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Management of Central Nervous System Infections, Vientiane, Laos, 2003-2011.

Central nervous system (CNS) infections, which can be caused by a number of different viruses, bacteria, fungi, and parasites, cause substantial disease and death in Southeast Asia (1). The etiologies of these infections are usually confirmed in <50% patients globally (2,3). Conventionally, most CNS infections are classified as meningitis or encephalitis by using a diverse set of clinical and laboratory definitions. The main causes of meningitis reported in Asia are Mycobacterium tuberculosis, Streptococcus pneumoniae, Streptococcus suis, Neisseria meningitidis, and Cryptococcus spp. (Appendix Table 1, https://wwwnc.cdc.gov/ EID/article/25/5/18-0914-App1.pdf). Physicians rarely consider rickettsial and leptospiral pathogens, but interest in these reemerging treatable etiologies is resurfacing (4). Emerging viruses are important causes of CNS infections in Asia. Japanese encephalitis virus (JEV) causes [approximately equal to]68,000 cases of encephalitis a year (5), and dengue virus is increasingly reported as a cause of neurologic disease, occurring in 0.5%-6.2% of dengue patients (6-9). Other common viral causes of encephalitis include enterovirus and herpes simplex viruses (HSVs) 1 and 2 (10).

Few data globally are available to guide policy on the prevention, diagnosis, and treatment of CNS infections, and the diversity of definitions for different CNS infection syndromes is confusing (11); some case definitions use clinical criteria only (12,13), and others include additional laboratory variables (10,14). Meningitis (i.e., meningeal infection) and encephalitis (i.e., parenchymal infection) presumably represent a continuum, but the diversity of clinical and laboratory features and etiologies across this wide spectrum is poorly understood. The standard for differentiating encephalitis from meningitis is histopathology, but biopsies and autopsies are rarely performed in Asia.

In Laos, the only comprehensive routine cerebrospinal fluid (CSF) diagnostic service available is in the capital city, Vientiane, at Mahosot Hospital (15-17). After a publication reporting rickettsial and leptospiral pathogens as important causes of CNS infections in Laos (4), we present the results of the full investigation conducted on the causes of CNS infection in this hospital to guide public health policy and treatment guidelines.

Methods

Study Site and Patient Recruitment

This study was prospectively conducted (January 2003-August 2011) with inpatients on all wards of Mahosot Hospital in Vientiane (17.959431[degrees]N, 102.613144[degrees]E, 188 m above mean sea level), an [approximately equal to]400-bed hospital providing primary, secondary, and tertiary care and admitting [approximately equal to]2,000 patients/month. We recruited inpatients of all ages for whom diagnostic lumbar puncture was indicated for suspicion of CNS infection because of altered consciousness or neurologic findings and for whom lumbar puncture was not contraindicated. For patient inclusion, we used no formal definition for CNS infection; patient recruitment was at the discretion of the responsible physician, reflecting local clinical practice. We recorded patient history and examination findings on standardized forms.

Ethics Statement

We obtained verbal (2003-2006) or written (2006-2011) informed consent from all recruited patients or close relatives. Ethics clearance was granted by the Ethical Review Committee of the Faculty of Medical Sciences, National University of Laos (Vientiane, Laos), and the Oxford University Tropical Ethics Research Committee (Oxford, UK).

Encephalitis and Meningitis Clinical Case Definitions

We classified febrile patients meeting the World Health Organization (WHO) criteria for encephalitis or meningitis (Figure 1) (18) as patients with WHO clinical CNS (hereafter WHO CNS) infection. Because of the overlapping WHO case definitions for encephalitis and meningitis, which both include a Glasgow Coma Scale (GCS) score <15 as criteria, we created additional classifications for febrile patients: those with stiff neck; reduced GCS score (<15), seizures, or both; stiff neck and reduced GCS score, seizures, or both; no stiff neck but reduced GCS score, seizures, or both; and stiff neck, a GCS score of 15, and no seizures (Table 1).

Laboratory Tests

Cerebrospinal fluid (CSF) was collected from patients ([approximately equal to]8 mL for adults [defined as patients [greater than or equal to] 15 years of age], [approximately equal to] 3.5 mL for children 1-14 years of age, and [approximately equal to] 2.5 mL for children <1 year of age), and opening pressure was recorded. Venous blood ([approximately equal to] 18.5 mL for adults, 10 mL for children 1-14 years of age, and 5.5 mL for children <1 year of age) was drawn on the same day. We aimed to collect [approximately equal to] 2 mL follow-up serum 7-10 days after lumbar puncture. Specimens were transported to the laboratory within [approximately equal to]30 minutes, and we aliquoted and immediately tested or stored them at -80[degrees]C. We submitted all patient samples for a panel of laboratory tests: complete blood count; biochemistry panel; culture; and serologic and molecular assays for a range of bacteria, viruses, parasites, and fungi (Table 2; Appendix). HIV-1 and HIV-2 rapid diagnostic tests were performed when indicated by the physician. Computed tomography brain scan was available starting in 2002 but rarely used, especially for intensive care patients, because of difficulties transferring patients. Magnetic resonance imaging and electroencephalographic facilities were not available.

Interpretation

The confirmed etiology was determined by the results of a panel of diagnostic tests (Table 2), which included tests for the direct detection of pathogens in CSF or blood, specific IgM in CSF, seroconversion, or a 4-fold rise in antibody titer between admission and follow-up serum samples. Pathogen detection was confirmed after critical analysis of test results to rule out possible contamination. When evidence of >1 pathogen was obtained for a patient, we defined the confirmed etiology as detection by direct tests over indirect tests (antibody-based tests) and prioritized CSF detection over blood detection (39). We defined a confirmed co-infection as the direct (or indirect, if only indirect tests were positive) detection of >1 pathogen in the same matrix (CSF or blood).

Statistical Analyses

We compared patients with confirmed bacterial infection (including co-infections involving only bacteria) and patients with confirmed viral infection (including co-infections involving only viruses) with all other patients, excluding those with mixed co-infections (i.e. coinfections with fungi or infections with both bacteria and viruses). We investigated the factors associated with death (died in hospital or discharged moribund), bacterial infection, or viral infection by univariate analysis using the [chi square] or Fisher exact test for categorical variables or the Mann-Whitney U test for continuous variables. We analyzed the independent predictors of death, bacterial infection, and viral infection using multivariate logistic regression models. In multivariate analyses, we included all factors having a p value <0.010 in the univariate analysis.

For variables with 6%-20% of the values missing, we executed multiple imputation models using chained equations and used a number of imputations that exceeded the highest proportion of missing values (40). We added age and sex to imputation models as auxiliary variables. We specified the imputation methods as linear for continuous normally distributed variables, logistic for binary variables, ordered logistic for ordinal variables, and predictive mean matching for continuous skewed variables. We performed logistic regression with the dependent variable (death, bacterial or viral infection) and all relevant covariates on each imputed data set and combined results using Rubin rules to take into account the variability in estimates among imputed data sets (41). Only variables that were significant (p<0.050) were retained in the final models. For comparison of analysis methods, we provided the results using the corresponding complete case analysis. We conducted analyses using Stata/SE version 14.0 (StataCorp, https://www.stata.com).

Results

Patients

In total, 1,065 inpatients with suspected CNS infection consented to study participation (Appendix Figure 1); 80% were recruited from the pediatric and adult intensive care wards and adult infectious disease ward. On each ward, [approximately equal to] 8 physicians were in charge of patient recruitment. All were general hospital or infectious disease physicians; none were neurologists. We collected information on patient demographics, clinical presentation, and blood and CSF parameters (Table 3-4; Figure 2). More patients were recruited during the rainy season (Figure 3). The median time between admission and follow-up blood collection was 9 (interquartile range [IQR] 6-16) days. One third (33.6%, 358/1,065) were children <15 years of age (Table 3; Appendix Table 2).

Of 476 adults tested for HIV, 118 (24.8%) were seropositive; of 227 children tested, 1 (0.4%) was seropositive. More than half (61.9%, 590/953) of patients had a history or hospital chart evidence of antibiotic use before lumbar puncture. Most (90.8%, 962/1,059) patients had a history of fever or documented admission fever. The median length of fever at admission was 4 (IQR 2-8) days. The most frequent symptoms and signs were headache (88.1%, 787/893); neck stiffness (64.2%, 683/1,064); confusion (57.4%, 608/1,060); GCS score <15 (52.6%, 551/1,047); and vomiting, diarrhea, or both (54%, 575/1,064). All symptoms and signs were more frequent in children than adults (p<0.05), except headache, which was more frequent in adults (p = 0.023). Most (93.6%, 832/889) patients had CSF findings outside reference ranges (elevated CSF white cell count, elevated CSF lactate, elevated CSF protein, low CSF glucose, or any combination of these parameters) (Table 4; Appendix Table 3, Figure 2).

Etiology was confirmed in 450 (42.3%) patients; 413 (38.8%) had monoinfections and 37 (3.5%) co-infections (Appendix Tables 4-8). The identified monoinfections were JEV (8.8%, 94/1,065), Cryptococcus spp. (6.6%, 70/1,065; 9 C. gattii), Orientia tsutsugamushi (2.9%, 31/1,065), dengue virus (2.5%, 27/1,065), Leptospira spp. (2.3%, 25/1,065), Rickettsia spp. (2.3%, 24/1,065), S. pneumoniae (2.1%, 22/1,065), M. tuberculosis (1.9%, 20/1,065), HSV1 or HSV-2 (1.4%, 15/1,065), human cytomegalovirus (1.1%, 12/1,065), enterovirus (0.9%, 10/1,065), varicella zoster virus (0.6%, 6/1,065), mumps virus (0.5%, 5/1,065), and Plasmodium falciparum (0.4%, 4/1,065). Other bacteria were detected in 48 (4.5%) patients (Figure 4; Appendix Table 5). All samples were negative for West Nile virus, influenza A and B, Henipavirus, and measles virus by PCR. Infection by M. tuberculosis, Cryptococcus spp., or varicella zoster virus was not detected in children (Appendix Table 8). The median age of children with enterovirus infection was 4.5 (IQR 1-11) years and JEV infection 13 (IQR 8-20) years. The proportion of patients with JEV infection was higher for children (14%, 50/358) than adults (6%, 44/707, p<0.001). Significantly more enterovirus patients (80%) than nonenterovirus patients (33%; p = 0.002) were children.

Factors Associated with Bacterial and Viral Infections

We compared patients with single (n = 170) or multiple (n = 5) bacterial infections (excluding co-infections with viruses or fungi) with all other patients (n = 875). Factors significantly associated with bacterial infections on univariate analysis (p<0.01; Appendix Table 9) were included in multivariate analysis. Diabetes (adjusted odds ratio [aOR] 3.1, 95% CI 1.2-7.7), history of fever or fever at admission (aOR 3.9, 95% CI 1.4-11.1), higher serum C-reactive protein (aOR 1.08, 95% CI 1.05-1.11), and higher CSF lactate (aOR 3.5, 95% CI 2.3-5.4) were independent predictors of bacterial infection (Appendix Table 10).

We compared patients with single (n = 169) or multiple (n = 3) viral infections (excluding co-infections with bacteria or fungi) with all other patients (n = 867). Factors significantly associated with viral infections on univariate analysis (p<0.01; Appendix Table 11) were included in multivariate analysis. Neck stiffness (aOR 1.9, 95% CI 1.32.8) and higher hematocrit (aOR 1.4, 95% CI 1.1-1.9) were associated with viral infection, whereas higher CSF lactate (aOR 0.3, 95% CI 0.1-0.5), older age (aOR 0.8, 95% CI 0.7-0.9), and longer interval between admission and lumbar puncture (aOR 0.9, 95% CI 0.8-1.0) were negatively associated with viral infection (Appendix Table 12).

Relationships between Clinical Presentation and Etiology

In total, 771 (74.1%) of 1,040 patients had WHO CNS infection; 44.2% of these patients had confirmed etiologies compared with 37.9% of patients not fulfilling WHO CNS infection criteria (p = 0.063; Appendix Table 13). Because of the considerable overlap between the WHO encephalitis and meningitis definitions, 551 (71.5%) patients were classified as having meningoencephalitis. Therefore, we analyzed the frequency of neck stiffness, reduced GCS score, and seizures among febrile patients with clinical CNS infection (Table 1).

When comparing viral and bacterial infections, we observed no significant differences (p>0.05) in the proportions of encephalitis and meningitis syndromes, although differences were observed for some specific etiologies (Figure 4). In total, 90 (53.6%) febrile patients with viral infection and 86 (49.7%) with bacterial infection had neck stiffness and reduced GCS score, seizures, or both; 17 (10.1%) patients with viral infection and 16 (9.3%) with bacterial infection had reduced GCS score, seizures, or both without neck stiffness; and 36 (21.4%) patients with viral infection and 38 (22.0%) with bacterial infection had neck stiffness, a GCS score of 15, and no seizures (Figure 4). We obtained similar results using the WHO definitions. In total, 25 (14.9%) patients with viral infection and 33 (19.1%) with bacterial infection did not fulfill the WHO CNS infection definition.

In comparison with the distribution of syndromes observed for all patients, the distribution in patients with some etiologies were significantly different (p<0.05). Of the 89 JEV patients with WHO CNS infection, 75.3% had fever; neck stiffness; and reduced GCS score, seizures, or both. Of the 26 O. tsutsugamushi patients with WHO CNS infection, 50% had fever, neck stiffness, a GCS score of 15, and no seizures. Of note, almost half (47.8%) of the patients with cryptococcal infection did not fulfill the definition for WHO CNS infection, and of the 36 who did, 55.6% had fever, neck stiffness, a GCS score of 15, and no seizures.

Risk Factors for Death

Of 893 patients, 235 (26.3%) died, including those discharged moribund; we compared them to the 658 (73.7%) patients discharged alive and not moribund. For factors significantly associated with death (p<0.01; Appendix Table 14) in the univariate analysis, we conducted multivariate analysis. The variables strongly associated with death were higher CSF lactate (aOR 1.1, 95% CI 1.0--1.1) and reduced GCS score (aOR 0.8, 95% CI 0.8-0.9). Patients with viral infection were less likely to die than those with other diagnoses (aOR 0.4, 95% CI 0.3-0.7) (Appendix Table 15). Diabetes and hyperglycemia (glucose >7.7 mmol/L) at admission were not associated with death.

Indications for Antibiotic Treatment

In total, 56 patients (12.4% of the 450 patients with confirmed etiologies) were infected with bacteria treatable by ceftriaxone and 64 patients (14.2% of the patients with confirmed etiologies) with bacteria treatable by doxycycline but not ceftriaxone (Table 5). Twenty-eight patients were infected with a Leptospira spp. treatable by ceftriaxone or doxycycline, but 2 were co-infected with O. tsutsugamushi not treatable by ceftriaxone. Of 142 patients infected by bacteria treatable by ceftriaxone or doxycycline, 89 (62.7%) received appropriate treatment, 17% (13/77) of whom died. In comparison, 25% (12/48) of the patients who did not receive appropriate treatment died (p = 0.270).

Including the 450 patients with confirmed diagnoses, we analyzed the criteria for bacterial meningitis commonly considered when making decisions on antibiotic treatment: elevated CSF white cell count, elevated CSF lactate, elevated CSF protein, decreased CSF glucose, reduced GCS score, turbid CSF, and neck stiffness. A low percentage (<23%) of patients with any 1 of these criteria (except turbid CSF, 38.8%) or a combination of these criteria had bacterial infections treatable by ceftriaxone or doxycycline (Appendix Table 16). Furthermore, only 1 combination of criteria (elevated C-reactive protein, elevated CSF protein, or elevated CSF lactate or any combination of these criteria) could identify all patients infected with bacteria treatable by ceftriaxone (Table 5). However, because only 5% of our patient series did not display this combination of criteria, none of the analyzed clinical and biological results can be reliably used to guide decisions on antibiotic use.

Discussion

Etiology was confirmed in 42.3% of patients with suspected CNS infection, consistent with regional published data (Appendix Table 1); 16.2% had viral infections, and 16.4% had bacterial infections. We observed no significant differences in the distribution of clinical encephalitis and meningitis syndromes by bacterial or viral etiology; the most common infections in this patient population were JEV (8.8%) and Cryptococcus spp. (6.6%).

The results of this study provided evidence for the implementation of pneumococcal immunization in 2011 and JEV immunization in 2013 in Laos (16,17). Although the main etiology reported among patients with suspected CNS infection was JEV, this finding might be an overestimate; we have noted that the detection of JEV IgM in CSF has low predictive value (44). On the other hand, bacterial causes were probably underestimated; 61.9% of patients were known or thought to have received an antibiotic before lumbar puncture, potentially rendering bacteria uncultivable or reducing the bacterial load below the threshold needed for molecular detection.

The mortality rate we report in our study (26.3%) was higher than those reported in similar studies in neighboring countries ([approximately equal to] 10%; Appendix Table 1). Ineffective patient management or inappropriate treatment through lack of previous local data might have caused this higher mortality rate. The epidemiology of CNS infection varies by geography; therefore, regional evidence should be used to build regional policies on prevention, diagnosis, and treatment of these infections.

In this study, 17% (119/703) of the patients tested were HIV seropositive. The highest proportion of HlV-seropos itive patients was among those with cryptococcal infection (79%; Appendix Table 7). However, only 66% (703/1,065) of patients were tested. More patients need to receive HIV testing in Laos, and more investigations on the relationship between HIV and other infections are needed.

Our study had a number of limitations, including the partial use of stored samples; missing values; a low frequency of computed tomography brain scans and HIV testing; and a lack of magnetic resonance imaging, brain or postmortem examination, and diagnostics for autoimmune and eosinophilic CNS disease (45,46) and other pathogens (e.g., Toxoplasma gondii, Mycoplasma spp., and Zika virus). The absence of strict criteria for the inclusion of patients could have resulted in recruitment bias; however, the data reflect real-life medical practice. The proportion of patients who declined lumbar puncture is unknown. Almost all patients (93.6%) had CSF findings outside reference ranges. Although published data on this combined index are few, the proportion of patients with abnormal CSF findings is generally lower in routine practice (e.g., <40% at La Timone Hospital, Marseille; L. Ninove and J. Fromonot, La Timone Hospital, pers. comm., March 2017). This finding suggests a relatively low frequency of lumbar puncture at Mahosot Hospital, reflecting current practice but representing an unknown proportion of all patients admitted with CNS disease. The sample size was too small for a comparison of mortality rates between treated and nontreated patients.

Although CNS infection is a global public health burden, global consensus on the case definition is lacking (Appendix Table 17). In clinical studies, encephalitis and meningitis have been studied separately or together (11), and CSF findings might or might not be taken into account (e.g., CSF findings are not part of the WHO criteria). There is confusion regarding the clinical and laboratory definitions of encephalitis and meningitis, so we suggest pairing clinical, laboratory, or clinicolaboratory with these terms to reduce confusion. Further, altered consciousness and altered mental status, shared by encephalitis and meningitis in many definitions, are undefined in the WHO definitions. We used GCS score <15 to define both objectively, but this practice resulted in considerable overlap in clinical definitions: 71.4% of patients had WHO-defined meningitis and 53% WHO-defined meningoencephalitis. When we restricted the definition of meningitis to the presence of fever and neck stiffness, 61.9% of patients fulfilled those criteria; 43.6% had neck stiffness combined with low GCS score, seizures, or both.

Studies on the clinical and etiologic characteristics of patients requiring lumbar puncture in Asia have usually focused on particular pathogens or just meningitis or encephalitis (Appendix Table 1) (47). Although needed for treatment trials and pathophysiologic research, our data call into question the validity of defining criteria for patient management differently between encephalitis and meningitis (Figure 4; Appendix Table 13). In Laos, evidence suggests that brain (encephalitis) and meningeal (meningitis) infections have no clear distinguishable clinical manifestations relating to the responsible pathogen and that these classifications should be used with caution in the Asia tropics for guiding patient management.

We found that history of diabetes was independently associated with bacterial CNS infection. Indeed, some evidence suggests that diabetes is a risk factor for bacterial CNS disease (48) and poor outcome in tuberculous meningitis (49). In univariate analysis, higher blood glucose level was also associated with bacterial infection (p<0.001). Of 237 patients with hyperglycemia at admission (>7.7 mmol/L), 16 (6.8%) had a history of diabetes and 164 (69.2%) did not. Without convalescent glucose and hemoglobin A1c assays, however, we were unable to distinguish hyperglycemia resulting from severe disease or undiagnosed diabetes that might have predisposed to CNS infection. Intensive euglycemia management is difficult; can lead to hypoglycemia, especially in unconscious patients; and requires skilled dedicated nursing that is not available in hospitals in rural Asia. Whether such intensive therapy would save lives remains uncertain, but the development of an inexpensive computerized algorithm technology for resource-poor settings to facilitate safe euglycemia management (50) should be a priority for investigation of efficacy. The burgeoning global prevalence of diabetes calls for research regarding the relationship between hyperglycemia and CNS infections and optimizing their combined management (48).

Our data suggest that patient survival could be improved through 2 patient management interventions, the implementation of antibiotic use guidelines and strengthening of high-dependency units. The finding that poor outcomes were associated with a decreased GCS score at admission suggests that high-dependency units (a likely cost-effective intervention) could be used to enhance supportive care for unconscious patients with CNS infection. Creating these units and incorporating them into care could improve outcomes and reduce the burden of intensive care unit treatment for these patients. More investigation is needed on the efficacy and cost-effectiveness of high-dependency units in different contexts.

Ceftriaxone is conventionally used in Laos as a first-line treatment for CNS bacterial infection but lacks efficacy for emerging rickettsial pathogens, for which doxycycline is recommended (4). Because delays in antibiotic therapy could result in severe consequences for patients, the decision for administering these drugs is made on the basis of clinical signs and laboratory results at admission. However, in Laos, we found that no variable, even in combination, could permit objective selection of appropriate antibiotics. Therefore, the administration of early first-line empiric treatment with ceftriaxone and doxycycline for all patients with suspected CNS infection might save patient lives in Laos and elsewhere in rural Asia (4).

Acknowledgments

We thank the patients, Bounthaphany Bounxouei (Associate Professor and Director), and staff of Mahosot Hospital, especially the microbiology laboratory staff and the ward staff for their technical help and support. We also thank Bounnack Saysanasongkham (Associate Professor and Director of Department of Health Care, Ministry of Health) and Bounkong Syhavong (Associate Professor and Minister of Health), Laos, for their kind help and support. We thank the staff of the Meningococcal Reference Unit of the Health Protection Agency (Manchester, UK) for N. meningitidis typing and the staff of the Respiratory and Vaccine Preventable Bacteria Reference Unit of Public Health England (Colindale, UK) for Haemophilus influenzae typing. We also thank Mavuto Mukaka for his help with statistical analysis and Nicholas Day for comments on the paper.

This work was supported by the Wellcome Trust of Great Britain, the Institute of Research for Development, AixMarseille University, and the European Union's Horizon 2020 research and innovation program European Virus Archive global (grant agreement no. 653316).

Dr. Dubot-Peres is a virologist serving as the Head of Partnerships and Programmes of South Countries for the Unite des Virus Emergents (Aix-Marseille University, IRD 190, INSERM 1207, IHU Mediterranee Infection) in Marseille, France. She is an Honorary Visiting Research Fellow at the Nuffield Department of Medicine, University of Oxford, Oxford, UK, and the Head of Virology at the Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit in Vientiane, Laos. Her main research topics of interest are the study of undifferentiated fever, dengue epidemiology, infections of the CNS, and respiratory infections.

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Address for correspondence: Audrey Dubot-Peres, UVE, Faculte de Medecine, 27 Blvd Jean Moulin, 13005 Marseille, France; email: audrey@tropmedres.ac

Author affiliations: Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit, Mahosot Hospital, Vientiane, Laos (A. Dubot-Peres, M. Mayxay, R. Phetsouvanh, S. Rattanavong, M. Vongsouvath, V. Davong, V. Chansamouth, K. Phommasone, C. Moore, S. Dittrich, O. Lattana, J. Sirisouk, P. Phoumin, P. Panyanivong, A. Sengduangphachanh, B. Sibounheuang, A. Chanthongthip, M. Simmalavong, D. Sengdatka, A. Seubsanith, D. A.B. Dance, P.N. Newton); University of Oxford Nuffield Department of Clinical Medicine Center for Tropical Medicine and Global Health, Oxford, UK (A. Dubot-Peres, S.J. Lee, C. Moore, S. Dittrich, D.A.B. Dance, S.D. Blacksell, P.N. Newton); Unite des Virus Emergents (UVE: Aix-Marseille Univ-IRD 190-INSERM 1207-IHU Mediterranee Infection), Marseille, France (A. Dubot-Peres, X. de Lamballerie); University of Health Sciences Institute of Research and Education Development, Vientiane (M. Mayxay); Mahidol University Faculty of Tropical Medicine Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand (S.J. Lee, S.D. Blacksell); Mahosot Hospital, Vientiane (V. Keoluangkot, P. Phimmasone, K. Sisout, K. Detleuxay, K. Luangxay, I. Phouangsouvanh); Queensland Health Forensic and Scientific Service World Health Organization Collaborating Centre for Reference and Research on Leptospirosis, Brisbane, Queensland, Australia (S.B. Craig, S.M. Tulsiani, M.-A. Burns); London School of Hygiene and Tropical Medicine Faculty of Infectious and Tropical Diseases, London, UK (D.A.B. Dance, P.N. Newton)

DOI: https://doi.org/10.3201/eid2505.180914

Audrey Dubot-Peres, Mayfong Mayxay, Rattanaphone Phetsouvanh, [1] Sue J. Lee, Sayaphet Rattanavong, Manivanh Vongsouvath, Viengmon Davong, Vilada Chansamouth, Koukeo Phommasone, Catrin Moore, Sabine Dittrich, Olay Lattana, Joy Sirisouk, Phonelavanh Phoumin, Phonepasith Panyanivong, Amphonesavanh Sengduangphachanh, Bountoy Sibounheuang, Anisone Chanthongthip, Manivone Simmalavong, Davanh Sengdatka, Amphaivanh Seubsanith, Valy Keoluangkot, Prasith Phimmasone, Kongkham Sisout, Khamsai Detleuxay, Khonesavanh Luangxay, Inpanh Phouangsouvanh, Scott B. Craig, Suhella M. Tulsiani, Mary-Anne Burns, David A.B. Dance, Stuart D. Blacksell, Xavier de Lamballerie, Paul N. Newton

[1] Deceased.

Caption: Figure 1. WHO encephalitis and meningitis case definitions. * Definitions from WHO (18). [dagger] Defined here as a Glasgow Coma Scale score <15. [double dagger] Not "with sudden onset of fever >38.5[degrees]C" as recommended by the WHO because we saw patients, especially young children, with meningitis but with temperatures below the WHO temperature criterion. [section] Patients with history of fever or documented fever (>37.5[degrees]C). [paragraph] History of neck stiffness or neck stiffness on examination. WHO, World Health Organization.

Caption: Figure 2. Distribution of clinical manifestations among patients with suspected CNS infection, by age group and etiology, Laos, January 2003-August 2011. A) WHO criteria; B) additional criteria (Table 1). Children were patients <15 years of age and adults patients [greater than or equal to] 15 years of age. Numbers above bars indicate number of patients in group. CNS, central nervous system; GCS, Glasgow Coma Scale; WHO, World Health Organization.

Caption: Figure 3. Recruited patients with suspected central nervous system infection, by month, Laos, January 2003-August 2011. A) Total patients recruited by month cumulating all studied years. B) Patients recruited each month of each year. Light and dark shades of colors were used in an alternating pattern to facilitate graph reading.

Caption: Figure 4. Distribution of clinical presentations in patients with suspected central nervous system infection, by confirmed etiology, Laos, January 2003-August 2011. Analysis per pathogen includes only patients with monoinfections. Other bacteria include 7 Escherichia coli, 4 Streptococcus agalactiae, 4 Neisseria meningitidis, 1 Salmonella enterica group D, 1 S. enterica group B or C, 5 S. enterica serovar Typhi, 4 Streptococcus suis, 3 Klebsiella pneumoniae, 7 Haemophilus influenzae type b, 5 Burkholderia pseudomallei, 6 Staphylococcus aureus, and 1 Morganella morganii. Blue font indicates viruses, red font indicates bacteria, and black font indicates fungi. CNS, central nervous system; GCS, Glasgow Coma Scale; WHO, World Health Organization.
Table 1. Classifications of febrile patients with clinical
central nervous system infection (n = 771), Laos, January
2003-August 2011 *

         Clinical sign
Stiff    GCS                     No. (%)      WHO classification, %
                                              ([dagger])
 neck     score <15    Seizure    patients     MEN      E      ME

  +                              191 (24.8)   96.2
  +           +                  244 (31.6)           75.2    71.5
  +           +           +      171 (22.2)
  +                       +       38 (4.9)
              +           +       57 (7.4)
              +                   41 (5.3)
                          +       29 (3.8)

                 Additional classification, %
                 GCS score <15, seizure, or
                 both
Stiff    Stiff           Stiff   No stiff   Stiff neck + GCS
                                            score 15 + no
 neck    neck     All    neck      neck         seizure

  +      83.5                                     24.8
  +              75.2    58.8
  +
  +
                                   16.5

* Each line of the table corresponds to a given combination of
criteria presented on the left side of the table. Each combination
is then assigned (shaded cell) to [greater than or equal to] 1
classifications (WHO and additional classifications) as defined in
the Methods section. Green-shaded cells are the additional
classifications used throughout our study. E, encephalitis; GCS,
Glasgow Coma Scale; ME, meningoencephalitis; MEN, meningitis; WHO,
World Health Organization; +, clinical sign present.

([dagger]) Definitions of WHO classification provided in Figure 1.

Table 2. Diagnostic laboratory tests used to confirm etiology
in patients with suspected central nervous system infection,
by sample type, Laos, January 2003-August 2011 *

Pathogens tested       Cerebrospinal fluid    Blood
                       ([dagger])
Malaria pathogens      None                   Giemsa thick and
                                              thin smear (if
                                              patient from endemic
                                              area)

Leptospira spp.        Hydrolysis probe       Culturing of blood
                       real-time PCR (19)     clot on EMJH medium;
                                              microscopic
                                              agglutination test
                                              of admission and
                                              follow-up serum
                                              samples (4-fold rise
                                              considered positive
                                              result) (20);
                                              hydrolysis probe
                                              real-time RT-PCR
                                              from buffy coat (19)

Cryptococcus spp.      Indian ink stain; if   None
                       HIV suspected,
                       Cryptococcus Antigen
                       Latex Agglutination
                       Test (IMMY,
                       http://www.immy.
                       com); if Indian ink
                       positive and HIV
                       suspected, culture
                       on Sabouraud agar

Mycobacterium          Lowenstein-Jensen      None
tuberculosis           culture; auramine
                       and Ziehl-Neelsen
                       stains

Rickettsia spp.        Hydrolysis probe       Hydrolysis probe
([double dagger])      real-time PCR          real-time and
                       (21,22)                conventional PCR
                                              from buffy coat
                                              (21,22); sequencing

R. typhi, Orientia     Hydrolysis probe       Hydrolysis probe
tsutsugamushi          real-time PCR          real-time PCR on
([double dagger])      (21,23)                buffy coat (21,23);
                                              IgM and IgG indirect
                                              immunofluorescent
                                              assay of admission
                                              and follow-up serum
                                              samples (4-fold rise
                                              considered positive
                                              result) (24)

Community-acquired     Gram stain; culture    Blood culture bottle
bacterial infection    in blood agar and
                       chocolate agar

Streptococcus          Culture on blood       Blood culture bottle
pneumoniae,            agar, chocolate
Streptococcus suis,    agar, and MacConkey
Haemophilus            plates (for patients
influenzae,            <1 year of age);
Neisseria              hydrolysis probe
meningitidis           real-time RT-PCR
                       (25-27)

Dengue virus           Hydrolysis probe       Hydrolysis probe
                       real/time RT/PCR       real-time RT-PCR on
                       (28); NS1 ELISA        serum samples (28);
                       (Dengue Early ELISA,   NS1 ELISA on serum
                       Panbio, https://www/   samples; ELISA IgM
                       alere/com); ELISA      on admission and
                       IgM (Japanese          follow-up serum
                       Encephalitis/Dengue    samples (assessed
                       IgM Combo ELISA,       seroconversion)
                       Panbio)

JEV ([section])        ELISA IgM (Japanese    ELISA IgM on
                       Encephalitis/Dengue    admission and
                       IgM Combo ELISA,       follow-up serum
                       Panbio)                samples (assessed
                                              seroconversion)

Enterovirus, West      Hydrolysis probe       Hydrolysis probe
Nile virus,            real-time RT-PcR       real-time RT-PCR on
influenza viruses A    (29-31) (in house)     serum samples (29-
and B, Henipavirus                            31) (in house)

Flavivirus             SYBR Green real-       SYBR Green real-
([paragraph])          time RT-PCR (32,33)    time RT-PCR on serum
                                              samples (32,33)

Herpes simplex virus   Hydrolysis probe       None
1 and 2, Varicella     real-time RT-PCR
zoster virus, human    (34-36)
cytomegalovirus

Measles virus, mumps   Hydrolysis probe       Hydrolysis probe
virus                  real.time RT.PCR       real/time RT/PCR on
                       (37,38); if            serum samples
                       seropositive in        (37,38); IgM and IgG
                       blood sample, IgM      ELISAs: Enzygnost
                       ELISA with Enzygnost   Anti/Measles Virus/
                       Anti.Measles Virus.    IgM, Enzygnost Anti/
                       IgM or Enzygnost       Measles Virus/IgG,
                       Anti-Parotidis.IgM     Enzygnost
                       kits (Dade Behring,    Anti-Parotidis/IgM,
                       https://www.           and Enzygnost
                       healthcare.siemens.    Anti-Parotidis/IgG
                       com)                   kits (Dade Behring)
                                              (assessed
                                              seroconversion)

HIV                    None                   Determine HiV-1.2
                                              Combo (Alere,
                                              https://www.alere.
                                              com) or Uni.Gold HIV
                                              (Trinity Biotech,
                                              https://www.
                                              trinitybiotech.com)

* See Appendix
(https://wwwnc.cdc.goV/EID/article/25/5/18-0914-App1.pdf) for
further details on methods. Cerebrospinal fluid and serum samples
were inoculated on Vero and buffalo green monkey kidney cells for
viral isolation. The median (interquartile range) interval between
admission and follow-up serum sample collection was 9 (6-16) days.
EMJH, Ellinghausen-McCullough-Johnson-Harris; JEV, Japanese
encephalitis virus; NS1, nonstructural protein 1; RT-PCR, reverse
transcription PCR.

([dagger]) Contraindications for lumbar puncture included focal
neurologic signs on examination, clinical evidence for raised
intracranial pressure, skin or soft tissue sepsis at the proposed
puncture site, severe coagulopathy, or severe thrombocytopenia.

([double dagger]) Buffy coats were inoculated on Vero and L929
cells for O. tsutsugamushi and Rickettsia sp isolation.

([section]) Detection of JEV IgM in a single sample of serum is
considered as laboratory confirmation according to World Health
Organization criteria. However, in this study, to be conservative
and consistent with interpretation of other test results, a single
detection of JEV IgM in serum was not counted as confirming JEV
central nervous system infection.

([paragraph]) Flavivirus RT-PCR would have likely detected the main
flaviviruses circulating in Laos.

Table 3. Demographic and clinical data at admission of patients
with suspected CNS infection, by age group and etiology,
Laos, January 2003-August 2011 *

                                           Age group
Characteristic              All,           Children,      Adults,
                            n = 1,065      n = 358        n = 707
Demographic

M                           666 (62.5)     207 (57.8)     459 (64.9)
F                           399 (37.5)     151 (42.2)     248 (35.1)
Age, y, median (IQR)        23 (8-38)      3 (0.41-8)     32 (24-47)

History

HIV seropositive, n = 703   119 (16.9)     1 (0.4)        118 (24.8)

Diabetes, n = 850           24 (2.8)       0              24 (4.2)

Antibiotic use before       590 (61.9)     238 (71.9)     352 (56.6)
lumbar puncture, n = 953

Signs and symptoms

Days of fever at            4 (2-8)        4 (2-6)        5 (2-10)
admission, median (IQR),
n = 1,058

Fever, n = 1,059            962 (90.8)     340 (95.2)     622 (88.6)

Headache, ([dagger]) n =    787 (88.1)     155 (83.3)     632 (89.4)
893

Hearing loss, ([dagger])    51 (5.7)       10 (5.4)       41 (5.8)
n = 893

Dysuria, ([dagger]) n =     28 (3.1)       4 (2.2)        24 (3.4)
891

Visual loss, ([dagger]) n   66 (7.5)       14 (7.7)       52 (7.4)
= 885

Diplopia, ([dagger]) n =    36 (4.1)       4 (2.2)        32 (4.5)
889

Photophobia, n = 850        52 (5.8)       14 (7.4)       38 (5.4)

Focal neurologic signs, n   22! (2.3)      5 (1.6)        17 (2.7)
= 939

Neck stiffness, n = 1,064   683 (64.2)     245 (68.4)     438 (62.0)

Confusion, n = 1,060        608 (57.4)     232 (65.5)     376 (53.3)

Convulsions, n = 1,063      319 (30.0)     233 (65.3)     86 (12.2)

GCS score, median (IQR),    14 (11-15)     14 (10-15)     15 (11-15)
n = 1,010

GCS score <15,              551 (52.6)     220 (63.4)     331 (47.3)
([section]) n = 1,047

WHO clinical CNS            771 (74.1)     313 (90.7)     458 (65.9)
infection, ([paragraph])
n = 1,040

Outcome

Days of hospitalization,    9 (5-14)       8 (5-13)       10 (5-15.5)
n = 846, median (IqR)

Death,# n = 893             235 (26.3)     70 (22.5)      165 (28.4)

                                           Etiology
                                           None           Confirmed
Characteristic              Confirmed,     confirmed,     viral,
                            n = 450        n = 615        n = 172
Demographic

M                           288 (64.0)     378 (61.5)     111 (64.5)
F                           162 (36.0)     237 (38.5)     61 (35.5)
Age, y, median (IQR)        23 (10-38)     24 (6-40)      16 (7-28)

History

HIV seropositive, n = 703   75 (27.1)      44 (10.33)     8 (8.0)

Diabetes, n = 850           12 (3.5)       12 (2.4)       1 (0.8)

Antibiotic use before       252 (64.0)     338 (60.5)     109 (69.9)
lumbar puncture, n = 953

Signs and symptoms

Days of fever at            5 (3-10)       4 (1-7)        5 (3-7)
admission, median (IQR),
n = 1,058

Fever, n = 1,059            425 (94.9)     537 (87.9)     162 (95.3)

Headache, ([dagger]) n =    369 (92.5)     418 (84.6)     139 (90.9)
893

Hearing loss, ([dagger])    20 (5.0)       31 (6.3)       8 (5.2)
n = 893

Dysuria, ([dagger]) n =     10 (2.5)       18 (3.7)       3 (2.0)
891

Visual loss, ([dagger]) n   23 (5.8)       43 (8.8)       11 (7.2)
= 885

Diplopia, ([dagger]) n =    15 (3.4)       21 (4.3)       6 (4.0)
889

Photophobia, n = 850        23 (5.8)       29 (5.9)       7 (4.6)

Focal neurologic signs, n   8 (2.1)        14 (2.5)       1 (0.7)
= 939

Neck stiffness, n = 1,064   316 (70.2)     367 (59.8)     130 (75.6)

Confusion, n = 1,060        254 (56.7)     354 (57.8)     114 (66.3)

Convulsions, n = 1,063      119 (26.5)     200 (32.6)     65 (37.8)

GCS score, median (IQR),    15 (11-15)     14 (10-15)     13 (10-15)
n = 1,010

GCS score <15,              225 (50.5)     326 (54.2)     101 (59.4)
([section]) n = 1,047

WHO clinical CNS            341 (77.0)     430 (72.0)     143 (85.1)
infection, ([paragraph])
n = 1,040

Outcome

Days of hospitalization,    11 (6-17)      8 (5-13)       10 (6-14)
n = 846, median (IqR)

Death,# n = 893             94 (25.0)      141 (27.3)     23 (15.7)

                            Confirmed
Characteristic              bacterial,
                            n = 175
Demographic

M                           117 (66.9)
F                           58 (33.1)
Age, y, median (IQR)        23 (9-45)

History

HIV seropositive, n = 703   6 (6.2)

Diabetes, n = 850           10 (7.5)

Antibiotic use before       100 (62.5)
lumbar puncture, n = 953

Signs and symptoms

Days of fever at            5 (3-8)
admission, median (IQR),
n = 1,058

Fever, n = 1,059            171 (97.7)

Headache, ([dagger]) n =    135 (91.2)
893

Hearing loss, ([dagger])    7 (4.7)
n = 893

Dysuria, ([dagger]) n =     3 (2.0)
891

Visual loss, ([dagger]) n   5 (3.4)
= 885

Diplopia, ([dagger]) n =    6 (4.1)
889

Photophobia, n = 850        10 (6.8)

Focal neurologic signs, n   6 (4.1)
= 939

Neck stiffness, n = 1,064   128 (73.1)

Confusion, n = 1,060        103 (59.5)

Convulsions, n = 1,063      44 (25.3)

GCS score, median (IQR),    14 (11-15)
n = 1,010

GCS score <15,              94 (54.0)
([section]) n = 1,047

WHO clinical CNS            140 (80.9)
infection, ([paragraph])
n = 1,040

Outcome

Days of hospitalization,    11 (7-17)
n = 846, median (IqR)

Death,# n = 893             43 (27.9)

* Values are no. (%) unless indicated otherwise. We defined
children as patients <15 years of age and adults [greater than or
equal to] 15 years of age. History or physical examination or both,
were taken into account for confusion, neck stiffness, photophobia,
fever (history of fever or >37.5[degrees] C during physical
examination). In total, 8 women in the patient population were
pregnant; 26 (2.4%) patients had computed tomography brain scans,
and 2 of these scans demonstrated brain abscesses. The confirmed
viral group includes patients infected with multiple viruses, and
the confirmed bacterial group includes patients infected with
multiple bacteria. CNS, central nervous system; GCS, Glasgow Coma
Scale; IQR, interquartile range; WHO, World Health Organization.

([dagger]) Data from children <3 years of age were considered not
reliable and were thus excluded from analysis.

([double dagger]) Of these patients, 7 had hemiplegia, 11 had limb
weakness, and 1 had paraplegia; 13 patients had admission or
discharge diagnoses of Guillain-Barre syndrome. Retrospective
evaluation of the likelihood of this diagnosis by using the
Brighton system suggested that 4 patients met level 3 criteria for
Guillain-Barre syndrome diagnostic certainty (42).

([section]) Includes confused and disoriented patients.

([paragraph]) Defined as fever with GCS score <15, neck stiffness
(history of or present during examination), or history of seizures
or any of these signs in combination. Patients with missing data
for 1 of these criteria were not counted.

(#) Includes patients who died at the hospital and those taken home
to die.

Table 4. Characteristics of peripheral blood and cerebrospinal
fluid at admission of patients with suspected central nervous
system infection, by age group and etiology, Laos,
January 2003-August 2011 *

Sample type and parameter                  Age group

                               All,       Children,      Adults,
Peripheral blood             n = 1,065      n = 358       n = 707

Elevated white cell         449 (47.2)    150 (47.9)    299 (46.8)
count, ([dagger]) n = 952

Low white cell count, n =    45 (4.7)      22 (7.0)      23 (3.6)
952

Anemia, n = 948             355 (37.5)    112 (35.7)    243 (38.3)

Thrombocytopenia, n = 649    55 (8.5)      16 (6.8)      39 (9.4)

Elevated C-reactive         547 (63.0)    145 (51.6)    402 (68.5)
protein, n = 868

Hyperglycemia, ([dagger])   237 (23.9)     81 (25.8)    156 (23.0)
n = 991

Severe hyperglycemia,        72 (7.3)      26 (8.3)      46 (6.8)
([dagger]) n = 991

Elevated serum              225 (27.9)     45 (17.8)    180 (32.5)
sodium,([double dagger])
n = 807

Low serum sodium,            63 (7.8)      31 (12.3)     32 (5.8)
([double dagger]) n = 807

Cerebrospinal fluid

Turbid, n = 999             145 (14.5)     40 (12.2)    105 (15.7)

Elevated opening            334 (34.2)     86 (27.6)    248 (37.3)
pressure, n = 977

Elevated white cell         729 (74.8)    237 (74.8)    492 (74.8)
count, ([section]) n =
975

Elevated lymphocyte         467 (52.5)    149 (51.2)    318 (53.1)
count, n = 890

Elevated neutrophil         644 (72.4)    213 (73.5)    431 (72.0)
count, n = 889

Elevated eosinophil          46 (4.6)       7 (2.1)      39 (5.8)
count, ([paragraph]) n =
1,001

Elevated protein, n = 955   601 (62.9)    177 (57.3)    424 (65.6)

Decreased glucose, n =      280 (29.3)     58 (18.8)    222 (34.3)
957

Decreased cerebrospinal     540 (58.1)    159 (54.8)    381 (59.6)
fluid: venous

glucose ratio, n = 929

Elevated lactate, n = 985   650 (66.0)    217 (67.8)    433 (65.1)

Sample type and parameter                  Etiology
                                             None        Confirmed
                            Confirmed,    confirmed,      viral,
Peripheral blood              n = 450       n = 615       n = 172

Elevated white cell         198 (49.0)    251 (45.8)     84 (53.9)
count, ([dagger]) n = 952

Low white cell count, n =    22 (5.5)      23 (4.2)       6 (3.9)
952

Anemia, n = 948             160 (39.8)    195 (35.7)     44 (28.2)

Thrombocytopenia, n = 649    22 (7.8)      33 (9.0)       4 (3.5)

Elevated C-reactive         265 (69.2)    282 (58.1)     98 (64.9)
protein, n = 868

Hyperglycemia, ([dagger])   105 (24.5)    132 (23.5)     40 (24.0)
n = 991

Severe hyperglycemia,        35 (8.2)      37 (6.6)      12 (7.2)
([dagger]) n = 991

Elevated serum               82 (22.8)    143 (31.9)     40 (28.6)
sodium,([double dagger])
n = 807

Low serum sodium,            31 (8.6)      32 (7.1)       8 (5.7)
([double dagger]) n = 807

Cerebrospinal fluid

Turbid, n = 999              80 (18.4)     65 (11.5)     21 (12.4)

Elevated opening            155 (36.4)    179 (32.5)     42 (24.9)
pressure, n = 977

Elevated white cell         341 (80.2)    388 (70.6)    141 (84.9)
count, ([section]) n =
975

Elevated lymphocyte         234 (59.5)    233 (46.9)    106 (68.4)
count, n = 890

Elevated neutrophil         309 (78.8)    335 (67.4)    130 (83.9)
count, n = 889

Elevated eosinophil          11 (2.5)      35 (6.2)       9 (5.3)
count, ([paragraph]) n =
1,001

Elevated protein, n = 955   281 (66.9)    320 (59.8)    112 (66.3)

Decreased glucose, n =      138 (32.8)    142 (26.5)     45 (26.6)
957

Decreased cerebrospinal     253 (61.7)    287 (55.3)     97 (58.8)
fluid: venous

glucose ratio, n = 929

Elevated lactate, n = 985   298 (69.8)    352 (63.1)     93 (56.0)

Sample type and parameter
                            Confirmed
                            bacterial,
Peripheral blood              n = 175

Elevated white cell          84 (53.5)
count, ([dagger]) n = 952

Low white cell count, n =     7 (4.5)
952

Anemia, n = 948              68 (43.9)

Thrombocytopenia, n = 649    12 (10.6)

Elevated C-reactive         114 (79.7)
protein, n = 868

Hyperglycemia, ([dagger])    53 (32.3)
n = 991

Severe hyperglycemia,        22 (13.4)
([dagger]) n = 991

Elevated serum               26 (19.4)
sodium,([double dagger])
n = 807

Low serum sodium,            16 (11.9)
([double dagger]) n = 807

Cerebrospinal fluid

Turbid, n = 999              38 (23.2)

Elevated opening             60 (37.3)
pressure, n = 977

Elevated white cell         129 (80.1)
count, ([section]) n =
975

Elevated lymphocyte          91 (62.3)
count, n = 890

Elevated neutrophil         116 (80.0)
count, n = 889

Elevated eosinophil           2 (1.2)
count, ([paragraph]) n =
1,001

Elevated protein, n = 955   108 (69.7)

Decreased glucose, n =       51 (32.9)
957

Decreased cerebrospinal      97 (64.2)
fluid: venous

glucose ratio, n = 929

Elevated lactate, n = 985   132 (80.5)

* Values are no. (%). We defined children as patients <15 years of
age and adults >15 years of age. The confirmed viral group includes
patients infected with multiple viruses, and the confirmed
bacterial group includes patients infected with multiple bacteria.
Elevated and low parameters mean above or below reference ranges.
Anemia is defined as hematocrit below reference range.
Thrombocytopenia is defined as platelet count below reference
range. See Appendix Table 3
(https://wwwnc.cdc.gov/EID/article/25/5/18-0914-App1.pdf) for
reference ranges. CSF, cerebrospinal fluid.

([dagger]) Hyperglycemia was defined as a blood glucose level of
>7.7 mmol/L and severe hyperglycemia as a blood glucose level
>11.1 mmol/L.

([double dagger]) Serum sodium levels >150 mmol/L were considered
elevated and <130 mmol/L considered low; 5 patients (0.6%) had
serum sodium <115 mmol/L.

([section]) Samples with high turbidity could not be counted
and were thus not included.

([paragraph]) An eosinophil count >10% was considered elevated.

Table 5. Frequency of criteria consistent with bacterial meningitis
among patients with suspected central nervous system infection,
by etiology and antibiotic susceptibility, Laos, January
2003-August 2011 *

                                       Patients with confirmed
                                       etiology, n = 450
                                       Patients infected by bacteria
                                       treatable by ([dagger])
                                       Ceftriaxone
Variables                     All       Not including     Including
                                         Leptospira      Leptospira
                                         infections,     infections,
                                           n = 56           n = 84
                                       ([double dagger)

Neck stiffness            316 (70.2)      41 (73.2)       60 (71.4)
([paragraph])

GCS score <15             225 (50.5)      34 (61.8)       47 (56.6)

Elevated CRP              265 (69.2)      44 (91.7)       60 (87.0)

CSF turbid                 80 (18.4)      27 (49.1)       31 (37.8)

Elevated CSF lactate      298 (69.8)      44 (83.0)       63 (78.8)

Elevated CSF protein      281 (66.9)      44 (81.5)       57 (73.1)

Decreased CSF glucose     138 (32.8)      23 (42.6)       26 (33.3)

Decreased CSF:venous      253 (61.7)      40 (76.9)       49 (64.5)
glucose ratio

Elevated CSF leukocyte    341 (80.2)      44 (86.3)       64 (82.1)
count (#)

Combinations of [greater
than or equal to] 1 of
the above findings

Elevated CSF lactate,     418 (95.9)      53 (96.4)       76 (93.8)
protein, leukocyte
count; decreased CSF
glucose; CSF turbid (#)

Elevated CRP;             427 (96.4)       56 (100)        82 (100)
elevated CSF lactate,
protein; CSF turbid

Elevated CRP;             425 (95.4)       56 (100)        82 (100)
elevated CSF lactate,
protein

Elevated CRP;             385 (91.2)      54 (98.2)       78 (98.7)
elevated CSF lactate

Elevated CRP;             382 (90.1)      54 (98.2)       75 (94.9)
elevated CSF protein

Elevated CRP; GCS         348 (83.9)      50 (100.0)      72 (98.6)
score <15

GCS score <15;            348 (81.1)      49 (90.7)       68 (85.0)
elevated CSF protein

GCS score <15;            361 (84.1)      48 (88.9)       69 (85.2)
elevated CSF lactate

GCS score <15;            404 (92.9)      52 (94.5)       75 (91.5)
elevated CSF lactate,
protein

                          Doxycycline
Variables                 Not including    Including
                            Leptospira     Leptospira
                           infections,     infections,    Other,
                              n = 64         n = 90       n = 305
                           ([section])

Neck stiffness               46 (71.9)      63 (70.0)   213 (69.8)
([paragraph])

GCS score <15                27 (42.2)      40 (44.4)   152 (50.3)

Elevated CRP                 36 (70.6)      51 (72.9)   171 (64.3)

CSF turbid                   6 (10.7)       9 (11.1)     45 (15.1)

Elevated CSF lactate         44 (74.6)      62 (73.8)   193 (66.3)

Elevated CSF protein         32 (62.7)      43 (58.9)   195 (66.3)

Decreased CSF glucose        12 (23.5)      15 (20.5)   101 (34.2)

Decreased CSF:venous          27 (54)       35 (48.6)   179 (62.4)
glucose ratio

Elevated CSF leukocyte       39 (69.6)      57 (70.4)   241 (82.0)
count (#)

Combinations of [greater
than or equal to] 1 of
the above findings

Elevated CSF lactate,        54 (90.0)      75 (89.3)   291 (97.7)
protein, leukocyte
count; decreased CSF
glucose; CSF turbid (#)

Elevated CRP;                59 (92.2)      83 (94.3)   289 (96.3)
elevated CSF lactate,
protein; CSF turbid

Elevated CRP;                58 (92.1)      82 (94.3)   288 (96.3)
elevated CSF lactate,
protein

Elevated CRP;                56 (91.8)      78 (94.0)   254 (89.1)
elevated CSF lactate

Elevated CRP;                49 (89.1)      68 (88.3)   261 (89.1)
elevated CSF protein

Elevated CRP; GCS            49 (86.0)      70 (89.7)   229 (79.5)
score <15

GCS score <15;               44 (77.2)      61 (75.3)   239 (81.0)
elevated CSF protein

GCS score <15;               50 (83.3)      70 (82.4)   244 (83.8)
elevated CSF lactate

GCS score <15;               53 (88.3)      74 (87.1)   279 (94.3)
elevated CSF lactate,
protein

                          Patients
Variables                  without       Total,
                          confirmed     n = 1,065
                          etiology,
                            n = 615

Neck stiffness            367 (59.8)   683 (64.2)
([paragraph])

GCS score <15             326 (54.2)   551 (52.6)

Elevated CRP              282 (58.1)   547 (63.0)

CSF turbid                 65 (11.5)   145 (14.5)

Elevated CSF lactate      352 (63.1)   650 (66.0)

Elevated CSF protein      320 (59.8)   601 (62.9)

Decreased CSF glucose     142 (26.5)   280 (29.3)

Decreased CSF:venous      287 (55.3)   540 (58.1)
glucose ratio

Elevated CSF leukocyte    CO 00 00 o   729 (74.8)
Count (#)

Combinations of [greater
than or equal to] 1 of
the above findings

Elevated CSF lactate,     534 (93.2)   952 (94.4)
protein, leukocyte
count; decreased CSF
glucose; CSF turbid (#)

Elevated CRP;             526 (93.4)   953 (94.7)
elevated CSF lactate,
protein; CSF turbid

Elevated CRP;             525 (93.4)   950 (94.7)
elevated CSF lactate,
protein

Elevated CRP;             478 (88.5)   863 (89.7)
elevated CSF lactate

Elevated CRP;             442 (84.2)   824 (86.8)
elevated CSF protein

Elevated CRP; GCS         448 (83.1)   796 (83.4)
score <15

GCS score <15;            454 (80.8)   802 (80.9)
elevated CSF protein

GCS score <15;            466 (80.3)   827 (82.0)
elevated CSF lactate

GCS score <15;            515 (89.4)   919 (90.9)
elevated CSF lactate,
protein

* All values are no. (%). See Appendix Table 3
(https://wwwnc.cdc.goV/EID/article/25/5/18-0914-App1.pdf) for
reference ranges. Only patients with confirmed etiology strictly
sensitive to ceftriaxone or doxycycline are included in the
analysis. Classification was based on a combination of
susceptibility testing of isolates from patients and information
from Principles and Practice of Infectious Diseases (43). Patients
who were confused or disoriented who had their GCS score missing
were considered to have a GCS score <15. CRP, C-reactive protein;
CSP, cerebrospinal fluid; GCS, Glasgow Coma Scale.

([dagger]) In total, 28 patients were infected with Leptospira spp.
treatable by either ceftriaxone or doxycycline, but 2 were also
co-infected with Orientia tsutsugamushi not treatable with
ceftriaxone. One patient co-infected with Streptococcus suis and
Rickettsis typhi required therapy with both ceftriaxone and
doxycycline.

([double dagger]) Includes 24 patients infected with Streptococcus
pneumoniae and 32 infected with other bacteria (7 Escherichia coli,
4 Group B Streptococcus, 4 Neisseria meningitidis, 1 Salmonella
enterica group D, 1 S. enterica group B or C, 5 S. suis, 5 S.
enterica serovar Typhi, 2 Klebsiella pneumoniae, 2 Haemophilus
influenzae, and 1 Edwardsiella tarda).

([section]) Includes 31 patients with Rickettsia spp. infection and
33 with O. tsutsugamushi infection.

([paragraph]) History of neck stiffness or neck stiffness on
examination.

(#) Samples with high turbidity could not be counted and were thus
not included.
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Title Annotation:RESEARCH
Author:Dubot-Peres, Audrey; Mayxay, Mayfong; Phetsouvanh, Rattanaphone; Lee, Sue J.; Rattanavong, Sayaphet;
Publication:Emerging Infectious Diseases
Article Type:Disease/Disorder overview
Geographic Code:90SOU
Date:May 1, 2019
Words:10629
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