1. Perceptions of Lumbar Puncture for the Diagnosis and Treatment of Meningitis in Uganda Ann Vogt Lima, MD David B Meya, MbChB, MMed Kosuke Yasukawa, MD David R Boulware, MD, MPH

2. 2 Activity Disclaimer ACTIVITY DISCLAIMER It is the policy of the AAFP that all individuals in a position to control content disclose any relationships with commercial interests upon nomination/invitation of participation. Disclosure documents are reviewed for potential conflicts of interest (COI), and if identified, conflicts are resolved prior to confirmation of participation. Only those participants who had no conflict of interest or who agreed to an identified resolution process prior to their participation were involved in this CME activity. Ann V Lima (1), David B Meya (1,2,3,4), Kosuke Yakusawa (1), and David R Boulware (1,2) have indicated they have no relevant financial relationships to disclose. 1 Department of Medicine, University of Minnesota, Minneapolis, MN, USA 2 Center for Infectious Diseases & Microbiology Translational Research, University of Minnesota, Minneapolis, MN, USA 3 Infectious Disease Institute, Makerere University, Kampala, Uganda 4 School of Medicine, College of Health Sciences, Makerere University, Kampala, Uganda

3. Background and Significance Cryptococcus neoformans 3

4. Background and Significance Lumbar puncture (LP) –aka spinal tap, amazzi ku mugongo –Diagnostic –Therapeutic Refusal –Delayed diagnosis –Morbidity, neurologic sequelae –Mortality Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014; 59(11): 1607-14 Trachtenberg JD, Kambugu AD, McKellar M, et al. The medical management of central nervous system infections in Uganda and the potential impact of an algorithm-based approach to improve outcomes. Int J Infect Dis 2007; 11(6): 524-30. 4

5. Background and Significance Refusal –Malaysia (pediatric), 25% –Zambia, 12% –Uganda, 24% Why? Ling SG, Boey CC. Lumbar puncture refusal in febrile convulsion. Singapore Med J 2000; 41(10): 485-8. Thakur KT, Mateyo K, Hachaambwa L, et al. Lumbar puncture refusal in sub-Saharan Africa: A call for further understanding and intervention. Neurology 2015; 84(19): 1988-90. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46(11): 1694-701. 5

6. Methods Prospective cohort Mulago Hospital - Kampala, Uganda –1500 bed –Teaching hospital –National referral center 6

7. Methods IRB –University of Minnesota –Infectious Disease Institute Scientific Research Committee –Makerere University Faculty of Medicine Research Ethics Committee –Mulago Hospital Office of Director –Uganda National Council of Science and Technology 7

8. Methods Inclusion criteria –Admitted with possible CNS infection –LP recommended Informed consent Interpreter Patient vs surrogate 8

9. Methods In-depth interviews –Demographics –Medical knowledge –Past experience –Perceptions –Medical decision making Second interview attempt, post-LP 9

10. Methods Clinical parameters obtained –Refusal vs acceptance –Decision time for acceptance –Time to LP, and time to results –Preliminary diagnosis –Time to empiric treatment –Definitive diagnosis, and time to diagnosis –Time to definitive treatment –Length of stay –Exit status 10

11. Methods Asymptomatic HIV-infected clinic patients –6 men, 6 women –Same questions Health-care providers –10 interviews –Differing levels of education, intern to registrar 11

12. Methods Qualitative content analysis –Inductive method –No pre-determined categorization theme –Immersion, coding, categorizing –Common themes Quantitative content analysis –Demographics –Acceptance vs refusal –Exit status –Correlation of acceptance vs refusal with interview responses, exit status 12

13. Results 13 103 Patients 7 Not offered LP 96 Offered LP 30 Refused 10 LP not performed 20 Delayed acceptance 66 Accepted 5 Not performed 61 LP performed

14. Results 14 114 Interviews 10 Health Care Professionals 12 Asymptomatic Clinic Patients 92 Hospitalized Patients 59 Surrogate Interviews 33 Patient Interviews

15. Results Lumbar puncture cohort (n=103) Sex –50 men –53 women Age –35.3 (SD+12.2) years HIV status –90 infected –11 not infected –2 unknown 15

16. Results DiagnosisProvenPresumed Cryptococcal Meningitis232 Bacterial Meningitis21 Cerebral Malaria02 Disseminated TB14 Pulmonary TB52 Tuberculous Meningitis08 Viral Meningitis01 Malaria01 Cerebral Malaria02 Psychosis02 Sinusitis01 Toxoplasmosis01 Hysteria/Malingering01 Transverse Myelitis01 Cerebrovascular accident20 Total3329 16 Note: Proven diagnosis based on culture-proven or imaging diagnosis. Presumed diagnoses based on treatment and/or final diagnosis on chart. Remaining 41 patients did not have a documented proven or presumed diagnosis.

17. Results Therapeutic LP –19 recommended –12 (63%) accepted –7 (37%) refused Exit status –50 (48.5%) died –50 (48.5%) discharged home alive –2 (2%) left against medical advice –1 (1%) was lost to follow up 17

18. Results Themes N (n=104) Percentage of Respondents Death6260% Pain2019% Disability1514% Procedure1111% Back problems109.6% Weakness109.6% Mental disturbance65.8% Decrease lifespan54.8% Sexual side effects32.9% Other health condition1110.6% 18 Themes including a variety of codes: Pain = procedure pain, general pain, back pain, chronic pain Disability = disability, lameness, sight, paralysis, crippled, visual effects, distorted life Procedure = inexperienced doctors, procedure pain Back problems = broken back, back pain Mental disturbance = mental disturbance, confusion, mental disorder, lose consciousness Other Health condition = Worsens situation, lack of improvement, fluid will be used up, lose fluid, long recovery, decreased life span, deterioration of condition, using fluid for other purpose, affected bone marrow, negative

19. Results Perceived Harm Themes Total interview responses (N=91) LP Acceptance (n=61) LP Refusal (n=30) Odds Ratio 95% C.I.P-value Death54 (59%)30 (49%)24 (80%)4.131.5-12<0.001 Pain19 (21%)14 (23%)5 (17%)0.670.22-2.10.34 Disability15 (16%)8 (13%)7 (23%)2.020.65-6.20.17 Procedure10 (11%)8 (13%)2 (6.7%)0.470.094-2.40.29 Back problems9 (10%)8 (13%)1 (3.3%)0.230.027-1.90.14 Weakness9 (10%)4 (6.6%)5 (17%)2.850.71-120.13 Mental disturbance6 (10%)3 (4.9%)3 (10%)2.15 0.41-110.31 Decrease lifespan4 (4%)1 (1.6%)3 (10%)6.670.66-670.10 Sexual side effects3 (3%)2 (3.3%)1 (3.3%)1.020.089-120.70 Other health conditions 10 (11%)6 (9.8%)4 (13.3%)1.410.37-5.40.43 19

20. Results No association between acceptance and survival –p=0.52 –Limited diagnostics –Small sample size 20

21. Discussion 31% refusal rate Misperception: LPs cause death Majority HIV-infected Women 68% had no diagnosis at exit status 21

22. Discussion Overwhelmed medical officers Lack of equipment needed Secondary acceptance – possibly associated with interview? Refusal of therapeutic – not enough relief? –Not using manometers 22

23. Discussion 25% refusal documented previously 31% in this study <1% in subsequent study How did we improve?! 23

24. Discussion Developed patient information handout –English and Luganda –Color poster on walls of wards –Pocket cards with diagnostic algorithm based on local epidemiology, available tests, test performance, and cost-effectiveness Screening consent form, had to be explained 24

25. Discussion 25

26. Discussion 26

27. References 1. Castelnuovo B, Manabe YC, Kiragga A, Kamya M, Easterbrook P, Kambugu A. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 2009; 49(6): 965-72. 2. Bahr NC, Boulware DR. Methods of rapid diagnosis for the etiology of meningitis in adults. Biomark Med 2014; 8(9): 1085-103. 3. Kisenge PR, Hawkins AT, Maro VP, et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis 2007; 7(1): 39. 4. Lindquist L, Linne T, Hansson LO, Kalin M, Axelsson G. Value of cerebrospinal fluid analysis in the differential diagnosis of meningitis: a study in 710 patients with suspected central nervous system infection. Eur J Clin Microbiol Infect Dis 1988; 7(3): 374-80. 5. Boyles TH, Thwaites GE. Appropriate use of the Xpert(R) MTB/RIF assay in suspected tuberculous meningitis. Int J Tuberc Lung Dis 2015; 19(3): 276-7. 6. Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002; 360(9342): 1287-92. 7. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 2010; 50(3): 291-322. 8. Rolfes MA, Hullsiek KH, Rhein J, et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin Infect Dis 2014; 59(11): 1607-14. 9. Thakur KT, Mateyo K, Hachaambwa L, et al. Lumbar puncture refusal in sub-Saharan Africa: A call for further understanding and intervention. Neurology 2015; 84(19): 1988-90. 10. Ramakrishnan M, Ulland AJ, Steinhardt LC, Moisi JC, Were F, Levine OS. Sequelae due to bacterial meningitis among African children: a systematic literature review. BMC Med 2009; 7: 47. 27

28. References 11. Trachtenberg JD, Kambugu AD, McKellar M, et al. The medical management of central nervous system infections in Uganda and the potential impact of an algorithm-based approach to improve outcomes. Int J Infect Dis 2007; 11(6): 524- 30. 12. Jarvis JN, Bicanic T, Loyse A, et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated Cryptococcal meningitis: implications for improving outcomes. Clin Infect Dis 2014; 58(5): 736-45. 13. Butler EK, Boulware DR, Bohjanen PR, Meya DB. Long term 5-year survival of persons with cryptococcal meningitis or asymptomatic subclinical antigenemia in Uganda. PLoS One 2012; 7(12): e51291. 14. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46(11): 1694-701. 15. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010; 7(12): e1000384. 16. Ling SG, Boey CC. Lumbar puncture refusal in febrile convulsion. Singapore Med J 2000; 41(10): 485-8. 17. Durski KN, Kuntz KM, Yasukawa K, Virnig BA, Meya DB, Boulware DR. Cost-effective diagnostic checklists for meningitis in resource-limited settings. J Acquir Immune Defic Syndr 2013; 63(3): e101-8. 18. Hakim JG, Gangaidzo IT, Heyderman RS, 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. 19. Boulware DR, Meya DB, Muzoora C, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370(26): 2487-98. 28

29. Acknowledgements We would like to thank Dr. Andrew Kambugu, Lynn Atuyambe, Kiong Sen Liao, Darius Fewlass, Grant Botker. This work was supported by the Walter H. Judd International Graduate and Professional Fellowship Program, the Infectious Disease Society of America Medical Scholars Award, the Wesley W. Spink Award for Infectious Disease Research, the National Institute of Neurologic Disorders and Stroke, the National Institute of Allergy and Infectious Disease, and the Fogarty International Center at the National Institutes of Health (R01NS086312, R25TW009345, U01AI089244). None of the funders had a role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript. 29

30. ann.lima@smh-cvhc.org 30