Acute encephalitis in childhood : clinical characteristics and outcome with special reference to tick-borne encephalitis

Acute encephalitis is relatively uncommon but potentially devastating. The prognosis varies from complete recovery to severe sequelae or death. The diagnosis is difficult to establish and the etiology often remains unclear. Furthermore, the long-term prognosis of acute encephalitis in children is poorly described and prognostic markers in the acute phase are lacking. In this thesis, the aim was to characterize acute encephalitis in childhood in regard to etiology, clinical presentation and long-term outcome. Another aim was to study biomarkers in CSF of children with TBE and to identify markers predicting the long-term outcome. Methods: We retrospectively studied the medical records of all children with acute encephalitis at Astrid Lindgren Children´s hospital in Stockholm during 2000–2004 (study I). This cohort was followed-up 3-8 years later using 2 questionnaires grading persisting symptoms and every day functioning. Seventy-one children were eligible for the follow-up (study II). In study III, 55 children with TBE in 2004-2008 were evaluated 2-7 years later. Two questionnaires were used grading persisting symptoms and executive functioning in everyday life. General cognitive ability was also investigated in a subgroup, using WISC-IV. In study IV, cytokines, chemokines and markers of neuronal damage were analyzed in CSF samples from 37 children with TBE in 2004-2010, using a multiplex assay. Results: The etiology of childhood encephalitis was dominated by TBE, EV, VZV, influenza virus and RSV, but remained unknown in 52% of cases. Fever and encephalopathy were present in a majority of the children, seizures or focal neurological deficits were seen in 40%. EEG-examinations were pathological in 90%, and 55% of the children with acute encephalitis had pleocytosis. There were no mortalities, but 60% of the children had persisting symptoms at the time of discharge. In the long-term follow-up, persisting symptoms were reported by 54%, both in children with and without symptoms at discharge. Cognitive problems and personality changes were the dominating complaints. No other prognostic marker than the severity of the encephalitis leading to admission to the PICU was found. All children with encephalitis who made a full recovery did so within 6 to 12 months. In the acute phase of TBE, fever and headache were present in nearly all children, whereas seizures and focal neurological findings were less frequently seen. Nearly half of the children with TBE were classified as meningitis and the clinical picture were in these cases often unspecific and symptoms of CNS involvement vague. All children with TBE had pleocytosis. At follow-up, 69% experienced persistent problems; headache, fatigue and cognitive problems dominated. On more detailed tests of cognitive functions, problems with working memory and executive functioning were seen both in children with mild and with severe symptoms in the acute phase. In TBE, children with problems at follow-up had significantly higher levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF than children with a good outcome. Markers of neuronal damage did not discriminate between children with good or poor outcome. Conclusion: We conclude that the etiology of encephalitis among Swedish children is at large the same as in other European countries endemic for TBE. EEG examination and analysis of CSF are essential for diagnosing CNS involvement, especially since CNS symptoms may be vague. Persisting symptoms were present in a substantial number of children at long-term follow-up, cognitive problems, headache, personality changes and fatigue dominated. The clinical picture in the acute phase cannot be used to predict outcome. In TBE, high levels of IFN-γ, IL-4, IL-6 and IL-8 in CSF might indicate a risk of incomplete recovery. All children with acute encephalitis or TBE should be offered follow-up evaluations in order to detect long-term sequelae

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions

The Kynurenine Pathway is Differentially Activated in Children with Lyme Disease and Tick-Borne Encephalitis

In children, tick-borne encephalitis and neuroborreliosis are common infections affecting the central nervous system. As inflammatory pathways including cytokine expression are activated in these children and appear to be of importance for outcome, we hypothesized that induction of the kynurenine pathway may be part of the pathophysiological mechanism. Inflammatory biomarkers were analyzed in cerebrospinal fluid from 22 children with tick-borne encephalitis (TBE), 34 children with neuroborreliosis (NB) and 6 children with no central nervous system infection. Cerebrospinal fluid levels of kynurenine and kynurenic acid were increased in children with neuroborreliosis compared to the comparison group. A correlation was seen between expression of several cerebrospinal fluid cytokines and levels of kynurenine and kynurenic acid in children with neuroborreliosis but not in children with tick-borne encephalitis. These findings demonstrate a strong induction of the kynurenine pathway in children with neuroborreliosis which differs from that seen in children with tick-borne encephalitis. The importance of brain kynurenic acid (KYNA) in both immune modulation and neurotransmission raises the possibility that abnormal levels of the compound in neuroborreliosis might be of importance for the pathophysiology of the disease. Drugs targeting the enzymes of this pathway may open the venue for novel therapeutic interventions

Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies

Urinary Leukotriene E4 and Prostaglandin D2 Metabolites Increase in Adult and Childhood Severe Asthma Characterized by Type 2 Inflammation: A Clinical Observational Study

Rationale: New approaches are needed to guide personalized treatment of asthma. Objectives: To test if urinary eicosanoid metabolites can direct asthma phenotyping. Methods: Urinary metabolites of prostaglandins (PGs), cysteinyl leukotrienes (CysLTs), and isoprostanes were quantified in the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) study including 86 adults with mild-to-moderate asthma (MMA), 411 with severe asthma (SA), and 100 healthy control participants. Validation was performed internally in 302 participants with SA followed up after 12–18 months and externally in 95 adolescents with asthma. Measurement and Main Results: Metabolite concentrations in healthy control participants were unrelated to age, body mass index, and sex, except for the PGE2 pathway. Eicosanoid concentrations were generally greater in participants with MMA relative to healthy control participants, with further elevations in participants with SA. However, PGE2 metabolite concentrations were either the same or lower in male nonsmokers with asthma than in healthy control participants. Metabolite concentrations were unchanged in those with asthma who adhered to oral corticosteroid treatment as documented by urinary prednisolone detection, whereas those with SA treated with omalizumab had lower concentrations of LTE4 and the PGD2 metabolite 2,3-dinor-11β-PGF2α. High concentrations of LTE4 and PGD2 metabolites were associated with lower lung function and increased amounts of exhaled nitric oxide and eosinophil markers in blood, sputum, and urine in U-BIOPRED participants and in adolescents with asthma. These type 2 (T2) asthma associations were reproduced in the follow-up visit of the U-BIOPRED study and were found to be as sensitive to detect T2 inflammation as the established biomarkers. Conclusions: Monitoring of urinary eicosanoids can identify T2 asthma and introduces a new noninvasive approach for molecular phenotyping of adult and adolescent asthma