-->PONE-D-26-06135-->-->Prevalence of sepsis and outcome of adult patients admitted in Intensive care unit patients in a tertiary teaching hospital in Tanzania: A Prospective Cross-Sectional Study-->-->PLOS One

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Reviewer #1: Peer Review

Manuscript: PONE-D-26-06135

Prevalence of Sepsis and Outcome of Adult Patients Admitted to the Intensive Care Unit at a Tertiary Teaching Hospital in Tanzania: A Prospective Cohort Study

1. Summary

This manuscript reports a prospective observational study conducted in adult medical and surgical ICUs at Muhimbili National Hospital, Tanzania (May–November 2023). Among 248 ICU admissions, 103 patients met the authors' sepsis criteria, yielding a reported prevalence of 41.5% and an ICU mortality rate of 55.3%. The study further examines predictors of mortality, identifying higher SOFA scores, multiple comorbidities, and delayed antibiotic administration as key contributing factors.

The research topic is clinically significant given the substantial burden of sepsis in low- and middle-income countries (LMICs) and sub-Saharan Africa (SSA). However, major methodological and reporting concerns—particularly the sepsis case definition, internal inconsistencies in statistical methods, and high risk of time-related and severity confounding in the antibiotic timing analysis—currently preclude reliable interpretation of the findings.

2. Major Comments

1. Sepsis case definition is not aligned with Sepsis-3 and conflates screening tools with diagnostic criteria

The manuscript invokes the Sepsis-3 framework conceptually, yet the Methods section defines sepsis as qSOFA ≥ 2 and/or SIRS ≥ 2 and/or NEWS ≥ 5. These are screening or triage tools, not diagnostic definitions; their use is likely to produce substantial misclassification and poor comparability with the broader literature.

Required revision: Clearly distinguish between “suspected/possible sepsis” and “Sepsis-3–defined sepsis.” Where feasible, provide a sensitivity analysis using suspected infection plus SOFA increase ≥ 2 (or SOFA ≥ 2 within 24 hours), and report how prevalence estimates and effect measures change accordingly.

2. Study design is mislabeled as “cross-sectional” despite time-to-outcome follow-up

Patients were followed through ICU discharge or death, and the analysis examines longitudinal predictors of outcome—features consistent with a prospective cohort design rather than a true cross-sectional study.

Required revision: Revise the study design designation throughout the manuscript (title, Methods, and Abstract) and ensure that STROBE reporting elements align with cohort study standards.

3. Statistical methods are internally inconsistent and may be incorrectly implemented or interpreted

The Abstract and Results sections report modified Poisson regression with prevalence ratios (cPR and aPR), whereas the Methods section describes logistic regression. Furthermore, the multivariable results for SOFA score categories appear inconsistent with the observed crude mortality patterns—for example, a reported 100% mortality in the SOFA > 14 group is difficult to reconcile with adjusted PRs at or below 1.0 for certain categories.

Required revision: Align the statistical methods described in the Methods with those actually used in the Analysis. Provide a clear and internally consistent presentation of regression results, and verify that the direction and magnitude of adjusted estimates are analytically coherent.

3. Minor Comments

1. Provide a participant flow diagram illustrating the progression from total ICU admissions through exclusions and readmissions, to sepsis identified on admission versus ICU-acquired, and through to final outcomes.

2. Report missing data explicitly for key variables, including SOFA component scores, laboratory values, infection site determination, and antibiotic administration timing.

3. Clarify whether the “ICU-acquired infection” subgroup (onset ≥ 48 hours after admission) differs from early-onset cases with respect to causative pathogens and clinical outcomes. At minimum, present stratified descriptive results for this subgroup.

4. Recommendation

Decision: Major Revision

This manuscript addresses an important public health question with valuable ICU-level data from Tanzania. Nonetheless, the current version contains fundamental definitional and analytic problems—particularly regarding the sepsis case definition, potential antibiotic timing bias, and internal statistical inconsistencies—that must be resolved before the results can be interpreted with confidence. The authors are encouraged to address all major comments thoroughly and to revisit the study design classification, which appears inconsistent with the longitudinal nature of the data.

Reviewer #2: This manuscript addresses an important topic: the epidemiology and outcomes of sepsis in a tertiary ICU in a LMIC country. The study provides useful descriptive information on the burden of sepsis and mortality in this setting. However, several methodological and reporting issues limit the technical validity of the conclusions and require substantial revision.

1) the definition of sepsis is unclear and does not appear to follow the Sepsis-3 criteria. The manuscript states that sepsis was identified using qSOFA ≥2, SIRS ≥2, or NEWS ≥5. These scores are screening tools and should not be used as diagnostic criteria. The authors should clarify how sepsis was defined and consider aligning the case definition with Sepsis-3 (infection plus SOFA ≥2).

2) the analysis regarding “antibiotics within 1 hour” lacks a clearly defined time reference point (e.g., time of sepsis recognition, ED arrival, or ICU admission). Without a defined time zero, this variable is vulnerable to temporal bias and confounding by illness severity.

3) there is inconsistency in the statistical methods. The methods section describes logistic regression, while the results present modified Poisson regression estimates. The modeling strategy and rationale for the chosen regression approach should be clarified.

4) the multivariable model may be over-specified given the relatively small sample size and number of events. The authors should explain the variable selection process and consider simplifying the model.

Finally, the manuscript would benefit from language editing and improved table formatting. The data availability statement should also be clarified to ensure compliance with journal requirements.

Addressing these methodological and reporting issues would substantially improve the clarity and reliability of the findings.

Reviewer #3: Thank you for the opportunity to review “Prevalence of sepsis and outcome of adult patients admitted in an intensive care unit patients in a tertiary teaching hospital in Tanzania: A prospective cross-sectional Study”, which, as the title states, is a cross-sectional study of patients with sepsis at a single tertiary center in the nation of Tanzania. While the results of single-center cross sectional studies such as these are not usually practice-changing, they provide a profile of disease prevalence and characteristics in a particular geographic region which is relevant to the medical literature, particularly in lower and middle-income countries (LMICs) where resource availability may be different than that in the resource rich countries which produce most of the medical literature.

In terms of novelty, I do not find other papers addressing sepsis incidence and outcomes among adult ICU patients in the nation of Tanzania, though I did note this similar paper which examined sepsis outcomes among adult emergency department patients with sepsis in Tanzania (Bonnewell et al, Open Forum Infect Dis, 2024, PMID: 39877396).

Publication is possible, but significant changes to the analysis and conclusions would be needed.

Major concerns:

1. The criteria the authors have used to identify sepsis (qSOFA 2 or more, SIRS 2 or more, or NEWS 5 or more) are not entirely robust. Since the sepsis-3 criteria were published (Singer JAMA 2016), the use of qSOFA as a screening tool has fallen out of favor and is no longer recommended in the 2021 surviving sepsis guidelines. SIRS and NEWS may be used as screening tools, but an established diagnosis of sepsis is made by a SOFA score increase of 2 or more from baseline in concert with a known or suspected infection. The authors state that they calculated SOFA scores within 24 hours of ICU admission for all patients; using this as the basis for sepsis diagnoses would be more reliable than the screening tools, and results would be more readily comparable with results from other studies.

2. One of the authors’ main conclusions is that their observed ICU sepsis mortality rate of 55% is much higher than that observed in resource-rich countries. While resource availability is undoubtedly linked to survival rates, the degree of discrepancy should be further explored. I recommend one of two approaches. First, the authors could provide literature citations of mortality rates among ICU-admitted patients with sepsis in resource rich countries (the citations the authors provide all seem to apply to LMICs). Alternatively, the authors could state the number of septic patients in their study who also qualify as having septic shock (Shankar-Hari, JAMA, 2016, PMID: 26903336). This would give a better idea of how sick the cohort is and whether the expected mortality rate would be closer to the 10% seen in sepsis alone (Singer, JAMA, 2016) or the 42% expected for septic shock (Shankar-Hari).

3. The motivation for and application of the univariate regression analysis needs to be clearer. Use of the multivariable logistic regression analysis makes sense, but what was the univariable regression meant to show that couldn’t be determined from the other single variable analyses utilized by the authors (chi-squared and fisher exact testing)? It adds clutter to the results without significantly changing the conclusions; I would recommend removing the univariable regression analysis unless there was a specific purpose for which the authors have included it (if so, this should be stated).

4. The authors conclude that younger age is associated with improved survival because of a statistically significant decrease in sepsis mortality in the 26-30 year old age bracket, and such a conclusion would align with widely accepted prior research. However, the distribution of mortality risk, when taken as a whole, actually shows a relatively flat risk of sepsis mortality relative to age, particularly when adjusted odds ratios are considered (table 4). That the adjusted odds ratio of mortality for the 18-25 age group is identical to the >50 age group is particularly striking. Rather than trying to sweep over this the authors should lean into it and further explore in their discussion what could be driving it. To me this is the most interesting finding of the paper.

Minor concerns:

Introduction:

1. In the second paragraph the authors note several statistics as percentages but it’s unclear what the percentages refer to. “…with approximately 85% of all cases and 84% of all sepsis-related deaths”: is this saying 85% of all ICU admissions are patients with sepsis and 84% of all hospital deaths are sepsis related? This needs to be more clear. Similarly “…17% of all adult hospital admissions and 31% of ICU admissions” what are the 17% and 31% referring to?

2. In the third paragraph of the introduction (“Patients with sepsis…”), the authors should state the specific population they are referring to here. Are these statements about sepsis trends worldwide? Sepsis trends specific to LMICs? Or specific to a particular geographic region? Based on the citations used it appears to be specific to LMICs or particular parts of Africa, but that should be stated in the text.

3. In the fourth paragraph of the introduction, what are “under-fives”? This needs to be defined in the text.

Methods:

1. In study duration, I recommend writing out the dates of the study longhand (e.g. May 16, 2023) to avoid international differences related to ordering day and month in shortform.

2. Per the methods section, the MICU/SICU at the study site admits about 300 patients per year, but in 6 months of sampling there were 248 patients admitted and included in the study (suggesting a typical annual volume of more like 500 patients per year). There needs to be some explanation about how these numbers are coherent with one another.

3. More description of the capabilities of the study center would be helpful. Is continuous renal replacement therapy available? What about hemodialysis more generally? VA- or VV-ECMO? For subjects with severe sepsis-induced ARDS is there a protocol for prone positioning? Inhaled prostacyclins (e.g. velitri or flolan)?

4. An INR of >1.5 was utilized to establish a diagnosis of liver dysfunction, but among septic patients and elevated INR could also be caused by disseminated intravascular coagulopathy (DIC) or simply sepsis-associated coagulopathy.

5. The authors should state why in their singe variable analysis they sometimes used chi-squared testing and sometimes used Fisher Exact testing. It appears they are appropriately using Fisher Exact testing for variables with low frequency outcomes, but this should be explicitly stated.

Results:

1. In Table 3, p-values should not be expressed as “0”, but rather as an upper boundary (e.g. “P < 0.0001”).

2. [Related to major concern 3 above]: Table 4 is not very clear. What do the acronyms cPR and aPR refer to? I think these are some type of crude and adjusted odds ratios from the regression analyses but the acronyms should be defined. Additionally, the cPR and aPR column titles should be changed to match the format in which they are reported in the table (ie. “cPR (95% CI)”). Finally, if the univariate regression is kept (see major concern 3) the authors should be very deliberate about which regression analysis they are referring to. In the paragraph starting with “In a univariate modified Poisson analysis…” it appears both cPRs and aPRs are referenced without clear distinction between univariate and multivariate analysis models.

Discussion:

1. The authors note that their LOS among non-survivors was longer than that for non-survivors elsewhere in Sub Saharan Africa (SSA) and attribute this a slow decline after an initial period of stabilization. The important question raised by this, though, is why the patients in the study center were able to achieve the initial period of stabilization whereas this was not achieved at other sites in SSA. Does this have to do with the way resources are allocated, or something else? The authors should comment on this.

Typos:

Overall the manuscript reads well but the authors should again proofread their manuscript for typos. A few that I found:

1. The word "patient" appears duplicated in the title. I recommend modification to "Prevalence of Sepsis and Outcome among Adult Intensive Care Unit Patients in a Tertiary Teaching Hospital in Tanzania: A Prospective Cross-Sectional Study"

2. In the abstract background paragraph, I believe the authors intend "...particularly in low- and middle-income countries, which face a disproportionate burden...”

3. Last sentence of the abstract results paragraph should read "were independent predictors of high mortality"

4. At the top of the page containing Table 4, I believe the authors intend “were independent predictors of high mortality, and early initiation of antibiotics…”

5. In the discussion section titled Outcomes among adult patients with sepsis in the ICU, first paragraph, I believe the authors intend: “Early initiation of antibiotics allows rapid elimination of…”

Reviewer #4: The working group of Jongo et al. presents here data from original research in a single centre tertiary teaching hospital of Muhimbili University in Tanzania, it is a prospective Analysis of sepsis and the corresponding mortality rate in ICUs of this hospital.

2. Results reported have not been published elsewhere.

The results are not published elsewhere so far as we can evaluate this.

3. Experiments, statistics, and other analyses are performed to a high technical standard and are described in sufficient detail.

The scientific data is collected of 248 patients, inclusion criteria are mentioned, different scoring systems are mentioned. Was SOFA and News Score used the same way, in different patients. What is the exact sepsis definition they used? What was the exact criteria for diagnosing Coagulopathy/disseminated intravascular coagulation (DIC) to account for organ failure, was thrombocytopenia significant for diagnosing DIC?

4. Conclusions are presented in an appropriate fashion and are supported by the data.

The conclusions are presented appropriate, the comparison to exact data of other countries is missing, and the critical view on definitions of sepsis in other countries, i.e. criteria for diagnosing sepsis in DRG related countries.

It would be more elegant and interesting for the reader to place greater emphasis on the importance of early antibiotic administration, which is crucial for survival, and on the challenges of rapid yet accurate diagnosis through the early collection of blood cultures and antibiotic administration within one hour. This fact also presents a significant challenge for Western countries; the authors' perspective on this would be interesting.

5. The article is presented in an intelligible fashion and is written in standard English.

In the part of restriction, I don’t understand “6 period time and asses to care provisions “, please explain on this.

6. The research meets all applicable standards for the ethics of experimentation and research integrity.

The research integrity and standards is adherent to reporting guideline and community standard.

All in all, the paper is well written, data should be more focused on precise sepsis definition, this is even difficult for other countries, what is the problem in Tanzania, it is lacking a critical view on documentation problems, that is normal for this diagnosis.

7. The article adheres to appropriate reporting guidelines and community standards for data availability.

The article adheres to the standard guidelines of scientific writing; I miss a critical examination of the conditions that lead to the diagnosis of sepsis or sepsis with organ complications.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: Yes: David A Wacker

Reviewer #4: No

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Submitted filename: Review for manuscript PONE-D-26-06135.docx

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Submitted filename: sepsis in tanzania review.docx

<p>Prevalence, Outcomes, and Predictors of Mortality Among Adult Intensive Care Unit Patients with Sepsis at a Tertiary Hospital in Tanzania: A Prospective Cohort Study

PONE-D-26-06135R1

Dear Dr. JONGO,

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.

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Kind regards,

Ramya Iyadurai

Academic Editor

PLOS One

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