Globally, meningitis is estimated to kill children each year.

Transcription

1 Bacterial Meningitis in Children <2 Years of Age in a Tertiary Care Hospital in South India: An Assessment of Clinical and Laboratory Features Sean Patrick Fitzwater, MHS 1, Padmanabhan Ramachandran, MD 2, Krishnamoorthy Nedunchelian, MD 2, Geoffrey Kahn, MHS 1, Mathuram Santosham, MD, MPH 1, and Aruna Chandran, MD, MPH 1 Objectives To assess the clinical and laboratory features of suspected meningitis to assist in the accurate diagnosis of bacterial meningitis in young Indian children. Study design Children <2 years of age with clinical suspicion of meningitis were enrolled. Clinical and laboratory information was collected, and cases were classified based on cerebrospinal fluid findings as clinical, aseptic, or probable and confirmed bacterial meningitis. Results A total of 2564 children with suspected meningitis were enrolled over 45 months; 156 cases of aseptic and 51 cases of bacterial meningitis were identified. Stiff neck and bulging fontanelle were more common in bacterial meningitis (P <.05), but were present in <15% of patients. The World Health Organization and American Academy of Pediatrics classifications for high suspicion of bacterial meningitis were met in 84% and 88% of cases of bacterial meningitis, respectively, but were also present in 54% and 74% cases of aseptic meningitis. Culture and gram stain were positive in 7 (14%) and 4 (8%) cases of bacterial meningitis. Conclusions Signs of bacterial meningitis and proposed criteria for high suspicion of bacterial meningitis are non-specific in this population. Standard microbiological tests for bacteria are insensitive in this setting, necessitating highly sensitive methods to identify bacterial meningitis. (J Pediatr 2013;163:S32-7). Globally, meningitis is estimated to kill children each year. 1 In India approximately children die each year from meningitis; this accounts for 2% of all deaths in children <5 years of age. 2 Although the rate of disease associated with meningitis is lower than other major causes of childhood morality, the high case fatality rates and neurologic sequelae in survivors result in considerable emotional and financial burden on the family and presents a major challenge to the health care system in financial and human resources. Meningitis generally is classified into aseptic versus bacterial, based on etiology. Aseptic meningitis predominantly is caused by viruses, usually is a diagnosis of exclusion based on the lack of bacterial findings, and generally has lower rates of case fatality and neurologic sequelae. 3 Bacterial meningitis, although less common than aseptic meningitis, 4 carries a greater risk of morbidity and mortality. In low- and middle-income countries, case fatality rates from bacterial meningitis range from 22%-73% depending on the setting and if there is access to appropriate care. 5,6 Additionally, approximately one-half of the children who survive bacterial meningitis develop neurologic sequelae, which include intellectual deficits, behavioral problems, and hearing loss. 7 Rapidly identifying bacterial meningitis is critical for proper treatment and maximal outcomes. The key to diagnosis of bacterial meningitis is timely lumbar puncture (LP) to identify bacteria or their markers. However, the clinical presentation of meningitis in infants, who comprise the bulk of cases of pediatric meningitis, is nonspecific compared with symptoms seen in older children or adults and can be similar to other febrile illnesses. 8 Furthermore, the clinical presentations of bacterial and aseptic meningitis are similar, making identification of bacterial pathogens in the cerebrospinal fluid (CSF) critical. 3 Because meningitis can result in fatality and high rates of sequelae, clinical signs with high sensitivity and poor specificity are used to ensure that all cases are often captured. In India, the clinical and laboratory picture of meningitis is further complicated by the widespread availability of antibiotics, reducing the utility of standard microbiological methods in confirming bacterial meningitis and in formulating appropriate treatment difficult. Antibiotics are known to rapidly sterilize the CSF, making identification of bacterial by culture problematic. 9 Additionally, the impact of pretreatment with antibiotics on other laboratory indicators of meningitis, such as the total white blood cell (WBC) count, glucose, or protein in the CSF, are not consistent, which makes the differentiation of bacterial versus aseptic meningitis difficult. Molecular tests, such as latex agglutination test (LAT) BMS CSF Hib ICH&HC LAT LP WBC WHO Bacterial Meningitis Score Cerebrospinal fluid Haemophilus influenzae type b Institute of Child Health and Hospital for Children Latex agglutination test Lumbar puncture White blood cell World Health Organization From the 1 Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; and the 2 Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India Funded by The GAVI Hib Initiative, a consortium project funded by GAVI Alliance. Please see the Author Disclosures at the end of this article /$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. S32

2 Vol. 163, No. 1, Suppl. 1 July 2013 and polymerase chain reaction, are more sensitive at detecting bacterial meningitis in antibiotic pretreated patients, 8,10 but are generally unavailable in low-income settings. The combination of antibiotic use and the expense of molecular tests make routine confirmation of bacterial meningitis difficult in India. Therefore, it is important to assess which features of meningitis can be used to accurately diagnose bacterial meningitis. In this prospective study, commonly used clinical and laboratory criteria for bacterial meningitis were examined to determine which criteria are useful in diagnosing bacterial meningitis and differentiating it from aseptic meningitis in young children in India. Methods This study, part of a wider pediatric meningitis surveillance effort in India, 11 took place at the Institute of Child Health and Hospital for Children (ICH&HC) in Chennai, Tamil Nadu, India. ICH&HC is a 537 bed public referral pediatric hospital that serves an urban population. All children admitted to ICH&HC aged >30 days to <24 months were screened prospectively for signs and symptoms of clinically suspected meningitis through daily surveillance in the hospital wards. Enrollment criteria for clinically suspected meningitis were based on the World Health Organization (WHO) s recommended case definition for bacterial meningitis surveillance: acute onset fever with 1 or more signs of meningitis. 12 Acute fever was defined as fever with onset within 5 days of hospitalization, either confirmed to be >38 C at admission or a history of fever as described by the child s guardian. Signs of meningitis were altered mental status (including lethargy and prostration), seizure (simple or complex), bulging fontanelle, and/or neck stiffness. A complex seizure was defined as a seizure lasting >5 minutes, demonstrating focal seizure activity, or had more than one episode of seizure; a simple seizure had none of these characteristics. Additionally, children were enrolled if their attending physician suspected meningitis, regardless of the presence of the above mentioned signs. After enrollment, demographic, health history, and clinical data were collected. Demographic data was obtained by interviewing the patient s caregiver (most often the parent/ guardian). The child s clinical history prior to admission was taken from the patients case sheet or, if information was missing or unclear, from interviewing the child s caregiver. Treatment with antibiotics prior to hospitalization was confirmed, when possible, by visual verification of the antibiotics, receipts, or records from previous medical care. History of vaccination was taken from immunization cards or, if no card was available, was obtained from parent recall. Clinical findings and treatment in the hospital were taken from the patient s case sheet and from the attending physician. Final clinical outcome and diagnosis information were taken from the hospital records. This study had no effect on the clinical care of the patients. All treatment decisions were carried out by the regular staff as per the hospital s standard of care. The decision to perform a LP was made by the patient s attending physician and conducted after the attending physician obtained permission from the child s parent/guardian. LP kits were provided by the study to ensure that the LP could be done with ease, and attendants were made available 24 hours a day to ensure that samples were rapidly transported to the laboratory. Laboratory infrastructure was updated to ensure high quality results and laboratory staffing was expanded to be around-the-clock to ensure accurate and timely laboratory testing. CSF samples were examined for total WBC count, WBC differential, Gram staining, protein concentration, glucose concentration, and bacterial culture using chocolate agar plates incubated at 37 CinaCO 2 enriched atmosphere. Samples with 10 or more WBCs per mm 3 were tested using a LAT kit specific for Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, group B Streptococcus, Neisseria meningitidis groups A/Y, Neisseria meningitidis groups C/ W135, and Neisseria meningitidis group B or Escherichia coli K1 (Directigen Meningitis Combo Test; Becton, Dickinson and Company, Franklin Lakes, New Jersey). In the event of limited CSF volume, laboratory tests were prioritized as follows: WBC count, LAT (for samples with $10 WBC per mm 3 ), bacterial or microbial culture, Gram stain, and finally biochemistries. Clinically suspected cases of bacterial meningitis were further classified based on laboratory findings. Abnormal CSF findings were defined as any CSF sample with $10 WBC per mm 3. Bacterial meningitis was considered confirmed if any of the following criteria was met in a patient with abnormal CSF findings: positive LAT test, positive CSF culture, or positive gram stain. Samples with abnormal CSF findings but no bacterial identifications were classified as aseptic meningitis. Additional classifications were made using the WHO definition for probable meningitis (CSF with $100 WBC per mm 3, WBC per mm 3 plus increased protein concentration [$100 mg/dl] or decreased glucose concentration [<40 mg/dl], or visually turbid CSF) 12 and the Bacterial Meningitis Score (BMS) for high likelihood of bacterial meningitis ($10 WBC in the CSF with any of the following: positive CSF gram stain, CSF neutrophil count $1000 cells/mm 3, CSF protein $80 mg/dl, or seizure before or at presentation). 13 The criterion of blood neutrophil count of $ cells/ml was not utilized as peripheral blood samples were not obtained for this study. Internal and external quality control procedures were put in place, and training of research staff was undertaken as part of the ongoing surveillance program. Technical assistance for surveillance, laboratory methods, and data analysis was provided by Johns Hopkins School of Public Health, (Baltimore, Maryland) and the All India Institute of Medical Sciences (New Delhi, India). Data entry was done using double data entry into and managed using Access 2007 (Microsoft, Redmond, Washington). Analysis was performed using Stata IC 10 (StataCorp, College Station, Texas) and Excel 2007 (Microsoft). Statistical difference for continuous variables were determined using the 2-sample Wilcoxon rank-sum test, Bacterial Meningitis in Children <2 Years of Age in a Tertiary Care Hospital in South India: An Assessment of Clinical and Laboratory Features S33

3 THE JOURNAL OF PEDIATRICS Vol. 163, No. 1, Suppl. 1 statistical differences for binomial variables were determined using Pearson c2, and 95% CI for binomial variables were calculated using the binomial exact method. The project was approved by the Institutional Review Boards at ICH&HC and the International Clinical Epidemiology Network. Written informed consent was obtained by study investigators from caregivers prior to obtaining demographic and pre-admission clinical information, and for sample storage. Results Between January 2008 and September 2011, 2564 children were identified with clinical indicators of bacterial meningitis. The ages of children were fairly evenly distributed with 25% of enrollees aged 1-5 months, 35% aged 6-11 months, 28% months, and 12% months. Severe malnutrition (defined as a weight for age Z-score >3 SD below WHO average) 14 was seen in 31% of children at the time of hospitalization. Forty-one percent of enrollees were female. The population was well-vaccinated; 91% of children had received 1 or more doses of diphtheria, pertussis, and tetanus vaccine. The Hib conjugate vaccine, which during this time was not part of the Universal Immunization Program in India, was relatively uncommon, with only 7% of patients having received the vaccine. Only 1 patient was reported to have received a pneumococcal vaccine. Hospitalization within the last 14 days had occurred in 17% of children, and 24% had received antibiotic therapy prior to admission to ICH&HC. The WHO suggests that a successful bacterial meningitis surveillance program should meet the following indicators: $90% of abnormal CSF samples should be tested with either microbial culture, LAT, or another highly sensitive method; $15% of samples with $10 WBC should have an etiology confirmed; $40% of samples with $100 WBC should have an etiology confirmed; and $20% of bacterial meningitis cases should be Hib cases. 12 This surveillance study met all these marks: 99% (128) of abnormal CSF samples were tested with LAT or culture, 25% of the samples with $10 WBC per mm 3 and 41% of samples with $100 WBC had an etiology confirmed, and 59% of cases of bacterial meningitis were due to Hib. LAT alone identified pathogens in 35% of patients with WBC $100 per mm 3. Clinical Characteristics A total of 1783 patients had clinically suspicious meningitis with normal CSF findings, 156 had aseptic meningitis, and 51 had bacterial meningitis. The 3 most common clinical signs (fever, altered consciousness, and seizure) were present in the majority of patients enrolled. Not unexpectedly, neck stiffness, altered consciousness, and bulging fontanelle were more common in cases of confirmed bacterial meningitis than patients who had clinical suspicion of meningitis alone (65% vs 38%, 14% vs 3%, and 6% vs 1%; P <.05 for all) (Table I). There was no difference in the presence of these symptoms between bacterial and aseptic meningitis; in fact in this study, there was no symptom that differed significantly between patients with aseptic versus bacterial meningitis. Interestingly, seizure was most common (91%) in children with clinical suspicion alone (P <.05 compared with confirmed bacterial meningitis); this indicates that even though seizures leads clinicians to strongly suspect meningitis, it is more likely a non-specific symptom that could be indicative of many illnesses. Cases of bacterial meningitis did present with moderately higher number of indicative symptoms, with a mean of 3 symptoms per patient compared with 2.6 in clinically suspected cases alone. Again, no statistically significant differences were found in the number of symptoms in patients between bacterial meningitis and those with aseptic meningitis. Laboratory Confirmed Meningitis LP was performed in 1990 (78%) of the children with clinical suspicion of meningitis. Of the 574 children who did not receive an LP, the most common reasons for not performing an LP were that the attending physician decided against an LP (384, 67%), parent refusal (51, 9%), and clinical contraindication (39, 7%). Of the children who received an LP, 78% (1551) received antibiotics prior to LP, either in the hospital or prior to admission. The types of the antibiotic given prior to LP were confirmed in 99% Table I. Clinical characteristics of cases with clinically suspected, aseptic, or bacterial meningitis Characteristic Clinical (n = 1783) Aseptic (n = 156) Bacterial (n = 51) P value % (95% CI) % (95% CI) % (95% CI) C vs B* AvsB Fever 97% (96-98) 97% (94-99) 98% (89-100) Temperature, C (SD) 37.5 (2.1) 37.2 (1.2) 37.5 (0.7) Seizure 91% (89-92) 74% (66-80) 80% (67-90) Simple seizure 18% (16-20) 17% (12-24) 18% (8-31) Complex seizure 73% (71-75) 56% (48-64) 63% (48-76) Altered consciousness 38% (36-40) 59% (51-67) 65% (50-78) < Stiff neck 1% (0-1) 4% (2-9) 6% (1-16) < Bulging fontanelle 3% (2-4) 11% (7-18) 14% (6-26) < Shock 24% (22-26) 34% (27-42) 35% (22-50) Rash 3% (2-4) 3% (1-7) 2% (0-10) Mean # of signs (SD) 2.6 (0.9) 2.8 (1.0) 3.0 (0.9) < *Clinical compared with bacterial meningitis. Aseptic compared with bacterial meningitis. S34 Fitzwater et al

4 July 2013 SUPPLEMENT of the children. The most common antibiotics recorded were third generation cephalosporins (1299, 84%), aminopenicillins (484, 31%), and aminoglycosides (289, 19%). A total of 677 children were treated with more than 1 type of antibiotic. Of the patients who received an LP, 207 had abnormal CSF findings. A total of 51 cases of bacterial meningitis were confirmed: 30 Hib (58%), 10 S pneumoniae (19%), 4 group B Streptococcus (8%), 2 N meningitis (1 group A/Y, 1 group C/W135, 4%), and 5 other bacteria (1 each Acinetobacter sp, Citrobacter freundii, Enterobacter sp, Pseudomonas sp, and Salmonella sp). Confirmation of bacterial etiology was made by LAT in 46 (90%) cases, culture in 7 (14%), and Gram stain in 4 (8%). Two samples were positive by LAT and Gram stain, 1 of which was also culture positive. Six of the 1986 (0.03%) CSF cultures were classified as contaminated based on otherwise normal CSF findings and etiology suggesting contamination. The remaining 156 were considered cases of aseptic meningitis. No seasonal variation in the number of patients with clinical meningitis, aseptic meningitis, or bacterial meningitis was noted. Case fatality rates were 26% for bacterial meningitis, 13% for aseptic meningitis, and 5% for patients without meningitis. Based on physician request, 14 LATs were done on CSF samples with WBC counts below the study cut-off of 10 mm 3. Two (14%) of these were positive, one for Hib and the other for group B Streptococcus. The LAT positivity rate in samples tested with WBC $ 10 WBC per mm 3 was 24% (46 of 189). Both were Gram stain and culture negative, and both had been treated with antibiotics before LP. Following study inclusion criteria, neither of these cases was included in the final study tables. The CSF findings of patients with bacterial meningitis compared with aseptic meningitis demonstrated statistically higher WBC counts and protein levels, and lower glucose levels (P <.01 for all) (Table II). Seventy-one percent of bacterial meningitis had >100 WBC per mm 3, 40% had glucose levels <40 mg/dl, and 58% had protein concentrations >100 mg/dl, compared with 33%, 21%, and 23% in patients with aseptic meningitis. Eighty-four percent of cases of confirmed bacterial meningitis met WHO criteria for probable bacterial meningitis, and 54% of aseptic meningitis cases met these criteria (P <.001). In contrast, the criteria for high suspicion of bacterial meningitis based on the BMS criteria was met in Table II. Characteristics of the CSF of cases with aseptic or bacterial meningitis Characteristic 88% of cases of confirmed bacterial meningitis and 74% of cases of aseptic meningitis, (P =.039). Antibiotic treatment prior to LP was common; 44 (86%) cases of bacterial meningitis and 187 (91%) cases of aseptic meningitis received one or more antibiotic before LP. Antibiotics appeared to have some effect on CSF findings in the cases of confirmed bacterial meningitis (Table III). As expected, treatment with antibiotics had a clear effect on the rates of positive culture in cases of bacterial meningitis, with 9% of treated patients having a positive CSF culture compared with 45% of those not treated (P =.016). The mean WBC and protein levels were lower in pretreated patients; however, neither of these observations was statistically significant. Discussion Aseptic (n = 156) Bacterial (n = 51) Mean (SD) Median Mean (SD) Median P value WBC/mm (627) (4037) Neutrophils, % 34 (23) (28) 60 <.001 Glucose, mg/dl 59 (33) (24) Protein, mg/dl 110 (235) (762) 121 <.001 % (95% CI) % (95% CI) WBC, % > 100/mm 3 33% (26-41) 71% (56-82) <.001 WBC, % > 1000/mm 3 5% (2-10) 29% (17-44) <.001 Glucose, % < 40 mg/dl 21% (14-28) 40% (26-54).006 Protein, % > 100 mg/dl 23% (17-31) 58% (43-72) <.001 Probable bacterial* 54% (46-62) 84% (71-93) <.001 High suspicion 74% (66-81) 88% (76-96).039 *WHO criteria. BMS criteria. Clinical signs and symptoms of bacterial meningitis are notoriously nonspecific in very young children, and classic meningeal signs often are not present. However, continuing to explore possible methods to clinically differentiate children with bacterial meningitis from other illnesses is critical, particularly in resource-poor clinical settings such as often seen in India where the capability to conduct a LP and accurately test the specimen promptly are limited. This study confirms that the classic signs of bacterial meningitis are very uncommon in young Indian children. Table III. Comparison of CSF findings of bacterial meningitis with or without antibiotic treatment prior to LP Characteristic Antibiotics (n = 44) No antibiotics (n = 7) Mean (SD) Median Mean (SD) Median WBC/mm (4173) (3273) Neutrophils, % 56 (28) (31) Glucose, mg/dl 45 (21) (38) Protein, mg/dl 454 (812) (235) Culture, % positive (95% CI) 9% (3-22) 43% (0-92).016 Gram stain, % positive (95% CI) 7% (1-19) 14% (0-49).495 LAT, % positive (95% CI) 93% (81-99) 71% (29-96).072 P value Bacterial Meningitis in Children <2 Years of Age in a Tertiary Care Hospital in South India: An Assessment of Clinical and Laboratory Features S35

5 THE JOURNAL OF PEDIATRICS Vol. 163, No. 1, Suppl. 1 The proportion of patients with meningeal findings in this study was much lower than what was seen in a systematic review of 10 studies looking at clinical features of bacterial meningitis in thousands of patients, where 51% of cases of bacterial meningitis were found to have neck stiffness and 36% had bulging fontanelle. 15 However, other India studies have shown a wide variation in symptoms, with meningeal signs present in 26%-62% of bacterial meningitis. 16,17 Additionally, there was a distinct lack of difference in symptoms between cases of bacterial and aseptic meningitis, with no sign or symptom statistically associated with bacterial meningitis compared with aseptic meningitis. This is in contrast to a study from The Gambia, which, despite similar enrollment criteria, found clinical difference between cases of bacterial and aseptic meningitis. 18 Bulging fontanelle, stiff neck, and lethargy were present in 51%, 78%, and 84% of cases of bacterial meningitis, and in 16%, 37%, and 55% of patients with aseptic meningitis (all statistically significant), with little difference between cases of aseptic meningitis and children whose CSF was normal. 18 One major difference between the present study and The Gambian study was the rate of LPs done; only 15% of the 2097 children in The Gambia received an LP. Additionally, a high proportion of our study children were pretreated with antibiotics; it could be that this partial treatment masked certain clinical symptoms prior to admission. The findings in this study reiterate support for the continued use of broad criteria for clinical suspicion of meningitis, as is the current recommendations of the WHO s Integrated Management of Childhood Illness of indicators of serious bacterial infection and the WHO definition of clinically suspected meningitis, 12,19 followed by conducting an LP whenever possible. CSF laboratory findings are considered the most rapid method to differentiate bacterial meningitis from nonmeningitis and aseptic meningitis. Our study findings support the use of typical criteria for assessment including high WBC counts, high protein, and low glucose findings as suggestive of bacterial etiology. 20 However, only LAT accurately identified bacterial meningitis in the Indian context out of the laboratory methods used in the study. In the US, the BMS has been proposed by a working group of the American Academy of Pediatrics to determine which children with pleocytosis are at risk of bacterial meningitis. 13 However, in the present study, BMS was not useful in differentiating bacterial meningitis from aseptic meningitis; 88% of cases of bacterial meningitis met the criteria for high suspicion, but 74% of cases of aseptic meningitis also met the criteria. The WHO criteria for probable meningitis was also lacking in specificity: it did detect a higher proportion of cases of bacterial meningitis (84%), but at the same time classified most cases of aseptic meningitis (54%) as having probable meningitis. One possible reason for these discrepancies is the wide use of antibiotics prior to LP. 21 A retrospective study demonstrated that patients who received antibiotics showed significant improvement in glucose and protein values and decreased CSF culture yields, but no statistical difference in S36 WBC count. 22 In our study, 86% of cases of bacterial meningitis had received antibiotics that are highly active against the common bacterial pathogens, with low reported rates of resistance to these antibiotics in India, the impact of these antibiotics is likely high However, because of the limited number of patients with bacterial meningitis who did not receive antibiotics, no statistical association could be drawn from this study except for a marked reduction in culture yield. As the surveillance continues at ICH&HC and data on patients with bacterial meningitis accumulates, the impact of antibiotics warrants re-evaluation. The bacterial pathogens found in this study, part of which has been reported previously, 11 are similar to other studies in India and other parts of Asia in young children, where Hib and S pneumoniae are responsible for the majority of cases, but differs from Africa where N meningitidis is more prevalent. 16,17,25-28 However, the etiologic findings are in marked contrast to what was found at ICH&HC prior to the initiation of this project. Prior to the implementation of this study, most CSF samples took longer than 1 hour to reach the laboratory, and less than 50% of samples had WBC counts performed. Over the 10 years before the study, only 5 cases of H influenzae were found, and 8 cases of S pneumoniae were identified by CSF culture. The improvement in diagnosis is credited to the expansion of timely and quality laboratory services, which made rapid analysis possible and the use of LAT, from which the most cases of bacterial meningitis were confirmed in the back ground of extensive pretreatment antibiotic use. It is likely that additional cases of bacterial meningitis were missed. Pathogens that were not present in the LAT kit are likely underrepresented in the culture results because of the common use of antibiotics. Antibiotics are known to affect LAT results, although to a lesser extent than culture. 26,28 Additionally, the LAT tests were not routinely done on CSF samples with less than 10 WBC per mm 3. Although bacterial meningitis is thought to be rare in low WBC counts, we found that 2 out of 14 (14%) cases with less than 10 WBC per mm 3 that were tested with LAT were positive. The latter finding in addition to the high prevalence of antibiotic use among the study population suggests that the rates of bacterial meningitis that were documented in this study are an under estimate of the true rates of bacterial meningitis. A polymerase chain reaction study at ICH&HC currently is underway to determine etiology more completely. We hope this will help resolve the above issues. The signs of bacterial meningitis in this population are nonspecific, necessitating broad clinical criteria for surveillance, and meningeal signs are less common compared with what has been found in other studies. Laboratory criteria remain the best way to raise suspicion of bacterial meningitis, although criteria set by the WHO and BMS to identify bacterial meningitis are nonspecific. The high prevalence of antibiotics use prior to LP may account, in part, for nonspecific laboratory findings. Highly sensitive methods for detecting pathogens are important in Fitzwater et al

6 July 2013 SUPPLEMENT this setting, where the majority of patients have been treated with antibiotics. n The authors acknowledge the contributions of the clinical and laboratory team at the ICH&HC (Chennai, Tamil Nadu); Dr Saradha Suresh, Dr Mohamed Meeran, Ms G. S. Chamundeeswari, as well as the members of the Bacterial Meningitis Surveillance Working Group at All India Institute of Medical Sciences (New Delhi), Chhatrapati Shahuji Maharaj Medical University (Lucknow, Uttar Pradesh), Christian Medical College (Vellore, Tamil Nadu), INCLEN Trust International (Lucknow, Uttar Pradesh), and Kalawati Saran Children s Hospital (New Delhi). Author Disclosures M.S. has received research funding from GlaxoSmithKline, Merck, and Pfizer (previously Wyeth Lederle Vaccines), has served on the scientific advisory boards of GlaxoSmithKline, Merck, and Pfizer, and received honoraria for these activities. The other authors declare no conflicts of interest, real or perceived. 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