Clinical Infectious Diseases MAJOR ARTICLE

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1 Clinial Infetious Diseases MAJOR ARTICLE Predition of Outome From Adult Baterial Meningitis in a High-HIV-Seroprevalene, Resoure-Poor Setting Using the Malawi Adult Meningitis Sore (MAMS) Emma C. Wall, 1,2,3,a Mavuto Mukaka, 1,4,5,a Matthew Sarborough, 6 Katherine M. A. Ajdukiewiz, 7 Katharine E. Cartwright, 8 Mulinda Nyirenda, 9 Brigitte Denis, 1 Theresa J. Allain, 10 Brian Faragher, 1,2 David G. Lalloo, 1,2,a and Robert S. Heyderman 1,3,a 1 Malawi-Liverpool-Wellome Trust Clinial Researh Programme, College of Mediine, University of Malawi, Blantyre; 2 Liverpool Shool of Tropial Mediine, and 3 Division of Infetion and Immunity, University College London, United Kingdom; 4 Mahidol-Oxford Clinial Researh Unit, Faulty of Tropial Mediine, Mahidol University, Bangkok, Thailand; 5 Oxford Centre for Tropial Mediine and Global Health, Nuffield Department of Mediine Researh Building, University of Oxford, 6 Oxford University Hospitals, 7 University of Manhester Aademi Health Siene Centre, North Manhester General Hospital, and 8 Sheffield Teahing Hospitals, United Kingdom; and 9 Department of Emergeny Mediine, Queen Elizabeth Central Hospital, and 10 Department of Mediine, College of Mediine, University of Malawi, Blantyre, Malawi (See the Editorial Commentary by Quagliarello on pages ) Bakground. Aute baterial meningitis (ABM) in adults residing in resoure-poor ountries is assoiated with mortality rates >50%. To improve outome, interventional trials and standardized linial algorithms are urgently required. To optimize these proesses, we developed and validated an outome predition tool to identify ABM patients at greatest risk of death. Methods. We derived a nomogram using mortality preditors derived from a logisti regression model of a disovery database of adult Malawian patients with ABM (n = 523 [65%] erebrospinal fluid [CSF] ulture positive). We validated the nomogram internally using a bootstrap proedure and subsequently used the nomogram sores to further interpret the effets of adjuntive dexamethasone and glyerol using linial trial data from Malawi. Results. ABM mortality at 6-week follow-up was 54%. Five of 15 variables tested were strongly assoiated with poor outome (CSF ulture positivity, CSF white blood ell ount, hemoglobin, Glasgow Coma Sale, and pulse rate), and were used in the derivation of the Malawi Adult Meningitis Sore (MAMS) nomogram. The C-index (area under the urve) was 0.76 (95% onfidene interval,.71.80) and alibration was good (Hosmer-Lemeshow C-statisti = 5.48, df = 8, P =.705). Harmful effets of adjuntive glyerol were observed in groups with relatively low predited risk of poor outome (25% 50% risk): Case Fatality Rate of 21% in the plaebo group and 52% in the glyerol group (P <.001). This effet was not seen with adjuntive dexamethasone. Conlusions. MAMS provides a novel tool for prediting prognosis and improving interpretation of ABM linial trials by risk stratifiation in resoure-poor settings. Whether MAMS an be applied to non-hiv-endemi ountries requires further evaluation. Keywords. baterial meningitis, HIV, Afria, outome, severity sore. Aute baterial meningitis (ABM) in sub-saharan Afria is ommon and assoiated with high rates of death and omorbidity in both adults and hildren [1, 2]. Throughout the Afrian ontinent, baterial meningitis is predominately aused by Streptoous pneumoniae [3 5], with the exeption of the meningitis belt Sahel region, where seasonal epidemi meningooal meningitis also ours [6]. In Malawi, the inidene of ABM in adults is 12 per , and the assoiated Reeived 9 June 2016; editorial deision 21 Otober 2016; aepted 20 November 2016; published online Deember 2, a E. C. W., M. M., D. G. L., and R. S. H. ontributed equally to this work. Correspondene: E. Ceilia Wall, Malawi-Liverpool-Wellome Trust Clinial Researh Programme, Department of Clinial Researh, Chihiri 3, Blantyre, PO Box 30096, Malawi (e. wall@ul.a.uk). Clinial Infetious Diseases 2017;64(4):413 9 The Author Published by Oxford University Press on behalf of the Infetious Diseases Soiety of Ameria. This is an Open Aess artile distributed under the terms of the Creative Commons Attribution Liense ( whih permits unrestrited reuse, distribution, and reprodution in any medium, provided the original work is properly ited. DOI: /id/iw779 mortality is 54% ompared with 20% 30% in Europe and the United States [1, 2, 7, 8]. Despite intensive efforts, high mortality remains unhanged region-wide; adjuntive treatments suh as ortiosteroids and glyerol are ineffetive and possibly harmful [9 12]. To improve ABM outome, interventional trials testing new treatment approahes and resoure-appropriate standardized linial algorithms are urgently required. A robust outome predition tool would help optimize these proesses and provide a basis to examine why previous adjuntive interventions have been unsuessful [13]. Well-validated sores used for risk stratifiation in life-threatening infetion inlude Confusion Urea Respiratory Rate age 65 (CURB-65) for pneumonia, and Aute Physiology And Chroni Health Evaluation (APACHE II) and Sepsis-related Organ Failure Assessment (SOFA) for sepsis [14 17]. Two good-quality sores have been reported for ABM in developed settings [18, 19]. A meningitis sore has been developed in the Afrian Predition of Outome From Adult Baterial Meningitis CID 2017:64 (15 February) 413

2 subontinent [20] but was developed speifially for outome predition during meningooal outbreaks. We have previously identified linial preditors of death from adult ABM in Malawi [1]. In the present study, we grouped these outome preditors to generate and validate a severity sore nomogram for use in resoure-poor settings. We used the validated sore to analyze data from large plaebo-ontrolled trials of adjuntive dexamethasone and glyerol in Malawi, to better understand why these treatments were ineffetive. PATIENTS AND METHODS Patient Seletion Clinial data from the Malawi Meningitis Database (MMD) [1], and patient data from a reent linial trial of goal-direted therapy (ISRCTN ) were used (Figure 1). All patients had been enrolled in linial studies of adult ABM in Queen Elizabeth Central Hospital in Blantyre, Malawi, between 2000 and 2013 (Figure 1). The inlusion riteria for the MMD were age >14 years with proven erebrospinal fluid (CSF) infetion on ulture, polymerase hain reation, or Gram stain of bateria known to ause meningitis (proven meningitis), or appropriate linial history <5 days with a CSF white blood ell (WBC) ount >50 ells/µl and >50% neutrophils (probable meningitis). In human immunodefiieny virus (HIV) oinfeted individuals, the CSF WBC ount threshold for probable meningitis was lowered to >5 ells/µl, (100% neutrophils), to inlude HIVoinfeted individuals with low CD4 ounts who mount a weak CSF inflammatory response in ABM [1, 4]. Cases were exluded if there was CSF evidene of Cryptoous neoformans or Myobaterium tuberulosis, CSF WBC ount >50% lymphoytes with no doumented prehospital antibiotis, or trial-speifi exlusion riteria suh as diabetes for the glyerol trial [9, 10]. Diagnosti testing for viral meningitis was not available and is an unommon ause of neurologial infetion in our enter [21]. MMD patients randomized to reeive glyerol were exluded from the nomogram development, as glyerol reeipt was an independent preditor of poor outome [10]. Asertainment of Clinial Charateristis and Outomes All prospetive linial trial data were utilized with permission from the prinipal investigator. Individual study protools were examined; only idential variables aross the studies were olleted (data olleted in the same units, at similar time points, using the same normal ranges). All studies were undertaken in the same hospital, using the same laboratories and similar ase reord forms. Physiologial data are from the first reording to minimize both heterogeneity and biases assoiated with delays to antibioti therapy, and inrease appliability for linial use in the region. Outome was measured as death or survival at day 40 postadmission to aount for additional aute postdisharge mortality, whih has been reported to our due to late ompliations in 5% 10% of initial survivors of ABM [9, 22]. Data on in-hospital delays and morbidity (prinipally deafness) were olleted variably aross the studies and were not inluded to minimize heterogeneity. Ethial Approvals All ontributing linial studies were granted ethial approval by the College of Mediine Researh and Ethis Committee, University of Malawi, and the Liverpool Shool of Tropial Mediine Researh Ethis Committee and onformed to institutional guidelines. All trial partiipants or named patient guardians provided written informed onsent. Figure 1. Consolidated Standards of Reporting Trials (CONSORT) diagram demonstrating seletion of data for the Malawi Meningitis Database. Seletion of Preditor Variables A literature searh was performed to determine preditor variables for adults with baterial meningitis [1]. Individual preditors of mortality from the published analysis of the MMD (oma, seizures, anemia, and tahyardia) [1] and variables assoiated in other studies with poor outome (age, sex, HIV status, CSF WBC ount, and CSF ulture) were finally used [7, 19, 23, 24]. 414 CID 2017:64 (15 February) Wall et al

3 Statistial Methods, Derivation of the Nomogram, and Validation Methods Data were summarized as follows: ontinuous normally distributed data using means and standard deviations, skewed data using medians and interquartile range, and ategorial data using perentages. Analyses using a univariate logisti regression model were performed on all relevant ovariates and fators to assess any assoiation with day 40 outome. The unadjusted estimates were reported using odds ratios (ORs) and 95% onfidene intervals (CIs). Multivariable analyses followed on the disovery ohort using a logisti regression model to assess fators and ovariates independently assoiated with the day 40 outome; this model inluded all variables with statistial signifiane on univariate analysis. Variables with high proportions (>50%) of missing data were exluded to redue risks of overfitting. All analyses were performed using IBM SPSS software version 20.0 (IBM Statistis, Armonk, New York) and Stata software version 13.0 (StataCorp, College Station, Texas). Statistial signifiane was set at P <.05. All variables with signifiane in the multivariable model were used to model the preditive tool, using R software version R-i ( using rms pakage and the lrm and nomogram ommands. The developed model was validated to estimate the potential model performane. Beause external data for validation have not yet been identified, an internal validation proedure was performed using bootstrapping (5000 samples), based on alibration, and disrimination [25, 26]. This proedure was seleted to optimize the number of ases available while minimizing risks of overfitting. A logisti regression model was used to obtain the predited deaths. The Hosmer-Lemeshow C-statisti was used to assess alibration; low insignifiant Hosmer-Lemeshow C-statisti indiated good fit [27]. The alibration assessment was supplemented by the use of a Brier sore (range 0 and 1); an α value <.05 (5% signifiane level) was used to determine model fit [28, 29]. A reeiver operating harateristi (ROC) urve was plotted and used to alulate the validated onordane index (C-index). The ROC urve was obtained with the C-index (area under the urve [AUC]) and assoiated 95% CIs. The sensitivity and speifiity of the model is based on a utoff of 50% risk sore. The individual Malawi Adult Meningitis Sore (MAMS) was alulated for patients using IBM SPSS software version Analysis of Clinial Trial Data Using MAMS The MAMS was alulated for all patients who had been reruited to linial trials testing adjuntive dexamethasone and glyerol. Cases were risk stratified by quartile risk of poor outome, and separated by plaebo or intervention. Case fatality rate (CFRs) were alulated within eah quartile group and ompared to the predited risk of poor outome; statistial signifiane was determined using χ 2 test. Data were analyzed using both original omplete ase and bootstrapped data. RESULTS Clinial Charateristis of the Patients Data on patients meeting the inlusion riteria were available for 607 ABM ases and were used for univariate analyses. Five hundred ninety-three patients had CSF results available; of these, 384 (65%) were CSF ulture positive (Supplementary Table 1). Complete ase data were available for 523 ases of baterial meningitis, whih were used for the multivariable analyses and development of the nomogram. Mean age was 32.5 years (SD, 10.8 years), 50.7% (308/607) were female, 87% (506/584) were HIV oinfeted, and 31% (171/551) had an aute seizure within the first 6 hours of admission. Presenting harateristis by outome group are detailed in Table 1. The ase fatality rate (CFR) was 44% (267/607) at day 10 and 54% (320/593) at day 40. The following assoiations with death at day 40 were observed univariately in the disovery ohort (Table 1): age, temperature, low Glasgow Coma Sale (GCS), low oxygen saturation, high pulse rate, low CSF WBC ount, and low hemoglobin level (Table 1). Other inluded variables showed no assoiation with outome on univariate analysis: sex, HIV serostatus, mean arterial blood pressure, respiratory rate, CSF ulture, seizures, and blood gluose (Table 1). All variables tested were inluded in the multivariable analysis model, with the exeption of oxygen saturation, temperature, and respiratory rate (>50% missing data) (Table 1). All variables with univariate signifiane, with the exeption of age, also had an assoiation with outome on multivariable analysis (ORs per unit of measure hange): GCS: OR, 0.77 [95% CI,.72.83], P <.001; pulse rate: OR, 1.01 [95% CI, ], P =.01; log 10 CSF WBC ount: OR, 0.66 [95% CI,.53.80], P <.001; and hemoglobin: OR, 0.84 [95% CI,.78.90], P <.001. Although CSF pneumooal ulture had no signifiant assoiation with outome on univariate analysis, the multivariable model demonstrated a signifiant assoiation with survival (OR, 0.36 [95% CI,.23.57], P <.001). Outome data by organism (Supplementary Table 1) showed that inreased mortality was observed in patients with nonpneumooal meningitis. Although numbers were small, inreased mortality in the nonpneumooal groups (CFR, 56.5% vs 51.5% for S. pneumoniae) was orrelated with lower GCS and thus assoiated with poor outome in the multivariable model. The lak of signifiant assoiation with mortality on univariate analysis for the remainder of the variables, inluding HIV status, was retained on multivariable analysis. Results of the Nomogram Five variables strongly assoiated with day 40 mortality were used to develop the nomogram: GCS, pulse rate, CSF WBC ount, pneumooal ulture, and hemoglobin level (Figure 2). To alibrate the nomogram, the ontinuous variables were ategorized either by quartile around the median, or by standard normal linial ranges. To optimize the nomogram, alibration Predition of Outome From Adult Baterial Meningitis CID 2017:64 (15 February) 415

4 Table 1. Results of the Univariate Analysis and Preditors of Outome From the Complete Case Data Parameter Day 40 Univariate Analysis (Unadjusted) Multivariable Analysis (Adjusted) a Alive Dead Odds Ratio (95% CI) P Value Odds Ratio (95% CI) P Value Sample size n = Age, y, mean (SD) 31.5 (10.9) 32 (10.6) 1.01 ( ) ( ).84 >40 y 42 (14.6) 53 (16.6) 1.30 ( ).42 Sex, male 136 (47) 163 (50.9) 1.17 ( ).32 HIV status Infeted 226 (78) 280 (87) 0.79 ( ).61 Unknown 10 (3.5) 13 (4.1) Admission out of hours 122 (42.5) 139 (43.9) 1.20 ( ).40 Unknown 30 (10.5) 29 (9.1) GCS, mean (SD) 12 (2.8) 9.9 (3.5) 0.82 (.78.86) < (.72.83) <.001 Aute seizure episodes 1 seizure 45 (16) 70 (22) 0.61 ( ).16 2 seizures 18 (6.3) 37 (11.6) 0.75 ( ).49 Temperature, C, mean (SD) 38.2 (1.1) 38.4 (1.3) 1.17 ( ) b.02 SpO 2, %, mean (SD) 95.5 (2.5) 96 (6.5) 0.90 ( ) b.07 Pulse rate, beats/min, mean (SD) 98.6 (19) (19.8) 1.01 ( ) b < ( ).01 MAP, mm Hg, mean (SD) 89.9 (15.1) 90.5 (16.7) 1.00 ( ).81 Respiratory rate, breaths/min, mean 24.7 (6.6) 26.9 (7.9) 1.04 ( ) b.11 (SD) CSF WBC ount, ells/µl d, median 356 ( ) 215 (35 630) 0.49 (.37.64) b < (.53.80) <.001 (IQR) CSF ulture positive for 160 (55) 165 (51.6) 1.06 ( ) b (.23.57) <.001 Streptoous pneumoniae Plasma gluose, mmol/l, mean (SD) 7.5 (2.7) 7.6 (3.8) 1.00 ( ).87 Hemoglobin, g/dl, mean (SD) 11.2 (2.6) 10.1 (2.6) 0.86 (.80.91) b < (.78.90) <.001 Data are presented as No. (%) unless otherwise indiated. Abbreviations: CI, onfidene interval; CSF, erebrospinal fluid; GCS, Glasgow Coma Sale; HIV, human immunodefiieny virus; IQR, interquartile range; MAP, mean arterial pressure; SD, standard deviation; SpO 2, Oxygen Saturations (%); WBC, white blood ell. a Performed on omplete ase data only (n = 523). b Odds ratio for a unit hange in preditor variable. Proportion of missing data >50%, so variable was exluded from multivariable analysis. d Odds ratios alulated on log 10 data. Fifteen patients were CSF ulture negative with CSF WBC ount >50 ells/µl; an additional 6 were HIV oinfeted white ell ounts >5 ells/µl. data derived from the ategorial data were ompared with ontinuous data [30]. Categorial data led to overfitting and poorer performane; therefore, the nomogram using ontinuous data is reported (Figure 2). The database was subjet to 5000 bootstraps, and the entire derivation proess was then repeated using the bootstrapped data. The log (OR) and assoiated bootstrapped CIs are reported (Supplementary Table 2). The data show shrinkage fator (bias) used to adjust the estimated regression oeffiients in the final model for overfitting. Supplementary Table 2 details the bootstrapped CIs for estimated oeffiients. The orresponding ROC urve for the final nomogram is shown in Figure 3. The AUC was 0.76 (95% CI,.71.80). The sensitivity of this model using a utoff of 50% risk sore is 71.7% (95% CI, 66.0% 76.9%) with a speifiity of 63.1% (95% CI, 56.7% 69.2%). Calibration Goodness-of-fit analysis was assessed to alibrate the nomogram. Hosmer-Lemeshow C-statisti was χ 2 = 5.48, df = 8, P =.705. Calibration was good aross individual entiles of estimated mortality probability (Table 2). The Brier sore was 0.2 (95% bootstrap CI, ). Both the C-statisti and Brier sore indiate good alibration. Disrimination was primarily determined by the C-index (AUC). The observed C-index was from the original sample; the optimism orreted or adjusted C-index (mean over 5000 bootstraps) was (95% bootstrapped CI,.71.79). MAMS, the European Meningitis Sore (EMS), and an older outome sore developed in the United States were all derived using similar methods. Therefore, when the C-index of MAMS was ompared diretly to the published C-index of these sores [18, 19, 31], MAMS was equivalent. When tested using Malawi data, the EMS C-index was 0.68 (95% CI,.63.73), ompared with the MAMS C-index of 0.76 (95% CI,.71.80), suggesting that MAMS may be a better sore than EMS in this setting. Mortality Effets of Glyerol and Dexamethasone Case fatality rate were ompared by quartile of predited risk in 2 linial trials of dexamethasone and glyerol [9, 10]. In the 416 CID 2017:64 (15 February) Wall et al

5 Table 2. Summary of the Agreement of the Nomogram per Risk Centile Figure 2. Malawi Adult Meningitis Sore (MAMS) nomogram. A variable is measured and its value is mathed to the orresponding point on the first row of the nomogram. The points are then added for all 5 variables for eah patient. The total points for the patient are mathed to the orresponding risk sore perentage at the bottom (ie, math up the 2 last rows of the nomogram). Abbreviations: CSF, erebrospinal fluid; GCS, Glasgow Coma Sale; WBC, white blood ell ount. dexamethasone study, an inreased CFR was seen in the lowest risk quartile, but no differenes were observed in other risk quartiles (Table 3). In ontrast, glyerol was assoiated with inreased risk of death aross all but the highest risk quartile in that study (Table 3). The same trends were observed when nonbootstrapped data were used, but were not statistially signifiant (data not shown). DISCUSSION This analysis shows that estimation of mortality risk from baterial meningitis in adults in sub-saharan Afria is possible using simple linial parameters. MAMS is derived from ommunity-aquired meningitis data, from an Afrian region with a high HIV prevalene and burden of adult baterial meningitis. This sore is therefore likely to be relevant to similar settings but not to regions where epidemis of both Neisseria meningitidis and Figure 3. Reeiver operating harateristi (ROC) urve for the Malawi Adult Meningitis Sore (MAMS). Group Probability Centile of Death Observed Deaths, No. (%) Predited Deaths, No. (%) Total (11.3) 9 (17.0) (26.9) 15 (28.8) (44.2) 19 (36.5) (45.3) 22 (41.5) (48.1) 26 (50.0) (57.7) 30 (57.7) (56.6) 34 (64.2) (76.9) 37 (71.2) (80.8) 42 (80.8) (86.5) 46 (88.5) 52 Total Hosmer-Lemeshow C-statisti, χ 2 = 5.48, df = 8, P =.705. S. pneumoniae our seasonally [2, 6, 32]. We demonstrate the utility of MAMS in the assessment of linial trials, showing that ompared to plaebo, adjuntive glyerol is assoiated with the greatest inreased risk of death in those patients predited to have a lower risk of poor outome. The only other sore published from Afria was derived in the Sahel region and, therefore, while appliable to settings with epidemi of meningooal meningitis [20], is of limited utility elsewhere. We used similar data proesses to develop MAMS as used in the EMS and a sore developed in the United States [18, 19]. The EMS was developed on a disovery ohort of 691 patients [7] and underwent validation on 301 separate patients from the European Dexamethasone Study [33]. Patients reeiving either dexamethasone or plaebo were inluded and, interestingly, the authors omment that EMS performed better in those in reeipt of dexamethasone who had better outomes, ompared with plaebo [18, 33]. In the development of our sore, we inluded patients who reeived dexamethasone, but exluded those reeiving glyerol to minimize biases; glyerol was independently assoiated with mortality in Malawi [1, 9, 10]. The C-index of MAMS falls within the 95% CI for the C-index of both the EMS and the US-based sore, and therefore an be onsidered of equal strength as the other sores in their validation settings. The EMS performed less well in an external validation exerise, utilizing data from dexamethasone linial trials from Vietnam and Malawi [9, 31, 34]. This may simply be due to differing methodology, inluding the use of ategorized data in the EMS nomogram, and the seletion of ategorial utoffs may have been less appropriate for these younger Afrian patients [18]. However, we believe that the poorer performane of the EMS in those settings highlights ritial differenes between developed and developing ountry ABM populations, inluding longer time to presentation, a higher prevalene of HIV and anemia, greater frequeny of ompliations, and fewer resoures available for linial management [35, 36]. Predition of Outome From Adult Baterial Meningitis CID 2017:64 (15 February) 417

6 Table 3. Day 40 Mortality Outomes From Dexamethasone and Glyerol Compared to Plaebo by Malawi Adult Meningitis Sore Risk Centile (Bootstrapped Data) Plaebo (n = 1293) Dexamethasone (n = 1268) MAMS Risk Probability of Death at Day 40 <25% 61 0 (0) 48 6 (11) % 50% (31) (35) % 75% (55) (60).100 >75% (80) (78).210 Total (53) (56).120 CFR% P Value Plaebo (n = 549) Glyerol (n = 592) CFR% Signifiane of CFR Intervention vs Plaebo P Value <25% 51 6 (10) (22) % 50% (21) (52) < % 75% (51) (70) <.001 >75% (83) (75).140 Total (45) (61).001 Abbreviations: CFR, ase fatality rate; MAMS, Malawi Adult Meningitis Sore. The original trial of adjuntive glyerol in Malawi was stopped early due to unexpeted inrease in mortality in the glyerol arm [10]. Why this effet ourred predominately in those with lower predited risk of death as determined by MAMS is unertain. However, we hypothesize that in less severely ill patients, glyerol-indued vasodilation of pial miroarterioles and osmoti effets may deompensate fragile but balaned fluid ompartments in the brain and the systemi irulation, with adverse effets on brain swelling and perfusion [37, 38]. By omparison, in severely ill patients, breakdown of the blood brain barrier is advaned; hene, glyerol has no additive adverse effet. A major limitation in the development both of EMS and MAMS was missing data, managed using bootstrapping for both sores to redue the risk of overfitting [18]. The developed model was validated to estimate the potential for overfitting and optimism in model performane using an internal validation proedure. This methodology is advised in the absene of external validation data, instead of use of split samples or ross-validation without repliation [25, 26]. The nomogram was optimized using standard validation exerises to redue overlap, and high levels of agreement were observed. Cohort assembly was done using data from multiple studies in the same hospital; biases from interobserver disagreement were minimized by only seleting variables that were olleted uniformly aross all studies. All data were olleted prospetively in the same units, by researh staff trained in the same institution, using the same equipment to minimize potential biases assoiated with post ho ohort assembly. We used data from the first reording after admission to hospital in all studies to minimize the effet of in-hospital delays on alterations on physiologial variables that may otherwise affet the prognosti power of the sore. Other limitations inlude use of data from only 1 ountry, relative infrequeny of HIV-uninfeted patients, lak of inlusion data on morbidity endpoints and proesses of are inluding antibioti delays, and relatively few patients with meningooal vs pneumooal meningitis [6]. The MAMS nomogram requires external prospetive validation in other populations, inluding speifi validation in ountries at risk of epidemi meningooal disease. It is lear that in the development of a severity sore, other fators beyond those measured in the sore may be important in determining outome of adults with baterial meningitis in sub-saharan Afria. Although HIV oinfetion was not assoiated with mortality and not inluded in the nomogram, it is possible that low CSF WBC ount and low hemoglobin level may both orrelate with advaned immunosuppression. CD4 ell ount data are urrently laking in this setting. In onlusion, the MAMS risk stratifiation tool has a good preditive power for use in ABM in adults in sub-saharan Afria outside the epidemi meningitis belt. MAMS an be used in the analysis of prospetive linial trial data, testing effiay of interventions in different risk groups. The differenes between MAMS and EMS sores highlight important differenes between ABM patients in these ontrasting environments. Further work is required to explore these differenes, to test MAMS prospetively, and to design optimal interventions to redue the unaeptable mortality from meningitis in Afria. 418 CID 2017:64 (15 February) Wall et al

7 Supplementary Data Supplementary materials are available at Clinial Infetious Diseases online. Consisting of data provided by the author to benefit the reader, the posted materials are not opyedited and are the sole responsibility of the author, so questions or omments should be addressed to the author. Notes Aknowledgments. The authors thank Philip Gihiru for his help with the generation of the original Malawi database; Malango Msukwa for his assistane with data from the Bundles of are for Adult Meningitis trial; and Professor Diedrik van de Beek for his sharing his experiene with the generation of meningitis severity sores. In addition, we thank Professor E. Ziljstra for his support of the data olletion for both the steroid and glyerol trials. Dislaimer. The funding body had no role in study design, data olletion, data analysis, data interpretation, or writing of the report. The orresponding author had full aess to all the data in the study and had final responsibility for the deision to submit for publiation. Finanial support. This work was supported by a linial PhD fellowship in Global Health (089671/B/09/Z) to E. C. W. from the Wellome Trust; and the MLW ore grant from the Wellome Trust. The original onstituent studies in the disovery ohort were funded by the Meningitis Researh Foundation (Steroids for Adult Meningitis and Glyerol for Adult Meningitis) and by the MLW ore grant from the Wellome Trust. Potential onflits of interest. Author ertifies no potential onflits of interest. All authors have submitted the ICMJE Form for Dislosure of Potential Conflits of Interest. Conflits that the editors onsider relevant to the ontent of the manusript have been dislosed. Referenes 1. Wall EC, Cartwright K, Sarborough M, et al. High mortality amongst adolesents and adults with baterial meningitis in sub-saharan Afria: an analysis of 715 ases from Malawi. 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