Bahr, Nathan C

Bangdiwala, Ananta S

Boulware, David R

Cresswell, Fiona V

Meya, David B

Thao, Le Thi Phuong

Thwaites, Guy E

Török, M Estée

Vidal, Jose E

International Journal of Infectious Diseases

English

LSHTM Research Online

Accepted ManuscriptTitle: Absence of Cerebrospinal Fluid Pleocytosis inTuberculous Meningitis is a Common Occurrence in HIVCo-infection and a Predictor of Poor OutcomesAuthor: Fiona V. CresswellPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: Ananta S. BangdiwalaPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: David B. MeyaPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: Nathan C. BahrPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: Jose E. VidalPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: M. Este´e To¨ro¨kPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: Le Thi Phuong ThaoPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: Guy E. ThwaitesPII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesAuthor: David R. BoulwarePII: S1201-9712(18)30015-8DOI: https://doi.org/10.1016/j.ijid.2018.01.014Reference: IJID 3144To appear in: International Journal of Infectious DiseasesReceived date: 15-11-2017Please cite this article as: Boulware David R.Absence of Cerebrospinal FluidPleocytosis in Tuberculous Meningitis is a Common Occurrence in HIV Co-infectionand a Predictor of Poor Outcomes.International Journal of Infectious Diseaseshttps://doi.org/10.1016/j.ijid.2018.01.014This is a PDF file of an unedited manuscript that has been accepted for publication.As a service to our customers we are providing this early version of the manuscript.The manuscript will undergo copyediting, typesetting, and review of the resulting proofbefore it is published in its final form. Please note that during the production processerrors may be discovered which could affect the content, and all legal disclaimers thatapply to the journal pertain.1  Absence of Cerebrospinal Fluid Pleocytosis in Tuberculous Meningitis is a Common Occurrence in HIV Co-infection and a Predictor of Poor Outcomes  Fiona V Cresswell1,2 Ananta S Bangdiwala3 David B Meya2,4 Nathan C Bahr5 Jose E Vidal6,7 M. Estée Török8 Le Thi Phuong Thao9 Guy E Thwaites9,10 David R Boulware3   1 Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK 2 Infectious Diseases Institute, Kampala, Uganda 3 Department of Medicine, University of Minnesota, Minneapolis, MN, USA 4 College of Health Sciences, Makerere University, Kampala, Uganda 5 Division of Infectious Diseases, Department of Medicine, University of Kansas, Kansas City, KS, USA 6 Department of Neurology, Instituto de Infectologia Emílio Ribas, São Paulo, Brazil  7 Laboratório de Investigação Médica 49, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, Brazil 8 Department of Medicine, University of Cambridge, Cambridge, United Kingdom 9 Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam 10 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, UK   Corresponding Author  Fiona V Cresswell. Infectious Diseases Institute, Kampala, P.O. Box 22418. Uganda. fionacresswell@doctors.org.uk   Keywords: TB meningitis, TBM, HIV, CSF pleocytosis, acellular, outcomes  Main Text:  We read with interest the article by Erdem et al. reporting absence of cerebrospinal fluid (CSF) pleocytosis (≤5 cells/l) in 3% (19/507) of HIV-negative tuberculous meningitis (TBM) patients (Erdem et al., 2017).   ACCEPTED ANUSCRIPT2  We wish to highlight both the significance and higher incidence of acellular CSF among HIV-infected adults with TBM. In reviewing 85 microbiologically-confirmed, HIV-associated TBM cases in Uganda, 33% (28/85) had acellular CSF. Acellular CSF was also commonly reported among other HIV-infected microbiologically-confirmed TBM cohorts: 26% (5/19) in Zimbabwe, 19% (20/108) in Brazil, and 21% (18/91) in Argentina (Table1)(Cecchini et al., 2007, Croda et al., 2010, Hakim et al., 2000, Vidal et al., 2010). Prevalence of acellular CSF correlated with the severity of immunosuppression in the Argentinian cohort and occurred twice as often in CD4 counts <50 cells/l (33%, 9/28) than with >50 cells/l (15%, 5/31) (Cecchini et al., 2009). In Vietnam, acellular CSF is less common (4%, 20/461) despite advanced immunosuppression (median CD4 39 cells/l). Variation between cohorts may be attributable to variable time to CSF analysis, M. tuberculosis strain type, or genetic differences in host immune responses between geographically distinct cohorts (Caws et al., 2008).   In cryptococcal meningitis, both acellular CSF and elevated CSF neutrophil counts have been associated with poorer outcomes (Scriven et al., 2015). Recently, the observation of a paucity of inflammation or inappropriate neutrophil-mediated inflammation adversely impacting survival has also been confirmed in TBM. Thao et al. demonstrated that in Vietnamese adults lower CSF lymphocyte count was an independent predictor of mortality, regardless of HIV-status (Thao et al., 2017) and van Laarhoven et al. found that high CSF neutrophils were associated with death in a large Indonesian, predominantly HIV-negative, cohort (van Laarhoven et al., 2017).    In HIV-infection, the degree of immunosuppression affects the intracerebral inflammatory phenotype.  Those with CD4+ T-cell count <150 cells/μl had a higher median CSF neutrophil percentage than those with CD4+ count >150 cells/μl (25% versus 10%, P=0.021) and this correlated with higher CSF cytokine concentrations (Thuong et al., 2017).  Both increased CSF neutrophils and raised inflammatory mediator concentrations predispose to clinical deterioration after starting HIV therapy, resulting in higher morbidity and mortality (Marais S et al., CID 2014). This inflammation may contribute to the 44% mortality reported by Thuong in those with <150 CD4 cells/l compared with 13% mortality in >150 CD4 cells/l.  Improved understanding of the drivers and consequences of the inflammatory phenotype in HIV-associated TBM may enable optimised use of adjunctive corticosteroids or host-directed therapy.   “Typical” CSF findings (cells >5/l, protein >45g/l, glucose <45mg/dl) occur in under two-thirds of HIV-infected TBM patients, so clinical acumen and highly sensitive diagnostic tests are critical (Croda et al., 2010). The new Xpert MTB/Rif ‘Ultra’ assay has greater analytical sensitivity and may reduce diagnostic dilemma in HIV-associated TBM (Bahr et al., 2018). These data should reinforce that acellular CSF is a poor prognostic sign and is relatively common among HIV-infected persons, 12% ACCEPTED MANUSCRIPT3  (91/776) among the cohorts summarized. High clinical index of suspicion remains vital for timely, often empiric TBM therapy to reduce death and disability.   Acknowledgements: FVC is supported by Wellcome Trust, UK (ITCRZL80). ASB, DBM, and DRB are supported by Fogarty International Center and National Institute of Neurologic Diseases and Stroke (R01NS086312). MET is supported by the Academy of Medical Sciences, the Health Foundation and the NIHR Cambridge Biomedical Research Centre. GT and LTPT were supported by the Wellcome Trust, UK.   Conflicts of Interests: No conflicts of interest are declared.    ACCEPTED MANUSCRIPT4  References  Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, et al. Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2018;18(1):68-75. Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculous meningitis in HIV-infected patients: drug susceptibility and clinical outcome. AIDS 2007;21(3):373-4. Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculous meningitis in HIV-infected and non-infected patients: comparison of cerebrospinal fluid findings. Int J Tuberc Lung Dis 2009;13(2):269-71. Croda MG, Vidal JE, Hernandez AV, Dal Molin T, Gualberto FA, de Oliveira AC. Tuberculous meningitis in HIV-infected patients in Brazil: clinical and laboratory characteristics and factors associated with mortality. Int J Infect Dis 2010;14(7):e586-91. Erdem H, Ozturk-Engin D, Cag Y, Senbayrak S, Inan A, Kazak E, et al. Central Nervous System Infections in the Absence of Cerebrospinal Fluid Pleocytosis. Int J Infect Dis 2017. Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, et al. Impact of HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406 predominantly adult patients. AIDS 2000;14(10):1401-7. Marais S, Wilkinson KA, Lesosky M, Couseens AK, Deffur A, Pepper DJ et al. Neutrophil-associated central nervous system inflammation in tuberculous meningitis immune reconstitution inflammatory syndrome. Clin Infect Dis. 2014;59(11):1638-47  Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, et al. Early ART After Cryptococcal Meningitis Is Associated With Cerebrospinal Fluid Pleocytosis and Macrophage Activation in a Multisite Randomized Trial. J Infect Dis 2015;212(5):769-78. Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, et al. Prognostic models for 9 month mortality in tuberculous meningitis. Clin Infect Dis 2017:In Press. Thuong NTT, Heemskerk D, Tram TTB, Thao LTP, Ramakrishnan L, Ha VTN, et al. Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis. J Infect Dis 2017;215(7):1020-8. van Laarhoven A, Dian S, Ruesen C, Hayati E, Damen M, Annisa J, et al. Clinical parameters, routine inflammatory markers, and LTA4H genotype as predictors of mortality among 608 patients with tuberculous meningitis in Indonesia. J Infect Dis 2017;215(7):1029-39. Vidal JE, de Oliveira AC, Hernandez AV. CD4+ T-cell count and cerebrospinal fluid findings in HIV-infected patients with tuberculous meningitis. Int J Tuberc Lung Dis 2010;14(11):1496-7; author reply 7.    ACCEPTED MANUSCRIPT5   Table 1. Summary HIV-infected cohorts with microbiologically confirmed tuberculous meningitis    Values represent N (%) or median (range). * microbiologically confirmed HIV-associated TBM cases from Thao et al. Vietnam cohort included  N/A is not data available a “Normal CSF” defined as white cells <5/mm3, protein <45g/l, glucose >45mg/dl (2.5mmol/l).  b CSF data available for n=19. c CSF data available for n=91. d CSF data available for 458. e outcome known for n=69.    Cohort Uganda Zimbabwe (Hakim et al.) Brazil (Croda et al.) Argentina (Cecchini et al.) Vietnam (Thao et al.)* Study Period 2011 - 2017 1994 1999-2007 1996-2004 2004-2015 N 85 21 108 101 461 Median CD4 cells/l 81 131 65  53 39 CSF lymphocytes /mm3 75 (0-2450) N/A 49 (0-100) N/A 103 (0-6004) Acellular CSF with <5 cells/l 28 (33%) 5 (26%)b 20 (19%) 18 (21%)c 20 (4%)d Normal CSF (white cells, protein and glucose)a 3 (4%) 0 (0%) 4 (4%) N/A 2 (0.4%) In hospital Mortality  54% e 67% 29% 63%  N/A 9-month Mortality N/A N/A 41% N/A 51% Mortality in patients with acellular CSF 39% N/A 55% N/A 60% Mortality in patients with normal CSF 0% N/A 75% N/A 100% ACCEPTED MANUSCRIPT

Absence of cerebrospinal fluid pleocytosis in tuberculous meningitis is a common occurrence in HIV co-infection and a predictor of poor outcomes.

Fiona V. Cresswell

Ananta S. Bangdiwala

David B. Meya

Nathan C. Bahr

Jose E. Vidal

M. Estée Török

Le Thi Phuong Thao

Guy E. Thwaites

David R. Boulware

Crossref

Absence of cerebrospinal fluid pleocytosis in tuberculous meningitis is a common occurrence in HIV co-infection and a predictor of poor outcomes

Apollo (Cambridge)

International Journal of Infectious Diseases 68 (2018) 77–78Letter to the EditorContents lists available at ScienceDirectInternational Journal of Infectious Diseasesjournal home page: www.elsevier .com/ locat e/ i j idAbsence of cerebrospinal fluid pleocytosis intuberculous meningitis is a common occurrencein HIV co-infection and a predictor of pooroutcomesWe read with interest the article by Erdem et al. reportingabsence of cerebrospinal fluid (CSF) pleocytosis (25 cells/ml) in 3%(19/507) of HIV-negative tuberculous meningitis (TBM) patients(Erdem et al., 2017).We wish to highlight both the significance and higher incidenceof acellular CSF among HIV-infected adults with TBM. In reviewing85 microbiologically-confirmed, HIV-associated TBM cases inUganda, 33% (28/85) had acellular CSF. Acellular CSF was alsocommonly reported among other HIV-infected microbiologically-confirmed TBM cohorts: 26% (5/19) in Zimbabwe, 19% (20/108) inBrazil, and 21% (18/91) in Argentina (Table 1) (Cecchini et al., 2007;Croda et al., 2010; Hakim et al., 2000; Vidal et al., 2010). Prevalenceof acellular CSF correlated with the severity of immunosuppres-sion in the Argentinian cohort and occurred twice as often in CD4counts <50 cells/ml (33%, 9/28) than with >50 cells/ml (15%, 5/31)(Cecchini et al., 2009). In Vietnam, acellular CSF is less common(4%, 20/461) despite advanced immunosuppression (median CD439 cells/ml). Variation between cohorts may be attributable tovariable time to CSF analysis, M. tuberculosis strain type, or geneticdifferences in host immune responses between geographicallydistinct cohorts.In cryptococcal meningitis, both acellular CSF and elevated CSFneutrophil counts have been associated with poorer outcomesTable 1Summary HIV-infected cohorts with microbiologically confirmed tuberculous meningitCohort Uganda Zimbabwe (Hakim et al., 200Study period 2011–2017 1994 N 85 21 Median CD4 cells/mL 81 131 CSF lymphocytes/mm3 75 (0–2450) N/A Acellular CSF with 5 cells/mL 28 (33%) 5 (26%)bNormal CSF (white cells, protein and glucose)a 3 (4%) 0 (0%) In hospital mortality 54%e 67% 9-month mortality N/A N/A Mortality in patients with acellular CSF 39% N/A Mortality in patients with normal CSF 0% N/A Values represent N (%) or median (range).N/A is not data available.* Microbiologically confirmed HIV-associated TBM cases from Thao et al. Vietnam coa “Normal CSF” defined as white cells 5/mm3, protein <45 g/l, glucose >45 mg/dl (b CSF data available for n = 19.c CSF data available for n = 91.d CSF data available for 458.e Outcome known for n = 69.https://doi.org/10.1016/j.ijid.2018.01.0141201-9712/© 2018 The Authors. Published by Elsevier Ltd on behalf of International Soclicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).(Scriven et al., 2015). Recently, the observation of a paucity ofinflammation or inappropriate neutrophil-mediated inflammationadversely impacting survival has also been confirmed in TBM. Thaoet al. demonstrated that in Vietnamese adults lower CSFlymphocyte count was an independent predictor of mortality,regardless of HIV-status (Thao et al., 2017) and van Laarhoven et al.found that high CSF neutrophils were associated with death in alarge Indonesian, predominantly HIV-negative, cohort (van Laar-hoven et al., 2017).In HIV-infection, the degree of immunosuppression affects theintracerebral inflammatory phenotype. Those with CD4+ T-cellcount <150 cells/ml had a higher median CSF neutrophilpercentage than those with CD4+ count >150 cells/ml (25% versus10%, P = 0.021) and this correlated with higher CSF cytokineconcentrations (Thuong et al., 2017). Both increased CSF neutro-phils and raised inflammatory mediator concentrations predisposeto clinical deterioration after starting HIV therapy, resulting inhigher morbidity and mortality (Marais et al., 2014). Thisinflammation may contribute to the 44% mortality reported byThuong in those with <150 CD4 cells/ml compared with 13%mortality in >150 CD4 cells/ml. Improved understanding of thedrivers and consequences of the inflammatory phenotype inHIV-associated TBM may enable optimised use of adjunctivecorticosteroids or host-directed therapy.“Typical” CSF findings (cells >5/ml, protein >45 g/l, glucose<45 mg/dl) occur in under two-thirds of HIV-infected TBMpatients, so clinical acumen and highly sensitive diagnostic testsare critical (Croda et al., 2010). The new Xpert MTB/Rif ‘Ultra’ assayhas greater analytical sensitivity and may reduce diagnosticis.Brazil Argentina Vietnam0) (Croda et al., 2010) (Cecchini et al., 2007, 2009) (Thao et al., 2017)*1999–2007 1996–2004 2004–2015108 101 46165 53 3949 (0–100) N/A 103 (0–6004)20 (19%) 18 (21%)c 20 (4%)d4 (4%) N/A 2 (0.4%)29% 63% N/A41% N/A 51%55% N/A 60%75% N/A 100%hort included.2.5 mmol/l).iety for Infectious Diseases. This is an open access article under the CC BY-NC-ND78 Letter to the Editor / International Journal of Infectious Diseases 68 (2018) 77–78dilemma in HIV-associated TBM (Bahr et al., 2018). These datashould reinforce that acellular CSF is a poor prognostic sign and isrelatively common among HIV-infected persons, 12% (91/776)among the cohorts summarized. High clinical index of suspicionremains vital for timely, often empiric TBM therapy to reducedeath and disability.Conflicts of interestsNo conflicts of interest are declared.AcknowledgementsFVC is supported by Wellcome Trust, UK (ITCRZL80). ASB, DBM,and DRB are supported by Fogarty International Center andNational Institute of Neurologic Diseases and Stroke(R01NS086312). MET is supported by the Academy of MedicalSciences, the Health Foundation and the NIHR CambridgeBiomedical Research Centre. GT and LTPT were supported by theWellcome Trust, UK.ReferencesBahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV, Byamukama A, et al.Diagnostic accuracy of Xpert MTB/RIF Ultra for tuberculous meningitis in HIV-infected adults: a prospective cohort study. Lancet Infect Dis 2018;18(1):68–75.Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculousmeningitis in HIV-infected patients: drug susceptibility and clinical outcome.AIDS 2007;21(3):373–4.Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez M, et al. Tuberculousmeningitis in HIV-infected and non-infected patients: comparison of cerebro-spinal fluid findings. Int J Tuberc Lung Dis 2009;13(2):269–71.Croda MG, Vidal JE, Hernandez AV, Dal Molin T, Gualberto FA, de Oliveira AC.Tuberculous meningitis in HIV-infected patients in Brazil: clinical andlaboratory characteristics and factors associated with mortality. Int J InfectDis 2010;14(7):e586–91.Erdem H, Ozturk-Engin D, Cag Y, Senbayrak S, Inan A, Kazak E, et al. Central nervoussystem infections in the absence of cerebrospinal fluid pleocytosis. Int J InfectDis 2017;65:107–9.Hakim JG, Gangaidzo IT, Heyderman RS, Mielke J, Mushangi E, Taziwa A, et al. Impactof HIV infection on meningitis in Harare, Zimbabwe: a prospective study of 406predominantly adult patients. AIDS 2000;14(10):1401–7.Marais S, Wilkinson KA, Lesosky M, Couseens AK, Deffur A, Pepper DJ, et al.Neutrophil-associated central nervous system inflammation in tuberculousmeningitis immune reconstitution inflammatory syndrome. Clin Infect Dis2014;59(11):1638–47.Scriven JE, Rhein J, Hullsiek KH, von Hohenberg M, Linder G, Rolfes MA, et al. EarlyART after cryptococcal meningitis is associated with cerebrospinal fluidpleocytosis and macrophage activation in a multisite randomized trial. J InfectDis 2015;212(5):769–78.Thao LTP, Heemskerk AD, Geskus RB, Mai NTH, Ha DTM, Chau TTH, et al. Prognosticmodels for 9 month mortality in tuberculous meningitis. Clin Infect Dis 2017;66(4):523–32.Thuong NTT, Heemskerk D, Tram TTB, Thao LTP, Ramakrishnan L, Ha VTN, et al.Leukotriene A4 hydrolase genotype and HIV infection influence intracerebralinflammation and survival from tuberculous meningitis. J Infect Dis 2017;215(7):1020–8.van Laarhoven A, Dian S, Ruesen C, Hayati E, Damen M, Annisa J, et al. Clinicalparameters, routine inflammatory markers, and LTA4H genotype as predictorsof mortality among 608 patients with tuberculous meningitis in Indonesia. JInfect Dis 2017;215(7):1029–39.Vidal JE, de Oliveira AC, Hernandez AV. CD4+ T-cell count and cerebrospinal fluidfindings in HIV-infected patients with tuberculous meningitis. Int J Tuberc LungDis 2010;14(11)1496–7 author reply 7.Fiona V. Cresswella,b,*aDepartment of Infectious and Tropical Diseases, London School ofHygiene and Tropical Medicine, London, UKbInfectious Diseases Institute, Kampala, UgandaAnanta S. BangdiwalaDepartment of Medicine, University of Minnesota, Minneapolis, MN,USADavid B. Meyaa,baInfectious Diseases Institute, Kampala, UgandabCollege of Health Sciences, Makerere University, Kampala, UgandaNathan C. BahrDivision of Infectious Diseases, Department of Medicine, University ofKansas, Kansas City, KS, USAJose E. Vidala,baDepartment of Neurology, Instituto de Infectologia Emílio Ribas, SãoPaulo, BrazilbLaboratório de Investigação Médica 49, Instituto de MedicinaTropical, Universidade de São Paulo, São Paulo, BrazilM. Estée TörökDepartment of Medicine, University of Cambridge, Cambridge, UKLe Thi Phuong ThaoOxford University Clinical Research Unit, Ho Chi Minh City, VietnamGuy E. Thwaitesa,baOxford University Clinical Research Unit, Ho Chi Minh City, VietnambCentre for Tropical Medicine and Global Health, Nuffield Departmentof Medicine, University of Oxford, UKDavid R. BoulwareDepartment of Medicine, University of Minnesota, Minneapolis, MN,USA* Corresponding author at: Infectious Diseases Institute, Kampala,P.O. Box 22418, Uganda.E-mail address: fionacresswell@doctors.org.uk (F. Cresswell).Corresponding Editor: Eskild Petersen, Aarhus, DenmarkReceived 15 November 2017

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Absence of cerebrospinal fluid pleocytosis in tuberculous meningitis is a common occurrence in HIV co-infection and a predictor of poor outcomes.

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