HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts

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

doi:10.1093/infdis/jiy602

Cited by 45 publications

(38 citation statements)

References 19 publications

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“…t1IFN-mediated cryptococcal resistance predicts that the early stage of HIV infection, which generates high levels of t1IFN, would render the host resistant to cryptococcal infection by either species. This is consistent with clinical observations that cryptococcosis is not common during early stage HIV, before CD4 T-cell levels are very low (8,54). Our data also suggest that once CD4 T cells are depleted during advanced AIDS, the t1IFN resistance to C. neoformans infection would be lost even if t1IFN levels are maintained.…”

Section: Discussionsupporting

confidence: 91%

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Davis

Moyer

Hoke

et al. 2019

mBio

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Cryptococcus neoformans causes deadly mycosis primarily in AIDS patients, whereas Cryptococcus gattii infects mostly non-HIV patients, even in regions with high burdens of HIV/AIDS and an established environmental presence of C. gattii. As HIV induces type I IFN (t1IFN), we hypothesized that t1IFN would differentially affect the outcome of C. neoformans and C. gattii infections. Exogenous t1IFN induction using stabilized poly(I·C) (pICLC) improved murine outcomes in either cryptococcal infection. In C. neoformans-infected mice, pICLC activity was associated with C. neoformans containment and classical Th1 immunity. In contrast, pICLC activity against C. gattii did not require any immune factors previously associated with C. neoformans immunity: T, B, and NK cells, IFN-γ, and macrophages were all dispensable. Interestingly, C. gattii pICLC activity depended on β-2-microglobulin, which impacts iron levels among other functions. Iron supplementation reversed pICLC activity, suggesting C. gattii pICLC activity requires iron limitation. Also, pICLC induced a set of iron control proteins, some of which were directly inhibitory to cryptococcus in vitro, suggesting t1IFN regulates iron availability in the pulmonary air space fluids. Thus, exogenous induction of t1IFN significantly improves the outcome of murine infection by C. gattii and C. neoformans but by distinct mechanisms; the C. gattii effect was mediated by iron limitation, while the effect on C. neoformans infection was through induction of classical T-cell-dependent immunity. Together this difference in types of T-cell-dependent t1IFN immunity for different Cryptococcus species suggests a possible mechanism by which HIV infection may select against C. gattii but not C. neoformans. IMPORTANCE Cryptococcus neoformans and Cryptococcus gattii cause fatal infection in immunodeficient and immunocompetent individuals. While these fungi are sibling species, C. gattii infects very few AIDS patients, while C. neoformans infection is an AIDS-defining illness, suggesting that the host response to HIV selects C. neoformans over C. gattii. We used a viral mimic molecule (pICLC) to stimulate the immune response, and pICLC treatment improved mouse outcomes from both species. pICLC-induced action against C. neoformans was due to activation of well-defined immune pathways known to deter C. neoformans, whereas these immune pathways were dispensable for pICLC treatment of C. gattii. Since these immune pathways are eventually destroyed by HIV/AIDS, our data help explain why the antiviral immune response in AIDS patients is unable to control C. neoformans infection but is protective against C. gattii. Furthermore, pICLC induced tighter control of iron in the lungs of mice, which inhibited C. gattii, thus suggesting an entirely new mode of nutritional immunity activated by viral signals.

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Section: Discussionsupporting

confidence: 91%

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Davis

Moyer

Hoke

et al. 2019

mBio

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“…Our findings build on previous studies, which have individually reported the prevalence of CrAg and cryptococcal meningitis or death for PLWH with CD4 100-200 cells/ mm 3 , but not their association. One study located in Uganda previously found that 9% of cryptococcal meningitis cases in PLWH presented in patients with a CD4 > 100 cells/mm 3 [9], and another study from South Africa found a prevalence of 12.5% in this group [8].…”

Section: Discussionmentioning

confidence: 96%

“…South Africa is one of many countries in sub-Saharan Africa that now incorporates CrAg screening into its national HIV guidelines for people with CD4 < 100 cells/ mm 3 [6]. A previous meta-analysis established a pooled CrAg positivity prevalence of 2.0% for PLWH with CD4 100-200 cells/mm 3 [7], and recent data from sub-Saharan Africa suggests that at least 9% of cases of cryptococcal meningitis present in individuals with CD4 > 100 cells/ mm 3 [8,9]. We sought to characterize the association of CrAg positivity by the standard of care serum enzyme immunoassay (EIA) with cryptococcal meningitis or death among PLWH with CD4 100-200 cells/mm 3 .…”

Section: Introductionmentioning

confidence: 99%

Cryptococcal antigenemia is associated with meningitis or death in HIV-infected adults with CD4 100–200 cells/mm3

et al. 2020

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Background: Cryptococcal antigen (CrAg) screening with fluconazole prophylaxis has been shown to prevent cryptococcal meningitis and mortality for people living with HIV (PLWH) with CD4 < 100 cells/mm 3 . While cryptococcal meningitis occurs in individuals with CD4 100-200 cells/mm 3 , there is limited evidence that CrAg screening predicts cryptococcal meningitis or mortality among this group with moderate immunosuppression. Current IDSA and WHO clinical guidelines recommend restricting CrAg screening to PLWH with CD4 < 100 cells/ mm 3 . Methods: We conducted a prospective cohort study of PLWH 18+ years who had not initiated ART in South Africa. We followed participants for 14 months to determine onset of cryptococcal meningitis or all-cause mortality. At study completion, we retrospectively tested stored serum samples for CrAg using an enzyme immunoassay (EIA). We calculated CD4-stratified incidence rates of outcomes and used Cox proportional hazards to measure associations between CrAg positivity and outcomes. Results: We enrolled 2383 PLWH, and 1309 participants had serum samples tested by CrAg EIA. The median CD4 was 317 cells/mm 3 (interquartile range: 173-491 cells/mm 3 ). By CD4 count at baseline, there were 209 individuals with a CD4 count of 100-200 cells/mm 3 and available CrAg test results. Of these, four (1.9%) tested positive. Two of four (IR: 58.8 per 100 person-years) CrAg+ participants and 11 of 205 (IR: 5.6 per 100 person-years) CrAgparticipants developed cryptococcal meningitis or died for an overall rate of death or cryptococcal meningitis that was 10.0-times higher for those who were CrAg+ (95% confidence interval: 2.2-45.3). Among those with CD4 < 100 cell/mm 3 and CrAg EIA test results (N = 179), ten (5.6%) participants tested CrAg+. Among this group, seven of ten (IR: 137.6 per 100 person-years) CrAg+ participants and 26 of 169 (IR: 17.8 per 100 person-years) CrAg-participants developed cryptococcal meningitis or died, for a rate of death or cryptococcal meningitis that was 6.3-times higher for those who were CrAg+ (95% confidence interval: 2.7-14.6). Conclusions: Although few PLWH with moderate immunosuppression screened CrAg positive, a positive CrAg test was predictive of increased risk of cryptococcal meningitis or death. Similar to those with a CD4 < 100 cell/mm 3 , systematic CrAg screening may reduce morbidity and mortality in PLWH with CD4 100-200 cells/mm 3 .

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“…The quality was judged to be good for most studies (details on therapeutic lumbar puncture details in 12/18, timing of ART initiation in 17/18 and description of antifungal regimen in all studies), and most RCTs had been previously evaluated using GRADE criteria [30]. Nine countries were represented (including several multi-country RCTs); greatest representation was from South Africa (six studies) [85][86][87][88][89][90], Uganda (six studies) [22,[91][92][93][94][95] and Malawi (four studies) [7,22,96,97], with other countries represented in two or fewer studies [98][99][100]. Ten of the eighteen studies excluded patients on ART at the time of enrolment.…”

Section: Cryptococcal Meningitis Outcomes For Treatment Provided Unmentioning

confidence: 99%

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

et al. 2020

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Introduction HIV‐associated cryptococcal, TB and pneumococcal meningitis are the leading causes of adult meningitis in sub‐Saharan Africa (SSA). We performed a systematic review and meta‐analysis with the primary aim of estimating mortality from major causes of adult meningitis in routine care settings, and to contrast this with outcomes from clinical trial settings. Methods We searched PubMed, EMBASE and the Cochrane Library for published clinical trials (defined as randomized‐controlled trials (RCTs) or investigator‐managed prospective cohorts) and observational studies that evaluated outcomes of adult meningitis in SSA from 1 January 1990 through 15 September 2019. We performed random effects modelling to estimate pooled mortality, both in clinical trial and routine care settings. Outcomes were stratified as short‐term (in‐hospital or two weeks), medium‐term (up to 10 weeks) and long‐term (up to six months). Results and discussion Seventy‐nine studies met inclusion criteria. In routine care settings, pooled short‐term mortality from cryptococcal meningitis was 44% (95% confidence interval (95% CI):39% to 49%, 40 studies), which did not differ between amphotericin (either alone or with fluconazole) and fluconazole‐based induction regimens, and was twofold higher than pooled mortality in clinical trials using amphotericin based treatment (21% (95% CI:17% to 25%), 17 studies). Pooled short‐term mortality of TB meningitis was 46% (95% CI: 33% to 59%, 11 studies, all routine care). For pneumococcal meningitis, pooled short‐term mortality was 54% in routine care settings (95% CI:44% to 64%, nine studies), with similar mortality reported in two included randomized‐controlled trials. Few studies evaluated long‐term outcomes. Conclusions Mortality rates from HIV‐associated meningitis in SSA are very high under routine care conditions. Better strategies are needed to reduce mortality from HIV‐associated meningitis in the region.

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HIV-Associated Cryptococcal Meningitis Occurring at Relatively Higher CD4 Counts

Cited by 45 publications

References 19 publications

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Pulmonary Iron Limitation Induced by Exogenous Type I IFN Protects Mice from Cryptococcus gattii Independently of T Cells

Cryptococcal antigenemia is associated with meningitis or death in HIV-infected adults with CD4 100–200 cells/mm3

Mortality from HIV‐associated meningitis in sub‐Saharan Africa: a systematic review and meta‐analysis

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