The case fatality ratio (CFR) of Ebola virus disease (EVD) can vary over time and space for reasons that are not fully understood. This makes it difficult to define the baseline CFRs needed to evaluate treatments in the absence of randomized controls. Here, we investigate whether viremia in EVD patients may be used to evaluate baseline EVD CFRs.
Methods and Findings
We analyzed the laboratory and epidemiological records of patients with EVD confirmed by reverse transcription PCR hospitalized in the Conakry area, Guinea, between 1 March 2014 and 28 February 2015. We used viremia and other variables to model the CFR. Data for 699 EVD patients were analyzed. In the week following symptom onset, mean viremia remained stable, and the CFR increased with viremia, V, from 21% (95% CI 16%–27%) for low viremia (V < 104.4 copies/ml) to 53% (95% CI 44%–61%) for intermediate viremia (104.4 ≤ V < 105.2 copies/ml) and 81% (95% CI 75%–87%) for high viremia (V ≥ 105.2 copies/ml). Compared to adults (15–44 y old [y.o.]), the CFR was larger in young children (0–4 y.o.) (odds ratio [OR]: 2.44; 95% CI 1.02–5.86) and older adults (≥45 y.o.) (OR: 2.84; 95% CI 1.81–4.46) but lower in children (5–14 y.o.) (OR: 0.46; 95% CI 0.24–0.86). An order of magnitude increase in mean viremia in cases after July 2014 compared to those before coincided with a 14% increase in the CFR. Our findings come from a large hospital-based study in Conakry and may not be generalizable to settings with different case profiles, such as with individuals who never sought care.
Viremia in EVD patients was a strong predictor of death that partly explained variations in CFR in the study population. This study provides baseline CFRs by viremia group, which allow appropriate adjustment when estimating efficacy in treatment studies. In randomized controlled trials, stratifying analysis on viremia groups could reduce sample size requirements by 25%. We hypothesize that monitoring the viremia of hospitalized patients may inform the ability of surveillance systems to detect EVD patients from the different severity strata.
In a retrospective cohort study, Simon Cauchemez and colleagues find viral load can predict case fatality ratios among patients with Ebola Virus.
During the current outbreak of Ebola virus disease (EVD) in West Africa, which started in December 2013, there have been more than 28,000 confirmed, probable, and suspected cases of EVD and more than 11,000 deaths from the disease. Ebola virus is transmitted to people from wild animals and spreads in human populations through direct contact with the bodily fluids (including blood, saliva, and urine) or organs of infected people or through contact with bedding and other materials contaminated with bodily fluids. The symptoms of EVD, which start 2–21 days after infection, include fever, headache, vomiting, diarrhea, and internal and external bleeding. Infected individuals are not infectious until they develop symptoms but remain infectious as long as their bodily fluids contain virus. There is no proven treatment or vaccine for EVD, although several treatments are now being assessed in people following promising laboratory studies. Supportive care—given under strict isolation conditions to prevent the spread of the disease to other patients or to healthcare workers—improves survival.
Why Was This Study Done?
Ideally, the efficacy of a potential treatment for any disease is assessed in a randomized controlled trial, a study that compares outcomes among people chosen at random to receive the treatment with outcomes among people given a placebo (dummy treatment). However, because EVD is frequently fatal, randomized controlled trials of potential treatments are considered unethical. Instead, studies evaluating treatments for EVD usually compare the case fatality ratio (CFR; the number of deaths caused by a disease divided by the number of cases of that disease; a CFR of 100% indicates that everyone who develops the disease dies) among treated patients with a baseline CFR estimated from historical data. But the CFR of EVD varies markedly over time and space for poorly understood reasons (for example, changes in patient care or variations in the detection of people with disease of different severity might change the CFR). Thus, the CFR in the treatment group could differ from the baseline CFR for reasons that are independent of the treatment. To find a way around this problem, in this retrospective cohort study, the researchers investigate whether there is a relationship between viremia (the amount of virus in the blood) and the CFR among patients with EVD.
What Did the Researchers Do and Find?
The researchers used laboratory and epidemiological data (for example, patient age and date of symptom onset and death; epidemiology is the study of disease patterns in populations) to investigate the relationship between viremia and CFR among 699 patients with confirmed EVD hospitalized in the Conakry area of Guinea between March 2014 and February 2015. In the week following symptom onset, mean (average) viremia remained stable, and the CFR among the patients increased with the level of viremia. Thus, the CFRs for patients with low, intermediate, and high viremia (defined by the number of virus copies per milliliter of blood) were 21%, 53%, and 81%, respectively. Compared to adults aged 15–44 years, young children (aged less than five years) and older adults had a higher CFR, but children aged 5–14 years had a lower CFR. Notably, the CFR in the study population was 14% higher after July 2014 than in the months of March–July 2014, an increase that coincided with a ten-fold increase in the average level of viremia in the population.
What Do These Findings Mean?
These findings suggest that viremia is a strong predictor of death that can partly explain variations in the CFR of EVD. Because these findings are based on data collected from hospitalized patients, they may not be generalizable to other settings. Importantly, however, these findings provide estimates of CFR by viremia group that can now be used to adjust risk when undertaking clinical evaluations of EVD-specific treatments. That is, by allowing for differing levels of viremia, it will be possible to assess the efficacy of treatments for EVD more accurately in nonrandomized clinical trials. Moreover, the researchers calculate that stratification of patients by viremia group could reduce the sample size needed in any randomized trials that are undertaken (for example, comparisons of two potential treatments) by 25%. Finally, the researchers suggest that monitoring viremia among patients hospitalized for EVD might provide information about the ability of different surveillance systems to detect patients with different levels of disease severity (probability of death).
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001908.
The World Health Organization (WHO) provides information about EVD, information about potential EVD therapies, and regular updates on the current EVD epidemic; a summary of the discussion of a WHO Ethics Working Group Meeting on the ethical issues related trials of EVD treatments is available; the WHO website also provides information about efforts to control Ebola in the field and personal stories from people who have survived EVD
The UK National Health Service Choices website provides detailed information on EVD
The US Centers for Disease Control and Prevention also provides information about http://www.cdc.gov/vhf/ebola/EVD