PMID- 36303432 OWN - NLM STAT- MEDLINE DCOM- 20230323 LR - 20231029 IS - 1537-6591 (Electronic) IS - 1058-4838 (Print) IS - 1058-4838 (Linking) VI - 76 IP - 6 DP - 2023 Mar 21 TI - Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies. PG - 1080-1087 LID - 10.1093/cid/ciac853 [doi] AB - 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/muL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/muL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/muL; IQR: 47-142; WBC: 45 cells/muL; IQR: 8-128). Among those with CSF WBC <5 cells/muL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/muL, 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. CI - (c) The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. FAU - Bahr, Nathan C AU - Bahr NC AUID- ORCID: 0000-0002-9431-8938 AD - Division of Infectious Diseases, Department of Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA. FAU - Skipper, Caleb P AU - Skipper CP AD - Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Huppler-Hullsiek, Kathy AU - Huppler-Hullsiek K AD - Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Ssebambulidde, Kenneth AU - Ssebambulidde K AD - Infectious Diseases Institute, Makerere University, Kampala, Uganda. FAU - Morawski, Bozena M AU - Morawski BM AD - Cancer Data Registry of Idaho, Idaho Hospital Association, Boise, Idaho, USA. FAU - Engen, Nicole W AU - Engen NW AD - Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Nuwagira, Edwin AU - Nuwagira E AD - Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda. FAU - Quinn, Carson M AU - Quinn CM AD - Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA. AD - Weill Institute of Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, USA. FAU - Ramachandran, Prashanth S AU - Ramachandran PS AD - Weill Institute of Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, USA. FAU - Evans, Emily E AU - Evans EE AD - Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Lofgren, Sarah M AU - Lofgren SM AD - Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Abassi, Mahsa AU - Abassi M AD - Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Muzoora, Conrad AU - Muzoora C AD - Department of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda. FAU - Wilson, Michael R AU - Wilson MR AD - Weill Institute of Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco, California, USA. FAU - Meya, David B AU - Meya DB AD - Infectious Diseases Institute, Makerere University, Kampala, Uganda. FAU - Rhein, Joshua AU - Rhein J AD - Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. FAU - Boulware, David R AU - Boulware DR AD - Division of Infectious Diseases and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA. LA - eng SI - ClinicalTrials.gov/NCT01802385 GR - R01 AI145437/AI/NIAID NIH HHS/United States GR - R01 NS086312/NS/NINDS NIH HHS/United States GR - K23 NS110470/NS/NINDS NIH HHS/United States GR - K23 NS122601/NS/NINDS NIH HHS/United States GR - K01 TW010268/TW/FIC NIH HHS/United States GR - K23 MH121220/MH/NIMH NIH HHS/United States GR - D43 TW009345/TW/FIC NIH HHS/United States GR - HHSN261201800006I/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Clin Infect Dis JT - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JID - 9203213 RN - 0 (Antifungal Agents) SB - IM MH - Humans MH - *Meningitis, Cryptococcal/diagnosis/drug therapy MH - *AIDS-Related Opportunistic Infections/drug therapy MH - *HIV Infections/complications/drug therapy MH - Antifungal Agents/therapeutic use MH - Recurrence PMC - PMC10226736 OTO - NOTNLM OT - cryptococcal meningitis OT - cryptococcosis OT - immune reconstitution inflammatory syndrome OT - meningitis OT - relapse COIS- 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. EDAT- 2022/10/29 06:00 MHDA- 2023/03/24 06:00 PMCR- 2023/10/28 CRDT- 2022/10/28 01:43 PHST- 2022/08/09 00:00 [received] PHST- 2022/10/29 06:00 [pubmed] PHST- 2023/03/24 06:00 [medline] PHST- 2022/10/28 01:43 [entrez] PHST- 2023/10/28 00:00 [pmc-release] AID - 6776123 [pii] AID - ciac853 [pii] AID - 10.1093/cid/ciac853 [doi] PST - ppublish SO - Clin Infect Dis. 2023 Mar 21;76(6):1080-1087. doi: 10.1093/cid/ciac853.