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. 2023 Mar 21;76(6):1080-1087.
doi: 10.1093/cid/ciac853.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies

Nathan C Bahr  1 , Caleb P Skipper  2 , Kathy Huppler-Hullsiek  3 , Kenneth Ssebambulidde  4 , Bozena M Morawski  5 , Nicole W Engen  3 , Edwin Nuwagira  6 , Carson M Quinn  7   8 , Prashanth S Ramachandran  8 , Emily E Evans  9 , Sarah M Lofgren  2 , Mahsa Abassi  2 , Conrad Muzoora  6 , Michael R Wilson  8 , David B Meya  4 , Joshua Rhein  2 , David R Boulware  2
Affiliations

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies

Nathan C Bahr et al. Clin Infect Dis. .

Abstract

Background: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence.

Methods: We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate.

Results: 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/μL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/μL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/μL; IQR: 47-142; WBC: 45 cells/μL; IQR: 8-128). Among those with CSF WBC <5 cells/μL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/μL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS.

Conclusions: Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results.

Clinical trials registration: NCT01802385.

Keywords: cryptococcal meningitis; cryptococcosis; immune reconstitution inflammatory syndrome; meningitis; relapse.

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Conflict of interest statement

Potential conflicts of interest. N. C. B. reports Data and Safety Monitoring Board (DSMB) participation for an investigator-initiated trial of losartan safety in coronavirus disease 2019 (COVID-19) [Bengston CD, Montgomery RN, Nazir U et al. Front Med (Lausanne). 2021], doi: 10.3389/fmed.2021.630209 and grants or contracts from NIH NINDS (K23 NS110470). D. R. B. and C. P. S. report grants or contracts from NIH NIAID (T32 AI055433). C. P. S. also reports grants or contracts from NIH NIAID (T32AI055433). J. R. reports grants or contracts from NIH-FIC (K01TW010268). M. A. reports grants or contracts from NINDS/FIC (D43TW009345), NIH-NINDS (K23 NS122601), and NIH NIAID (T32 AI055433). S. M. L. reports grants or contracts from NINDS/FIC (D43TW009345) and NIH National Institute of Mental Health (NIMH) (K23 MH121220). 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.

Figures

Figure 1.
Figure 1.
Summary of participant inclusion. *Seventeen excluded due to persistent infection, 46 due to missing data. Missing data in this context refers to incomplete data, such that an adjudication could not reasonably be determined; missing data that did not change the ability to adjudicate the cause of the syndrome were allowed.
Figure 2.
Figure 2.
Kaplan-Meier curves for mortality over time among those with primary-episode cryptococcal meningitis, relapse of cryptococcal meningitis, and IRIS related to cryptococcal meningitis.
See this image and copyright information in PMC

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