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. 2020 Feb 21;15(2):e0228966. doi: 10.1371/journal.pone.0228966

The inability to walk unassisted at hospital admission as a valuable triage tool to predict hospital mortality in Rwandese patients with suspected infection

Arthur Kwizera 1, Olivier Urayeneza 2,3, Pierre Mujyarugamba 2, Jens Meier 4, Andrew J Patterson 5, Lori Harmon 6, Joseph C Farmer 7, Martin W Dünser 4,*; for the “Sepsis in Resource-Limited Nations” Task Force of the Surviving Sepsis Campaign
Editor: José Moreira8
PMCID: PMC7034857  PMID: 32084167

Abstract

Objective

To assess the value of the inability to walk unassisted to predict hospital mortality in patients with suspected infection in a resource-limited setting.

Methods

This is a post hoc study of a prospective trial performed in rural Rwanda. Patients hospitalized because of a suspected acute infection and who were able to walk unassisted before this disease episode were included. At hospital presentation, the walking status was graded into: 1) can walk unassisted, 2) can walk assisted only, 3) cannot walk. Receiver operating characteristic (ROC) analyses and two-by-two tables were used to determine the sensitivity, specificity, negative and positive predictive values of the inability to walk unassisted to predict in-hospital death.

Results

One-thousand-sixty-nine patients were included. Two-hundred-one (18.8%), 315 (29.5%), and 553 (51.7%) subjects could walk unassisted, walk assisted or not walk, respectively. Their hospital mortality was 0%, 3.8% and 6.3%, respectively. The inability to walk unassisted had a low specificity (20%) but was 100% sensitive (CI95%, 90–100%) to predict in-hospital death (p = 0.00007). The value of the inability to walk unassisted to predict in-hospital mortality (AUC ROC, 0.636; CI95%, 0.564–0.707) was comparable to that of the qSOFA score (AUC ROC, 0.622; CI95% 0.524–0.728). Fifteen (7.5%), 34 (10.8%) and 167 (30.2%) patients who could walk unassisted, walk assisted or not walk presented with a qSOFA score count ≥2 points, respectively (p<0.001). The inability to walk unassisted correlated with the presence of risk factors for death and danger signs, vital parameters, laboratory values, length of hospital stay, and costs of care.

Conclusions

Our results suggest that the inability to walk unassisted at hospital admission is a highly sensitive predictor of in-hospital mortality in Rwandese patients with a suspected acute infection. The walking status at hospital admission appears to be a crude indicator of disease severity.

Introduction

Infectious diseases and sepsis are leading causes of death in resource-limited nations [1,2]. Unfortunately, in a resource-limited environment differentiating between patients with significant infection who will develop life-threatening sepsis complications versus patients who will manifest serious infection only is difficult. Furthermore, lack of routine diagnostic technology hampers the identification of patients with the highest risk of developing life-threatening sepsis [1,3]. We aimed to seek an additional assessment methodology that is simple, directly applicable to this patient population, and easy to accomplish and interpret. Longer term, it is our goal to translate improved identification of patients at hospital admission with the highest risk of death from infection into increased clinical support where appropriate.

In a recent prospective, before-and-after feasibility trial, our working group showed that a focused education program and implementation of an infection treatment bundle in clinical practice increased the rate of early evidence-based interventions in patients with acute infections (mostly malaria) admitted to a Sub-Saharan African district hospital [4]. In view of the fact that all patients who were hospitalized with an acute infection were included into the study, the overall disease severity and mortality (3.8%) was low [4]. In order to reduce the death toll from infectious diseases in this setting, future research efforts should focus primarily on patients with an acute infection who are at risk of in-hospital death. While some modified illness scores have shown promise [5,6], no triage tool exists which could early and reliably differentiate between patients with a minimal risk of death and patients who are at risk of dying from their infectious process.

In this analysis, we assessed the value of the inability to walk unassisted at hospital presentation to predict in-hospital mortality in patients with suspected infection hospitalized at the Gitwe District Hospital in rural Rwanda. We hypothesized that this simple prognostic indicator of disease severity accurately portended in-hospital death.

Materials and methods

This is a post hoc analysis of an investigator-initiated, single-center, prospective, before-and-after feasibility trial, which was conducted at the adult and pediatric emergency department of the Gitwe District Hospital in Rwanda between March 2016 and March 2017 [4]. The trial protocol was pre-published (www.clinicaltrials.gov; NCT02697513), reviewed and approved by the National Health and Research Committee as well as the Rwanda National Ethics Committee (No. 007/RNEC/2016). Written informed consent was obtained from all study patients or parents/next of kin in children.

Setting

Details about the study site were previously published [4]. Briefly, the Gitwe District Hospital serves a population of approximately 160,000, has 200 beds and one emergency department with a separate adult and a pediatric admission room. No intensive care or high dependency unit is available, and supporting facilities such as the laboratory or radiology department are only modestly equipped. The hospital laboratory cannot provide chemical analyses to systematically evaluate organ functions and cannot process microbiological samples. Patients usually reach the hospital by foot, private cars, or when referred from regional healthcare centers, by the hospital’s own ambulance.

Study patients

All patients who were hospitalized because of a suspected acute infection were enrolled. Patients who were not able to walk unassisted before this disease episode (e.g. because of young age, neurological conditions, severe chronic disease or frailty) were excluded.

Data extraction

The walking status was evaluated at hospital admission by recording how the patient entered the emergency department. The patient’s ability to walk was graded into three categories: 1) can walk unassisted, 2) can walk assisted only, 3) cannot walk. This information was extracted from the trial database. In addition, the following variables were extracted: patient demographics, number of chronic diseases, HIV status, pre-existent malnutrition, presumed etiology and type of infection, danger signs (altered mental state, respiratory distress, systemic hypoperfusion), vital parameters (heart rate, respiratory rate, systolic blood pressure, capillary refill time, temperature), laboratory results (blood sugar, white cell count, hemoglobin levels whenever determined) and the quick Sequential Organ Failure Assessment (qSOFA) score count [7] at hospital admission. The length of hospital stay, total costs of care and survival status at hospital discharge were also extracted.

Risk factors for death

The qSOFA score (≥2 points) was used to identify adult patients with an increased risk of death as suggested by the Sepsis3 study group [7]. In children (<15 years), an increased risk of death was assumed if the child had a suspected or proven infection with any one of the following criteria [8]: body temperature <36°C, body temperature >38°C plus altered mental status, body temperature >38°C plus respiratory distress, body temperature >38°C plus a history of not feeding, or body temperature >38°C plus convulsions.

Study endpoints and statistical analysis

The primary endpoint of this analysis was to determine the value of the inability to walk unassisted at hospital admission as a predictor of in-hospital mortality. Secondary outcomes were the relationship between the walking status at hospital admission and the presence of risk factors for death or danger signs, vital parameters, length of hospital stay, as well as total costs of care.

The statistical analysis was performed using the PASW statistical software package (IBM SPSS Statistics 20; IBM, Vienna, Austria). Receiver operating characteristic (ROC) analyses and two-by-two tables were used to determine the sensitivity, specificity, as well as the negative and positive predictive values of the inability to walk unassisted at hospital admission to predict in-hospital death. For this analysis, we grouped patients into subjects who could walk unassisted and those who could not (thus combining the categories can walk assisted only and cannot walk). Descriptive methods were used to evaluate in-hospital mortality of patients with a qSOFA score count ≥2 points as categorized by their walking status at hospital admission. The Chi squared test and an analysis of variance were used to compare binary and linear variables between the three categories of walking status at hospital admission, as appropriate. In view of the fact that 16 comparisons were performed between the three categories, we adjusted the p-value for the number of comparisons (Bonferroni correction) and considered p<0.003 to indicate statistical significance. All data are given as median values with interquartile ranges, if not otherwise stated.

Results

One-thousand-sixty-nine patients were included into this post hoc analysis (Table 1). Two-hundred-one (18.8%), 315 (29.5%), and 553 (51.7%) study patients could walk unassisted, walk assisted or not walk at hospital presentation, respectively. The inability to walk unassisted at hospital admission had a low specificity but was 100% sensitive to predict in-hospital mortality (p = 0.00007) (Fig 1). Vice versa, the ability to walk unassisted at hospital admission had a 100% specificity but low sensitivity to predict in-hospital survival. The value of the inability to walk unassisted to predict in-hospital death (AUC ROC, 0.636; CI95%, 0.564–0.707) was comparable to that of the qSOFA score at hospital admission (AUC ROC, 0.622; CI95%, 0.524–0.721).

Table 1. Clinical and demographic features of 1,069 patients admitted to the study hospital with suspected infection.

Variable All patients
N 1,069
Age (years) 20 (7–40)
Age <15 years [n (%)] 466 (43.6)
Male gender [n (%)] 486 (45.5)
Chronic diseases (n) 0 (0–0)
HIV positive [n (%)] 33 (3.1)
Malnutrition [n (%)] 7 (0.7)
Duration of symptoms before hospital presentation (days) 2 (1–5)
Etiology of infection [n (%)]
Bacterial 205 (28.5)
Viral 86 (8)
Fungal 15 (1.4)
Malaria* 610 (57.1)
Parasitic other than malaria 61 (5.7)
Infectious focus [n (%)]
Meninges 18 (1.7)
Respiratory 131 (12.3)
Abdominal 13 (1.2)
Puerperal 11 (1)
Gastrointestinal 81 (7.6)
Urinary tract 49 (4.6)
Skin/soft tissue 21 (2)
Other 806 (75.4)
Length of hospital stay (days) 3 (2–5)
Hospital Mortality [n (%)] 47 (4.4)
Hospital costs (1,000 RWF) 29 (18–45)
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*, 61 (5.7%) patients had a co-infection of malaria and another infectious disease.

HIV, human immunodeficiency virus; RWF, Rwandan Francs.

Data are given as median values with interquartile range, if not otherwise indicated.

Fig 1. Hospital survival in patients with proven or suspected infection categorized by their ability to walk.

Fig 1

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AUC ROC, area under the receiver operating characteristic curve; PPV, positive predictive value; NPV, negative predictive value; *, Chi2 test.

Fifteen (7.5%), thirty-four (10.8%) and one hundred sixty-seven (30.2%) study patients who could walk unassisted, walk assisted or not walk at hospital admission had a qSOFA score count ≥2 points at hospital admission (Fig 2A), respectively. Hospital mortality differed between these patients when they were categorized by their walking status but this did not reach statistical significance (Fig 2B).

Fig 2.

Fig 2

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Incidence of a qSOFA score count ≥2 points at hospital admission (A) and in-hospital mortality (B) in patients categorized by their ability to walk at hospital admission. *, Chi2 test.

The walking status at hospital admission correlated with an altered mental state, respiratory distress, the qSOFA count, presence of risk factors for death in children, heart rate, respiratory rate, body temperature, white cell count and hemoglobin levels at hospital admission, as well as length of hospital stay, costs of care and survival status at hospital discharge (Table 2).

Table 2. Relationships between the ability to walk at hospital admission and infection source, danger signs, vital parameters, laboratory values at hospital admission, outcome parameters, and costs of care.

Variable Can walk unassisted Can walk assisted Cannot walk Spear-man Rho p-value
N 201 315 553
Danger signs at hospital admission
Altered mental state [n (%)] 3 (1.5) 14 (4.4) 171 (30.9) 0.35 <0.001*
Respiratory distress [n (%)] 8 (4) 20 (6.3) 77 (13.9) 0.14 <0.001*
Systemic hypoperfusion [n (%)] 37 (18.4) 69 (21.9) 84 (15.2) -0.06 0.06
qSOFA score (points) 0 (0–1) 0 (0–1) 1 (0–1.3) 0.29 <0.001*
Pediatric risk factors for death [n (%)] 7 (3.5) 19 (6) 112 (20.3) 0.15 0.001*
Vital parameters at hospital admission
Heart rate (bpm) 95 (80–112) 100 (84–112) 104 (88–117) 0.13 <0.001*
Respiratory rate (bpm) 20 (19–22) 20 (20–22) 22 (20–26) 0.31 <0.001*
SBP (mmHg) 112 (99–122) 108 (98–121) 107 (94–121) -0.08 0.05
Capillary refill time (sec) 2 (2–2) 2 (2–3) 2 (2–3) 0.05 0.11
Temperature (°C) 37 (36.5–37.9) 37.1 (36.6–38.2) 37.3 (36.7–38.5) 0.12 <0.001*
Laboratory values at hospital admission
Blood sugar (mg/dL) 123 (93–161) 123 (90–156) 130 (101–166) 0.11 0.12
WCC (G/L) 6.1 (4.6–8.7) 6.1 (4.1–8.6) 7.8 (5.3–10.8) 0.17 <0.001*
Hemoglobin (g/dL) 12.3 (10.6–13.8) 12.2 (10.1–14) 11.6 (9.8–13) -0.13 <0.001*
Hospital outcome
Length of stay (days) 3 (2–5) 3 (2–6) 4 (2–6) 0.11 0.001*
Costs of care (1,000 RWF) 23.7 (16.2–33.1) 30.2 (16.9–49.9) 30.8 (18.6–48.3) 0.11 <0.001*
Survival [n (%)] 201 (100) 303 (96.2) 518 (93.7) 0.11 <0.001*
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qSOFA, quick Sequential Organ Failure Assessment; RWF, Rwandan Francs; SBP, systolic blood pressure; WCC, white cell count.

Discussion

Rapid identification of patients with serious infection at hospital admission who have the highest risk of death is vitally important if we are to improve their outcome. In a resource limited setting, existing methodologies are not feasible. We believe that there is a need for a simple, binary (Y/N) assessment technique that informs bedside care providers that a patient with serious infection has an increased risk of death.

The results of this post hoc analysis suggest that the inability to walk unassisted at hospital was a highly sensitive predictor of in-hospital death in Rwandese patients with a proven or suspected infection. Its value to predict in-hospital death was even comparable to the qSOFA score in our study population. When interpreting this finding, it is important to note that over seventy-five percent [4] of the study population received evidence-based interventions for the management of their underlying infectious disease. These evidence-based interventions included: initiation of antimicrobial therapy; surgical source control; blood glucose measurement and intravenous glucose administration (in cases of altered mental state and hypoglycemia, respectively); placement of patient in recovery position (in cases of unresponsiveness to touch and/or pain); oxygen administration (in cases of respiratory distress); fluid administration (in cases of systemic hypoperfusion) [4]. In our cohort, any further intervention to reduce mortality would have only been meaningful in patients who could not walk unassisted at hospital admission. Therefore, future research efforts to test advanced interventions to reduce mortality in patients with an acute infection in a resource-limited setting should focus on subjects who cannot walk unassisted at hospital admission.

It is highly likely that certain confounding factors other than the infectious disease process (e.g. age, comorbidities) influenced the walking status at hospital admission in our patient population. Indeed, both age and comorbidities have been shown to be significantly associated with mortality in patients with severe infection and sepsis in resource-limited settings [9,10]. However, the aim of our study was not to evaluate the independent association between the (in)ability to walk and hospital survival status, but to identify an easy and reliable triage tool with a high sensitivity to predict in-hospital mortality. Therefore, we chose an unadjusted model to determine the crude value of the walking status to predict in-hospital death.

An interesting finding of our analysis was that the walking status at hospital admission was correlated with the qSOFA score count. The qSOFA score has been shown to be a significant risk factor for sepsis and death both in high- [7] as well as low- and middle-income countries [11]. Notably, the fifteen study patients of our cohort who could walk unassisted to hospital admission and had a qSOFA score ≥2 points all survived. On the other hand, the hospital mortality of study patients with a qSOFA score ≥2 points who could only walk assisted or who could not walk at all was 2.9% and 8.4%, respectively. Although this difference did not reach statistical significance, it is conceivable and biologically plausible that the ability to walk unassisted may be an indicator of the (otherwise difficult to measure) physiologic reserve of a patient suffering from an acute infection.The walking status at hospital admission was also related to several other indicators of disease severity including danger signs, heart rate, respiratory rate and body temperature, white cell count and hemoglobin levels at hospital admission. Except for the relationship between the ability to walk and altered mental status, and respiratory rate, most of the relationships observed were vague with correlation coefficients <0.2. This suggests that the walking status at hospital admission is a non-specific indicator of the patient’s overall functional condition.

In concordance with our findings, a prospective cohort study from Tanzania reported a clear association between walking status and mortality among medical patients presenting to two hospitals. The ability to walk unaided into the consultation room had a negative predictive value of 97% for hospital mortality [12]. Similarly, the World Health Organization included inability to walk unaided as one of four danger signs to facilitate rapid initiation of empiric anti-tuberculosis treatment among HIV-positive adults with cough [13].

Certain limitations need to be considered when interpreting the results of our analysis. First, we performed multiple comparisons by testing the correlation between 16 parameters and the ability to walk at hospital admission. Although we adjusted the level of significance for this number of comparisons to p<0.003, we cannot exclude the possibility that some relationships were chance findings or reflect collinearity. Second, extrapolation of our results to children who cannot walk unassisted or those with premorbid conditions is not possible. Furthermore, extrapolation to other healthcare facilities, other low-/middle-income countries or even high-income countries may neither be possible as the epidemiology of infection (e.g. malaria), modes of transport and standards of care may differ.

Conclusions

Our results suggest that the inability to walk unassisted at hospital admission is a highly sensitive predictor of in-hospital mortality in Rwandese patients with a suspected acute infection. The walking status at hospital admission appears to be a crude indicator of disease severity.

Acknowledgments

Members of the “Sepsis in Resource-Limited Nations” Task Force of the Surviving Sepsis Campaign (in alphabetical order): John I. Baelani, PhD; Danstan Bagenda, PhD; Martin W. Dünser, MD; Joseph C. Farmer, MD, FCCM; Lori A. Harmon, RRT, MBA; Julia T. Hoffman, RN, BSN; Niranjan Kissoon, MD, FCCM; Arthur Kwizera, MD; Mervyn Mer, MD,PhD; Ashok Mudgapalli, PhD; Pierre Mujyarugamba, MSc; Ndidiamaka Musa, MD; Polyphile Ntihinyurwa, MD; Vincent Nyiringabo, MD; Andrew J. Patterson, MD, PhD; Austin M. Porter; Zacharie Rukemba, MD; Hanno Ulmer, PhD; Olivier Urayeneza, MD, FACS.

Data Availability

Data cannot be shared publicly because of ownership rights. Data are made available from the Surviving Sepsis Campaign for medical reseachers upon request. Please contact ssc@sccm.org.

Funding Statement

This study was funded by the Life Priority Fund, the Hellman Foundation and the King Baudouin Foundation. The research project was supported by the European Society of Intensive Care Medicine and the Society of Critical Care Medicine through the Surviving Sepsis Campaign. Arthur Kwizera is supported by DELTAS Africa Initiative grant #DEL-15-011 to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS)’s Alliance for Accelerating Excellence in Science in Africa (AESA) and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust grant #107742/Z/15/Z and the UK government. The views expressed in this publication are those of the author(s) and not necessarily those of AAS, NEPAD Agency, Wellcome Trust or the UK government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

José Moreira

23 Oct 2019

PONE-D-19-20519

The ability to walk at hospital admission as a valuable triage tool to predict disease severity and outcome in Rwandese patients with suspected infection

PLOS ONE

Dear Dr. Dünser,

Thank you for submitting your manuscript to PLOS ONE. Your submission has now been peer reviewed by three experts in the field. I agree that the manuscript would benefit from being revised according to the suggestions following and encourage you to do so.​

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ACADEMIC EDITOR:

My main point is concerning the methodology. I would suggest that you explicit describe how did you define infection (proven or confirmed). Throughout the manuscript you interchangeably use sepsis and infection accompanied by qSOFA with 2 or more points. That is not true as qSOFA did not define sepsis rather than readily identifying those with infection at higher risk of bad outcomes.

Minor issues

  • Please provide more details about the underlying etiology of infection seen at your study setting. Proportion of bacterial? Viral? Parasitic? Proportion of antibiotic prescription? How many were microbiological confirmed? How many had accompanying organ dysfunction? That information will help the readers understand the context where your investigation was conducted.

  • Page 7. The 95% CI for the PPV/NPV are missing. The prognostic accuracy of the inability to walk at admission should be assessed using the area under the receiver operating characteristic curve (AUROC) and, if possible, compared with qSOFA.

  • Table 1 -  Malaria is not a infection focus but a disease itself (it should move to etiology of infections).

  • Pag 9. I would remove the association between specific disease states and walking status at admission as it did not make much sense.

  • Discussion. I am not sure if measurement of procalcitonin is useful to identify patients and stratify their risk of bad outcomes even in resource-rich settings. 

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Reviewer #1: Reviewer comments

1. This is a post hoc analysis of a bigger study. In the methods the authors should clearly state this is a nested study of a bigger study and clarify their patient population and refrain from reporting the patient population which was not part of this analysis.

2. There are some results of the bigger study in the methods. This is confusing I would strongly recommend the sentence be removed.

3. The authors state they included patients who could walk before they sought care for this specific disease. Nothing has been reported of the time frame between the last time the patient walked and this disease.

4. The criteria for suspected infection for the adults which was used in patients with a qSOFA score should be clearly defined the way they have defined the pediatric group.

5. Complete reporting of the sensitivity, specificity and all c-statistics would be helpful.

6. Table 1 can be rearranged and remove the unit column and add those in the first column after the variable name.

7. The title and the results do not connect completely.

8. The figures 1 and 2 can easily be reported in text.

Reviewer #2: The idea behind the study is relevant and novel. I understand why they decided to use the crude value instead of correcting for probable confouders.

The relevance of some of the associations described puzzles me. Association between menigitis or UTI and walking status for example. Walking status is a crude indicator of being sick and I would not try to couple any diagnosis with the walking status. I would ommit these reduntant analysis and keep the message simple. "If a patient with suspected/poven infection cannot walk beware".

In the page 12 they imply that measurement of procalcitonine status is of help in the ED setting. To do what? What is the evidence for this statement?

The authors say that qSOFA > 2 indicate sepsis? (page 13) In my opinion this is not correct. qSOFA.2 indicate bad out comes in sepsis or may be even other diseas states.

In spite of a few methdological shortcomings I think the message is relevant in a resourse limited setting. Therefore I would publish this paper.

Reviewer #3: I read with interest the paper "The ability to walk at hospital admission as a valuable triage tool to predict disease severity and outcome in Rwandese patients with suspected infection". I think it is clearly written and conveys an important message. I have minor comments only, which I have addressed in the attached file. I found the tables and figures unattractive, perhaps the authors could improve this.

**********

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PLoS One. 2020 Feb 21;15(2):e0228966. doi: 10.1371/journal.pone.0228966.r002

Author response to Decision Letter 0

11 Dec 2019

We thank the editor and reviewers for their critical and thoughtful comments which helped to improve the quality of our manuscript.

Editor:

Specific thanks for the editorial comments to the manuscript itself. All of these have been accepted and included in the revised manuscript.

1. My main point is concerning the methodology. I would suggest that you explicit describe how did you define infection (proven or confirmed). Throughout the manuscript you interchangeably use sepsis and infection accompanied by qSOFA with 2 or more points. That is not true as qSOFA did not define sepsis rather than readily identifying those with infection at higher risk of bad outcomes.

Authors’ response: The author raises an important point. Due to the lack of advanced imaging technology and unavailability of microbiological tests in the hospital laboratory, infection could not be confirmed in the majority of patients (as performed under trial conditions). Pragmatically, the initial suspicion of infection at hospital admission was finally confirmed at hospital discharge based on the clinical response to treatment and exclusion of alternative diagnosis. In the revised manuscript, we clarified this and consistently use the term “suspected acute infection”.

Regarding the diagnosis of sepsis, we agree with the editor that we could not diagnose sepsis in our study population (as suggested by the Sepsis3 definitions), since we did not systematically evaluate organ dysfunction. Therefore, in the revised manuscript, we omitted the term sepsis and only used the term infection. In order to describe patients with an increased risk of death we were more specific and indicated this with a qSOFA Score of 2 points or higher and with the presence of risk factors for death in children. A new paragraph was included into the Materials and Methods section defining these risk factors. The respective paragraph is sub-headed as “Risk Factors for Death” and reads as follows: “The qSOFA score (≥2 points) was used to identify adult patients with an increased risk of death as suggested by the Sepsis3 study group [7]. In children (<15 years), an increased risk of death was assumed if the child had a suspected or proven infection with any one of the following criteria [8]: body temperature <36°C, body temperature >38°C plus altered mental status, body temperature >38°C plus respiratory distress, body temperature >38°C plus a history of not feeding, or body temperature >38°C plus convulsions.”

2. Please provide more details about the underlying etiology of infection seen at your study setting. Proportion of bacterial? Viral? Parasitic? Proportion of antibiotic prescription? How many were microbiological confirmed? How many had accompanying organ dysfunction? That information will help the readers to understand the context where your investigation was conducted.

Authors’ response: In the revised manuscript, Table 1 was relevantly expanded and now includes most of the information suggested by the editor. Some aspects could not be provided as, for example, organ dysfunction could not be systematically evaluated as laboratory tests to do so were not consistently available. This information has also been introduced to the Materials and Methods section of the revised manuscript.

3. Page 7. The 95% CI for the PPV/NPV are missing. The prognostic accuracy of the inability to walk at admission should be assessed using the area under the receiver operating characteristic curve (AUROC) and, if possible, compared with qSOFA.

Authors’ response: All the requested information was added to Figure 1 of the revised manuscript.

Thank you very much for the suggestion to compare the predictive value of the inability to walk unassisted at hospital presentation with that of the qSOFA score. We found that, in our population, the AUC ROC of the inability to walk unassisted was comparable to that of the qSOFA score (0.636 vs. 0.622). This new finding was added to the Results section and addressed in the Discussion section of the revised manuscript.

4. Table 1 – Malaria is not a infection focus but a disease itself (it should move to etiology of infections).

Authors’ response: This was re-arranged. For further details, please refer to our response to the editor’s second comment.

5. Pag 9. I would remove the association between specific disease states and walking status at admission as it did not make much sense.

Authors’ response: In the revised manuscript, the association between specific disease states and walking status at admission were omitted. According changes were made to the Abstract, Materials and Methods, Results, Table 2 and Discussion sections.

6. Discussion. I am not sure if measurement of procalcitonin is useful to identify patients and stratify their risk of bad outcomes even in resource-rich settings.

Authors’ response: The statement referring to procalcitonin was excluded from the Discussion section of the revised manuscript.

Reviewer 1

1. This is a post hoc analysis of a bigger study. In the methods the authors should clearly state this is a nested study of a bigger study and clarify the patient population and refrain from reporting the patient population which was not part of this analysis.

Authors’ response: We agree with this reviewer. Accordingly, the Materials and Methods section of the revised manuscript was largely re-written in order to comply with these points.

2. There are some results of the bigger study in the methods. This is confusing. I strongly recommend the sentence be removed.

Authors’ response: The respective sentences were removed from the revised manuscript.

3. The authors state they included only patients who could walk before they sought care for this specific disease. Nothing has been reported of the time frame between the last time the patient walked and this disease.

Authors’ response: In the Materials and Methods section of the revised manuscript, we clarified that patients who were not able to walk unassisted before this disease episode (e.g. because of young age, neurological conditions, severe chronic disease or frailty) were excluded from the analysis.

Unfortunately, we did not record the time between the last time the patient walked unassisted and this disease. Therefore, we are sorry that we cannot provide these data. On the other hand, we collected the duration of symptoms before hospital presentation. This new information has been added to Table 1 of the revised manuscript.

4. The criteria for suspected infection for the adults which was used in patients with a qSOFA score should be clearly defined they way they have defined the pediatric group.

Authors’ response: In response to the editor’s comments, we omitted the term sepsis in our revised manuscript. The reason for this was that we did not systematically evaluate organ dysfunction in our study population due to the inconsistent availability of laboratory resources to do so. This information has been included into the Materials and Methods section of the revised manuscript. However, in order to describe patients with an increased risk of death we were more specific and indicated this with a qSOFA Score of 2 points or higher and with the presence of risk factors for death in children. A new paragraph was included into the Materials and Methods section defining these risk factors. The respective paragraph is sub-headed as “Risk Factors for Death” and reads as follows: “The qSOFA score (≥2 points) was used to identify adult patients with an increased risk of death as suggested by the Sepsis3 study group [7]. In children (<15 years), an increased risk of death was assumed if the child had a suspected or proven infection with any one of the following criteria [8]: body temperature <36°C, body temperature >38°C plus altered mental status, body temperature >38°C plus respiratory distress, body temperature >38°C plus a history of not feeding, or body temperature >38°C plus convulsions.”

5. Complete reporting of the sensitivity and specificity and all c-statistics would be helpful.

Authors’ response: This information has been added to Figure 1 of the revised manuscript.

6. Table 1 can be re-arranged and remove the unit column and add those in the first column after the variable name.

Authors’ response: Changes to Table 1 of the revised manuscript have been made as suggested by this reviewer. Similar changes were made to Table 2 of the revised manuscript.

7. The title and results do not connect completely.

Authors’ response: Thanks for rising this important point. The title was changed and now reads as follows: “The inability to walk unassisted at hospital admission as a valuable triage tool to predict hospital mortality in Rwandese patients with suspected infection”. The short title was accordingly changed to: “Inability to walk as a predictor of mortality in infection”.

8. The figures 1 and 2 can easily be reported in the text.

Authors’ response: We agree with the reviewer that the information presented in Figure 1 and 2 could be included into the text. However, we feel that figures are an important and effective way to present key study results. Therefore, we decided to retain the two figures in the revised manuscript. If the reviewer and/or editor feel strong about omitting the figures and transforming their information into written text, we will revise our decision.

Reviewer 2:

1. The idea behind the study is relevant and novel. I understand why they decided to use the crude value instead of correcting for probable confouders.

The relevance of some of the associations described puzzles me. Association between menigitis or UTI and walking status for example. Walking status is a crude indicator of being sick and I would not try to couple any diagnosis with the walking status. I would ommit these reduntant analysis and keep the message simple. "If a patient with suspected/poven infection cannot walk beware".

Authors’ response: In the revised manuscript, the association between specific disease states and walking status at admission were omitted. According changes were made to the Abstract, Materials and Methods, Results, Table 2 and Discussion sections.

2. In the page 12 they imply that measurement of procalcitonine status is of help in the ED setting. To do what? What is the evidence for this statement?

Authors’ response: The statement referring to procalcitonin was excluded from the Discussion section of the revised manuscript.

3. The authors say that qSOFA > 2 indicate sepsis? (page 13) In my opinion this is not correct. qSOFA.2 indicate bad out comes in sepsis or may be even other diseas states.

Authors’ response: Regarding the diagnosis of sepsis, we agree with the reviewer that we could not diagnose sepsis in our study population (as suggested by the Sepsis3 definitions), since we did not systematically evaluate organ dysfunction. Therefore, in the revised manuscript, we omitted the term sepsis and only used the term infection. In order to describe patients with an increased risk of death we were more specific and indicated this with a qSOFA Score of 2 points or higher and with the presence of risk factors for death in children. A new paragraph was included into the Materials and Methods section defining these risk factors. The respective paragraph is sub-headed as “Risk Factors for Death” and reads as follows: “The qSOFA score (≥2 points) was used to identify adult patients with an increased risk of death as suggested by the Sepsis3 study group [7]. In children (<15 years), an increased risk of death was assumed if the child had a suspected or proven infection with any one of the following criteria [8]: body temperature <36°C, body temperature >38°C plus altered mental status, body temperature >38°C plus respiratory distress, body temperature >38°C plus a history of not feeding, or body temperature >38°C plus convulsions.”

Reviewer 3:

1. I read with interest the paper "The ability to walk at hospital admission as a valuable triage tool to predict disease severity and outcome in Rwandese patients with suspected infection". I think it is clearly written and conveys an important message. I have minor comments only, which I have addressed in the attached file. I found the tables and figures unattractive, perhaps the authors could improve this.

Authors’ response: We thank the reviewer for the kind words and the corrections made to the attached file. We have included all suggestions into the revised version of the manuscript as indicated.

Attachment

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Decision Letter 1

José Moreira

28 Jan 2020

The inability to walk unassisted at hospital admission as a valuable triage tool to predict hospital mortality in Rwandese patients with suspected infection

PONE-D-19-20519R1

Dear Dr. Dünser,

Your manuscript has now been formally accepted for publication in Plos One. Please see the essential details concerning the publication process below. Your efforts during the process of revision are acknowledged, and I hope you are also pleased with the final results. 

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Academic Editor

PLOS ONE

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Reviewers' comments:

Acceptance letter

José Moreira

6 Feb 2020

PONE-D-19-20519R1

The inability to walk unassisted at hospital admission as a valuable triage tool to predict hospital mortality in Rwandese patients with suspected infection

Dear Dr. Dünser:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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Associated Data

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

    Supplementary Materials

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    Data Availability Statement

    Data cannot be shared publicly because of ownership rights. Data are made available from the Surviving Sepsis Campaign for medical reseachers upon request. Please contact ssc@sccm.org.

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