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. 2026 Jun 26;21(6):e0340951. doi: 10.1371/journal.pone.0340951

Inpatient mortality and associated clinical factors among people living with HIV with cryptococcal meningitis in Uganda: A retrospective cohort study

Joshua Kitimbo 1,*, Esther Buregyeya 2, Geofrey Mutole 3, John Paul Ibanda 4, Joseph Tumwine 4, Noah Kiwanuka 5, Thomas Buyinza 5,6
Editor: Mohamed Fawzy Mohamed Hamed Shehata7
PMCID: PMC13308784  PMID: 42361014

Abstract

Introduction

Cryptococcal meningitis remains a leading cause of HIV-related mortality in sub-Saharan Africa despite expanded antiretroviral therapy coverage. Evidence on the burden of disease and inpatient mortality among people living with HIV (PLHIV) in routine care settings in Uganda remains limited. This study assessed the proportion of cryptococcal meningitis among HIV-related admissions and examined clinical factors associated with inpatient mortality.

Methods

We conducted a retrospective cohort study of adult PLHIV admitted with cryptococcal meningitis between 1st/01/2017–31st/12/2022 at a national referral hospital in Uganda. Diagnosis was based on cerebrospinal fluid cryptococcal antigen or India ink positivity. Data were abstracted from medical records and analysed using descriptive statistics and multivariable logistic regression to identify factors associated with inpatient mortality. Specific antifungal treatment regimens were not consistently documented and could not be analysed.

Results

Of 3,042 HIV-related admissions, cryptococcal meningitis accounted for 21.4% (650/3,042). Medical records for 634 patients were analysed, among whom 39.3% (249/634) died during hospitalization. Factors independently associated with higher odds of inpatient mortality included convulsions, headache, vomiting, cryptococcal meningitis–associated immune reconstitution inflammatory syndrome, concurrent opportunistic infections, chronic kidney disease, anaemia, and severe immunosuppression (low CD4 cell count). Longer duration of hospitalization (≥7 days) and symptom duration of one to two weeks before admission were associated with lower odds of mortality.

Conclusion

Cryptococcal meningitis continues to account for a substantial proportion of HIV-related hospital admissions and inpatient deaths in Uganda. Mortality is associated with identifiable clinical and health-system factors, underscoring the need for early diagnosis, risk stratification, and optimized inpatient management for PLHIV with cryptococcal meningitis in resource-limited settings.

Introduction

Cryptococcal meningitis (CM) is a life-threatening opportunistic fungal infection of the central nervous system that occurs predominantly among people living with HIV (PLHIV) with advanced immunosuppression. It is caused mainly by Cryptococcus neoformans and less frequently by Cryptococcus gattii, with infection typically acquired through inhalation of environmental spores followed by hematogenous dissemination to the brain, resulting in severe meningoencephalitis [1]. Without timely diagnosis and effective antifungal treatment, cryptococcal meningitis is associated with rapid clinical deterioration, neurological complications, and high short-term mortality [2,3].

Despite substantial progress in HIV care and expanded access to antiretroviral therapy (ART), cryptococcal meningitis remains a major cause of HIV-related morbidity and mortality globally, with the greatest burden concentrated in sub-Saharan Africa (SSA) [4]. Of the estimated 38.4 million PLHIV worldwide, more than two-thirds reside in SSA [5], where late HIV diagnosis, advanced disease at presentation, and limited access to optimal management of opportunistic infections persist [6]. Cryptococcal meningitis accounts for over 70% of cryptococcal disease among HIV-infected individuals and is responsible for approximately 20% of HIV-related deaths globally, highlighting its continued contribution to preventable mortality [7,8].

In Uganda, CM is the leading cause of adult HIV-associated meningitis and remains a major contributor to inpatient morbidity, mortality, and long-term neurological disability among PLHIV [9]. Although national and international guidelines recommend routine cryptococcal antigen (CrAg) screening and standardized antifungal therapy for individuals with advanced HIV disease, implementation gaps remain common [7,10]. Limited access to rapid diagnostics, inconsistent availability of amphotericin-based regimens, inadequate monitoring and management of raised intracranial pressure, and delayed care-seeking continue to undermine survival outcomes in routine hospital settings [3,11].

Clinical factors such as severe immunosuppression, anaemia, seizures, concurrent opportunistic infections, renal dysfunction, and cryptococcal meningitis–associated immune reconstitution inflammatory syndrome (CM-IRIS) have consistently been associated with increased risk of inpatient mortality [12–14]. However, much of the existing evidence is derived from clinical trials, short-term cohorts, or mixed inpatient–outpatient populations, which may not adequately reflect routine care conditions in high-burden, resource-limited settings [4,15]. In Uganda, contemporary evidence quantifying the burden of cryptococcal meningitis among HIV-related admissions and systematically examining inpatient mortality and its correlates over extended periods remains limited.

To address this gap, we analysed six years of routinely collected inpatient data from Kiruddu National Referral Hospital (KNRH) to quantify the proportion of cryptococcal meningitis among HIV-related admissions and to examine clinical and health-system factors associated with inpatient mortality. Generating such real-world evidence is critical for informing risk stratification, strengthening inpatient management, and guiding targeted interventions to reduce preventable deaths among PLHIV with cryptococcal meningitis in resource-limited settings.

Methods

Study design and setting

We conducted a retrospective cohort study using routinely collected medical records of adult PLHIV admitted with cryptococcal meningitis at Kiruddu National Referral Hospital (KNRH) in Kampala, Uganda, from 1 January 2017–31 December 2022. KNRH provides specialised inpatient care for HIV-related opportunistic infections, including cryptococcal meningitis and tuberculosis, and receives referrals from across Uganda.

Study population and eligibility criteria

The study population comprised adult PLHIV whose medical records documented HIV-associated cryptococcal meningitis during the study period. ART-naïve and ART-experienced patients were eligible, including both referral and non-referral cases. Records were excluded if they lacked documented inpatient outcomes, involved HIV-negative patients diagnosed with cryptococcal meningitis, or were unavailable for review.

Sampling procedure

A total population sampling approach was used. All available medical records of eligible adult PLHIV admitted with cryptococcal meningitis during the study period were consecutively reviewed to maximise statistical power and minimise selection bias. Of 3,042 HIV-related admissions, 650 cryptococcal meningitis cases were identified; records for 634 patients (97.5%) were successfully retrieved and included in the final analysis.

Data abstraction and quality assurance

Data were abstracted from hard-copy medical records using a structured abstraction tool programmed in Kobo Collect. Medical records were accessed, retrieved, and abstracted between 12 December 2022 and 31 January 2023. The tool was developed based on a review of published literature on predictors of cryptococcal meningitis mortality and relevant clinical guidelines. Variables captured included sociodemographic characteristics, clinical presentation, laboratory findings, comorbidities, and in-hospital outcomes.

The abstraction tool underwent expert review by clinicians experienced in HIV and cryptococcal meningitis management and by epidemiologists familiar with retrospective cohort studies. Trained research assistants conducted data abstraction using mobile devices, following standardized procedures. Data quality was ensured through comprehensive training, pilot testing of the abstraction tool, and daily supervisory checks for completeness and internal consistency.

Cryptococcal meningitis was defined by a positive cerebrospinal fluid cryptococcal antigen (CrAg) test or India ink microscopy, while, cryptococcal meningitis–associated immune reconstitution inflammatory syndrome (CM-IRIS) was retrospectively defined based on documented positive CSF CrAg, clinical deterioration (e.g., worsening headache, fever, photophobia, or convulsions), and occurrence within 2–10 weeks following initiation of antiretroviral therapy. CD4 T cell count was categorised into three groups: < 50 cells/µL, 50–200 cells/µL, and >200 cells/µL, based on clinical relevance and prior literature on advanced HIV disease. Data on antifungal treatment regimens were not consistently documented in medical records and were therefore not included in the analysis.

Data management

Data were exported from Kobo Collect to Microsoft Excel for cleaning and management and subsequently analysed using Stata version 15. Data were checked for completeness and consistency prior to analysis. Missing data were assessed for all variables included in the analysis. No missingness was observed (S1 File); therefore, complete-case analysis was conducted.

Statistical analysis

Descriptive statistics were used to summarize patient characteristics, with categorical variables presented as frequencies and percentages and continuous variables summarized using means and standard deviations or medians and interquartile ranges, as appropriate. The proportion of cryptococcal meningitis among HIV-related admissions was calculated as the percentage of confirmed cases relative to all PLHIV admissions. In-hospital mortality was defined as death occurring during the admission in which cryptococcal meningitis was diagnosed.

Associations between explanatory variables and inpatient mortality were examined using logistic regression, as reliable time-to-event data were not consistently available to support survival analysis. Bivariate logistic regression analyses were initially conducted, and variables with p ≤ 0.20 were considered for inclusion in the multivariable model. Multicollinearity among candidate independent variables was assessed using variance inflation factors (VIF), with values greater than 10 considered indicative of problematic collinearity; no evidence of multicollinearity was detected (all VIF values were below 10, with a mean VIF of 1.10). A multivariable logistic regression model was subsequently fitted using a forward stepwise approach. Statistical significance was set at p ≤ 0.05, and results are presented as adjusted odds ratios (AORs) with 95% confidence intervals.

Ethical considerations

Ethical approval was obtained from the Makerere University School of Public Health Higher Degrees Research and Ethics Committee (study protocol number 131), with a waiver of informed consent granted for retrospective review of de-identified medical records. Permission to access patient records was granted by KNRH. Data abstractors had no access to patient records that could identify them during and after data abstraction. All data were anonymised prior to analysis to ensure confidentiality.

Results

Patient admissions and records retrieval

Between January 2017 and December 2022, a total of 3,042 HIV-related inpatient admissions were recorded at KNRH in Uganda (Fig 1). Among these admissions, 650 patients (21.4%) were diagnosed with HIV-associated cryptococcal meningitis according to inpatient registers. Medical records for 634 of these patients (97.5%) were successfully retrieved and included in the analysis. Sixteen records (2.5%) could not be retrieved due to incomplete documentation and were excluded.

Fig 1. Flow diagram of patient selection and inclusion in the study.

Fig 1

Of the 634 patients included, 249 died during hospitalization, corresponding to an overall in-hospital mortality of 39.3%.

Socio-demographic and clinical characteristics

The median age of participants was 36 years (IQR = 15), with the majority aged 30–39 years (38.0%) (Table 1); 52.2% were male. Symptom duration prior to admission was evenly distributed, with 31.1% presenting within one week, 37.4% within one to two weeks, and 31.5% after more than two weeks.

Table 1. Socio-demographic and clinical characteristics of the patients in the study.

Parameter Frequency (n = 634) Percentage (%)
Age (years), median = 36 (IQR = 15)
<20 9 1.4
20–29 140 22.1
30–39 241 38.0
40–49 146 23.0
50–59 64 10.1
60+ 34 5.4
Sex
Male 331 52.2
Female 303 47.8
Duration of hospitalization (days), median = 6 (IQR = 10)
<7 days 319 50.3
7–14 days 198 30.2
>14 days 117 18.5
Duration of symptoms before hospitalization
Less than 1 week 197 31.1
1–2 weeks 237 37.4
Greater than 2 weeks 200 31.5
Duration of ART
ART-naive 97 15.3
Less than 1 year 206 32.5
1–5 years 223 35.2
Greater than 5 years 108 17.0
Previous history of cryptococcal meningitis
Yes 222 35.0
No 412 65.0
Signs, symptoms and comorbidities present at the time of diagnosis
Headache 553 87.2
Vomiting 372 58.7
Blurring of vision 151 23.8
Cryptococcal meningitis–associated IRIS 73 11.5
Concurrent opportunistic infection(s) 299 47.2
Specific opportunistic infections documented
Tuberculosis 183 28.9
Pneumonia 39 6.2
Oral and/or esophageal candidiasis 27 4.3
Sepsis 16 2.5
Kaposi sarcoma 14 2.2
Other opportunistic infections 96 15.1
Concurrent diabetes mellitus 30 4.7
Concurrent cardiovascular disease or hypertension 26 4.1
Concurrent chronic kidney disease 81 12.1
Hemoglobin level (g/dL), mean (SD) = 9.6 (3.3)
<8 223 35.2
8–10 163 25.7
10.1–12.5 109 17.2
>12.5 139 21.9
CD4 T cell count (cells/µL), median = 45 (IQR = 89)
<50 333 52.5
50–200 257 40.6
>200 44 6.9

Note: Percentages are calculated using N = 634. Specific opportunistic infection categories may not be mutually exclusive where more than one infection was documented.

Headache was the most common presenting symptom (87.2%), followed by vomiting (58.7%) and blurred vision (23.8%). A previous history of cryptococcal meningitis was reported in 35.0% of patients. The median hospital stay was 6 days (IQR = 10), with half (50.3%) admitted for fewer than seven days.

Laboratory findings indicated advanced immunosuppression (median CD4 = 45 cells/µL; IQR = 89), with 52.5% having CD4 < 50 cells/µL and only 6.9% > 200 cells/µL. Anaemia was common (mean haemoglobin 9.6 g/dL; SD = 3.3). Nearly half (47.2%) had at least one opportunistic infection, predominantly tuberculosis.

Burden of cryptococcal meningitis and inpatient mortality

Cryptococcal meningitis accounted for 21.4% (650/3,042) of all HIV-related inpatient admissions during the study period. Among patients admitted with cryptococcal meningitis and included in the analysis, 39.3% (249/634) died during hospitalization.

Factors associated with inpatient mortality among PLHIV with cryptococcal meningitis

At the bivariate level, several clinical and laboratory factors were associated with inpatient mortality at p ≤ 0.20 (Table 2). Longer duration of hospitalization was associated with lower odds of death, with patients hospitalized for 7–14 days (crude odds ratio [COR] = 0.66; 95% CI: 0.46–0.95) and more than 14 days (COR = 0.57; 95% CI: 0.36–0.89) having reduced mortality compared with those hospitalized for fewer than seven days.

Table 2. Clinical factors associated with inpatient mortality among PLHIV with cryptococcal meningitis at a national referral hospital in Uganda, between 2017 and 2022.

Variable Inpatient mortality COR (95%CI) AOR (95% CI)
Yes (%) No (%)
Sex
Female
Males
111 (36.6)
138 (41.7)
192 (63.37)
193 (58.31)
1
1.24 [0.90-1.71]
‒
Age (years)
60+
<20
20-29
30-39
40-49
50-59
18 (53.9)
4 (44.4)
49 (35.0)
90 (37.3)
64 (43.8)
27 (42.2)
16 (47.1)
5 (55.6)
91 (65.0)
151 (62.7)
82 (56.2)
37 (57.8)
1
1.54 [0.30-2.56]
0.48 [0.22-1.12]
0.49 [0.24-1.20]
0.69 [0.33-1.47]
0.64 [0.28-1.50]
‒
Duration of hospitalization (days)



<7
7-14
>14
142 (45.5)
67 (33.8)
37 (31.6)
177 (55.5)
131 (66.2)
80 (68.4)
1
0.66 [0.46-0.95]
0.57 [0.36-0.89]
1
0.58 [0.37-0.88]
0.49 [0.30-0.85]
Duration of symptoms before:
<1 week
1-2 weeks
>2 weeks

90 (45.7)
60 (25.3)
96(48.0)

107 (54.3)
177(74.7)
104(52.0)

1
0.41 [0.28-0.61]
1.11 [0.77-1.69]

1
0.41 [0.26-0.65]
1.10 [0.71-1.72]
Duration of HAART
ART naïve
Less than 1 year
1-5 years
Greater than 5 years
45 (46.4)
79 (38.3)
85 (38.1)
40 (37.0)
52 (53.6)
127 (61.7)
138 (61.9)
68 (63.0)
1
0.72 [0.44-1.17] 0.71 [0.44-1.15]
0.71 [0.41-1.25]
‒
Previous history of CM
No
Yes
160(41.5)
78 (35.1)
241 (58.5)
144 (64.9)
1
1.30 [0.66-1.29]
Convulsions
Absent
Present
187 (36.2)
62 (47.5)
329 (63.8)
56 (52.5)
1
1.94 [1.30-2.91]
1
1.63 [1.03-2.56]
Headache
No
Yes
62 (76.5)
230 (41.0)
19 (23.5)
323 (59.0)
1
2.32 [1.35-3.99]
1
2.08 [1.13-3.85]
Vomiting
No
Yes
86 (32.8)
163 (43.8)
176 (67.2)
209 (56.2)
1
1.59 [1.17-2.28]
1
1.61 [1.10-2.36]
Blurring of vision
No
Yes
184 (38.1)
65 (43.1)
299 (61.9)
86 (56.9)
1
1.22 [0.85-1.78]
‒
CM- IRIS
No
Yes
198 (35.3)
51 (69.9)
363 (64.7)
22 (30.1)
1
4.25 [2.50-7.21]
1
3.96 [2.22-7.05]
Concurrent Opportunistic infections



No
Yes
113 (33.7)
136 (45.5)
222 (66.3)
163 (54.5)
1
1.63 [1.23-2.36]
1
1.56 [1.08-2.26]
Concurrent DM
Absent
Present

237 (38.7)
12 (40.0)

367 (61.3)
18 (60.0)

1
1.03 [0.50-2.23]

‒
Concurrent CVD
Present
Absent
240 (39.5)
9 (34.6)
368 (60.5)
17 (65.4)
1
0.81[0.36-1.85]
‒
Concurrent CKD
Present
Absent
347(62.7)
43 (53.1)
206 (37.3)
38 (46.9)
1
1.90 [1.15-2.94]
1
1.77 [1.05-2.99]
Hemoglobin (g/dl)
>12.5
<8
Hb 8–10
10.1-12.5
41 (70.5)
101 (45.3)
71 (43.6)
36 (33.0)
98 (29.5)
122 (54.7)
92 (56.4)
73 (67.0)
1
1.99 [1.28-3.16]
1.84 [1.15-3.01]
1.17 [0.71-2.10]
1
2.08 [1.25-3.44]
1.87 [1.10-3.18]
1.23 [0.67-2.34]
CD4 T cell count (cell/uL)
<50
50-200
>200
145 (43.3)
95 (37.2)
9 (20.4)
190 (56.7)
160(62.8)
35 (79.6)
1
0.78[0.55-1.08]
0.34[0.26-0.72]
1
0.34 [0.12-0.62]
0.27 [0.14-0.78]

Note: AORs are shown only for variables retained in the final multivariable model. Reference categories are indicated by 1

Symptom duration before admission of one to two weeks was associated with lower odds of death compared with presentation within one week (COR = 0.41; 95% CI: 0.28–0.61). Clinical features associated with higher mortality included convulsions, headache, vomiting, cryptococcal meningitis–associated immune reconstitution inflammatory syndrome (CM-IRIS), concurrent opportunistic infections, chronic kidney disease, anaemia, and CD4 cell count category.

After adjustment for potential confounders, several factors remained independently associated with inpatient mortality. Longer hospitalization was associated with reduced odds of death, including stays of 7–14 days (adjusted odds ratio [AOR] = 0.58; 95% CI: 0.37–0.88) and more than 14 days (AOR = 0.49; 95% CI: 0.30–0.85). Presentation after one to two weeks of symptoms was also associated with lower mortality (AOR = 0.41; 95% CI: 0.26–0.65). Clinical factors independently associated with increased odds of death included convulsions (AOR = 1.63; 95% CI: 1.03–2.56), headache (AOR = 2.08; 95% CI: 1.13–3.85), vomiting (AOR = 1.61; 95% CI: 1.10–2.36), CM-IRIS (AOR = 3.96; 95% CI: 2.22–7.05), concurrent opportunistic infections (AOR = 1.56; 95% CI: 1.08–2.26), and chronic kidney disease (AOR = 1.77; 95% CI: 1.05–2.99).

Anaemia remained strongly associated with mortality. Compared with patients with haemoglobin >12.5 g/dL, those with haemoglobin <8 g/dL (AOR = 2.08; 95% CI: 1.25–3.44) and 8–10 g/dL (AOR = 1.87; 95% CI: 1.10–3.18) had higher odds of death. CD4 cell count categories were also associated with inpatient mortality, with AORs of 0.34 (95% CI: 0.12–0.62) for 50–200 cells/µL and 0.27 (95% CI: 0.14–0.78) for >200 cells/µL.

Discussion

This study assessed inpatient mortality and associated clinical factors among adult PLHIV with cryptococcal meningitis admitted to a national referral hospital in Uganda between 2017 and 2022. Cryptococcal meningitis accounted for more than one-fifth of HIV-related inpatient admissions, and in-hospital mortality was high (39.3%). Mortality was associated with clinical severity, including neurological symptoms, CM-IRIS, anaemia, low CD4 cell count, and concurrent opportunistic infections. These findings provide real-world evidence on the burden and clinical correlates of cryptococcal meningitis outcomes in routine inpatient care in a high-burden setting.

The observed burden and mortality remain substantial and are consistent with reports from similar settings in sub-Saharan Africa [3,15].The concentration of mortality among young adults reflects a considerable burden in economically productive populations [16]. However, mortality appears to be more strongly influenced by clinical severity and comorbidity than by age alone, underscoring the importance of timely diagnosis and effective inpatient management.

Clinical presentation was strongly associated with mortality. Symptoms such as headache, convulsions, and vomiting likely reflect raised intracranial pressure, a key predictor of poor outcomes [3,11]. The lower mortality observed among patients presenting after one to two weeks of symptoms should be interpreted cautiously, as it may reflect differences in disease progression, survival to admission, or care-seeking patterns rather than a protective effect of delayed presentation. Limited documentation of intracranial pressure in this study suggests potential gaps in routine monitoring and adherence to recommended management practices in similar resource-limited settings [13,15].

Low CD4 cell count and concurrent opportunistic infections were also associated with mortality. This is consistent with evidence linking severe immunosuppression and co-infections to poorer outcomes in cryptococcal meningitis, driven by impaired immune response, higher pathogen burden, and increased risk of complications [15]. In addition, CM-IRIS and anaemia were both associated with increased mortality. The association between CM-IRIS and mortality aligns with evidence from high-burden settings showing increased risk of adverse outcomes following immune reconstitution in patients with cryptococcal infection [14,17]. Anaemia likely reflects advanced disease, comorbidity, and reduced physiological reserve among PLHIV with cryptococcal meningitis [13,18].

These findings suggest that reducing cryptococcal meningitis-related mortality in similar settings will require integrated strategies that prioritise early detection of advanced HIV disease, timely identification and management of intracranial pressure, and strengthened inpatient care for patients with complex comorbidities.

Study strengths and limitations

This study analysed a large, real-world dataset spanning six years from a national referral hospital in Uganda, providing sufficient temporal coverage and statistical power to estimate inpatient mortality and associated clinical factors among PLHIV with cryptococcal meningitis. The use of routinely collected inpatient data enhances external validity by reflecting actual care practices in a high-burden, resource-limited setting. Inclusion of a broad range of clinical, laboratory, and comorbidity variables enabled a comprehensive assessment of factors associated with mortality, while the high retrieval of medical records and application of multivariable regression strengthened the internal validity of the findings.

However, several limitations should be considered. The retrospective design relied on routine medical records, which limited availability of key management variables, including antifungal treatment regimens, intracranial pressure measurements, and adjunctive therapies; however, standardized data abstraction procedures were applied and analyses were restricted to consistently documented variables. Diagnostic approaches varied between cryptococcal antigen testing and India ink microscopy, which may have introduced misclassification due to differences in sensitivity; analyses were therefore restricted to documented laboratory-confirmed diagnoses. The study was limited to inpatient data, and post-discharge outcomes, including 90-day mortality, could not be assessed; findings were therefore interpreted specifically within the context of in-hospital mortality. The study period overlapped with the COVID-19 pandemic, but available data did not allow assessment of its impact on healthcare access, admission patterns, or inpatient outcomes. Residual confounding may remain due to unmeasured clinical and health-system factors, including variability in treatment practices and timing of care; however, multivariable regression was used to adjust for measured confounders.

Conclusion

Cryptococcal meningitis accounted for a substantial proportion of HIV-related inpatient admissions and was associated with high in-hospital mortality among adult PLHIV in this setting. Mortality was linked to clinical severity, including neurological manifestations, CM-IRIS, anaemia, low CD4 cell count, and concurrent opportunistic infections. These findings highlight the continued burden of advanced HIV disease and its complications in routine inpatient care. Strengthening early diagnosis, improving clinical monitoring, and optimising inpatient management may contribute to improved outcomes. Further research is needed to evaluate treatment-related and health-system factors influencing survival among PLHIV with cryptococcal meningitis in resource-limited settings.

Supporting information

S1 File. Missingness by variable.

(DOCX)

pone.0340951.s001.docx (14.4KB, docx)
S2 File. De-identified dataset analysed for this manuscript.

(XLSX)

pone.0340951.s002.xlsx (217.2KB, xlsx)

Data Availability

The dataset analyzed for this study is provided as supporting information (S1 File).

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Mohamed Hamed Shehata

4 Mar 2026

-->PONE-D-25-68621-->-->Inpatient mortality and associated clinical factors among people living with HIV with cryptococcal meningitis in Uganda: a retrospective cohort study-->-->PLOS One

Dear Dr. Kitimbo,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.-->

Kind regards,

Mohamed Fawzy Mohamed Hamed Shehata

Academic Editor

PLOS One

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->5. Review Comments to the Author

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Reviewer #1: The manuscript addresses an important public health issue and provides valuable data from a large retrospective cohort. The findings are relevant and generally well presented. However, clarification is needed regarding methodological details, particularly sampling justification, handling of missing data, and interpretation of associations such as length of hospital stay. Strengthening the limitations section and refining causal language would significantly improve the manuscript’s clarity and scientific rigor.

Reviewer #2: This is an automated report for PONE-D-25-68621. This report was solicited by the PLOS One editorial team and provided by ScreenIT.

ScreenIT is an independent group of scientists developing automated tools that analyze academic papers. A set of automated tools screened your submitted manuscript and provided the report below. Each tool was created by your academic colleagues with the goal of helping authors. The tools look for factors that are important for transparency, rigor and reproducibility, and we hope that the report might help you to improve reporting in your manuscript. Within the report you will find links to more information about the items that the tools check. These links include helpful papers, websites, or videos that explain why the item is important. While our screening tools aim to improve and maintain quality standards they may, on occasion, miss nuances specific to your study type or flag something incorrectly. Each tool has limitations that are described on the ScreenIT website. The tools screen the main file for the paper; they are not able to screen supplements stored in separate files. Please note that the Academic Editor had access to these comments while making a decision on your manuscript. The Academic Editor may ask that issues flagged in this report be addressed. If you would like to provide feedback on the ScreenIT tool, please email the team at ScreenIt@bih-charite.de. If you have questions or concerns about the review process, please contact the PLOS One office at plosone@plos.org.

Reviewer #3: Major concerns:

1. While multiple imputation is mentioned (lines 138-143), the authors should: add a table or supplementary material showing missingness patterns by variable, specify the number of imputations, and include pooled estimates. Lines 138-143 need expansion with methodological detail.

2. The manuscript provides no information about the actual CM treatment received: which antifungal regimens were used (amphotericin B-based? fluconazole monotherapy?) - Add treatment variables/data to Table 1. It would be interesting if the authors analyze the association between treatment type and mortality. Discuss treatment barriers and their contribution to mortality.

3. State whether multicollinearity was detected and how it was handled.

4. CD4 >200 cells/μL is the reference category, but only 6.9% (44/634) fall into this group. This creates a very small reference group with wide confidence intervals, therefore, CD4 <50 vs. 50-200 comparison might be more clinically meaningful. The authors may consider alternative categorization (e.g., CD4 <50 as reference).

5. For symptom duration (Lines 190-191, 213-214, 222-223), the protective effect of a 1–2 week symptom duration is inadequately explained.

6. CM-IRIS diagnosis requires specific criteria, but no definition is provided. Describe how CM-IRIS was diagnosed retrospectively from records

7. What proportion had tuberculosis specifically (line 200), and what other opportunistic infections were present?

8. Line 33-34: "CD4 <200 cells/μL", the authors should specify "CD4 <50" and "CD4 50-200" as both categories showed elevated risk vs. >200.

9. In abstract: please condense methods slightly and add key treatment/management findings.

10. Limited Context (Lines 242-244): "Higher than pooled estimates" - which estimates? Provide specific comparison.

11. What was the impact of the COVID-19 pandemic (overlaps with the study period)?

12. Expand the limitations section to include these points: treatment data, diagnostic heterogeneity (CrAg vs. India ink sensitivity), and no data on outpatient outcomes or 90-day mortality.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

**********

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Attachment

Submitted filename: report_10.64898+2026.01.01.26343321.pdf

pone.0340951.s003.pdf (596.7KB, pdf)

Decision Letter 1

Mohamed Hamed Shehata, Mohamed Hamed Shehata

2 Jun 2026

Inpatient mortality and associated clinical factors among people living with HIV with cryptococcal meningitis in Uganda: a retrospective cohort study

PONE-D-25-68621R1

Dear Dr. Kitimbo,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Mohamed Fawzy Mohamed Hamed Shehata

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Mohamed Hamed Shehata, Mohamed Hamed Shehata

PONE-D-25-68621R1

PLOS One

Dear Dr. Kitimbo,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS One. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

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Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Mohamed Fawzy Mohamed Hamed Shehata

Academic Editor

PLOS One

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Missingness by variable.

    (DOCX)

    pone.0340951.s001.docx (14.4KB, docx)
    S2 File. De-identified dataset analysed for this manuscript.

    (XLSX)

    pone.0340951.s002.xlsx (217.2KB, xlsx)
    Attachment

    Submitted filename: report_10.64898+2026.01.01.26343321.pdf

    pone.0340951.s003.pdf (596.7KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0340951.s004.docx (28.8KB, docx)

    Data Availability Statement

    The dataset analyzed for this study is provided as supporting information (S1 File).


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