1-IgG assay and the neutralization test, the protection and infection rates in blood donors of the Austrian Federal State of Upper Austria.It is one of the first areas in Austria, where the TBEV vaccine had been rolled out and broadly used. Samples from blood donors of all districts of the Federal State of Upper Austria were screened for anti-TBEV-IgG. Positive sera were differentiated for infection- and vaccine-induced antibodies. The results were matched with donor age, gender, and geographical origin. Results: 2162 samples were analyzed. A total of 87.0% of the blood donors tested showed anti-TBEV-IgG related to past TBEV vaccination. Within the unvaccinated group, a total of 13.3% of male and 9.9% of female blood donors exhibited anti-TBEV-NS1-IgG, indicating a past TBEV infection. The anti-TBE-NS1-IgG seroprevalence was determined at 74/100,000 for the whole population and at 594/100,000 in the non-vaccinated population. The manifestation index (MI) was calculated at 2.8%. The MI is defined as the probability or percentage of infected individuals who develop clinical symptoms of a disease. Conclusions: Our data provide evidence of a continuing high risk of TBEV infection in the Federal state of Upper Austria. The non-vaccinated population has an eightfold higher infection prevalence compared to the whole population. The MI of TBEV for severe infection seems lower as detailed in previous reports. Full article

Introduction: Acute encephalitis is a severe neurological complication whose association with SARS-CoV-2 infection is increasingly recognized. However, the precise pathophysiological mechanisms remain incompletely understood. Understanding the factors contributing to central nervous system involvement in COVID-19 is crucial for guiding clinical management and improving patient outcomes. Methods: This single-center, retrospective cohort study analyzed data from 450 adult critically ill patients with RT-qPCR-confirmed SARS-CoV-2 infection admitted to our ICU between May 2021 and March 2023. All SARS-CoV-2-positive patients with suspected CNS involvement were included and categorized into encephalitis-positive (E+, n = 38) and encephalitis-negative (E−, n = 58) groups according to neurological examination, imaging, and lumbar puncture findings during ventilator weaning. Key patient characteristics, laboratory parameters at ICU admission (including SARS-CoV-2 Ct values and D-dimer levels), and clinical outcomes were analyzed with appropriate statistical methods, including ROC curve analysis and Cox regression. Results: Patients in the E+ group, compared with the E− group, were significantly older (mean 69 ± 15 vs. 61 ± 12 years, p = 0.006) and exhibited significantly lower median SARS-CoV-2 Ct values (23.7 vs. 27.0, p < 0.001) indicative of higher viral loads. The median D-dimer levels were also significantly elevated in the E+ group (4.6 vs. 1.1, p < 0.001). Other baseline characteristics and inflammatory markers were comparable between groups. Patients with encephalitis experienced significantly longer mechanical ventilation durations (median 19 vs. 14 days, p = 0.006) and ICU stays (median 21 vs. 15 days, p = 0.009) compared to those without encephalitis. No significant difference was observed in overall mortality between the groups (50.0% vs. 56.9%, p = 0.507). Multivariate analysis identified lower Ct values (HR: 1.9, p = 0.032) and higher D-dimer levels (HR: 2.9, p < 0.010) at ICU admission as independent risk factors for encephalitis development. Conclusions: Our findings indicated that higher SARS-CoV-2 viral loads (lower Ct values), older age, and higher D-dimer levels were significantly associated with a greater risk of COVID-19-associated encephalitis in critically ill patients. These markers might aid in identifying patients at high risk of neurological complications, thereby facilitating earlier monitoring and potentially improving patient management. Further prospective studies are warranted to fully elucidate the pathophysiological mechanisms underlying this association. Full article

Background: Syndromic testing panels, such as the BioFire FilmArray^® Meningitis/Encephalitis (M/E) panel, have become essential in altering the way that central nervous system diseases are diagnosed in the rapidly changing fields of molecular diagnostics, infectious diseases, and neurology. Long turnaround times, minimal pathogen output, and the requirement for live organisms are some of the common limitations of traditional cerebrospinal fluid culture techniques. A potential addition to traditional diagnostics is the FilmArray^® M/E panel, which uses multiplex polymerase chain reactions to identify many diseases quickly and simultaneously in a very short time, which affects multiple outcomes for the patient. Aims: Despite the M/E panel’s considerable speed and detection benefits, there are some issues related to cost, erroneous findings, and contextual interpretation. Methods: This narrative review highlights fundamental research and meta-analyses that have studied the FilmArray^® M/E panel’s practical performance while comparing its diagnostic accuracy, clinical impact, and cost-effectiveness with the CSF culture. The latter occurs across different demographics and contexts. Results: Different studies have demonstrated that the M/E panel significantly shortens hospital stays, decreases unnecessary antibiotic usage, and speeds up the diagnosis of meningitis or encephalitis. Nonetheless, the necessity for cautious diagnostic management and supplementary testing strategies is underlined as there exist variations in sensitivity and specificity across pathogens, especially in viral ones. By facilitating quick, focused, and data-driven treatment for patients, the BioFire FilmArray^® M/E panel provides an advancement in meningitis and encephalitis diagnostics, which is consistent with the concept of precision medicine. Conclusions: To adequately guarantee fair and efficient results, its best application into clinical practice requires integration with clinical judgment, conventional culture techniques, and economic optimization strategies. Full article

Reports of acute Jamestown Canyon Virus (JCV) cases have increased markedly over the last 15 years, associated with improved diagnostic testing protocols. Analysis of these cases and the criteria used for their diagnosis could benefit clinicians encountering this under-recognized disease. In the current study, we analyzed all published reports of acute human JCV infections in North America from the first in 1982 through 2022, including retrospective studies. A total of 50 reports with 416 cases of JCV were found. The primary illness associated with JCV infection involved the nervous system. Of reported encephalitis cases, the fatality rate was 2.4 percent in hospitalized patients. Of the cases with detailed patient outcome information, approximately 40 percent had prolonged hospitalization and/or long-term neurological sequelae. Although case incidence has increased over the last few decades, the overall time from admission/clinical onset to testing for JCV has not substantially changed from the 1980s. Confounding factors such as being immunocompromised, as well as previous or concurrent infections, were associated with a greater risk of more severe outcomes. Thus, the complexity of JCV infection with other conditions may impact the overall outcomes of JCV encephalitis. Full article

Background/Objectives: Encephalitis and related acute encephalopathic syndromes represent severe neurological conditions with diverse etiologies and variable clinical outcomes. This study aimed to analyze nationwide hospitalization patterns for encephalitis-related diagnoses in Ecuador between 2018 and 2024. Methods: We used data from the Ecuadorian National Institute of Statistics and Census to estimate age-adjusted hospitalization and mortality rates according to ICD-10 codes. Binary and multinomial logistic regression models were employed to identify sociodemographic factors and diagnostic categories of encephalitis associated with hospitalization and in-hospital mortality. Results: A total of 1560 hospitalizations related to encephalitis-spectrum diagnoses were recorded, with an overall age-adjusted rate of 0.127 per 100,000 inhabitants and 6.0% in-hospital mortality. Unspecified encephalitis and encephalomyelitis were the most common diagnostic categories. Adolescents (10–19 years) were more frequently diagnosed with acute disseminated and bacterial meningoencephalitis, while patients aged ≥70 had higher odds of “other” encephalitis subtypes and the highest mortality risk (aOR = 0.265; 95% CI: 0.116–0.608). Indigenous individuals were more likely to be diagnosed with acute disseminated encephalitis, and Black individuals showed a higher risk for myelopathy associated with human T-cell lymphotropic virus type 1-associated myelopathy. Conclusions: Age and ethnicity significantly influence hospitalization due to encephalitis-related diagnoses in Ecuador. These findings provide epidemiological rates for a lower-middle–income country where the lack of precise diagnosis, age, and ethnicity contribute to the vulnerability of encephalitis. Full article

Rabies is an acute, progressive, viral encephalitis. Warm-blooded vertebrates are susceptible. Major reservoirs reside in the Chiroptera and Carnivora. Among the latter, representatives include dogs, ferret badgers, foxes, jackals, mongooses, raccoons, and skunks. Within the Carnivora, pinnipeds represent a diverse group of >30 extant species. These marine mammals range from the Arctic to Antarctica, but there is no review about rabies in this group. Apparently, only a single 1980 case of rabies occurred from Svalbard in a ringed seal (Phoca hispida). However, in 2024, incidental cases appeared within South African Cape fur seals (Arctocephalus pusillus). Retrospective testing of archival material identified suspect cases dating back to 2022. Currently, more than 80 cases have been documented in seals. Moreover, a new 2025 focus appeared in Namibia and cases in Angola are predictable. Viral characterization supports spillover infection via rabid black-backed jackals (Lupulella mesomelas). A host shift appears likely, with ongoing seal intraspecific transmission. Given the unique nature of this epizootic, implications for the southern hemisphere abound. Unfortunately, comprehensive data are lacking on pinniped specimens examined outside of southern Africa. For example, although Antarctica is considered ‘rabies-free’, minimal international standards for support are unmet. No routine laboratory-based surveillance occurs. This enzootic rabies focus among seals in southern Africa presents unique challenges for the region and a rare opportunity for considering broader surveillance. Besides targeted parenteral vaccination of fur seals, local engagement involves vagrant species, including elephant (Mirounga leonina) and leopard seals (Hydrurga leptonyx). The void of regional pinniped surveillance, especially encompassing the Southern Ocean would require considerable proactive local resolution and much wider collaboration regarding future concerns to both public health and conservation biology. Full article

Flaviviruses are arthropod-borne RNA viruses associated with significant human diseases globally. There are no effective direct-acting antivirals approved to treat these viral infections. Given its critical role in viral replication, the RNA-dependent RNA polymerase (RdRp) is a logical target for antiviral drug development. Remdesivir (formerly GS-5734), a 1′-cyano modified C-adenosine monophosphate prodrug, was the first US Food and Drug Administration (FDA) approved antiviral for coronavirus disease 2019 (COVID-19) and was also shown to inhibit flavivirus replication. GS-7682, a 4′-cyano modified C-adenosine prodrug, exhibits a broad-spectrum antiviral activity. Here, we determined the anti-flavivirus potency of both remdesivir and GS-7682 and characterized their active triphosphate forms, GS-443902 and GS-646939, respectively, against a panel of purified flavivirus RdRps. These include dengue, Japanese encephalitis, West Nile, yellow fever, and Zika. Enzyme kinetics demonstrate efficient RNA incorporation of GS-443902 and GS-646939. GS-646939 acts as an immediate chain terminator. Conversely, GS-443902 acts through a template-dependent inhibition mechanism by impeding the incorporation of the complementary UTP. Both mechanisms correlate with anti-flavivirus activity, although remdesivir is generally superior. The data demonstrate that immediate chain termination is not necessarily a preferred mechanism of action of nucleotide analogs. Template-dependent inhibition should also be considered, especially for viruses lacking intrinsic proofreading activities. Full article

Mycoplasma pneumoniae is traditionally recognized as a leading cause of community-acquired pneumonia, yet growing evidence demonstrates that its clinical impact extends far beyond the respiratory tract. Increasing reports of neurologic, cardiac, hematologic, dermatologic, renal, gastrointestinal, and thrombotic complications indicate that M. pneumoniae should be viewed as a systemic pathogen capable of inducing multisystem disease. Extrapulmonary manifestations may arise through three major mechanisms: direct bacterial invasion of tissues, immune-mediated injury driven by molecular mimicry or immune complexes, and vascular or thrombotic events related to endothelial dysfunction. These processes frequently occur independently of, or temporally dissociated from, respiratory symptoms, complicating early diagnosis. The diagnostic approach remains challenging because respiratory PCR may reflect colonization, serology is delayed, and pathogen detection in sterile sites is uncommon. Consequently, diagnosis often depends on the integration of clinical features, laboratory markers, and organ-specific imaging. Management requires a combined strategy: antimicrobial therapy to reduce bacterial load, organ-targeted supportive measures, and immunomodulatory interventions such as corticosteroids, IVIG, or plasma exchange for severe immune-mediated complications. The emergence of macrolide-resistant strains further underscores the need for tailored antimicrobial strategies and close clinical monitoring. Although many extrapulmonary complications are reversible, severe forms—including encephalitis, ADEM, myocarditis, Stevens–Johnson syndrome, and major thromboses—can lead to lasting morbidity or death. Significant knowledge gaps persist, including determinants of host susceptibility, mechanisms linking CARDS toxin to systemic inflammation, the impact of macrolide resistance on disease severity, and the absence of standardized diagnostic criteria. Advances in molecular immunology, multicenter registries, and development of targeted therapies or vaccines represent crucial next steps. Overall, the breadth and clinical relevance of extrapulmonary involvement support a paradigm shift: Mycoplasma pneumoniae infection should be regarded and managed as a systemic disease rather than a purely respiratory pathogen. Full article

Background: Tick-borne encephalitis (TBE) is a severe viral infection of the central nervous system transmitted by tick bites. Vaccination represents the only effective preventive measure, yet data on TBE vaccine effectiveness in Italy are lacking. This study aimed to evaluate TBE vaccine effectiveness and vaccination coverage in the province of Udine, an endemic area in the Friuli Venezia Giulia region of Northern Italy. Methods: We conducted a case–control study using linked anonymized health databases of the region, including vaccination, laboratory, and hospital admission records from 2017 to 2025. Cases were defined as residents hospitalized with a diagnosis of TBE (ICD-9-CM 063.x or 321.2) and a positive anti-TBE IgM result in serum or cerebrospinal fluid. Controls were residents tested for anti-TBE IgM during the same period but not hospitalized for TBE. Vaccination history was retrieved from the regional vaccination registry. Vaccine effectiveness was estimated through logistic regression models comparing vaccinated and unvaccinated individuals. Results: Between 2017 and 2025, 21 confirmed TBE hospitalizations were recorded (mean annual incidence: 0.45/100,000 inhabitants). The mean hospital stay was 13.8. Among 6065 individuals tested for anti-TBE IgM, 95.2% of cases and 81.8% of controls were unvaccinated. The estimated odds ratio of TBE hospitalization for individuals with ≥3 vaccine doses versus unvaccinated was 0.11 (95% CI: 0.02–0.88). Vaccination coverage in 2025 reached about 10% of the provincial population, with markedly higher coverage (up to 34%) in mountain districts compared with lowland areas (<5%). Conclusions: Although limited by small sample size, this study provides the first real-world evidence of TBE vaccine effectiveness in an Italian endemic area. Vaccination is an effective preventive measure. Given the regional epidemiology and expected increase in tick activity due to climate change, strengthening vaccination uptake and public awareness in endemic districts is strongly recommended. Full article

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen causing low mortality but high morbidity in humans, with 4–14% cases exhibiting neurological complications. While the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is canonically associated with double-stranded DNA (dsDNA) detection, it has been shown to respond to RNA viruses and subsequently limit viral pathogenesis. Several viruses antagonize this signaling cascade, underscoring the importance that cGAS–STING plays in host immunity. Previous studies regarding single-stranded RNA viruses revealed that cGAS–STING limits viral replication in Old World alphavirus chikungunya virus infections, but little is known about New World alphaviruses such as VEEV. Here, we investigate the impact that STING activation has on VEEV infection as a potential prophylactic and therapeutic intervention. VEEV infection alone did not induce STING phosphorylation at Ser366, but interferon-stimulated genes (ISGs) were upregulated during the late phase of infection. Loss of STING through siRNA showed a partial dependency on STING for ISG transcription, suggesting that STING activation may occur through a noncanonical process. Priming of the STING pathway prior to infection was found to be critical in limiting viral replication; however, targeting STING activation post-infection abrogated the antiviral effects that dsDNA had on VEEV. VEEV suppressed STING phosphorylation in a multiplicity of infection (MOI)-dependent manner with the most robust pSTING (Ser366) inhibition observed at an MOI of 10. Collectively, our results suggest that VEEV antagonizes canonical STING activation. Full article

Viral infections have been implicated in psychiatric outcomes through immune-mediated pathways. This 12-month prospective cohort study, designed as a pilot and hypothesis-generating investigation, compared psychiatric symptoms and inflammatory cytokine profiles in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hepatitis C virus (HCV), and tick-borne encephalitis virus (TBEV), and explored their potential predictive value. Thirty-seven patients hospitalized with viral infections and 32 healthy controls were evaluated, acknowledging the limited sample size. Psychiatric interviews and the Hospital Anxiety and Depression Scale (HADS) were used for assessment. The study was divided into two stages. In Stage 1, during the acute infection, a psychiatric assessment was conducted, and cytokine levels were measured in the patients’ blood. In Stage 2, one year later, the psychiatric assessment was repeated. No significant differences were found in psychiatric diagnosis rates or symptom severity between infection groups, regardless of viral type or neuroinvasive capacity. However, these findings should be interpreted as preliminary given the limited sample size. Some cytokines, eg., interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and soluble interleukin-2 receptor subunit alpha (sIL-2Rα), showed associations with individual symptoms, but these were inconsistent and did not demonstrate robust predictive value. Cluster analysis identified two distinct inflammatory profiles—one characterized by higher cytokine levels (predominantly in Coronavirus disease 2019 (COVID-19) and TBEV cases) and the other by lower cytokine levels (mostly in HCV and controls). However, different cytokine profiles did not correspond to clinical outcomes. The results suggest that psychiatric sequelae after viral infections are not directly driven by specific cytokines or infection type but rather emerge from a complex interaction of immune, psychological, and environmental factors. Single cytokine measurement is insufficient and cannot be used as a tool for assessing the risk of developing psychiatric disorders. Given the exploratory nature of the study, all results require confirmation in larger, adequately powered cohorts. Future studies should focus on composite biomarkers and systems-based models such as neuroimmune-metabolic-oxidative pathways (NIMETOX), or Immune-Inflammatory Response System (IRS)/Compensatory Immune Response System (CIRS)/Oxidative & Nitrosative Stress (O&NS) for improved predictive accuracy. Full article

Background/Objectives: Rapid pathogen identification is essential to optimize antimicrobial therapy and improve patient outcomes, particularly in severe infections. Syndromic molecular diagnostics have been introduced to overcome the limitations of conventional culture-based methods. This study evaluated the diagnostic performance and real-life implementation of BioFire^® FilmArray^® syndromic panels compared with routine microbiological diagnostics. Methods: A total of 955 clinical specimens collected between 2022 and June 2025 were retrospectively analyzed, including positive blood cultures (n = 400), lower respiratory tract samples (n = 309), cerebrospinal fluid (n = 158) and stool specimens (n = 88). FilmArray^® BCID2, Pneumonia Plus, Meningitis/Encephalitis and Gastrointestinal panels were performed on the Biofire Fimarray^® instrument according to clinical indication and compared with conventional culture-based identification and phenotypic antimicrobial susceptibility testing. Results: Overall diagnostic concordance between BioFire^® FilmArray^® syndromic panels and conventional methods was high across all specimen types, with the highest positive percent agreement (PPA) observed for bloodstream infections (97.7%) and gastrointestinal pathogens (100%). In respiratory samples, the Pneumonia Plus panel detected a considerable number of microorganisms that could not be identified by culture, including viral pathogens and fastidious bacteria. Molecular detection of antimicrobial resistance markers showed excellent concordance with phenotypic profiles, with 100% agreement for CTX-M, carbapenemases (KPC, NDM, OXA-48-like, IMP), and vanA/B, while lower concordance was observed for mecA/C in staphylococci. In parallel, semi-quantitative bacterial loads provided by the Pneumonia Plus panel showed a strong essential agreement with culture-based quantification (97.4%, ±1 log₁₀). Across all panels, syndromic testing significantly reduced diagnostic turnaround time. Conclusions: Syndromic molecular panels provide rapid and reliable simultaneous detection of pathogens, as well as early resistance marker detection, thereby supporting timely antimicrobial optimization and stewardship when integrated with conventional microbiological diagnostics. Full article

Background/Objectives: Miller–Fisher syndrome (MFS) is a rare Guillain–Barré variant defined by ophthalmoplegia, ataxia, and areflexia. Pediatric MFS is uncommon, and infectious triggers remain underrecognized. Human herpesvirus 6 (HHV-6) is neurotropic but rarely linked to immune-mediated neuropathies. In this paper, we describe a child with MFS associated with HHV-6 detected in cerebrospinal fluid (CSF) and review reported pediatric infections related to MFS. Methods: A 5-year-old girl presented with acute ophthalmoplegia, ataxia, and diminished reflexes. Neuroimaging, ophthalmologic tests, CSF analyses, and serologic andpolymerase chain reaction (PCR) assays were performed, including multiplex reverse transcription–PCR of cerebrospinal fluid using the BioFire^® Meningitis/Encephalitis panel. A literature search was performed on Pubmed to identify pediatric (0–18 years) MFS cases with infectious triggers. Two reviewers independently screened and summarized the literature, and a PRISMA-style flow diagram was used to transparently report the study selection process. Results: HHV-6 DNA was detected via CSF PCR twice, while tests for other pathogens were negative. Anti-GQ1b and related antibodies were negative or borderline. The patient received intravenous immunoglobulin and corticosteroids, with full recovery after one month. Among 20 published pediatric cases (1997–2021), Campylobacter jejuni was most frequent, followed by Mycoplasma pneumoniae and influenza viruses. Anti-GQ1b IgM positivity and favorable outcomes were commonly reported, including cases managed conservatively. Conclusions: This case raises the hypothesis that HHV-6 may represent a potential post-infectious association in pediatric MFS. The review findings indicate that pediatric MFS generally follows infection, responds well to immunotherapy, and has an excellent prognosis. Viral testing may be considered in selected, hypothesis-generating contexts in atypical or seronegative pediatric MFS presentations. Full article

Background/Objectives. Oxidative stress is a key contributor to HIV-associated neurocognitive disorders (HANDs), yet the regional organization and functional engagement of the NRF2 antioxidant pathway in the human brain remain incompletely defined. This study aimed to characterize NRF2 pathway architecture, baseline brain expression, and disease-associated transcriptional and coexpression remodeling across HAND stages. Methods. The NRF2 signaling network was reconstructed using curated pathway data and protein–protein interaction analysis to identify central hub genes. Baseline expression in the normal human cortex was assessed using the Human Protein Atlas. Transcriptomic profiling of postmortem brain samples from individuals with HAND (GSE35864) was performed using differential expression, hierarchical clustering, and region-specific coexpression analyses across white matter, frontal cortex, and basal ganglia. Results. Low-to-medium baseline expression of NRF2-related genes was observed in the normal cortex. Bulk differential expression revealed minimal NRF2 pathway modulation in the frontal cortex and basal ganglia. On the other hand, white matter exhibited robust NRF2 transcriptional activation specifically in HIV encephalitis (HIVE). Coexpression analysis performed specifically within HAND samples revealed a highly coordinated transcriptional organization of the NRF2 signaling network across all analyzed brain regions. Conclusions. NRF2 signaling in HAND is preserved as a coordinated transcriptional network but is selectively activated in white matter during encephalitic disease, highlighting region- and cell-type-targeted therapeutic opportunities. Full article

Acyclovir is an antiviral drug effective against infections caused by herpes simplex and varicella zoster viruses. It is given intravenously to treat serious infections such as herpes encephalitis. High acyclovir concentrations could cause toxicity, observed mainly as nephrotoxicity and, to a lesser extent, neurotoxicity. Acyclovir nephrotoxicity is primarily attributed to the crystallization of acyclovir within the renal tubules, although additional mechanisms may also contribute. However, the mechanism of acyclovir-induced neurotoxicity is unknown. Acyclovir is mainly eliminated from the body through renal excretion; however, around 15–20% of acyclovir is metabolized subsequently by alcohol and aldehyde dehydrogenase to the main metabolite 9-carboxymethoxymethylguanine (CMMG), and around 2% is metabolized by aldehyde oxidase to the minor metabolite, 8-hydroxyl acyclovir. It has been suggested that CMMG levels above 10 µmol/mL in the serum and 1 µmol/mL in the cerebrospinal fluid are highly associated with neurotoxicity. Studies have shown that there is a potential contribution of CMMG to acyclovir-induced neurotoxicity and of the acyclovir aldehyde to nephrotoxicity. In this narrative review, we approach the topic of acyclovir metabolites and their association with acyclovir toxicity. Moreover, we identify the research gap of the mechanisms by which these metabolites contribute to toxicity. Full article