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BMC Infectious Diseases Aug 2019Definitive diagnosis of meningitis is made by analysis of cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) obtained from a lumbar puncture (LP),...
BACKGROUND
Definitive diagnosis of meningitis is made by analysis of cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) obtained from a lumbar puncture (LP), which may take days. A timelier diagnostic clue of meningitis is pleocytosis on CSF analysis. However, meningitis may occur in the absence of pleocytosis on CSF. Areas of Uncertainty: A diagnosis of meningitis seems less likely without pleocytosis on CSF, leading clinicians to prematurely exclude this. Further, there is little available literature on the subject.
METHODS
Ovid/Medline and Google Scholar search was conducted for cases of CSF culture-confirmed meningitis with lack of pleocytosis. Inclusion criterion was reported cases of CSF culture-positive or PCR positive meningitis in the absence of pleocytosis on LP. Exclusion criteria were pleocytosis on CSF, cases in which CSF cultures/PCR were not performed, and articles that did not include CSF laboratory values.
RESULTS
A total of 124 cases from 51 articles were included. Causative organisms were primarily bacterial (99 cases). Outcome was reported in 86 cases, 27 of which died and 59 survived. Mortality in viral, fungal and bacterial organisms was 0, 56 and 31%, respectively. The overall percentage of positive initial CSF PCR/culture for viral, fungal and bacterial organisms was 100, 89 and 82%, respectively. Blood cultures were performed in 79 of the 124 cases, 56 (71%) of which ultimately cultured the causative organism. In addition to bacteremia, concomitant sources of infection occurred in 17 cases.
CONCLUSIONS
Meningitis in the absence of pleocytosis on CSF is rare. If this occurs, causative organism is likely bacterial. We recommend ordering blood cultures as an adjunct, and, if clinically relevant, concomitant sources of infection should be sought. If meningitis is suspected, empiric antibiotics/antifungals should be administered regardless of initial WBC count on lumbar puncture.
Topics: Blood Culture; Cerebrospinal Fluid; Diagnostic Tests, Routine; Humans; Leukocyte Count; Leukocytosis; Meningitis; Polymerase Chain Reaction; Retrospective Studies; Spinal Puncture
PubMed: 31382892
DOI: 10.1186/s12879-019-4204-z -
BMC Pediatrics Feb 2019The early recognition of meningococcal disease in children is vital. During the prodrome however, meningococcal infection presents similarly to many self-limiting viral...
BACKGROUND
The early recognition of meningococcal disease in children is vital. During the prodrome however, meningococcal infection presents similarly to many self-limiting viral infections. This mandates a cautious approach with many children receiving unnecessary broad-spectrum parenteral antibiotics. Advances in nucleic acid amplification techniques mean that it is now possible to test for Neisseria meningitidis DNA using Loop-mediated-isothermal AMPlification (LAMP). This technique is quicker than traditional PCR techniques and can be performed using simple equipment.
METHODS
Prior to performing this systematic review, a protocol was developed adhering to PRISMA P standards and underwent full external peer review. This systematic review was registered with PROSPERO (CRD42017078026). The index test assessed was LAMP for Neisseria meningitidis and the reference standard was culture or qPCR of a sterile site detecting Neisseria meningitidis.
RESULTS
We identified 95 records in total: 94 records from the electronic databases and 1 additional study from the grey literature. After removal of duplicates, 36 studies were screened, and 31 studies excluded based on the title/abstract. Five full text studies underwent full text review and three studies, including 2243 tests on 1989 patients aged between 7 days and 18 years were included in the final systematic review. In all studies the LAMP assay and qPCR primers were directed against the ctrA region of the Neisseria meningitidis bacteria. The diagnostic accuracy of LAMP testing for invasive meningococcal disease was reported as high (sensitivity 0.84-1.0 and specificity 0.94-1.0) in all studies irrespective of the sample tested (CSF, Blood, Swab).
CONCLUSIONS
We included three studies with 2243 tests on 1989 patients using CSF, blood samples or naso/oropharyngeal swabs. The studies were all of a high quality and deemed at low risk of bias. Results show that LAMP testing on blood and CSF was highly accurate when compared to qPCR/culture. LAMP testing for Neisseria meningitidis is fast and highly accurate and therefore has the potential to be used to rapidly rule in/out meningococcal disease in children. Given the life-threatening nature of meningococcal infection further research is required to demonstrate the safety and efficacy of using LAMP testing for Neisseria meningitidis as a rule in/out test.
TRIAL REGISTRATION
This systematic review was registered prospectively with PROSPERO on the 29/11/2017 (CRD42017078026).
Topics: Humans; Meningococcal Infections; Neisseria meningitidis; Nucleic Acid Amplification Techniques; Reproducibility of Results
PubMed: 30732581
DOI: 10.1186/s12887-019-1403-0 -
PloS One 2017We undertook a systematic review and meta-analysis to address the question "what is the impact of meningitis on IQ and development." (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
We undertook a systematic review and meta-analysis to address the question "what is the impact of meningitis on IQ and development."
METHODS
Search: conducted using standardized search terms across Medline, PsychInfo and EMBASE to 06/2014. Eligibility: human studies of any infectious aetiology of meningitis reporting IQ or infant developmental age or stage outcomes. Quality: Centre for Evidence Based Medicine, Oxford, quality tools. Analysis: random effects meta-analysis by organism.
RESULTS
39 studies were included in the review, 34 providing data on IQ (2015 subjects) and 12 on developmental delay (382 subjects). Across all bacterial organisms, meningitis survivors had a mean IQ 5.50 (95% CI: -7.19, -3.80; I2 = 47%, p = 0.02) points lower than controls. IQ was significantly lower than controls for Neisseria meningitides (NM: 5 points) and Haemophilus influenzae b (Hib: 6 points) but not in viral meningitis, with only single studies included for Streptococcus pneumoniae (SP) and group B streptococcus (GBS). The pooled relative risk (RR) for low IQ (IQ<70) in survivors of bacterial meningitis compared with controls was 4.99 (95% CI: 3.17, 7.86) with no significant heterogeneity (I2 = 49%, p = 0.07). Developmental delay of approximately 0.5SD was reported in studies of bacterial meningitis but no delay in the only study of viral meningitis.
CONCLUSIONS
We found moderate evidence that surviving bacterial meningitis has a deleterious impact on IQ and development but no evidence that viral meningitis had meaningful cognitive impacts. Survivors of bacterial meningitis should be routinely offered screening for cognitive deficits and developmental delay in addition to hearing loss.
Topics: Humans; Intelligence; Meningitis, Bacterial; Meningitis, Viral
PubMed: 28837564
DOI: 10.1371/journal.pone.0175024 -
Lancet (London, England) Sep 2017We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI)... (Review)
Review
Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.
BACKGROUND
We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015.
METHODS
We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity.
FINDINGS
We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population.
INTERPRETATION
Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group.
FUNDING
The Bill & Melinda Gates Foundation.
Topics: Child, Preschool; Developing Countries; Global Health; Hospital Mortality; Hospitalization; Humans; Incidence; Infant; Infant, Newborn; Models, Statistical; Respiratory Syncytial Viruses; Respiratory Tract Infections; Risk Factors
PubMed: 28689664
DOI: 10.1016/S0140-6736(17)30938-8 -
International Journal of Infectious... Sep 2015Clinically, it is often difficult to differentiate between bacterial and viral aetiologies in adults with suspected meningitis. Several studies have demonstrated the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Clinically, it is often difficult to differentiate between bacterial and viral aetiologies in adults with suspected meningitis. Several studies have demonstrated the potential use of serum procalcitonin (PCT) in making this differentiation. The aim was to pool these studies into a meta-analysis to determine the diagnostic accuracy of PCT.
METHODS
Major electronic databases were searched for articles studying the use of serum PCT in the differentiation of bacterial and viral meningitis in adult patients. No date or language restrictions were applied. Data analysis was performed using Meta-DiSc 1.4 and MIX 2.0.
RESULTS
Nine studies (n=725 patients) were included in the meta-analysis. Serum PCT was found to be a highly accurate test for diagnosing meningitis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) for PCT were 0.90 (95% confidence interval (CI) 0.84-0.94), 0.98 (95% CI 0.97-0.99), 27.3 (95% CI 8.2-91.1), 0.13 (95% CI 0.07-0.26), and 287.0 (95% CI 58.5-1409.0), respectively. PCT was found to be far superior to C-reactive protein, which had a pooled DOR of only 22.1 (95% CI 12.7-38.3).
CONCLUSIONS
Serum PCT is a highly accurate diagnostic test that can be used by physicians for rapid differentiation between bacterial and viral causes of meningitis in adults.
Topics: Adult; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Humans; Meningitis, Bacterial; Middle Aged; Protein Precursors; Sensitivity and Specificity
PubMed: 26188130
DOI: 10.1016/j.ijid.2015.07.011 -
PLoS Neglected Tropical Diseases Mar 2015Japanese encephalitis virus (JEV) is an important cause of encephalitis in most of Asia, with high case fatality rates and often significant neurologic sequelae among... (Review)
Review
BACKGROUND
Japanese encephalitis virus (JEV) is an important cause of encephalitis in most of Asia, with high case fatality rates and often significant neurologic sequelae among survivors. The epidemiology of JE in the Philippines is not well defined. To support consideration of JE vaccine for introduction into the national schedule in the Philippines, we conducted a systematic literature review and summarized JE surveillance data from 2011 to 2014.
METHODS
We conducted searches on Japanese encephalitis and the Philippines in four databases and one library. Data from acute encephalitis syndrome (AES) and JE surveillance and from the national reference laboratory from January 2011 to March 2014 were tabulated and mapped.
RESULTS
We identified 29 published reports and presentations on JE in the Philippines, including 5 serologic surveys, 18 reports of clinical cases, and 8 animal studies (including two with both clinical cases and animal data). The 18 clinical studies reported 257 cases of laboratory-confirmed JE from 1972 to 2013. JE virus (JEV) was the causative agent in 7% to 18% of cases of clinical meningitis and encephalitis combined, and 16% to 40% of clinical encephalitis cases. JE predominantly affected children under 15 years of age and 6% to 7% of cases resulted in death. Surveillance data from January 2011 to March 2014 identified 73 (15%) laboratory-confirmed JE cases out of 497 cases tested.
SUMMARY
This comprehensive review demonstrates the endemicity and extensive geographic range of JE in the Philippines, and supports the use of JE vaccine in the country. Continued and improved surveillance with laboratory confirmation is needed to systematically quantify the burden of JE, to provide information that can guide prioritization of high risk areas in the country and determination of appropriate age and schedule of vaccine introduction, and to measure the impact of preventive measures including immunization against this important public health threat.
Topics: Adolescent; Antibodies, Viral; Child; Child, Preschool; Encephalitis Virus, Japanese; Encephalitis, Japanese; Female; Humans; Infant; Japanese Encephalitis Vaccines; Male; Philippines; Public Health; Seroepidemiologic Studies; Vaccination
PubMed: 25794009
DOI: 10.1371/journal.pntd.0003630 -
Autoimmunity Reviews Sep 2013The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt-Koyanagi-Harada syndrome, including viral infection, genetic factors... (Review)
Review
OBJECTIVES
The objectives of this study are to review our current knowledge of the aetiopathogenesis of Vogt-Koyanagi-Harada syndrome, including viral infection, genetic factors and immunomediated mechanisms, and to discuss pathogenesis and its relevance to pharmacotherapy.
SYSTEMATIC REVIEW METHODOLOGY
Relevant publications from 1965 to 2012 on the aetiopathogenesis and pharmacotherapy of VKHS were analysed.
RESULTS AND CONCLUSION
Vogt-Koyanagi-Harada syndrome (VKHS) is a rare multisystemic autoimmune disease that affects tissues containing melanin, including the eye, inner ear, meninges, and skin. The disease is characterised by bilateral uveitis associated with a varying constellation of auditory, neurological and cutaneous manifestations. The disease occurs more frequently among people with darker skin pigmentation. Asians, Native Americans, and Hispanics are most frequently affected. It predominates in patients aged between 20 and 50years, and females are affected more frequently, with a female:male ratio of 2:1. The classic clinical course is characterised by bilateral panuveitis, hypoacusis, and meningitis, in addition to cutaneous involvement with poliosis, vitiligo, and alopecia. Although the exact cause of VKH disease remains unknown, it is thought to be a T-cell-mediated autoimmune process directed against melanocytes. VKHS classically begins with vague systemic symptoms suggestive of a viral infection, although a clear association between a specific viral agent and the disease has not been established. Genetic factors may play an important role in the loss of self-tolerance in VKHS. The HLA-DRB1*0405 allele is the main susceptibility allele for VKHS. Early and aggressive systemic corticosteroids are still the primary initial therapy for VKHS. Ocular complications may require an intravitreous injection of corticosteroids. Despite proper treatment with steroids, a number of patients experience recurrent attacks or steroid-associated complications. Thus, non steroid immunomodulatory therapy (IMT) has become necessary for the treatment of VKHS.
Topics: Autoimmune Diseases; HLA-DRB1 Chains; Humans; Self Tolerance; Uveomeningoencephalitic Syndrome
PubMed: 23567866
DOI: 10.1016/j.autrev.2013.01.004 -
The Cochrane Database of Systematic... Feb 2012Mumps, measles and rubella (MMR) are serious diseases that can lead to potentially fatal illness, disability and death. However, public debate over the safety of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Mumps, measles and rubella (MMR) are serious diseases that can lead to potentially fatal illness, disability and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness.
OBJECTIVES
To assess the effectiveness and adverse effects associated with the MMR vaccine in children up to 15 years of age.
SEARCH METHODS
For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, PubMed (July 2004 to May week 2, 2011) and Embase.com (July 2004 to May 2011).
SELECTION CRITERIA
We used comparative prospective or retrospective trials assessing the effects of the MMR vaccine compared to placebo, do nothing or a combination of measles, mumps and rubella antigens on healthy individuals up to 15 years of age.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed methodological quality of the included studies. One review author arbitrated in case of disagreement.
MAIN RESULTS
We included five randomised controlled trials (RCTs), one controlled clinical trial (CCT), 27 cohort studies, 17 case-control studies, five time-series trials, one case cross-over trial, two ecological studies, six self controlled case series studies involving in all about 14,700,000 children and assessing effectiveness and safety of MMR vaccine. Based on the available evidence, one MMR vaccine dose is at least 95% effective in preventing clinical measles and 92% effective in preventing secondary cases among household contacts.Effectiveness of at least one dose of MMR in preventing clinical mumps in children is estimated to be between 69% and 81% for the vaccine prepared with Jeryl Lynn mumps strain and between 70% and 75% for the vaccine containing the Urabe strain. Vaccination with MMR containing the Urabe strain has demonstrated to be 73% effective in preventing secondary mumps cases. Effectiveness of Jeryl Lynn containing MMR in preventing laboratory-confirmed mumps cases in children and adolescents was estimated to be between 64% to 66% for one dose and 83% to 88% for two vaccine doses. We did not identify any studies assessing the effectiveness of MMR in preventing rubella.The highest risk of association with aseptic meningitis was observed within the third week after immunisation with Urabe-containing MMR (risk ratio (RR) 14.28; 95% confidence interval (CI) from 7.93 to 25.71) and within the third (RR 22.5; 95% CI 11.8 to 42.9) or fifth (RR 15.6; 95% CI 10.3 to 24.2) weeks after immunisation with the vaccine prepared with the Leningrad-Zagreb strain. A significant risk of association with febrile seizures and MMR exposure during the two previous weeks (RR 1.10; 95% CI 1.05 to 1.15) was assessed in one large person-time cohort study involving 537,171 children aged between three months and five year of age. Increased risk of febrile seizure has also been observed in children aged between 12 to 23 months (relative incidence (RI) 4.09; 95% CI 3.1 to 5.33) and children aged 12 to 35 months (RI 5.68; 95% CI 2.31 to 13.97) within six to 11 days after exposure to MMR vaccine. An increased risk of thrombocytopenic purpura within six weeks after MMR immunisation in children aged 12 to 23 months was assessed in one case-control study (RR 6.3; 95% CI 1.3 to 30.1) and in one small self controlled case series (incidence rate ratio (IRR) 5.38; 95% CI 2.72 to 10.62). Increased risk of thrombocytopenic purpura within six weeks after MMR exposure was also assessed in one other case-control study involving 2311 children and adolescents between one month and 18 years (odds ratio (OR) 2.4; 95% CI 1.2 to 4.7). Exposure to the MMR vaccine was unlikely to be associated with autism, asthma, leukaemia, hay fever, type 1 diabetes, gait disturbance, Crohn's disease, demyelinating diseases, bacterial or viral infections.
AUTHORS' CONCLUSIONS
The design and reporting of safety outcomes in MMR vaccine studies, both pre- and post-marketing, are largely inadequate. The evidence of adverse events following immunisation with the MMR vaccine cannot be separated from its role in preventing the target diseases.
Topics: Adolescent; Age Factors; Autistic Disorder; Child; Child, Preschool; Clinical Trials as Topic; Crohn Disease; Epidemiologic Studies; Humans; Infant; Measles; Measles-Mumps-Rubella Vaccine; Mumps; Purpura, Thrombocytopenic; Rubella; Seizures, Febrile; Vaccines, Attenuated
PubMed: 22336803
DOI: 10.1002/14651858.CD004407.pub3 -
Archives of Pediatrics & Adolescent... Oct 2011To summarize the risk of occult serious bacterial infection in the youngest febrile infants presenting with either clinical bronchiolitis or respiratory syncytial virus... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To summarize the risk of occult serious bacterial infection in the youngest febrile infants presenting with either clinical bronchiolitis or respiratory syncytial virus infection.
DATA SOURCES
We performed a systematic search of the Medline database for studies reporting rates of serious bacterial infection in infants younger than 90 days with clinical bronchiolitis and/or respiratory syncytial virus infection.
STUDY SELECTION
Studies reporting on cultures performed at the time of presentation to care and providing a denominator, ie, total number of each type of culture obtained, were analyzed.
MAIN EXPOSURE
Admission for bronchiolitis.
MAIN OUTCOME MEASURES
Age-specific rates of urinary tract infection, bacteremia, and meningitis were extracted.
RESULTS
The weighted rate of urinary tract infections in the youngest infants in the 11 studies analyzed was 3.3% (95% confidence interval, 1.9%-5.7%). No case of bacteremia was reported in 8 of 11 studies. No case of meningitis was reported in any of the studies. Summary statistics for meningitis and bacteremia are not provided because of an excess of zero events in these samples.
CONCLUSIONS
A screening approach to culturing for serious bacterial infections in febrile infants presenting with bronchiolitis or respiratory syncytial virus infection is very low yield. The rate of urine cultures positive for bacteria remains significant, though asymptomatic bacteriuria may confound these results.
Topics: Bacteremia; Bacterial Infections; Bronchiolitis, Viral; Humans; Infant; Infant, Newborn; Meningitis, Bacterial; Respiratory Syncytial Virus Infections; Urinary Tract Infections
PubMed: 21969396
DOI: 10.1001/archpediatrics.2011.155 -
The Cochrane Database of Systematic... Jan 2009Tick-borne encephalitis (TBE) is a disease of the central nervous system caused by a tick-borne viral infection. TBE can lead to severe neurological syndromes such as... (Review)
Review
BACKGROUND
Tick-borne encephalitis (TBE) is a disease of the central nervous system caused by a tick-borne viral infection. TBE can lead to severe neurological syndromes such as meningitis, meningoencephalitis, and meningoencephalomyelitis, which can result in death. There is no treatment, and prevention with the vaccine is the only intervention currently available.
OBJECTIVES
To evaluate vaccines for preventing TBE in terms of effectiveness and adverse effects.
SEARCH STRATEGY
In June 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE, EMBASE, LILACS, and mRCT. We also checked reference lists of articles.
SELECTION CRITERIA
Randomized and quasi-randomized controlled trials comparing TBE vaccines against placebo, control vaccines, no intervention, or a different dose or schedule of the intervention vaccine.
DATA COLLECTION AND ANALYSIS
Two authors applied the inclusion criteria, extracted data, and assessed each trial's risk of bias. We could not combine the included trials in a meta-analysis because of differences in comparisons and outcomes.
MAIN RESULTS
Eleven trials (corresponding to 10 papers) involving 8184 participants (6586 adults and 1598 children) were included. Different versions of three types of TBE vaccines were tested (IPVE, FSME-IMMUN, and Encepur); out of which only three (Encepur children, Encepur Adults, and FSME-IMMUN "new") are currently licensed. No trials reported on cases of clinical TBE, but all reported on antibody titre (seroconversion). All the vaccines gave seroconversion rates of over 87%. Systemic and local adverse effects were common; none were severe or life threatening.
AUTHORS' CONCLUSIONS
Tick-borne encephalitis vaccines appear to be highly immunogenic, but the relationship between seroconversion and clinical protection has not been established. Although adverse effects were commonly reported, none were serious or life threatening.
Topics: Adult; Child; Encephalitis, Tick-Borne; Humans; Infant; Randomized Controlled Trials as Topic; Viral Vaccines
PubMed: 19160184
DOI: 10.1002/14651858.CD000977.pub2