{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T15:08:06Z","timestamp":1791644886982,"version":"4.3.4"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.15067.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000}},{"DOI":"10.12688\/wellcomeopenres.15067.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000}}],"reference-count":25,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T00:00:00Z","timestamp":1778112000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["100504"],"award-info":[{"award-number":["100504"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003323","name":"Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales","doi-asserted-by":"publisher","award":["ANRS12275"],"award-info":[{"award-number":["ANRS12275"]}],"id":[{"id":"10.13039\/501100003323","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["101113"],"award-info":[{"award-number":["101113"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns3:p>\n                    Background Cryptococcal meningitis (CM) is the commonest neurological complication in patients with advanced HIV. Visual disturbance is a frequent presenting symptom. Papilloedema is commonly reported but other ophthalmic findings are not well described. Methods We performed an observational study comparing severely immunocompromised HIV-infected patients with and without CM to determine the nature and prevalence of retinal pathology associated with CM. 70 adult patients were enrolled in Blantyre Malawi, 35 with CM and 35 HIV-infected patients without CM. Results 79% (19\/24) of CM patients examined on day one had evidence of retinal abnormalities compared to 17% (6\/35) of HIV-infected controls (p\u00a0&lt;\u00a00.001). In the CM group, retinal whitening was the commonest abnormality (50%), followed by optic disc swelling (29%), haemorrhage (25%) and vascular abnormalities (7%). Retinal whitening was the only abnormality observed in the comparator group (17%). In CM, there was no significant difference between those with and without retinal abnormalities in fungal burden (13,550\u00a0cfu\/ml vs. 9,150\u00a0cfu\/ml; p\u00a0=\u00a00.65), CD4 count (28 cells\/\u03bcl vs. 76 cells\/\u03bcl; p\u00a0=\u00a00.79) or CSF opening pressure (21\u00a0cm H20 vs. 27\u00a0cm H20; p\u00a0=\u00a00.5). There was no association between presence\/absence of retinal abnormalities and death (40% 10-week mortality vs. 26%; p\u00a0=\u00a00.6). Conclusions Whether the presence of CM retinopathy could be used as a marker of disease severity warrants further investigation. The observed ophthalmic findings provide a descriptive framework for CM retinopathy to be utilised in future CM studies. Trial registration ISRCTN (\n                    <ns3:ext-link xmlns:ns4=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns4:href=\"http:\/\/www.isrctn.com\/ISRCTN45035509\">ISRCTN45035509<\/ns3:ext-link>\n                    ) 19\/06\/2012.\n                  <\/ns3:p>","DOI":"10.12688\/wellcomeopenres.15067.3","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T10:29:06Z","timestamp":1778149746000},"page":"83","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ophthalmic features of HIV associated cryptococcal meningitis in Malawian Adults: an observational study"],"prefix":"10.12688","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-9144","authenticated-orcid":false,"given":"Jayne P.","family":"Ellis","sequence":"first","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"name":"London University College London Hospitals NHS Trust"},{"name":"Division of Infection and Immunity London University College London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4691-6359","authenticated-orcid":false,"given":"Kate","family":"Gaskell","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"name":"London London School of Hygiene & Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Peirse","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-7498","authenticated-orcid":false,"given":"Jack","family":"Gormley","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"name":"Department of Eye and Vision Science Liverpool University of Liverpool"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Newton","family":"Kalata","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"name":"Blantyre University of Malawi College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip I.","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Eye and Vision Science Liverpool University of Liverpool"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5084-4664","authenticated-orcid":false,"given":"Patty","family":"Mopamboli","sequence":"additional","affiliation":[{"name":"Blantyre University of Malawi College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chatonda A.","family":"Manda","sequence":"additional","affiliation":[{"name":"Blantyre University of Malawi College of Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Kiire","sequence":"additional","affiliation":[{"name":"Oxford Eye Hospital Oxford John Radcliffe Hospital"},{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8171-0332","authenticated-orcid":false,"given":"Ian","family":"Maccormick","sequence":"additional","affiliation":[{"name":"Department of Eye and Vision Science Liverpool University of Liverpool"},{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebbie","family":"Gondwe","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8847-2325","authenticated-orcid":false,"given":"S\u00edle F.","family":"Molloy","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity London St George's, University of London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity London St George's, University of London"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7680-2200","authenticated-orcid":false,"given":"David G.","family":"Lalloo","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences Liverpool Liverpool School of Tropical Medicine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4573-449X","authenticated-orcid":false,"given":"Robert S.","family":"Heyderman","sequence":"additional","affiliation":[{"name":"Blantyre Malawi-Liverpool-Wellcome Trust Clinical Research Programme"},{"name":"Division of Infection and Immunity London University College London"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"873-881","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.","volume":"17","author":"R Rajasingham","year":"2017","journal-title":"Lancet Infect Dis."},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052895","article-title":"Early clinical and subclinical visual evoked potential and Humphrey's visual field defects in cryptococcal meningitis.","volume":"7","author":"A Moodley","year":"2012","journal-title":"PLoS 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The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups.","volume":"30","author":"J Graybill","year":"2000","journal-title":"Clin Infect Dis."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"2119-2142","DOI":"10.1093\/brain\/awu001","article-title":"Cerebral malaria in children: using the retina to study the brain.","volume":"137","author":"I MacCormick","year":"2014","journal-title":"Brain."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"175-179","DOI":"10.1590\/S1413-86702004000200008","article-title":"Cerebral infarction related to cryptococcal meningitis in an HIV-infected patient: case report and literature review.","volume":"8","author":"A Leite","year":"2004","journal-title":"Braz J Infect Dis."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"57-65","DOI":"10.1177\/1747493017706240","article-title":"Cerebrovascular injury in cryptococcal meningitis.","volume":"13","author":"A Mishra","year":"2018","journal-title":"Int J Stroke."},{"key":"ref25","first-page":"623-683","article-title":"Ocular manifestations of HIV infection.","volume":"93","author":"D Jabs","year":"1995","journal-title":"Trans Am Ophthalmol Soc."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T09:09:15Z","timestamp":1778576955000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,7]]},"references-count":25,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.15067.3","relation":{"has-version":[{"id-type":"doi","id":"10.12688\/wellcomeopenres.15067.2","asserted-by":"subject"},{"id-type":"doi","id":"10.12688\/wellcomeopenres.15067.1","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.29220.r155182","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/wellcomeopenres.29220.r155182","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,7]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.16952.r36598, H\u00e9ctor P\u00e9rez, Claudia Frola, Infectious Diseases\u00a0Division, Fern\u00e1ndez Hospital, Buenos Aires, 24 Oct 2019, version 2, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v2#referee-response-36598","order":0,"name":"referee-response-36598","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Jayne Ellis<\/b>; \n<i>Posted: 24 Apr 2026<\/i>; \n<b>Thank you for your review, please find below a point by point response to each of the questions raised:<\/b> Background. How the retinal pathology attributable to cryptococcus was defined. \n<b><i>It was not clarified.<\/i><\/b> We thank the reviewer for this important point and we agree that this was unclear in the earlier version of the manuscript. We would like to clarify that, as this is an observational study, we did not attempt to define retinal pathology as being directly attributable to cryptococcal infection. Rather, our objective was to describe and compare the spectrum of retinal findings observed among adults with advanced HIV disease with cryptococcal meningitis vs. those with advanced HIV disease without cryptococcal meningitis. Accordingly, the study reports associations between retinal pathology and the presence of cryptococcal meningitis, without inferring causality. We have revised the manuscript to make this distinction clearer and to avoid any implication that the retinal findings are definitively caused by cryptococcal infection. This detail has now been added to the methods section.&nbsp; Methods When the duration&nbsp;of antiviral treatment&nbsp;and... \n<b><i>It was not clarified.<\/i><\/b> With respect to the duration of anti-retroviral therapy, this is already stated within the 2\n<sup>nd<\/sup> paragraph of the results section, under baseline characteristics. To clarify, amongst study participants with CM, the median duration of anti-retroviral therapy at time of study enrolment was 23 weeks. Amongst study participants without CM, the median duration of anti-retroviral therapy at time of study enrolment was 2 weeks. No other antiviral treatments were routinely provided to study participants. \n<b>From your responses:<\/b> If patients presented with symptoms and\/or signs consistent with ocular opportunistic infections (OIs) e.g. CMV retinitis or toxoplasmosis, these participants would be referred to the QECH ophthalmology department and or Medicine Department as appropriate for further assessment and management.&nbsp; \n<b><i>It was not clarified whether they are included or not.<\/i><\/b>&nbsp; &nbsp; Participants presenting with symptoms and\/or signs consistent with ocular opportunistic infections were not excluded from the study. This detail has now been added to the methods section. Results 28\/35 (80%) of participants underwent dilated indirect ophthalmoscopy and visual acuity testing in the first week Visual acuity was assessed for the two participants with ongoing evidence of retinal whitening at the week 4-10 assessment, using the logMAR scale neither had evidence of persistent functional low vision (defined as a visual acuity less than +0.50 logMAR).&nbsp; \n<b><i>Initial sample it should be 35 instead of 28?&nbsp;<\/i><\/b> Thank you for raising this point for clarification. Of the 35 study participants with CM included in the study, 28 participants had dilated indirect ophthalmoscopy and visual acuity testing performed in the first week following enrolment. 7 participants had dilated indirect ophthalmoscopy and visual acuity testing performed at a later time point, i.e. after 7 days of enrolment. Reasons for examinations being performed beyond day 7 included participant refusal, severe disease states and\/or non availability of the study ophthalmologist. This detail has now been added to the results section.&nbsp; &nbsp; Conclusions We have inevitably sampled patients with less severe CM, who were able to tolerate and consent to an ophthalmological assessment. However, we do not anticipate that the patients with more severe CM would have had fewer intraocular abnormalities. Our study was therefore underpowered to detect an association between presence of CM retinopathy and clinical outcomes including death.&nbsp; \n<b><i>We agree with the correction.<\/i><\/b> Thank you for this feedback.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3#referee-comment-6530","order":1,"name":"referee-comment-6530","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16952.r36599, Peter R. Williamson, Seher Anjum, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Baltimore, MD, 06 Nov 2019, version 2, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v2#referee-response-36599","order":2,"name":"referee-response-36599","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.29220.r155182, Ankit Varshney, Optometry, Veer Narmad South Gujarat University (Ringgold ID: 29035), Surat, 12 May 2026, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/4-83\/v3#referee-response-155182","order":3,"name":"referee-response-155182","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Wellcome Trust through a strategic award to the Malawi-Liverpool-Welcome Trust Clinical Research Programme [101113]\nThe Advancing Cryptococcal meningitis Treatment for Africa (ACTA) trial was funded by the Medical Research Council UK [100504], and Agence Nationale de Recherches sur le Sida et les H\u00e9patites Virales [ANRS12275]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}