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\"A family separated by racism against Japanese Americans and the discrimination of people with developmental disabilities--reunited seventy years later, returning to their roots on a farm and bound by family secrets\"-- Provided by publisher.

Background. Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. Methods. We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. Results. H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13–0.76; P = .010) and 0.39 (95% CI, 0.17–0.93; P = .033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25–0.76; P = .003) and 0.55 (95% CI, 0.32–0.93; P = .027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09–0.77; P = .014). Conclusion. Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

We assessed the performance of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis. This was a prospective multicenter study. Cerebrospinal fluid samples from patients with viral encephalitis and/or meningitis, tuberculous meningitis, bacterial meningitis, fungal meningitis, and non-central nervous system (CNS) infections were subjected to mNGS. In total, 213 patients with infectious and non-infectious CNS diseases were finally enrolled from November 2016 to May 2019; the mNGS-positive detection rate of definite CNS infections was 57.0%. At a species-specific read number (SSRN) ≥2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] = 0.659, 95% confidence interval [CI] = 0.566-0.751); the positivity rate was 42.6%. At a genus-specific read number ≥1, mNGS performance in the diagnosis of tuberculous meningitis (definite or probable) was optimal (AUC=0.619, 95% CI=0.516-0.721); the positivity rate was 27.3%. At SSRNs ≥5 or 10, the diagnostic performance was optimal for definite bacterial meningitis (AUC=0.846, 95% CI = 0.711-0.981); the sensitivity was 73.3%. The sensitivities of mNGS (at SSRN ≥2) in the diagnosis of cryptococcal meningitis and cerebral aspergillosis were 76.92 and 80%, respectively. mNGS of cerebrospinal fluid effectively identifies pathogens causing infectious CNS diseases. mNGS should be used in conjunction with conventional microbiological testing. Chinese Clinical Trial Registry, ChiCTR1800020442.

Can adjuvant treatment with dexamethasone reduce morbidity and mortality in adults with acute bacterial meningitis? In this randomized, double-blind trial, which involved 301 patients, the outcomes were clearly better in the group that received dexamethasone for four days, in addition to antibiotics, than in the group that received placebo and antibiotics. With dexamethasone treatment, the risk of an unfavorable outcome was greatly reduced (relative risk, 0.59), and mortality was reduced from 15 percent to 7 percent. In this carefully controlled trial in adults, the greatest benefits were in pneumococcal meningitis. The mortality rate among adults with acute bacterial meningitis and the frequency of neurologic sequelae among those who survive are high, especially among patients with pneumococcal meningitis. 1 , 2 Unfavorable neurologic outcomes are not the result of treatment with inappropriate antimicrobial agents, since cerebrospinal fluid cultures are sterile 24 to 48 hours after the start of antibiotic therapy. 3 Studies in animals have shown that bacterial lysis, induced by treatment with antibiotics, leads to inflammation in the subarachnoid space, which may contribute to an unfavorable outcome. 4 , 5 These studies also show that adjuvant treatment with antiinflammatory agents, such as dexamethasone, reduces both . . .

Cryptococcus is the most common cause of adult meningitis in Africa. We assessed the safety and microbiological efficacy of adjunctive sertraline, previously shown to have in-vitro and in-vivo activity against cryptococcus. In this open-label dose-finding study, we recruited HIV-infected individuals with cryptococcal meningitis who presented to Mulago Hospital in Kampala, Uganda between Aug 14, 2013, and Aug 30, 2014. To assess safety and tolerability, the first 60 participants were given sertraline at escalating doses of 100 mg/day, 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for an additional 8 weeks. From Nov 29, 2013, participants were randomly assigned (1:1) to receive open-label sertraline at predetermined doses of 200 mg/day, 300 mg/day, or 400 mg/day as induction therapy for 2 weeks, followed by consolidation therapy with 200 mg/day for 8 weeks. Dose assignment was made via computer-generated, permuted block randomisation stratified by antiretroviral therapy (ART) status for people with a first episode of meningitis. The primary outcome was 2-week cerebrospinal fluid (CSF) clearance rate of cryptococcus, termed early fungicidal activity, measured in patients with a first episode of culture-positive meningitis and two or more CSF cultures. This study is registered with ClinicalTrials.gov, number NCT01802385. Of the 330 individuals assessed, 172 HIV-infected adults with cryptococcal meningitis were enrolled. We gave 100 mg/day sertraline to 17 patients, 200 mg/day to 12 patients, 300 mg/day to 14 patients, and 400 mg/day to 17 patients. 112 participants were randomly assigned to receive sertraline at 200 mg (n=48), 300 mg (n=36), or 400 mg (n=28) daily for the first 2 weeks, and 200 mg/day thereafter. The final population consisted of 17 participants in the 100 mg group, 60 in the 200 mg group, 50 in the 300 mg group, and 45 in the 400 mg in group. Participants receiving any sertraline dose averaged a CSF clearance rate of −0·37 colony forming units per mL per day (95% CI −0·41 to −0·33). Incidence of paradoxical immune reconstitution inflammatory syndrome was 5% (two of 43 newly starting ART) and no cases of relapse occurred over the 12-week study period. 38 (22%) of 172 participants had died at 2 weeks, and 69 (40%) had died at 12 weeks. Six grade 4 adverse events occurred in 17 participants receiving 100 mg, 14 events in 60 participants receiving 200 mg, 19 events in 50 participants receiving 300 mg, and eight events in 45 participants receiving 400 mg. Grade 4 or 5 adverse event risk did not differ between current US Food and Drug Administration-approved dosing of 100–200 mg/day and higher doses of 300–400 mg/day (hazard ratio 1·27, 95% CI 0·69–2·32; p=0·45). Participants receiving sertraline had faster cryptococcal CSF clearance and a lower incidence of immune reconstitution inflammatory syndrome and relapse than that reported in the past. This inexpensive and off-patent oral medication is a promising adjunctive antifungal therapy. National Institutes of Health, Grand Challenges Canada.

Background Meningitis remains a top cause of premature death and loss of disability-adjusted life years in low-income countries. In resource-limited settings, proper laboratory diagnostics are often scarce and knowledge about national and local epidemiology is limited. Misdiagnosis, incorrect treatment and overuse of antibiotics are potential consequences, especially for viral meningitis. Methods A prospective study was conducted over three months in a teaching hospital in Ethiopia with limited laboratory resources. Cerebrospinal fluid (CSF) samples from patients with suspected meningitis were analysed using a multiplex PCR-based system (FilmArray, BioFire), in addition to basic routine testing with microscopy and culture. Clinical data, as well as information on treatment and outcome were collected. Results Two hundred and eighteen patients were included; 117 (54%) neonates (0–29 days), 63 (29%) paediatrics (1 month-15 years) and 38 (17%) adults (≥16 years). Of 218 CSF samples, 21 (10%) were PCR positive; 4% in neonates, 14% in paediatrics and 18% in adults. Virus was detected in 57% of the PCR positive samples, bacteria in 33% and fungi in 10%. All CSF samples that were PCR positive for a bacterial agent had a white cell count ≥75 cells/mm 3 and/or turbid appearance. The majority (90%) of patients received more than one antibiotic for treatment of the meningitis episode. There was no difference in the mean number of different antibiotics received or in the cumulative number of days with antibiotic treatment between patients with a microorganism detected in CSF and those without. Conclusions A rapid molecular diagnostic system was successfully implemented in an Ethiopian setting without previous experience of molecular diagnostics. Viral meningitis was diagnosed for the first time in routine clinical practice in Ethiopia, and viral agents were the most commonly detected microorganisms in CSF. This study illustrates the potential of rapid diagnostic tests for reducing antibiotic usage in suspected meningitis cases. However, the cost of consumables for the molecular diagnostic system used in this study limits its use in low-income countries.

The MenAfriNet Consortium supports strategic implementation of case-based meningitis surveillance in key high-risk countries of the African meningitis belt: Burkina Faso, Chad, Mali, Niger, and Togo. We describe bacterial meningitis epidemiology in these 5 countries in 2015-2017. Case-based meningitis surveillance collects case-level demographic and clinical information and cerebrospinal fluid (CSF) laboratory results. Neisseria meningitidis, Streptococcus pneumoniae, or Haemophilus influenzae cases were confirmed and N. meningitidis/H. influenzae were serogrouped/serotyped by real-time polymerase chain reaction, culture, or latex agglutination. We calculated annual incidence in participating districts in each country in cases/100 000 population. From 2015-2017, 18 262 suspected meningitis cases were reported; 92% had a CSF specimen available, of which 26% were confirmed as N. meningitidis (n = 2433; 56%), S. pneumoniae (n = 1758; 40%), or H. influenzae (n = 180; 4%). Average annual incidences for N. meningitidis, S. pneumoniae, and H. influenzae, respectively, were 7.5, 2.5, and 0.3. N. meningitidis incidence was 1.5 in Burkina Faso, 2.7 in Chad, 0.4 in Mali, 14.7 in Niger, and 12.5 in Togo. Several outbreaks occurred: NmC in Niger in 2015-2017, NmC in Mali in 2016, and NmW in Togo in 2016-2017. Of N. meningitidis cases, 53% were NmC, 30% NmW, and 13% NmX. Five NmA cases were reported (Burkina Faso, 2015). NmX increased from 0.6% of N. meningitidis cases in 2015 to 27% in 2017. Although bacterial meningitis epidemiology varied widely by country, NmC and NmW caused several outbreaks, NmX increased although was not associated with outbreaks, and overall NmA incidence remained low. An effective low-cost multivalent meningococcal conjugate vaccine could help further control meningococcal meningitis in the region.

Culture positive bacterial meningitis has fallen over a 12-year period in urban Malawi following Hib vaccination. Hib, NTS, and pneumococcal meningitis have fallen significantly in children. Pneumococcal meningitis has not fallen in adults; NTS and pneumococcal meningitis are seasonal. Background.  We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of Haemophilus influenzae type b (Hib) vaccination and the rollout of antiretroviral therapy (ART). Methods.  We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012. Results.  There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92–.94; P < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85–.88; P < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97–1.0; P = .135) despite rapid scale-up of ART provision. In children aged <5 years, Streptococcus pneumoniae, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. Streptococcus pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100 000 cases in children aged <14 years, 6 per 100 000 adolescents, and 10 per 100 000 adults. Conclusions.  Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic “meningitis belt” in Africa is essential.