Abstract
Background
Corticosteroids are recommended for the treatment of septic shock but are understudied in Africa. We aimed to determine (1) characteristics of patients with sepsis in Uganda who received corticosteroids, and (2) the association between receiving corticosteroids and outcomes.
Methods
We conducted a single centre retrospective observational cohort study of patients with sepsis at the Mbarara Regional Referral Hospital in Uganda. We included patients admitted from the emergency ward with suspected infection and ≥2 quick sequential organ failure assessment criteria. We determined predictors of receiving corticosteroids with logistic regression and predictors of 28-day mortality using Cox proportional hazards regression. We adjusted models for severity of illness using the Universal Vital Assessment (UVA) mortality risk score.
Results
Of the 300 patients analysed, 141 (47%) were female, and the median (IQR) age was 55 (43–66) years. Corticosteroids were received by 71 (23%) patients at a median (IQR) of 1 (0–2) day from admission. The UVA score (adjusted OR (aOR) 1.16, 95% CI 1.03 to 1.30) and meningitis (aOR 4.31, 95% CI 2.04 to 9.12) were predictors of receiving corticosteroids. The UVA score (adjusted HR (aHR) 1.14, 95% CI 1.02 to 1.26) and receiving corticosteroids (aHR 0.43, 95% CI 0.21 to 0.91) were predictors of increased and decreased 28-day mortality, respectively. Receiving corticosteroids remained an independent predictor of decreased 28-day mortality when entered into the model as a time dependent variable (aHR 0.33, 95% CI 0.13 to 0.83, p=0.02). In a sensitivity analysis adjusted for age, sex and severity of illness, receiving vasopressors (aHR 3.48, 95% CI 1.88 to 6.43, p<0.001) and receiving corticosteroids (aHR 0.40, 95% CI 0.19 to 0.85, p=0.02) were independent predictors of increased and decreased 28-day mortality, respectively.
Conclusions
In patients with sepsis in Uganda, receiving corticosteroids was associated with severity of illness and meningitis, and receiving corticosteroids was associated with improved outcomes.
INTRODUCTION
Sepsis is a syndrome of critical illness defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Sepsis is responsible for 1 in 5 global deaths and is the leading cause of global mortality.1 2 Africa carries the greatest sepsis burden with approximately 17 million incident sepsis cases and 3.5 million sepsis-related deaths each year.1 Yet, there are only two published randomised trials of sepsis therapy conducted in adults living in Africa.3 4 Both were conducted by the same group who investigated intravenous fluid resuscitation at a single site in Zambia. In contrast to recommendations based on data from high-income settings, case fatality rates were increased by early goal-directed fluid resuscitation; thus, a major knowledge gap in the management of sepsis in Africa exists.5
International guidelines recommend use of corticosteroids for the management of septic shock and acute respiratory distress syndrome (ARDS).5 6 The data considered for these recommendations did not include studies from Africa and comparatively few studies included persons with HIV or tuberculosis (TB), who comprise the majority of patients with sepsis in Africa.7 8 In several studies of sepsis subphenotypes in Africa, HIV and Mycobacterium tuberculosis coinfection was associated with a subphenotype of increased inflammation and mortality.9–11 The hyperinflammatory response to sepsis may be associated with critical illness-related corticosteroid insufficiency (CIRCI), but this phenomenon is not well described in Africa.12
Furthermore, in TB-endemic regions in Africa such as Uganda, the prevalence of adrenal insufficiency due to TB can be as high as 60%.13 14 Adrenal insufficiency is frequently observed in both pulmonary and extrapulmonary TB, as well as among those with HIV.15 Cytomegalovirus (CMV) antigenemia, a marker of critical illness, is also associated with sepsis and adrenal insufficiency in Africa.7 15 Given the synergistic risks of hyperinflammation and CIRCI, TB, HIV and CMV, corticosteroids may have significant benefit in patients with sepsis in Africa. Despite their potential benefit, there are limited published clinical data from Africa on the use of corticosteroids in sepsis. Given this knowledge gap, our objectives were to (1) identify the characteristics of emergency ward patients with sepsis in Mbarara, Uganda, who received corticosteroids, and (2) determine the association between receiving corticosteroids and outcomes from sepsis.
METHODS
Study design and setting
This was a single centre retrospective observational cohort study of patients with sepsis at the Mbarara Regional Referral Hospital (MRRH) located in southwestern Uganda. MRRH serves as the teaching hospital for the Mbarara University of Science and Technology Faculty of Medicine and is currently a 600-bed hospital after undergoing renovations as part of its transition from a regional to a national referral hospital including an expansion of the intensive care unit (ICU). The catchment area includes approximately 1 million people, including patients referred from throughout southwestern Uganda, neighbouring Democratic Republic of the Congo and Rwanda, and the lake region of Tanzania.
Selection of participants
The study included patients admitted from the emergency ward to the general medical ward with suspected infection who met ≥2 quick sequential organ failure assessment criteria, including respiration rate of ≥22 breaths per minute, systolic blood pres sure ≤100 mm Hg or altered mental status defined as a Glasgow Coma Scale (GCS) score <15 or documentation of altered mental status. As most patients with sepsis in our setting are managed outside the ICU, which is generally reserved for post-surgical patients, we excluded patients admitted to the ICU, as well as those with gastrointestinal bleeding or COVID-19. For patients meeting our inclusion criteria, we extracted clinical, physiological and laboratory data from paper medical records and stored them in a cloud-based Research Electronic Data Capture database.
Outcomes
The primary outcome of interest was 28-day mortality.
Sample size calculation
Our sample size calculation was based on an assumption that the overall mortality proportion was 30%.7 With an estimated 100 patients in the steroid group and 200 patients in the non-steroid group, the χ2 test had 80% power with a significance level of 5% when the true OR between receiving corticosteroids and mortality was 0.45. This corresponded to a mortality proportion of 20% in the corticosteroid therapy group and 35% in the non-corticosteroid therapy group.
Analysis
We summarised categorical variables as numbers and percentages and compared them using the χ2 test. We reported continuous variables as medians with IQRs. We determined predictors of receiving corticosteroids with binary logistic regression and predictors of 28-day mortality using Cox proportional hazards regression. We determined predictors of receiving corticosteroids with binary logistic regression and predictors of 28-day mortality using Cox proportional hazards regression. The multivariable models included age, sex and severity of illness using the Universal Vital Assessment (UVA) mortality risk score, which was derived from and then validated in studies from Africa.16 17 In the logistic regression model, we also included meningitis, a known indication for administering corticosteroids.18 In the Cox model, we also included receipt of corticosteroids. As a sensitivity analysis, we adjusted for severity of illness with the inclusion of mean arterial pressure and receipt of vasopressors instead of the UVA score in the Cox model.
In addition to the adjustments for potential confounders above, we also constructed three different propensity score models adjusted for: (1) age, sex and UVA score; (2) age, sex, mean arterial pressure and receipt of a vasopressor; and (3) age, sex, UVA score and meningitis. Within each model, we applied the following methods: (1) 1:2 treated (received corticosteroids): control (did not receive corticosteroids) propensity score matching; (2) propensity score stratification with five strata; and (3) inverse probability of treatment weighting.
As a further sensitivity analysis, to account for possible immortal time bias in patients who received corticosteroids, we also incorporated time-dependent covariates in the Cox model. Finally, in an exploratory analysis, we adjusted models for severe respiratory disease defined by the WHO as oxygen saturation <90% or a respiratory rate >30 breaths per minute, and a systolic blood pressure >90 mm Hg in the setting of infection and in the absence of clinical cardiac failure.19 We used SPSS (IBM SPSS Statistics; V.29.0.2.0; Armonk, New York, USA) for all analyses. We only report p values for comparisons of corticosteroid use and mortality, which address our primary hypothesis. We defined statistical significance as p<0.05.
RESULTS
Characteristics of study subjects
We included 300 patients who were admitted at MRRH from January 2019 to December 2023 in the analysis. Of the 300, 141 (47%) were female and the median (IQR) age was 55 (43–66) years (table 1). The median (IQR) UVA score for the cohort was 7 (5–9). Among the 262 patients with known HIV serostatus, 88 (34%) were living with HIV with a median (IQR) CD4+ T cell concentration of 177 (84–558) cells/μL. The most common infections were pneumonia (36%), gastrointestinal infections (29%) and meningitis (12%).
Table 1.
Characteristics according to receipt of corticosteroids of patients with sepsis at Mbarara Regional Referral Hospital, Uganda (2019–2023)
| Missing, N (%) | Total | Received corticosteroids | Did not receive corticosteroids | ||
|---|---|---|---|---|---|
| Received corticosteroids | Did not receive corticosteroids | ||||
| Age (years) | 0 (0) | 2 (<1) | 55 (43–66) | 51 (43–63) | 57 (43–67) |
| Female | 0 (0) | 1 (<1) | 141/299 (47) | 33/71 (23) | 108/228 (48) |
| Temperature (°C) | 0 (0) | 4 (2) | 37.5 (36.5–38.0) | 37.1 (36–37.1) | 37.6 (36.7–38.1) |
| Heart rate (bpm) | 0 (0) | 0 (0) | 127 (121–133) | 127 (120–134) | 127 (122–133) |
| Respiratory rate (brpm) | 0 (0) | 0 (0) | 33 (28–37) | 34 (28–38) | 32 (28–36) |
| Systolic blood pressure (mm Hg) | 0 (0) | 0 (0) | 90 (86–94) | 89 (82–94) | 90 (87–95) |
| Diastolic blood pressure (mm Hg) | 0 (0) | 0 (0) | 58 (52–62) | 55 (50–62) | 58 (53–62) |
| Mean arterial pressure (mm Hg) | 0 (0) | 0 (0) | 68 (63–72) | 66 (61–73) | 69 (64–72) |
| Oxygen saturation (%) | 1 (1) | 0 (0) | 94 (90–97) | 92 (90–95) | 95 (90–97) |
| Glasgow Coma Scale score (n) | 0 (0) | 5 (2) | 14 (13–14) | 13.5 (13–10) | 14 (13–14) |
| WBC (109/L) | 26 (37) | 94 (41) | 11 (9–13) | 10.2 (8.6–11.4) | 11.6 (9.5–13.6) |
| Haemoglobin (g/L) | 24 (34) | 93 (41) | 120 (110–130) | 124 (101–131) | 123 (108–128) |
| Platelets (109/L) | 24 (34) | 98 (43) | 171 (127–234) | 171 (123–250) | 171 (128–230) |
| Living with HIV | 11 (15) | 27 (12) | 88/262 (34) | 29/60 (48) | 59/202 (29) |
| CD4+ T cell concentration (/μL) | 9/29 (31) | 31/59 (52) | 177 (84–558) | 130 (80–520) | 247 (84–607) |
| UVA score (n) | 0 (0) | 0 (0) | 7 (5–9) | 8 (6–10) | 7 (5–8) |
| UVA <2, low risk | — | — | 12/300 (4) | 1/71 (1) | 11/229 (5) |
| UVA 2–4, medium-risk | — | — | 48/300 (16) | 6/71 (9) | 42/229 (18) |
| UVA >4, high-risk | — | — | 240/300 (80) | 64/71 (90) | 176/229 (77) |
| Infection type | 0 (0) | 0 (0) | — | — | — |
| Pulmonary | — | — | 109/300 (36) | 30/71 (42) | 78/229 (34) |
| Gastrointestinal | — | — | 88/300 (29) | 14/71 (20) | 74/229 (33) |
| Genitourinary | — | — | 39/300 (13) | 5/71 (7) | 34/229 (15) |
| Central nervous system | — | — | 37/300 (12) | 20/71 (28) | 17/229 (8) |
| Tuberculosis | — | — | 34/300 (11) | 13/71 (19) | 21/229 (9) |
| Malaria | — | — | 17/300 (6) | 2/71 (3) | 15/229 (7) |
| Skin or soft tissue | — | — | 17/300 (6) | 0/71 (0) | 17/229 (8) |
| Received antibiotics | 0 (0) | 0 (0) | 298/300 (99) | 71/71 (100) | 227/229 (99) |
| Received IV fluids | 0 (0) | 5 (2) | 299/299 (100) | 71/71 (100) | 228/228 (100) |
| Volume IV fluids (L) | 0 (0) | 5 (2) | 2 (1.6–2) | 2 (2–2) | 2 (1.5–2) |
| Received vasopressor | 0 (0) | 4 (2) | 55/296 (19) | 15/71 (21) | 40/225 (18) |
Values are presented as N (%) or median (IQR).
CD, cluster designation; IV, intravenous; UVA, Universal Vital Assessment; WBC, white blood cell concentration.
Main results
There were 71 (23%) patients who received corticosteroids at a median (IQR) of 1 (0–2) day from admission. Prednisolone, the most frequently prescribed corticosteroid, was administered to 28 (41%) patients (online supplemental table 1). The most frequently documented indication for receiving corticosteroids was meningitis. Among the 71 corticosteroid recipients, 20 (28%) had meningitis compared with 17 (7%) of 229 who did not receive corticosteroids (OR 4.89, 95% CI 2.39 to 10.00). Shock and adrenal insufficiency were documented indications for 6 (8%) and 2 (3%) patients, respectively.
Corticosteroid recipients had a median (IQR) oxygen saturation of 92% (90–95%) compared with 95% (90–97%) for those who did not receive corticosteroids. Other baseline characteristics, including temperature, heart rate, respiratory rate and blood pressure, were similar between groups. Patients who received corticosteroids had a median (IQR) UVA score of 8 (6–10) compared with 7 (5–8) for those who did not receive corticosteroids. Use of vasopressors and intravenous fluid resuscitation volumes was also similar between those who did and did not receive corticosteroids. Adverse events from corticosteroids, including hyperglycaemia, altered mental status or gastrointestinal bleeding, were rarely documented in patient charts. In the univariate logistic regression analysis, predictors of receiving corticosteroids included higher UVA scores (figure 1), living with HIV and a diagnosis of TB or meningitis (table 2). In the multivariable logistic regression model, after adjusting for age and sex, higher UVA scores (adjusted OR (aOR) 1.16, 95% CI 1.03 to 1.30) and meningitis (aOR 4.31, 95% CI 2.04 to 9.12) remained independent predictors of receiving corticosteroids (table 2).
Figure 1.
The proportion of patients who received corticosteroids according to (A) Universal Vital Assessment mortality risk score; and (B)Universal Vital Assessment mortality risk category among patients admitted with sepsis at the Mbarara Regional Referral Hospital (2019–2023). UVA, Universal Vital Assessment.
Table 2.
Univariate and multivariable logistic regression predictors of receiving corticosteroids among patients with sepsis at Mbarara Regional Referral Hospital, Uganda (2019–2023)
| OR | 95% CI | Adjusted OR | 95% CI | |
|---|---|---|---|---|
| Age (years) | 0.99 | 0.97 to 1.00 | 0.99 | 0.98 to 1.01 |
| Female | 0.97 | 0.57 to 1.65 | 1.12 | 0.63 to 1.99 |
| UVA score (n) | 1.21 | 1.09 to 1.35 | 1.16 | 1.03 to 1.30 |
| UVA >4, high-risk | 2.75 | 1.19 to 6.37 | --- | --- |
| Temperature (°C) | 0.71 | 0.55 to 0.92 | --- | --- |
| Heart rate (bpm) | 0.99 | 0.97 to 1.01 | --- | --- |
| Respiratory rate (brpm) | 1.03 | 0.98 to 1.08 | --- | --- |
| Systolic blood pressure (mm Hg) | 0.97 | 0.94 to 1.00 | --- | --- |
| Diastolic blood pressure (mm Hg) | 0.98 | 0.95 to 1.01 | --- | --- |
| Mean arterial pressure (mm Hg) | 0.97 | 0.94 to 1.01 | --- | --- |
| Oxygen saturation (%) | 0.93 | 0.88 to 0.99 | --- | --- |
| Glasgow Coma Scale score (n) | 0.81 | 0.67 to 0.99 | --- | --- |
| Received vasopressor | 1.24 | 0.64 to 2.41 | 0.99 | 0.49 to 2.04 |
| Meningitis | 4.89 | 2.39 to 9.99 | 4.31 | 2.03 to 9.12 |
| Tuberculosis | 2.26 | 1.07 to 4.79 | 1.76 | 0.76 to 4.09 |
| Pneumonia | 1.38 | 0.80 to 2.39 | --- | --- |
| Malaria | 0.41 | 0.09 to 1.85 | --- | --- |
| Living with HIV | 2.27 | 1.26 to 4.09 | --- | --- |
UVA, Universal Vital Assessment.
Death occurred in 49 (16%) of 300 patients (figure 2). In the univariate Cox regression analysis, UVA score, blood pressure, oxygen saturation, GCS score, living with HIV, receiving vasopressors and volume of intravenous fluids received were all associated with 28-day mortality (table 3). In the multivariable Cox regression model, after adjusting for age and sex, UVA score (adjusted HR (aHR) 1.14, 95% CI 1.02 to 1.26, p=0.02) and receiving corticosteroids (aHR 0.43, 95% CI 0.21 to 0.91, p=0.03) were independent predictors of increased and decreased 28-day mortality, respectively (table 4).
Figure 2.
Kaplan-Meier 28-day survival curves according to receipt of corticosteroids among (A) all patients; and (B) patients with HIV admitted with sepsis at the Mbarara Regional Referral Hospital (2019–2023).
Table 3.
Univariate Cox regression predictors of 28-day mortality among patients with sepsis at Mbarara Regional Referral Hospital, Uganda (2019–2023)
| HR | 95% CI | |
|---|---|---|
| Age (years) | 0.99 | 0.97 to 1.00 |
| Female | 1.75 | 0.99 to 3.08 |
| UVA score (n) | 1.13 | 1.01 to 1.26 |
| UVA >4, high-risk | 3.01 | 0.93 to 9.69 |
| Temperature | 0.77 | 0.59 to 1.01 |
| Heart rate (bpm) | 1.00 | 0.97 to 1.02 |
| Respiratory rate (brpm) | 1.00 | 0.96 to 1.06 |
| Systolic blood pressure (mm Hg) | 0.96 | 0.93 to 0.99 |
| Diastolic blood pressure (mm Hg) | 0.96 | 0.92 to 0.99 |
| Mean arterial pressure (mm Hg) | 0.95 | 0.92 to 0.99 |
| Oxygen saturation (%) | 0.94 | 0.91 to 0.97 |
| Glasgow Coma Scale score (n) | 0.75 | 0.64 to 0.89 |
| Living with HIV | 2.00 | 1.10 to 3.65 |
| Meningitis | 1.26 | 0.61 to 2.60 |
| Tuberculosis | 1.01 | 0.47 to 2.19 |
| Pneumonia | 1.34 | 0.76 to 2.38 |
| Received vasopressor | 3.98 | 2.27 to 7.00 |
| Volume intravenous fluids (L) | 0.17 | 0.08 to 0.39 |
| Received corticosteroids | 0.55 | 0.27 to 1.14 |
UVA, Universal Vital Assessment.
Table 4.
Multivariable Cox regression predictors of 28-day mortality among patients with sepsis at Mbarara Regional Referral Hospital, Uganda (2019–2023)
| Adjusted HR | 95% CI | P value | |
|---|---|---|---|
| Age (years) | 0.99 | 0.97 to 1.00 | 0.13 |
| Female | 1.78 | 1.01 to 3.14 | 0.05 |
| UVA score (n) | 1.14 | 1.02 to 1.26 | 0.02 |
| Received corticosteroids | 0.43 | 0.21 to 0.91 | 0.03 |
UVA, Universal Vital Assessment.
In a sensitivity analysis, after adjusting for age, sex and severity of illness, receiving vasopressors (aHR 3.48, 95% CI 1.88 to 6.43) was an independent predictor of increased 28-day mortality; and receiving corticosteroids (aHR 0.40, 95% CI 0.19 to 0.85, p=0.02) was an independent predictor of decreased 28-day mortality (online supplemental table 2). In an exploratory analysis in which we adjusted for age, sex and UVA score, WHO-defined severe respiratory disease (aHR 0.30, 95% CI 0.09 to 0.98) and receiving corticosteroids (aHR 0.44, 95% CI 0.21 to 0.91, p=0.03) were associated with decreased 28-day mortality. After adjusting for potential confounders, receiving corticosteroids was associated with decreased 28-day mortality in the propensity score models (online supplemental table 3).
The median (IQR) time to death for those who received corticosteroids was 8 (4–12.5) days compared with 7 (3–10) days for those who did not receive corticosteroids. Of the 71 patients who received corticosteroids, 1 (1.4%) died within 48 hours of admission compared with 3 (1.3%) of 228 patients who did not receive corticosteroids (OR 1.07, 95% CI 0.11 to 10.47, p=0.95). After removing patients who died within 24 hours of admission (the median time to corticosteroid treatment) and adjusting for age, sex and UVA score, the receipt of corticosteroids remained associated with decreased 28-day mortality (aHR 0.42, 95% CI 0.19 to 0.93, p=0.03). Finally, receiving corticosteroids remained an independent predictor of decreased 28-day mortality when entered into the initial Cox regression model as a time-dependent variable (aHR 0.33, 95% CI 0.13 to 0.83, p=0.02).
DISCUSSION
In this comprehensive evaluation of corticosteroid use in patients with sepsis at a regional referral hospital in Uganda, we found that corticosteroids were used commonly, administered soon after admission, and were associated with a diagnosis of meningitis and a high severity of illness. After adjusting for the patient’s severity of illness in multiple ways, receiving corticosteroids was associated with decreased 28-day mortality. Our findings suggest that use of corticosteroids may be beneficial in severely ill patients with sepsis or septic shock with or without severe respiratory disease in resource-limited settings similar to MRRH, but this needs to be confirmed in a clinical trial.
Although corticosteroids, usually dexamethasone, are recommended for inclusion in the empirical treatment of bacterial meningitis in high-income settings, their benefit in resource-limited settings is less clear.20 In a study from Malawi of patients with bacterial meningitis, 90% of whom were living with HIV, there was no difference in mortality in patients who received dexamethasone compared with those who did not.21 However, in a randomised study of dexamethasone for the treatment of bacterial meningitis from Vietnam, dexamethasone decreased mortality in those with confirmed bacterial meningitis.22 Furthermore, dexamethasone or prednisolone is recommended by the WHO as a component of the treatment of TB meningitis, which is relatively common in TB-endemic settings such as Uganda.23
Data regarding the use of corticosteroids in patients with severe illness including sepsis in Africa are scarce. In a study of hospitalised patients with sepsis in Rwanda, only 8% of patients received corticosteroids.24 On the other hand, in an ICU study from Ethiopia, 77% of patients received steroids.25 In both studies, no information was provided about the indications for steroid administration, or its association with clinical characteristics or outcomes. Thus, our study provides novel data regarding what clinical characteristics may prompt clinicians to administer corticosteroids to patients with sepsis in an African setting. Our finding that receiving corticosteroids was associated with increased severity of illness is consistent with international guidelines that recommend corticosteroids for the treatment of septic shock and ARDS.5 6 26
Corticosteroids are recommended for patients with septic shock due to improvements in time to shock reversal, and in some studies, mortality outcomes.5 26 Septic shock is a state of acute circulatory failure defined as hypotension requiring vasopressor administration despite adequate fluid resuscitation in order to maintain a mean arterial pressure of 65 mm Hg in the setting of a blood lactate of at least 2 mmol/L.2 In resource-limited settings, it can be challenging to diagnose septic shock as liberal fluid resuscitation leads to increased mortality and lactate testing is rarely available.4 However, we found that after adjusting for severity of illness by use of the UVA score, or other measures including mean arterial pressure and receipt of vasopressors, receiving corticosteroids was associated with decreased mortality. Accordingly, resource-appropriate tools to measure the severity of illness such as the UVA score may help identify patients at the greatest risk of death who may be responsive to corticosteroid therapy.
Sepsis is a common cause of severe respiratory disease even in the absence of shock. Trials of corticosteroids for the treatment of ARDS have shown decreased ICU mortality, hospital mortality and all-cause 60-day mortality as well as improved ventilator-free days at 28 days.27 28 Despite recent changes to ARDS definitions to accommodate low-resource settings, ARDS remains difficult to diagnose in many African clinical settings due to the requirements of the administration of supplemental oxygen and ultrasound imaging availability and expertise.29 However, using data from 7385 patients hospitalised in Africa, we found that WHO-defined severe respiratory disease without shock had a prevalence of 13% and an associated case fatality rate of 22%.19 Severe respiratory disease was associated with significantly increased in-hospital mortality when added to baseline models that included age, sex, HIV and GCS score. In the current study, we found that receiving corticosteroids was associated with improved outcomes after adjusting for severe respiratory disease.
Our study had limitations. First, this was a retrospective single centre cohort study and our findings should be confirmed at other institutions in Africa. A randomised clinical trial would ideally provide data to inform the use of corticosteroids in patients with sepsis in Africa. Second, use of corticosteroids was not standardised, so we were not able to determine which corticosteroid or dose was most associated with decreased mortality. Accordingly, the grouping of corticosteroids introduced variability that weakened the interpretability of the results of our analysis. Third, we did not find any documentation of blood cortisol or other measures of adrenal insufficiency. Similarly, documentation of adverse events related to corticosteroid use was scarce. Finally, immortal time bias for patients who received corticosteroids was a potential limitation of our study; however, it was mitigated by entering data as time-dependent variables in a sensitivity analysis, which also found that receiving corticosteroids was predictive of decreased mortality. Moreover, patients received corticosteroids at a median of only 1 day from admission, and we found consistent results after removing patients with early mortality from our analyses, which together decreased the likelihood of immortal time bias. Our results suggest that clinicians may have decided to treat patients with sepsis with corticosteroids based on their severity of illness or a concern for central nervous system infection, both of which are evidence-based decisions. Despite the limitations of this study, our findings suggest that the use of corticosteroids may be beneficial to patients with sepsis in similar clinical settings to ours, including those with severe respiratory disease. These results provide equipoise and impetus for the initiation of clinical trials of corticosteroids for the treatment of sepsis in Africa.
Supplementary Material
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
Additional supplemental material is published online only. To view, please visit the journal online (https://doi.org/10.1136/emermed-2025-214957).
WHAT IS ALREADY KNOWN ON THIS TOPIC
⇒ Sepsis is a severe illness marked by organ dysfunction due to an exaggerated immune response to infection. Sepsis causes significant global mortality, with Africa bearing a disproportionate burden. Despite this disparity, there is a paucity of data regarding therapies for patients with sepsis in Africa. International guidelines recommend corticosteroids for septic shock and acute respiratory distress syndrome management, but their use in Africa, where HIV and tuberculosis predominate as underlying causes of sepsis, has not been investigated.
WHAT THIS STUDY ADDS
⇒ This study provides evidence on the use of corticosteroids in patients with sepsis at a regional referral hospital in Uganda. Predictors of receiving corticosteroids included illness severity and a diagnosis of meningitis. After adjusting for severity of illness in different ways, receiving corticosteroids was consistently associated with reduced 28-day mortality. These findings suggest a potential benefit of corticosteroids for improving outcomes from sepsis for patients in Uganda and similar settings in Africa.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
⇒ This study contributes to filling the gap in sepsis research in Africa. The findings support further research on corticosteroid use in sepsis in Africa, including clinical trials. The findings of the study may also influence clinical practice by encouraging the use of corticosteroids in sepsis management in similar settings. Furthermore, the findings serve to shape future international guidelines and policy recommendations for patients with sepsis in Africa, for whom data are currently lacking.
Acknowledgements
The authors would like to acknowledge the patients whose data contributed to this study.
Funding
This work was supported in part by the National Institute of Allergy and Infectious Diseases (U01AI150508 to CM) and the American Thoracic Society (American Thoracic Society Diversity Grant, 2021 to EN).
Footnotes
Competing interests None declared.
Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Patient consent for publication Not applicable.
Ethics approval The Research Ethics Committee of Mbarara University of Science and Technology (MUST-2021–67) and the University of Virginia Institutional Review Board (human subjects research #231639) approved the study with waivers of consent.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement
Data are available on reasonable request.
REFERENCES
- 1.Rudd KE, Johnson SC, Agesa KM, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the Global Burden of Disease Study. The Lancet 2020;395:200–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Andrews B, Muchemwa L, Kelly P, et al. Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia. Crit Care Med 2014;42:2315–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Andrews B, Semler MW, Muchemwa L, et al. Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial. JAMA 2017;318:1233–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med 2021;49:e1063–143. [DOI] [PubMed] [Google Scholar]
- 6.Qadir N, Sahetya S, Munshi L, et al. An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 2024;209:24–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Moore CC, Jacob ST, Banura P, et al. Etiology of Sepsis in Uganda Using a Quantitative Polymerase Chain Reaction-based TaqMan Array Card. Clin Infect Dis 2019;68:266–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Byashalira K, Mbelele P, Semvua H, et al. Clinical outcomes of new algorithm for diagnosis and treatment of Tuberculosis sepsis in HIV patients. Int J Mycobacteriol 2019;8:313–9. [DOI] [PubMed] [Google Scholar]
- 9.Cummings MJ, Bakamutumaho B, Jain K, et al. Development of a Novel Clinicomolecular Risk Index to Enhance Mortality Prediction and Immunological Stratification of Adults Hospitalized with Sepsis in Sub-Saharan Africa: A Pilot Study from Uganda. Am J Trop Med Hyg 2023;108:619–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Cummings MJ, Bakamutumaho B, Jain K, et al. Brief Report: Detection of Urine Lipoarabinomannan Is Associated With Proinflammatory Innate Immune Activation, Impaired Host Defense, and Organ Dysfunction in Adults With Severe HIV-Associated Tuberculosis in Uganda. J Acquir Immune Defic Syndr 2023;93:79–85. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Cummings MJ, Bakamutumaho B, Tomoiaga AS, et al. A Transcriptomic Classifier Model Identifies High-Risk Endotypes in a Prospective Study of Sepsis in Uganda. Crit Care Med 2024;52:475–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Annane D, Pastores SM, Arlt W, et al. Critical illness-related corticosteroid insufficiency (CIRCI): a narrative review from a Multispecialty Task Force of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM). Intensive Care Med 2017;43:1781–92. [DOI] [PubMed] [Google Scholar]
- 13.Naggirinya AB, Mujugira A, Meya DB, et al. Functional adrenal insufficiency among tuberculosis-human immunodeficiency virus co-infected patients: a cross-sectional study in Uganda. BMC Res Notes 2020;13:224. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Azeez TA, Irojah OA, Lakoh S, et al. A systematic review of adrenal insufficiency among patients with pulmonary tuberculosis in Sub-Sahar an Africa. Int J Mycobacteriol 2021;10:1–7. [DOI] [PubMed] [Google Scholar]
- 15.Kibirige D, Owarwo N, Kyazze AP, et al. Prevalence, Clinical Features, and Predictors of Adrenal Insufficiency in Adults With Tuberculosis or HIV: A Systematic Review and Meta-analysis. Open Forum Infect Dis 2024;11:ofae098. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Moore CC, Hazard R, Saulters KJ, et al. Derivation and validation of a universal vital assessment (UVA) score: a tool for predicting mortality in adult hospitalised patients in sub-Saharan Africa. BMJ Glob Health 2017;2:e000344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Lal S, Luangraj M, Keddie SH, et al. Predicting mortality in febrile adults: comparative performance of the MEWS, qSOFA, and UVA scores using prospectively collected data among patients in four health-care sites in sub-Saharan Africa and South-Eastern Asia. EClinicalMedicine 2024;77:102856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.de Gans J, van de Beek D, European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549–56. [DOI] [PubMed] [Google Scholar]
- 19.Chang BH, Adakun SA, Auma MA, et al. Outcomes of World Health Organization-defined Severe Respiratory Distress without Shock in Adults in Sub-Saharan Africa. Am J Respir Crit Care Med 2024;209:109–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Brouwer MC, McIntyre P, de Gans J, et al. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2010;CD004405. [DOI] [PubMed] [Google Scholar]
- 21.Scarborough M, Gordon SB, Whitty CJM, et al. Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa. N Engl J Med 2007;357:2441–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Nguyen THM, Tran THC, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007;357:2431–40. [DOI] [PubMed] [Google Scholar]
- 23.Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2016;4:CD002244. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Hopkinson DA, Mvukiyehe JP, Jayaraman SP, et al. Sepsis in two hospitals in Rwanda: A retrospective cohort study of presentation, management, outcomes, and predictors of mortality. PLoS One 2021;16:e0251321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Getu SA, Legese GL, Gashu KD, et al. Mortality due to Sepsis and Its Associated Factors Among Patients Admitted to Intensive Care Units of Southern Amhara Public Hospitals, Ethiopia. Biomed Res Int 2024;2024:4378635. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Med 2024;52:e219–33. [DOI] [PubMed] [Google Scholar]
- 27.Villar J, Ferrando C, Martínez D, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respir Med 2020;8:267–76. [DOI] [PubMed] [Google Scholar]
- 28.Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. N Engl J Med 2006;354:1671–84. [DOI] [PubMed] [Google Scholar]
- 29.Matthay MA, Arabi Y, Arroliga AC, et al. A New Global Definition of Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med 2024;209:37–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
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Data Availability Statement
Data are available on reasonable request.