Patients

A total of 213 patients who had an illness that met the definition for suspected Lassa hemorrhagic fever or EVD were tested between May 25 and June 18, 2014, by means of conventional RT-PCR (Fig. S1 and Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Of these patients, 106 (50%) had positive results on testing for EBOV. The distribution of EVD according to age was bimodal, with peak incidences among children older than 15 years of age and among adults between the ages of 26 and 40 years (Fig. S2 in the Supplementary Appendix). Among confirmed cases, 59 patients (60%) were female, including 1 pregnant woman who had a miscarriage immediately before her diagnosis. The majority of patients (92%) originated in Kailahun District, and most of them (82%) came from two chiefdoms in that district, Jawei and Kissi Teng (Tables S1 and S2 and Fig. S3 in the Supplementary Appendix).

Our previous sequencing studies identified three genetically distinct clusters of EBOV among patients with EVD in Sierra Leone (Fig. S3, S4, and S5 in the Supplementary Appendix). Groups of patients with identical viral genomes or groups in which genetic variation was shared among patients showed temporal, geographic, and intrapersonal relationships. These relationships allowed us to observe incubation periods of 6 to 12 days, which is similar to that observed in the outbreak overall.14 The mean (±SE) time from the onset of symptoms to presentation and hospital admission was 5.7±0.5 days (Table S3 and Fig. S6 in the Supplementary Appendix), and the mean time from the patient-reported onset of symptoms to death was 9.8±0.7 days (Table S3 in the Supplementary Appendix). Patients who survived EVD were discharged after a mean duration of illness of 21.3±2.6 days and a mean hospital stay of 15.3±3.1 days. Discharge occurred when a patient was asymptomatic for at least 48 hours and blood samples were negative for EBOV on RT-PCR assay.

Figure 1. Figure 1. Case Fatality Rates among Patients with Ebola Virus Disease (EVD) in Sierra Leone. Shown are case fatality rates among patients with confirmed EVD, a known outcome, and available data, according to age and viral load.

An overall case fatality rate of 74% was observed among the 87 patients with a known outcome. Survival outcomes could not be determined for 19 patients because they could not be contacted after providing an initial blood sample, they died before arrival at Kenema Government Hospital, or they were lost to follow-up. Patients who were younger than 21 years of age had a significantly lower case fatality rate than did patients older than 45 years of age (57% vs. 94%, P=0.03 (Figure 1A, and Table S2 in the Supplementary Appendix). Patients between the ages of 21 and 45 years had an intermediate case fatality rate of 74%. There was no significant difference in the case fatality rate between males and females (73% and 75%, respectively).

Viral Load

We determined the viral load of EBOV at the time of presentation in 65 patients with a known outcome by means of quantitative RT-PCR. A positive correlation was noted between the viral load and the risk of death. Patients who presented with fewer than 100,000 EBOV copies per milliliter of serum had a case fatality rate of 33%, whereas those with a viral load of 10 million EBOV copies per milliliter or more had a significantly higher case fatality rate of 94% (P=0.003) (Figure 1B, and Table S2 in the Supplementary Appendix). Viral loads were quantified for a limited number of patients at multiple times during their hospitalization, with results suggesting that an inability to clear the virus was a risk factor for death, even though some patients with prolonged viremia survived (Fig. S7 in the Supplementary Appendix).

Symptoms, Vital Signs, Physical Findings, and Treatment

Figure 2. Figure 2. Signs and Symptoms in Patients with Fatal and Nonfatal EVD. Shown are signs and symptoms at presentation among patients with confirmed EVD, which were assessed by a review of the charts of patients who had known outcomes. The only symptoms that were significantly associated with a fatal outcome were weakness, dizziness, and diarrhea. Any fever at presentation was not associated with a fatal outcome. However, a temperature above 38°C (100.4°F) had such an association.

Data regarding signs and symptoms in patients at the time of presentation were available for 44 of 106 patients (Table S4 in the Supplementary Appendix). Although biased by the case definition, common findings included fever (in 89% of the patients), headache (in 80%), weakness (in 66%), dizziness (in 60%), diarrhea (in 51%), abdominal pain (in 40%), sore throat (in 34%), vomiting (in 34%), and conjunctivitis (in 31%) (Figure 2, and Table S5 in the Supplementary Appendix). The only symptoms that were significantly associated with a fatal outcome were weakness (P=0.003), dizziness (P=0.01), and diarrhea (P=0.04). Among patients with diarrhea, 94% died, whereas only 65% of those without diarrhea on presentation died. Evidence of bleeding was noted in only 1 patient. None of the other 43 patients were reported to have hemorrhagic signs during their hospital stays, but the possibility cannot be definitively excluded because of the limited charting.

Figure 3. Figure 3. Vital Signs in Patients with Fatal and Nonfatal EVD. Shown are findings for six vital signs at presentation in patients with confirmed EVD who had known clinical outcomes, according to a review of chart data. Blue shading indicates normal ranges for the measurements. The only vital sign at presentation that was significantly associated with a fatal outcome was increased body temperature (above 38°C [100.4°F]). The T bars indicate standard errors.

Vital signs were recorded at presentation and every 6 hours thereafter. A fever (temperature, >38.4°C [101.1°F]) was recorded at the time of initial presentation in 13% of the patients, whereas a temperature of 38°C (100.4°F) or more was noted in 29%. Temperature was the only vital sign that correlated with survival (Figure 3A, and Table S6 in the Supplementary Appendix). The mean temperature at the time of admission was significantly higher among patients who died than among those who survived (37.5°C [99.5°F] vs. 35.9°C [96.6°F], P=0.001). A review of all vital signs that were recorded showed that 20 patients had at least one temperature reading of 38.3°C or more during their hospital course. All but 5 patients met the criteria for relative bradycardia, with a mean temperature of 38.9±0.5°C (102.0±32.9°F) and a mean heart rate of 87±17.8 beats per minute (Fig. S8 in the Supplementary Appendix).15 There were no significant differences between case patients with fatal EVD and those with nonfatal EVD with respect to other vital signs (Figure 3B through 3F).

All 44 patients were given intravenous fluids. Four of the patients (9%) received antimalarial and antibacterial drugs before referral for EBOV testing. During their hospitalization on the viral hemorrhagic fever ward, 55% of the patients received antimalarial drugs and 93% received antibacterial drugs (Table S7 in the Supplementary Appendix). The most commonly administered antibiotic was ceftriaxone (in 80% of patients). Patients also received ampicillin (16%), metronidazole (14%), and ciprofloxacin (5%). Several patients received more than one antibacterial agent. A total of 27% of patients were also treated with paracetamol.

Metabolic Testing

Figure 4. Figure 4. Comparison of Metabolic Measures in Patients with Fatal and Nonfatal EVD. Laboratory measurements at presentation that were associated with a fatal outcome included elevated levels of blood urea nitrogen, creatinine, and aspartate aminotransferase (AST). Blue shading indicates normal ranges for the various measures. Results for sodium, potassium, chloride, glucose, calcium, albumin, total protein, and total bilirubin are provided in Table S10 in the Supplementary Appendix. The T bars indicate standard errors. ALT denotes alanine aminotransferase. To convert the values for blood urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter, multiply by 88.4.

At the time of presentation, abnormalities in several metabolic measurements were accurate predictors of the EVD diagnosis. Significant elevations in blood urea nitrogen, creatinine, AST, ALT, and alkaline phosphatase were noted among patients with EVD, as compared with febrile patients who were EBOV-negative and healthy volunteers (Table S8 and Fig. S9 in the Supplementary Appendix). EBOV-negative patients, many of whom had malaria or other febrile illnesses and were seriously ill, had lower levels of total carbon dioxide and higher AST and ALT levels than did healthy volunteers. High levels of creatinine, blood urea nitrogen, and AST were significantly associated with a fatal EVD outcome (Figure 4, and Tables S9 and S10 in the Supplementary Appendix). There was no significant difference between patients with fatal cases and those with nonfatal cases in other metabolic measures at presentation, including levels of total carbon dioxide, alkaline phosphatase, and ALT.

Analysis of metabolic measures in patients for whom more than one blood sample was obtained showed that normal or decreasing levels of blood urea nitrogen, creatinine, alkaline phosphatase, ALT, and AST and normal or increasing levels of total carbon dioxide heralded recovery (Fig. S10 in the Supplementary Appendix). Most patients who died from EVD had acidosis on admission or acidosis that developed during hospitalization. Among patients who died, levels of blood urea nitrogen and creatinine progressively increased over time, suggesting that dehydration and worsening renal function played a significant role in their hospital course. Patients who died were more likely to have sustained elevations in AST, ALT, or alkaline phosphatase (especially AST) than were patients who survived. Total bilirubin was mildly elevated in only one patient who died, suggesting that hemolysis and hepatic failure are not major components of EVD.

Development of a Scoring System

Scoring systems, such as the modified Acute Physiology and Chronic Health Evaluation (APACHE), have been used in resource-limited settings as prognostic indicators.16,17 Although such a system for the evaluation of EVD would require validation before it could be used, it may be possible to develop a system similar to APACHE to predict the risk of death with the use of clinical data that are available on presentation. Other measures that were found to differ significantly between patients with fatal EVD and those with nonfatal EVD are shown in Table S11 in the Supplementary Appendix.