Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa

Caleb Skipper; Mark R. Schleiss; Ananta S. Bangdiwala; Nelmary Hernandez-Alvarado; Kabanda Taseera; Henry W. Nabeta; Abdu K. Musubire; Sarah M. Lofgren; Darin L. Wiesner; Joshua Rhein; Radha Rajasingham; Charlotte Schutz; Graeme Meintjes; Conrad Muzoora; David B. Meya; David R. Boulware

doi:10.1093/cid/ciz864

Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa

Caleb Skipper, Mark R. Schleiss, Ananta S. Bangdiwala, Nelmary Hernandez-Alvarado, Kabanda Taseera, Henry W. Nabeta, Abdu K. Musubire, Sarah M. Lofgren, Darin L. Wiesner, Joshua Rhein, Radha Rajasingham, Charlotte Schutz, Graeme Meintjes, Conrad Muzoora, David B. Meya, David R. Boulware

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

17 Scopus citations

Abstract

BACKGROUND: Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections.

METHODS: We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010-2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia.

RESULTS: Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259-2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9-70) and did not differ by the presence of CMV viremia (P = .47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07-4.49; P = .03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49-7.10; P = .003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups.

CONCLUSIONS: Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect).

CLINICAL TRIALS REGISTRATION: NCT01075152.

Original language	English (US)
Pages (from-to)	525-531
Number of pages	7
Journal	Clinical Infectious Diseases
Volume	71
Issue number	3
DOIs	https://doi.org/10.1093/cid/ciz864
State	Published - Jul 27 2020

Bibliographical note

Funding Information:
Potential conflicts of interest. G. M. has received grants from the Wellcome Trust and South African Government. M. R. S. has received consulting fees from Sanofi Vaccines and GSK Vaccines, outside the submitted work. All other authors report no potential conflicts. 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.

Funding Information:
Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244, and K23AI138851); the Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number R01HD079918]); the National Institute of Neurologic Disorders and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268 and K43TW010718); and a combined National Institute of Neurologic Disorders and Stroke and Fogarty International Center award (grant number D43TW009345) via the Northern Pacific Global Health Fellows Program.

Publisher Copyright:
© The Author(s) 2019.

Keywords

CMV
Cryptococcal meningitis
Cryptococcus
Cytomegalovirus
HIV

UN SDGs

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

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10.1093/cid/ciz864

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Skipper, C., Schleiss, M. R., Bangdiwala, A. S., Hernandez-Alvarado, N., Taseera, K., Nabeta, H. W., Musubire, A. K., Lofgren, S. M., Wiesner, D. L., Rhein, J., Rajasingham, R., Schutz, C., Meintjes, G., Muzoora, C., Meya, D. B., & Boulware, D. R. (2020). Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa. Clinical Infectious Diseases, 71(3), 525-531. https://doi.org/10.1093/cid/ciz864

Skipper, C , Schleiss, MR, Bangdiwala, AS, Hernandez-Alvarado, N, Taseera, K, Nabeta, HW, Musubire, AK, Lofgren, SM, Wiesner, DL, Rhein, J , Rajasingham, R, Schutz, C, Meintjes, G, Muzoora, C, Meya, DB & Boulware, DR 2020, 'Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa', Clinical Infectious Diseases, vol. 71, no. 3, pp. 525-531. https://doi.org/10.1093/cid/ciz864

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title = "Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa",

abstract = "BACKGROUND: Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections.METHODS: We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010-2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia.RESULTS: Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259-2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9-70) and did not differ by the presence of CMV viremia (P = .47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07-4.49; P = .03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49-7.10; P = .003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups.CONCLUSIONS: Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect).CLINICAL TRIALS REGISTRATION: NCT01075152.",

keywords = "CMV, Cryptococcal meningitis, Cryptococcus, Cytomegalovirus, HIV",

author = "Caleb Skipper and Schleiss, {Mark R.} and Bangdiwala, {Ananta S.} and Nelmary Hernandez-Alvarado and Kabanda Taseera and Nabeta, {Henry W.} and Musubire, {Abdu K.} and Lofgren, {Sarah M.} and Wiesner, {Darin L.} and Joshua Rhein and Radha Rajasingham and Charlotte Schutz and Graeme Meintjes and Conrad Muzoora and Meya, {David B.} and Boulware, {David R.}",

note = "Funding Information: Potential conflicts of interest. G. M. has received grants from the Wellcome Trust and South African Government. M. R. S. has received consulting fees from Sanofi Vaccines and GSK Vaccines, outside the submitted work. All other authors report no potential conflicts. 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. Funding Information: Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244, and K23AI138851); the Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number R01HD079918]); the National Institute of Neurologic Disorders and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268 and K43TW010718); and a combined National Institute of Neurologic Disorders and Stroke and Fogarty International Center award (grant number D43TW009345) via the Northern Pacific Global Health Fellows Program. Publisher Copyright: {\textcopyright} The Author(s) 2019.",

year = "2020",

month = jul,

day = "27",

doi = "10.1093/cid/ciz864",

language = "English (US)",

volume = "71",

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journal = "Clinical Infectious Diseases",

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TY - JOUR

T1 - Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa

AU - Skipper, Caleb

AU - Schleiss, Mark R.

AU - Bangdiwala, Ananta S.

AU - Hernandez-Alvarado, Nelmary

AU - Taseera, Kabanda

AU - Nabeta, Henry W.

AU - Musubire, Abdu K.

AU - Lofgren, Sarah M.

AU - Wiesner, Darin L.

AU - Rhein, Joshua

AU - Rajasingham, Radha

AU - Schutz, Charlotte

AU - Meintjes, Graeme

AU - Muzoora, Conrad

AU - Meya, David B.

AU - Boulware, David R.

N1 - Funding Information: Potential conflicts of interest. G. M. has received grants from the Wellcome Trust and South African Government. M. R. S. has received consulting fees from Sanofi Vaccines and GSK Vaccines, outside the submitted work. All other authors report no potential conflicts. 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. Funding Information: Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grant numbers T32AI055433, U01AI089244, and K23AI138851); the Eunice Kennedy Shriver National Institute of Child Health and Human Development [grant number R01HD079918]); the National Institute of Neurologic Disorders and Stroke (grant number R01NS086312); the Fogarty International Center (grant numbers K01TW010268 and K43TW010718); and a combined National Institute of Neurologic Disorders and Stroke and Fogarty International Center award (grant number D43TW009345) via the Northern Pacific Global Health Fellows Program. Publisher Copyright: © The Author(s) 2019.

PY - 2020/7/27

Y1 - 2020/7/27

N2 - BACKGROUND: Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections.METHODS: We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010-2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia.RESULTS: Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259-2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9-70) and did not differ by the presence of CMV viremia (P = .47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07-4.49; P = .03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49-7.10; P = .003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups.CONCLUSIONS: Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect).CLINICAL TRIALS REGISTRATION: NCT01075152.

AB - BACKGROUND: Cryptococcal meningitis and tuberculosis are both important causes of death in persons with advanced human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) viremia may be associated with increased mortality in persons living with HIV who have tuberculosis. It is unknown whether concurrent CMV viremia is associated with mortality in other AIDS-related opportunistic infections.METHODS: We prospectively enrolled Ugandans living with HIV who had cryptococcal meningitis from 2010-2012. Subsequently, we analyzed stored baseline plasma samples from 111 subjects for CMV DNA. We compared 10-week survival rates among those with and without CMV viremia.RESULTS: Of 111 participants, 52% (58/111) had detectable CMV DNA (median plasma viral load 498 IU/mL, interquartile range [IQR] 259-2390). All samples tested were positive on immunoglobin G serology. The median CD4+ T cell count was 19 cells/µL (IQR 9-70) and did not differ by the presence of CMV viremia (P = .47). The 10-week mortality rates were 40% (23/58) in those with CMV viremia and 21% (11/53) in those without CMV viremia (hazard ratio 2.19, 95% confidence interval [CI] 1.07-4.49; P = .03), which remained significant after a multivariate adjustment for known risk factors of mortality (adjusted hazard ratio 3.25, 95% CI 1.49-7.10; P = .003). Serum and cerebrospinal fluid cytokine levels were generally similar and cryptococcal antigen-specific immune stimulation responses did not differ between groups.CONCLUSIONS: Half of persons with advanced AIDS and cryptococcal meningitis had detectable CMV viremia. CMV viremia was associated with an over 2-fold higher mortality rate. It remains unclear whether CMV viremia in severely immunocompromised persons with cryptococcal meningitis contributes directly to this mortality or may reflect an underlying immune dysfunction (ie, cause vs effect).CLINICAL TRIALS REGISTRATION: NCT01075152.

KW - CMV

KW - Cryptococcal meningitis

KW - Cryptococcus

KW - Cytomegalovirus

KW - HIV

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Cytomegalovirus viremia associated with increased mortality in cryptococcal meningitis in sub-saharan Africa

Abstract

Bibliographical note

Keywords

UN SDGs

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