The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis

Melissa A Rolfes, Kathy Huppler Hullsiek, Joshua Rhein, Henry W Nabeta, Kabanda Taseera, Charlotte Schutz, Abdu Musubire, Radha Rajasingham, Darlisha A Williams, Friedrich Thienemann, Conrad Muzoora, Graeme Meintjes, David B Meya, David R Boulware, Melissa A Rolfes, Kathy Huppler Hullsiek, Joshua Rhein, Henry W Nabeta, Kabanda Taseera, Charlotte Schutz, Abdu Musubire, Radha Rajasingham, Darlisha A Williams, Friedrich Thienemann, Conrad Muzoora, Graeme Meintjes, David B Meya, David R Boulware

Abstract

Introduction: Cryptococcal meningitis is the most common cause of adult meningitis in sub-Saharan Africa. Raised intracranial pressure (ICP) is common in cryptococcosis. Prior studies suggest elevated ICP is associated with mortality, and guidelines recommend frequent lumbar punctures (LPs) to control ICP. However, the magnitude of the impact of LPs on cryptococcal-related mortality is unknown.

Methods: In sum, 248 individuals with human immunodeficiency virus (HIV)-associated cryptococcal meningitis, screened for the Cryptococcal Optimal ART Timing (COAT) trial in Uganda and South Africa, were observed. Individuals received an LP to diagnose meningitis, and subsequent therapeutic LPs were recommended for elevated ICP (>250 mmH2O) or new symptoms. We compared survival, through 11 days, between individuals receiving at least 1 therapeutic LP with individuals not receiving therapeutic LPs. The COAT trial randomized subjects at 7-11 days; thus, follow-up stopped at time of death, randomization, or 11 days.

Results: Seventy-five (30%) individuals had at least 1 therapeutic LP. Individuals receiving therapeutic LPs had higher cerebrospinal fluid (CSF) opening pressures, higher CSF fungal burdens, and were more likely to have altered mental status at baseline than those with no therapeutic LPs. Thirty-one deaths (18%) occurred among 173 individuals without a therapeutic LP and 5 deaths (7%) among 75 with at least 1 therapeutic LP. The adjusted relative risk of mortality was 0.31 (95% confidence interval: .12-.82). The association was observed regardless of opening pressure at baseline.

Conclusions: Therapeutic LPs were associated with a 69% relative improvement in survival, regardless of initial intracranial pressure. The role of therapeutic LPs should be reevaluated.

Keywords: HIV; cryptococcal meningitis; epidemiology; mortality; therapeutic lumbar punctures.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Selection of cohort participants among HIV-infected individuals in South Africa and Uganda screened for cryptococcal meningitis. Abbreviations: ART, antiretroviral therapy; COAT, Cryptococcal Optimal ART Timing; HIV, human immunodeficiency virus; LP, lumbar puncture.
Figure 2.
Figure 2.
Time of the first therapeutic LP in days from diagnosis of cryptococcal meningitis, among 75 HIV-infected individuals in South Africa and Uganda who received at least 1 LP after an initial diagnostic LP. The median time after diagnosis until the first therapeutic LP was 3 days. Abbreviations: HIV, human immunodeficiency virus; LP, lumbar puncture.
Figure 3.
Figure 3.
Distribution of time to death among those with and without at least 1 therapeutic LP among HIV-infected individuals with cryptococcal meningitis in South Africa and Uganda. A total of 36 deaths occurred within 11 days after diagnosis with cryptococcal meningitis. The overall median time to death was 4 days after diagnosis. Abbreviations: HIV, human immunodeficiency virus; LP, lumbar puncture.

References

    1. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: A randomised trial. Lancet. 2004;363:1764–7.
    1. Heyderman RS, Gangaidzo IT, Hakim JG, et al. Cryptococcal meningitis in human immunodeficiency virus-infected patients in Harare, Zimbabwe. Clin Infect Dis. 1998;26:284–9.
    1. Jarvis JN, Meintjes G, Williams Z, Rebe K, Harrison TS. Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: The role of inadequate secondary prophylaxis. South African Med J. 2010;100:378–82.
    1. 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;58:736–45.
    1. 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;46:1694–701.
    1. Kisenge PR, Hawkins AT, Maro VP, et al. Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis. 2007;7:39.
    1. Loyse A, Wilson D, Meintjes G, et al. Comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin B for the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2012;54:121–8.
    1. McCarthy KM, Morgan J, Wannemuehler KA, et al. Population-based surveillance for cryptococcosis in an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS. 2006;20:2199–206.
    1. Mwaba P, Mwansa J, Chintu C, et al. Clinical presentation, natural history, and cumulative death rates of 230 adults with primary cryptococcal meningitis in Zambian AIDS patients treated under local conditions. Postgrad Med J. 2001;77:769–73.
    1. Van Der Horst C, Saag M, Cloud G, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med. 1997;337:15–21.
    1. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47–54.
    1. Fessler R, Sobel J, Guyot L, et al. Management of elevated intracranial pressure in patients with cryptococcal meningitis. J Acquir Immune Defic Syndr. 1998;17:137–42.
    1. World Health Organization. Rapid advice: Diagnosis, prevention and management of cryptococcal disease in HIV-infected adult, adolescents, and children. Geneva: 2011. World Health Organization.
    1. 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;50:291–322.
    1. Bicanic T, Brouwer AE, Meintjes G, et al. Relationship of cerebrospinal fluid pressure, fungal burden and outcome in patients with cryptococcal meningitis undergoing serial lumbar punctures. AIDS. 2009;23:701–6.
    1. Schaars CF, Meintjes GA, Morroni C, Post FA, Maartens G. Outcome of AIDS-associated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole. BMC Infect Dis. 2006;6:118.
    1. Meda J, Kalluvya S, Downs JA, et al. Cryptococcal meningitis management in Tanzania with strict schedule of serial lumber punctures using intravenous tubing sets: an operational research study. J Acquir Immune Defic Syndr Hum Retrovirol. 2014;66:e31–6.
    1. Zou G. A Modified Poisson regression approach to prospective studies with binary data. Am J Epidemiol. 2004;159:702–6.
    1. Spiegelman D, Hertzmark E. Easy SAS calculations for risk or prevalence ratios and differences. Am J Epidemiol. 2005;162:199–200.
    1. Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Wolters Kluwer Health/Lippincott Williams & Wilkins; 2008.
    1. Denning D, Armstrong R, Lewis B, Stevens D. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome. Am J Med. 1991;91:267–72.
    1. Loyse A, Wainwright H, Jarvis JN, et al. Histopathology of the arachnoid granulations and brain in HIV-associated cryptococcal meningitis: correlation with cerebrospinal fluid pressure. AIDS. 2010;24:405–10.
    1. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol. 1996;27:839–47.
    1. Shoham S, Cover C, Donegan N, Fulnecky E, Kumar P. Cryptococcus neoformans meningitis at 2 hospitals in Washington, DC: Adherence of healthcare providers to published practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2005;40:477–479.
    1. Harrison TS. The burden of HIV-associated cryptococcal disease. AIDS. 2009;23:531–2.
    1. Govender N, Meintjes GA, Bicanic T, et al. Guideline for the prevention, diagnosis and management of cryptococcal meningitis among HIV-infected persons: 2013 update. SAJHIVMED. 2013;14:76–86.

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