Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10.

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered.

Childhood meningitis in Kuwait in the era of post pneumococcal conjugate vaccination: A multicenter study.

This is a retrospective study to evaluate epidemiology and etiologies of childhood meningitis in Kuwait after the routine introduction of the pneumococcal conjugate vaccine. The data was collected from 196 patients in the period of 2010-2014. Aseptic meningitis accounted for 51% of the cases, bacterial meningitis accounted for 29% cases and partially treated meningitis were 20%. Organisms causing bacterial meningitis were: Streptococcus pneumoniae 40.4%, Neisseria meningitidis 17.6%, Haemophilus spp. 12.2%, other gram positive or negative 19.3%, and Group B Streptococcus 8.8%. The hospitalization was complicated by admission to the ICU in 16.3% patients. Sequelae on discharge were seen in 4%, and 2.5% died of complications of meningitis. In children with pneumococcal meningitis, 48% were admitted to the ICU, 35% were discharged with sequelae and 13% died. In the era of post pneumococcal conjugate vaccination, S. pneumoniae remains the leading cause of bacterial meningitis with the greatest morbidity and mortality.

Raised Proinflammatory Cytokine Production Within Cerebrospinal Fluid Precedes Fever Onset in Patients With Neurosurgery-Associated Bacterial Meningitis.

OBJECTIVE: The objective of the present study was to determine whether selective inflammatory cytokine concentrations within cerebrospinal fluid are useful markers for the differential diagnosis of aseptic and bacterial meningitis within neurosurgical patients. DESIGN: Prospective, open-label, observational, cohort study. SETTING: Neurosurgical ICU, Chang Gung Memorial Hospital. PATIENTS: Thirty-two consecutive neurosurgical patients who had postoperative fever following external ventricular drain insertion for the treatment of brain injury underwent serial cerebrospinal fluid cytokine analysis pre and post fever to determine the value of such markers in ascertaining the differential diagnosis of meningitis. INTERVENTION: Cerebrospinal fluid samples were collected on the day of fever onset, as well as on day 2 and 4 pre and post fever development. Tumor necrosis factor-α, interleukin-1ß, interleukin-6, interleukin-8, transforming growth factor-ß, and procalcitonin were subsequently analyzed using enzyme-linked immunosorbent assay analysis techniques. MEASUREMENT AND MAIN RESULTS: Inflammatory marker levels were compared among febrile aseptic, bacterial, and nonmeningitis patients to determine cerebrospinal fluid inflammatory changes over time. Significant increases in cerebrospinal fluid tumor necrosis factor -α, interleukin-1ß, interleukin-6, and interleukin-8 levels were observed within patients with bacterial meningitis at fever onset, which was not evident in aseptic or nonmeningitis patients. Furthermore, significant increases in cerebrospinal fluid tumor necrosis factor-α, interleukin-1ß, interleukin-6, and interleukin-8 levels were detected as early as 4 days prior to fever onset within patients with bacterial meningitis when compared with both aseptic and nonmeningitis groups. Interestingly, procalcitonin was only significantly increased in patients with bacterial meningitis on the fourth day post fever. CONCLUSION: The present study suggests that raised cerebrospinal fluid tumor necrosis factor -α, interleukin-1ß, and interleukin-8 in a temporal manner may indicate early bacterial meningitis development in neurosurgical patients, enabling earlier diagnostic certainty and improved patient outcomes.

[Molecular monitoring of non-polio enteroviruses in European territory of Russia in 2008 - 2011].

As a result of 4 year monitoring the landscape of enteroviruses circulating in European territory of Russia was established to be presented by at least 50 serologic types. Phylogenetic analysis of ECHO30, ECHO9, Coxsackie A9, ECHO6 virus strains that had caused a seasonal increase of aseptic meningitis morbidity in 2008 - 2011 was carried out.

Clinical features of echovirus 6 and 9 infections in children.

BACKGROUND: Clinical features of echovirus 6 and 9 infections in children have not been comprehensively evaluated, particularly for sporadic cases. OBJECTIVE: To describe the clinical features of children with echovirus 6 or 9 infections. STUDY DESIGNS: From 2000 to 2008, 199 children with culture-proven echovirus 6 or 9 infections identified in a university-affiliated hospital were included. Data extracted from 174 inpatients were further analyzed. RESULTS: Age ranged from 4 days to 15 years with a mean of 4.7 years. 123 (62%) were male. The disease spectrums were similar for echovirus 6 (n=100) and 9 (n=74) infections, with aseptic meningitis (49% and 51%, respectively) being the most common syndrome, followed by meningismus, upper respiratory tract infection, pneumonia, and herpangina. All 174 inpatients had fever but the duration of fever was significantly longer in patient with echovirus 9 infection than those with echovirus 6 infections (6.0 days vs. 3.8 days, p<0.001). The rate of leukocytosis (leukocyte count>15,000/µL) were significantly higher in patients with echovirus 6 infections than those with echovirus 9 infection (p<0.001). One neonate with echovirus 6 infection died from hepatic necrosis with coagulopathy, and one infant with echovirus 6 infection and one child with echovirus 9 infection died from brain involvement. Two children had long-term sequelae of seizure disorder. The remaining 169 children (97%) recovered uneventfully. CONCLUSION: For children with echovirus 6 or 9 infections requiring hospitalization, aseptic meningitis was the most common manifestation and fatal outcome or long-term sequel, though rare, might occur.

The value of serial cerebrospinal fluid 14-3-3 protein levels in adult community-acquired bacterial meningitis.

BACKGROUND: Increased levels of cerebrospinal fluid (CSF) 14-3-3 proteins have been reported in acute bacterial meningitis. We tested the hypothesis that CSF 14-3-3 protein levels are substantially increased in acute bacterial meningitis and decreased after anti-microbial therapy, and that CSF 14-3-3 protein levels can predict treatment outcomes. METHODS: We examined serial pan-CSF 14-3-3 (14-3-3-P) protein and five major isoform (beta, gamma, epsilon, eta, zeta) levels in 29 adult community-acquired bacterial meningitis (ACABM) patients. The CSF 14-3-3 protein levels were also evaluated in 12 aseptic meningitis patients during the study period. RESULTS: All of the meningitis patients had a positive result on admission. Levels of CSF 14-3-3 protein in ACABM cases were significantly increased initially, and substantially decreased thereafter. Most of those who survived (survivors = 25 and non-survivors = 4) had nearly cleared their 14-3-3 protein from the CSF before discharge. Conversely, patients who died never cleared their CSF 14-3-3 protein. The median value of CSF 14-3-3-P and 14-3-3 gamma, 14-3-3 eta and 14-3-3 epsilon isoforms on admission in the bacterial meningitis group were 173.7, 137.7, 42.2 and 9.1, respectively, which were statistically significant than those of the aseptic meningitis group (48.4, 39.6, 2.5 and 0, respectively). Stepwise logistic regression analysis showed only CSF 14-3-3 gamma isoform on admission was independently associated with outcome (P = 0.05, OR = 0.991). CONCLUSION: Serial 14-3-3 protein gamma isoform actually meets the major requirements for outcome prediction in the treatment of ACABM patients. Assay of the 14-3-3 protein gamma isoform should be added as a neuro-pathologic marker among the panel of conventional CSF parameters.

Aseptic meningitis among children in Kuwait.

OBJECTIVE: To describe the epidemiology, clinical features, and the morbidity caused by aseptic meningitis in children in Kuwait. SUBJECTS AND METHOD: A multicenter retrospective study of previously healthy children hospitalized with a diagnosis of aseptic meningitis in the period 2001-2003 was carried out. RESULTS: There were 172 children with the diagnosis of meningitis based on changes in the cerebrospinal fluid. Aseptic meningitis was diagnosed in 86 (50%) of the cases; their mean age was 3.2 +/- 3.8 years. There were two peaks of cases, one during the months of May and June and the other in November/December. Older children (>or=5 years) presented more frequently with signs and symptoms suggestive of meningeal irritation than younger children (<5 years) (p

Deaths in children during an outbreak of hand, foot and mouth disease in Peninsular Malaysia--clinical and pathological characteristics.

From July through December 1997, 11 previously healthy children in Peninsular Malaysia succumbed to an illness clinically characterised by an acute severe refractory left-ventricular failure, following a brief prodromal illness, in the midst of an outbreak of hand, foot and mouth disease (HFMD), similar to the reported experience in Sarawak and Taiwan. Retrospective reviews of the clinical features and results of laboratory, pathological and virological investigations of cases were conducted. The median age of the 11 case-patients was 31 months (range, 13 to 49 months); 6 were males. A brief prodromal illness of 3 days (range, 2 to 5 days) was characterised by fever (axillary temperature > 38 degrees C) (100%), oral ulcers (72%), extremity rashes (45%) and significant vomiting (55%). Upon hospitalisation, 7 of 11 case-patients had features suggestive of cardiogenic shock, while 4 of 11 case-patients developed shock during hospitalisation as evidenced by marked sustained tachycardia (heart rate > or = 180 beats per minute), poor peripheral pulses and peripheral perfusion, mottled extremities, pulmonary oedema (haemorrhagic pulmonary secretions in 8 of 11 cases during tracheal intubation, often precipitated by conservative crystalloid boluses, and radiographic evidence of acute pulmonary oedema in 5 of 7 cases) and markedly impaired left ventricular function on echocardiographic examination (7 of 7 cases). Three of 4 case-patients had aseptic meningitis while one case-patient also had an acute flaccid paraparesis. Despite supportive therapy, death occurred within a median of 13.4 hours following hospitalization. Post-mortem findings (all 8 specimens examined) consistently demonstrated brain-stem encephalitis with foci of neuronal necrosis and micro-abscesses. None of the 11 specimens examined revealed histological evidence of myocarditis. Enterovirus 71 (EV71) was detected in 10 of 11 case-patients, many (7) from various sterile tissue sites (5 from central nervous tissues). No other viruses were isolated or identified. Clinical features and pathological studies closely paralleled the reported experience in Sarawak and Taiwan. The uniform necropsy findings of necrotizing brain-stem encephalitis coupled with essentially normal myocardial histology, in concert with the concurrent and consistent detection of EV71 points to a primary EV71 encephalitis; as yet unclear neurogenic mechanisms may account for the cardiovascular manifestations.

Neoplastic meningitis-related encephalopathy: prognostic significance.

Two cohorts of 20 patients diagnosed with neoplastic meningitis (NM) with or without encephalopathy were matched with respect to age, sex, primary tumor, and performance status. Median survival was 10 weeks (range 6 to 20 weeks) in the cohort with NM-related encephalopathy compared to 24 weeks (range 8 to 40 weeks) in the cohort without NM-related encephalopathy (p < 0.001). NM-related encephalopathy is a clinical variable that predicts for poor survival in patients with NM.

Cerebrospinal fluid concentrations of soluble tumor necrosis factor receptor in bacterial and aseptic meningitis.

Soluble tumor necrosis factor receptor (sTNF-R) is the natural homeostatic regulator of the action of TNF-alpha. The level of sTNF-R reflects the true biologic activity of TNF-alpha. We investigated whether sTNF-R increases in CSF during patients' acute stage of bacterial and aseptic meningitis by measuring p60 sTNF-R in CSF by a sandwich enzyme immunoassay. The concentrations of sTNF-R were significantly higher in the CSF of children with bacterial meningitis than in the CSF of those with aseptic meningitis or of control subjects. The patients with bacterial meningitis who died or had severe neurologic sequelae had higher sTNF-R levels than those who survived. Our findings suggest that the sTNF-R level in CSF during acute bacterial meningitis is important for predicting neurologic sequelae.

Diagnosis and management of human B virus (Herpesvirus simiae) infections in Michigan.

Three men who had worked at the same animal research facility and had had contact with macaque monkeys were infected with B virus (Herpesvirus simiae). Their clinical presentations varied from self-limited aseptic meningitis syndrome to fulminant encephalomyelitis and death. Patient 1 was treated only after a respiratory arrest and other signs of advanced brain stem dysfunction had occurred. He died 8 days after hospital admission, despite treatment with acyclovir. Patient 2 presented with subtle signs and symptoms of brain stem encephalitis. He received antiviral therapy with intravenous ganciclovir. Patient 3 had a headache without meningismus and was also treated with acyclovir. Both patients 2 and 3 survived and did not have objective sequelae. Viral culturing, ELISA and western blot antibody testing, and magnetic resonance imaging all proved useful in the diagnosis of these patients' conditions.

[Meningitis in adults in Geneva. Review of 257 cases]. / Les méningites de l'adulte à Genève. Revue de 257 cas.

We review the 257 patients hospitalized for meningitis in the Cantonal University Hospital, Geneva between 1st January 1980 and 31st December 1986. 104 patients had acute bacterial meningitis (32 Str. pneumoniae, 21 N. meningitidis, 10 Listeria monocytogenes, 8 streptococci, 5 H. influenzae, 5 staphylococci, 4 gram negative bacilli and 19 without identified bacteria), 124 patients had viral meningitis and 29 meningitis of other etiologies (6 tuberculous meningitis, 2 fungal meningitis, 1 leptospiral meningitis, 5 neoplastic meningitis--one already counted because of a meningitis due to Staph. epidermidis--2 meningitis consecutive to a meningeal irritation, 4 already treated meningitis of undetermined etiology, 2 chronic meningitis and 8 meningoencephalitis). The total mortality was 14.4%. It was zero in viral meningitis and 28% in bacterial meningitis (47% in cases of Str. pneumoniae, 5% in cases of N. meningitidis, 20% in cases of Listeria monocytogenes, 38% in cases of streptococci, 0% in cases of H. influenzae, 60% in cases of staphylococci, 50% in cases of gram negative bacilli, 16% in cases of unidentified bacteria). The striking difference in mortality emphasizes the importance of recognizing a bacterial etiology in order to institute antibiotic therapy as soon as possible. The delay between admission and lumbar puncture averaged 15 hours (range 0.25-96 h) in patients with acute bacterial meningitis and 6.3 hours (0.5-80 h) in patients with viral meningitis. The delay between admission and institution of the antibiotics averaged 5.3 hours (1-48 h) in cases of acute bacterial meningitis and 4.8 hours (0.5-48 h) in cases of viral meningitis. A better clinical workup may provide a reliable diagnosis sooner. In the collective with bacterial and viral meningitis headaches, fever or nuchal rigidity were present in over 80% of the cases. The following features were significantly associated with a bacterial etiology: age over 30 years, alcoholism, concomitant neoplasm, cough, coma, pulmonary rales, new neurological signs or petechia. At least one of these 4 latter signs was present in more than 70% of the cases with acute bacterial meningitis compared to 6% in cases of viral meningitis. Thus the clinical presentation alone serves to recognize the meningitis and to differentiate between a bacterial or viral etiology, thus permitting an immediate therapeutic decision without waiting for complementary investigations. The 104 patients with acute bacterial meningitis were treated with antibiotics: 60 with penicillin, 17 with ampicillin and 26 with other antibiotics; one case did not receive antibiotics. More than the half of the cases with viral meningitis have got antibiotics (52%).

Encephalitis and aseptic meningitis, Olmsted County, Minnesota, 1950-1981: I. Epidemiology.

All cases fulfilling stated criteria for encephalitis and aseptic meningitis in Olmsted County, Minnesota, for the period 1950 through 1981 were identified. This is, to our knowledge, the first such incidence and trend study in a delineated population, providing rates per 100,000 person-years of 7.4 for encephalitis (189 cases) and 10.9 for aseptic meningitis (283 cases). These are about twelve and six times higher, respectively, than the rates reported by the Centers for Disease Control. The rates have been stable over successive 5- or 10-year periods except for a recent increase in aseptic meningitis. Both conditions were more common in the summer months, in childhood, and among males. Viral identification using conventional laboratory tests has improved with time; in the period 1970 through 1981, virus type was specified in about one-fourth of the cases. The most common agents identified were California and mumps viruses in encephalitis, and entero and mumps viruses in aseptic meningitis. Antecedent and/or concurrent infections were noted in 42 and 35% of encephalitis and aseptic meningitis cases, respectively. No case due to mumps, measles, or rubella viruses has occurred since 1972, reflecting the impact of immunizations. Recovery was reported at the end of the acute phase in 95% of patients with aseptic meningitis, and there were no deaths. Seventy-eight percent of encephalitis patients recovered completely; the case fatality rate was 3.8%. Of the encephalitis cases, 2% were diagnosed initially postmortem.