HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts

Lillian Tugume; Joshua Rhein; Kathy Huppler Hullsiek; Edward Mpoza; Reuben Kiggundu; Kenneth Ssebambulidde; Charlotte Schutz; Kabanda Taseera; Darlisha A. Williams; Mahsa Abassi; Conrad Muzoora; Abdu K. Musubire; Graeme Meintjes; David B. Meya; David R. Boulware; Henry W. Nabeta; Jane Francis Ndyetukira; Cynthia Ahimbisibwe; Florence Kugonza; Carolyne Namuju; Alisat Sadiq; Alice Namudde; James Mwesigye; Tadeo Kiiza Kandole; Richard Kwizera; Paul Kirumira; Michael Okirwoth; Andrew Akampurira; Tony Luggya; Julian Kaboggoza; Eva Laker; Leo Atwine; Davis Muganzi; Emily E. Evans; Sarah C. Bridge; Sruti S. Velamakanni; Radha Rajasingham; Katelyn Pastick; Anna Stadelman; Andrew Flynn; A. Wendy Fujita; Liliane Mukaremera; Sarah M. Lofgren; Bozena M. Morawski; Ananta Bangdiwala; Kirsten Nielsen; Paul R. Bohjanen; Andrew Kambugu

doi:10.1093/infdis/jiy602

HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts

Lillian Tugume
, Joshua Rhein
, Kathy Huppler Hullsiek
, Edward Mpoza
, Reuben Kiggundu
, Kenneth Ssebambulidde
, Charlotte Schutz
, Kabanda Taseera
, Darlisha A. Williams
, Mahsa Abassi
, Conrad Muzoora
, Abdu K. Musubire
, Graeme Meintjes
, David B. Meya
, David R. Boulware
, Henry W. Nabeta
, Jane Francis Ndyetukira
, Cynthia Ahimbisibwe
, Florence Kugonza
, Carolyne Namuju

Alisat Sadiq, Alice Namudde, James Mwesigye, Tadeo Kiiza Kandole, Richard Kwizera, Paul Kirumira, Michael Okirwoth, Andrew Akampurira, Tony Luggya, Julian Kaboggoza, Eva Laker, Leo Atwine, Davis Muganzi, Emily E. Evans, Sarah C. Bridge, Sruti S. Velamakanni, Radha Rajasingham, Katelyn Pastick, Anna Stadelman, Andrew Flynn, A. Wendy Fujita, Liliane Mukaremera, Sarah M. Lofgren, Bozena M. Morawski, Ananta Bangdiwala, Kirsten Nielsen, Paul R. Bohjanen, Andrew Kambugu

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

Abstract

BACKGROUND: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.

METHODS: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival.

RESULTS: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/μL (P = .04).

CONCLUSION: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.

CLINICAL TRIAL REGISTRATION: NCT01075152 and NCT01802385.

Original language	English (US)
Pages (from-to)	877-883
Number of pages	7
Journal	Journal of Infectious Diseases
Volume	219
Issue number	6
DOIs	https://doi.org/10.1093/infdis/jiy602
State	Published - Feb 23 2019

Bibliographical note

Funding Information:
Financial support. This work was supported by the National Institute of Neurologic Diseases and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268, R25TW009345); the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244); the Wellcome Trust (grant number 098316 to G. M.); and the Department of Science and Technology and National Research Foundation of South Africa Research Chairs Initiative (grant number 64787) and incentive funding (grant number UID: 85858). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Publisher Copyright:
© 2018 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

AIDS
CD4 T cells
CSF biomarkers
HIV
cryptococcal meningitis

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

Publisher link

10.1093/infdis/jiy602

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387427

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Tugume, L., Rhein, J., Hullsiek, K. H., Mpoza, E., Kiggundu, R., Ssebambulidde, K., Schutz, C., Taseera, K., Williams, D. A., Abassi, M., Muzoora, C., Musubire, A. K., Meintjes, G., Meya, D. B., Boulware, D. R., Nabeta, H. W., Ndyetukira, J. F., Ahimbisibwe, C., Kugonza, F., ... Kambugu, A. (2019). HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts. Journal of Infectious Diseases, 219(6), 877-883. https://doi.org/10.1093/infdis/jiy602

Tugume, L, Rhein, J, Hullsiek, KH, Mpoza, E, Kiggundu, R, Ssebambulidde, K, Schutz, C, Taseera, K, Williams, DA, Abassi, M, Muzoora, C, Musubire, AK, Meintjes, G, Meya, DB, Boulware, DR, Nabeta, HW, Ndyetukira, JF, Ahimbisibwe, C, Kugonza, F, Namuju, C, Sadiq, A, Namudde, A, Mwesigye, J, Kandole, TK, Kwizera, R, Kirumira, P, Okirwoth, M, Akampurira, A, Luggya, T, Kaboggoza, J, Laker, E, Atwine, L, Muganzi, D, Evans, EE, Bridge, SC, Velamakanni, SS, Rajasingham, R, Pastick, K, Stadelman, A, Flynn, A, Fujita, AW, Mukaremera, L, Lofgren, SM, Morawski, BM, Bangdiwala, A , Nielsen, K , Bohjanen, PR & Kambugu, A 2019, 'HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts', Journal of Infectious Diseases, vol. 219, no. 6, pp. 877-883. https://doi.org/10.1093/infdis/jiy602

@article{5080cc2508fc49d8a87fb49b82eb0aee,

title = "HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts",

abstract = "BACKGROUND: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.METHODS: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival.RESULTS: Among first episode of cryptococcosis, 9\% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52\% vs 39\%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47\% with CD4 <50, 35\% with CD4 50-99, and 40\% with CD4 ≥100 cells/μL (P = .04).CONCLUSION: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.CLINICAL TRIAL REGISTRATION: NCT01075152 and NCT01802385.",

keywords = "AIDS, CD4 T cells, CSF biomarkers, HIV, cryptococcal meningitis",

author = "Lillian Tugume and Joshua Rhein and Hullsiek, \{Kathy Huppler\} and Edward Mpoza and Reuben Kiggundu and Kenneth Ssebambulidde and Charlotte Schutz and Kabanda Taseera and Williams, \{Darlisha A.\} and Mahsa Abassi and Conrad Muzoora and Musubire, \{Abdu K.\} and Graeme Meintjes and Meya, \{David B.\} and Boulware, \{David R.\} and Nabeta, \{Henry W.\} and Ndyetukira, \{Jane Francis\} and Cynthia Ahimbisibwe and Florence Kugonza and Carolyne Namuju and Alisat Sadiq and Alice Namudde and James Mwesigye and Kandole, \{Tadeo Kiiza\} and Richard Kwizera and Paul Kirumira and Michael Okirwoth and Andrew Akampurira and Tony Luggya and Julian Kaboggoza and Eva Laker and Leo Atwine and Davis Muganzi and Evans, \{Emily E.\} and Bridge, \{Sarah C.\} and Velamakanni, \{Sruti S.\} and Radha Rajasingham and Katelyn Pastick and Anna Stadelman and Andrew Flynn and Fujita, \{A. Wendy\} and Liliane Mukaremera and Lofgren, \{Sarah M.\} and Morawski, \{Bozena M.\} and Ananta Bangdiwala and Kirsten Nielsen and Bohjanen, \{Paul R.\} and Andrew Kambugu",

note = "Funding Information: Financial support. This work was supported by the National Institute of Neurologic Diseases and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268, R25TW009345); the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244); the Wellcome Trust (grant number 098316 to G. M.); and the Department of Science and Technology and National Research Foundation of South Africa Research Chairs Initiative (grant number 64787) and incentive funding (grant number UID: 85858). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Publisher Copyright: {\textcopyright} 2018 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.",

year = "2019",

month = feb,

day = "23",

doi = "10.1093/infdis/jiy602",

language = "English (US)",

volume = "219",

pages = "877--883",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "6",

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TY - JOUR

T1 - HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts

AU - Tugume, Lillian

AU - Rhein, Joshua

AU - Hullsiek, Kathy Huppler

AU - Mpoza, Edward

AU - Kiggundu, Reuben

AU - Ssebambulidde, Kenneth

AU - Schutz, Charlotte

AU - Taseera, Kabanda

AU - Williams, Darlisha A.

AU - Abassi, Mahsa

AU - Muzoora, Conrad

AU - Musubire, Abdu K.

AU - Meintjes, Graeme

AU - Meya, David B.

AU - Boulware, David R.

AU - Nabeta, Henry W.

AU - Ndyetukira, Jane Francis

AU - Ahimbisibwe, Cynthia

AU - Kugonza, Florence

AU - Namuju, Carolyne

AU - Sadiq, Alisat

AU - Namudde, Alice

AU - Mwesigye, James

AU - Kandole, Tadeo Kiiza

AU - Kwizera, Richard

AU - Kirumira, Paul

AU - Okirwoth, Michael

AU - Akampurira, Andrew

AU - Luggya, Tony

AU - Kaboggoza, Julian

AU - Laker, Eva

AU - Atwine, Leo

AU - Muganzi, Davis

AU - Evans, Emily E.

AU - Bridge, Sarah C.

AU - Velamakanni, Sruti S.

AU - Rajasingham, Radha

AU - Pastick, Katelyn

AU - Stadelman, Anna

AU - Flynn, Andrew

AU - Fujita, A. Wendy

AU - Mukaremera, Liliane

AU - Lofgren, Sarah M.

AU - Morawski, Bozena M.

AU - Bangdiwala, Ananta

AU - Nielsen, Kirsten

AU - Bohjanen, Paul R.

AU - Kambugu, Andrew

N1 - Funding Information: Financial support. This work was supported by the National Institute of Neurologic Diseases and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268, R25TW009345); the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244); the Wellcome Trust (grant number 098316 to G. M.); and the Department of Science and Technology and National Research Foundation of South Africa Research Chairs Initiative (grant number 64787) and incentive funding (grant number UID: 85858). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Publisher Copyright: © 2018 The Author(s). Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved.

PY - 2019/2/23

Y1 - 2019/2/23

N2 - BACKGROUND: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.METHODS: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival.RESULTS: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/μL (P = .04).CONCLUSION: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.CLINICAL TRIAL REGISTRATION: NCT01075152 and NCT01802385.

AB - BACKGROUND: Cryptococcal meningitis can occur in persons with less-apparent immunosuppression. We evaluated clinical characteristics and outcomes of persons with HIV-related Cryptococcus presenting with higher CD4 counts.METHODS: We enrolled 736 participants from 2 prospective cohorts in Uganda and South Africa from November 2010 to May 2017. We compared participants with CD4 <50, 50-99, or ≥100 cells/μL by clinical characteristics, cerebrospinal fluid (CSF) parameters, and 18-week survival.RESULTS: Among first episode of cryptococcosis, 9% presented with CD4 ≥100 cells/μL. Participants with CD4 ≥100 cells/μL presented more often with altered mental status (52% vs 39%; P = .03) despite a 10-fold lower initial median CSF fungal burden of 7850 (interquartile range [IQR] 860-65500) versus 79000 (IQR 7400-380000) colony forming units/mL (P < .001). Participants with CD4 ≥100 cells/μL had higher median CSF levels of interferon-gamma, interleukin (IL)-6, IL-8, and IL-13, and lower monocyte chemokine, CCL2 (P < .01 for each). Death within 18 weeks occurred in 47% with CD4 <50, 35% with CD4 50-99, and 40% with CD4 ≥100 cells/μL (P = .04).CONCLUSION: HIV-infected individuals developing cryptococcal meningitis with CD4 ≥100 cells/μL presented more frequently with altered mental status despite having 10-fold lower fungal burden and with greater Th2 (IL-13) immune response. Higher CD4 count was protective despite an increased propensity for immune-mediated damage, consistent with damage-response framework.CLINICAL TRIAL REGISTRATION: NCT01075152 and NCT01802385.

KW - AIDS

KW - CD4 T cells

KW - CSF biomarkers

KW - HIV

KW - cryptococcal meningitis

UR - https://www.scopus.com/pages/publications/85059299272

UR - https://www.scopus.com/pages/publications/85059299272#tab=citedBy

U2 - 10.1093/infdis/jiy602

DO - 10.1093/infdis/jiy602

M3 - Article

C2 - 30325463

AN - SCOPUS:85059299272

SN - 0022-1899

VL - 219

SP - 877

EP - 883

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 6

ER -

HIV-Associated cryptococcal meningitis occurring at relatively higher CD4 counts

Abstract

Bibliographical note

UN SDGs

Keywords

PubMed: MeSH publication types

Publisher link

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