New research on Ebola: January 2016

A shockingly on-time update, covering all the material on Ebola epidemiology and proximate topics that’s new to me in January.  As ever, please let me know if I’ve missed or mis-interpreted something.

 

A. Clinical epidemiology and health systems

Xudong Gao and colleagues highlight a range of symptoms seen to be predictive of diagnosed Ebola, and of mortality, in 773 suspected cases admitted to Jui hospital in Freetown: vomiting, diarrhoea, weakness, loss of appetite, conjunctivitis, hiccups, and confusion. The authors note that rapid, specific diagnostics would still be preferable.

A couple of papers considered survival predictors. The WHO Ebola Response Team highlight a couple of key gender differences in the >20,000 cases seen in the West African epidemic, based on individual-level data: first, women reached treatment facilities an average of 12 hours earlier following symptom onset; and second they were some 15% less likely to die (63% vs 67%), even after adjusting for various potential confounders. Samuel Crowe and colleagues provide evidence from Bo District in Sierra Leone that symptomatology at facility admission was not associated with survival, but first PCR cycle threshold (a proxy for viral load) was predictive of survival at a cutpoint of 24.

There is also more on Ebola survivors. Abrar Chughtai and colleagues review the 12 published papers (to October 2015) on EBOV in convalescent patients’ body fluids. Viral RNA has been found in urine, aqueous humor, sweat, semen, vaginal secretions, breast milk, faeces and conjunctival fluid up to 9 months post-recovery; EBOV itself has been found in semen, aqueous humor, urine and breast milk. There are also two recent additions to this literature this month. John Chancellor and colleagues provide a detailed case description of a returning US doctor who survived EVD and his subsequent ophthalmologic complications. Helena Nordensted and colleagues report a case of a lactating mother who was admitted to care testing positive for EVD in her breast milk. The authors could neither tell whether virus was transmissible via milk, nor whether it lasted beyond EVD clearance from the woman’s blood, but this will add another way in which Ebola might be spread. Anna Thorson and colleagues review the literature specifically on sexual transmission, highlighting positive RNA tests up to nine months post-recovery in semen, and recommending condom use in the absence of abstinence (although no study of condom effectiveness for EBOV prevention yet exists).

Several other papers present research on healthcare-related topics. Two papers consider treatment protocols during the Ebola outbreak. Emmie de Wit and colleagues examine the feasibility of PCR testing for malaria in parallel with Ebola PCR testing. They note that even though presumptive antimalarial treatment was given for any febrile illness, the marginal resource cost of PCR malaria testing was minimal, and it might help with treatment plans. Indi Trehan and colleagues present the paediatric management protocols for Maforki ETU in Port Loko, Sierra Leone, including how they evolved over three months of use between December 2014 and March 2015.

Jianping You and Qing Mao describe the architecture of the Chinese-built ETC in Monrovia, and its strengths and weakness compared to more temporary structures. Abdoulaye Touré and colleagues report on HCW knowledge, attitudes and practices in Conakry, showing high levels of knowledge about Ebola symptoms and transmission risks, but also a preponderant belief that they did not know enough about the disease. Ibrahim Bundu and colleagues describe the rapid and almost-complete fall-off in surgical activity at Sierra Leone’s main teaching hospital in August 2014 as the Ebola epidemic took off in Freetown, and point to key lessons for surgery in future similar outbreaks. Similarly, Catherine Cooper and colleagues describe the development of infection prevention and control (IPC) guidance in the face of the Ebola epidemic and highlight the importance of sector-wide coordination and in-place national protocols in advance of future epidemics.

 

B. Diagnostics, Therapies and Vaccines

On the diagnostic front, following up from last month’s clutch of papers on the Xpert Ebola assay, Rafael Van den Bergh and colleagues review the field-effectiveness of the test in Guinea. The authors report a halving (from 334 to 165 minutes) of time to results compared to PCR, with no false-negatives amongst 218 tests for the Xpert system; they recommend Xpert as an improvement of current standard of care.

There is also an incredibly rich set of papers up this month, from a special issue of Clinical Trials (Pubmed hack, no direct link yet) curated by Lori Dodd and covering trial designs. I have only scratched the surface of the 19 research and perspective articles, but can already recommend it to the more statistically minded amongst you. Hopefully I will one day have a hard-copy of this on my shelf for dipping into. Several of the Clinical Trials articles touch on the ethics of study designs, and in a separate article Annette Rid and Franklin Miller review the ethical rationale for the Ebola ça Suffit ring vaccination trial, highlighting that although it attempted to avoid leaving participants in a placebo arm, it remained a research study – rather than a vaccine rollout operation.

Emelissa Mendoza and colleagues review the evolution of testing therapeutic candidates during the West Africa outbreak, with detailed descriptions for Amiodarone, Brincidofovir, Favipiravir, convalescent plasma and TKM-Ebola. Mendoza et al. were upbeat about convalescent plasma, however Johan van Griensven and colleagues report no significant impact of such plasma on survival in an 84-person non-randomized trial using historical controls. (van Griensven’s team also has a paper in the Clinical Trials special issue on how this analysis was designed.) Researchers may now focus on more concentrated forms of plasma.  On another tack, Stephen McCarthy and colleagues searched for existing drugs that have antiviral activity against Ebola, identifying Interferon-\beta and combinations of various other drugs as candidates.

 

C. Epidemic dynamics and prevention

There were a grab-bag of modelling and field-methods papers this month:

• Mosoka Fallah and colleagues http://annals.org/article.aspx?articleid=2480063 detail the setup of a community-based initiative model in Liberia, and its impact in West Point, a low-income, highly affected neighbourhood of Monrovia. This need for community engagement is echoed in a paper by Samuel Cohn and Ruth Kutalek, which shows parallels between community resistance to external control measures for Ebola and that seen for European Cholera outbreaks in the 19^th century.
• Tom Koch provides a detailed overview of various approaches to mapping both human and physical geographies, and suggests how such methods might inform future outbreak responses.
• Alessandro Rizzo and colleagues present a neat agent-based model of Ebola dynamics that allows for changes in individuals’ contact networks following infection, and more rapid removal via the implementation of behaviour change interventions. The authors reach similar conclusions to previous modelling studies, but with the benefit of added realism that may be crucial for some questions.
• Eva Santermans and colleagues built an instructive two-part model of the West African epidemic using publically available data: first, a spatio-temporal regression model to understand how infections spread across districts; and second a state-transition model to understand growth within districts. The authors propose such methods for real-time outbreak monitoring and prediction.

 

D. Miscellenea

As ever, there are a few articles that I cannot neatly shoehorn into categories; as ever, this reflects my shortcomings, not the relative importance of the work.

• First, the Pan-African Medical Journal devoted its October 2015 issue to Ebola in West Africa, with a range of articles covering Nigeria, Senegal and Ghana, in addition to the three most-affected nations.
• Second, Solomon Benetar outlines three levels of ethical responsibilities in the Ebola outbreak: interpersonal, public health and global.
• Third, South African clinicians Rosie Burton and Tom Boyles reflect on their experiences working in Liberia and Sierra Leone.
• And finally, Eugene T. Richardson and colleagues conduct a biosocial analysis based on four interviews with Ebola survivors in Kono District, Sierra Leone, highlighting political, economic, ecological, and cultural factors that led to the distribution of Ebola infection seen globally over the past three years.

 

New research on Ebola: December 2015

The holidays seem to have cast their pall over my productivity, so this post is emerging three weeks late.  Hopefully January’s will be a little prompter.  As ever, do let me know if I’ve missed/misinterpreted anything important.

Epidemic dynamics

First up, Jean-Paul Chretien and colleagues take on the monumental task of reviewing all 66 Ebola modelling studies from the past 18 months. Chapeau! They highlight variability in methods and approaches and call for best practice guidelines for future outbreaks.

At the national level, Jason T. Ladner and colleagues use genomic analysis of 140 Liberian genomes to show that almost all cases of Ebola in Liberia most-likely all came from a single introduction – probably from Sierra Leone. Given the importance of intense personal contact, models reflecting network structure are often informative.  Anca Radulescu and Joanna Herron investigate the implications of community structures (internal and external, static and dynamic) for key quarantine choices (e.g. focus on breaking local or global ties), and in turn of these choices on epidemic spread. Also at the community level, Mosoka Fallah and colleagues use a stochastic model framework populated with individual-level data on cases in Montserrado county, Liberia – including contact tracing information on a subset – to suggest that the poorest communities were not only the most affected areas, but also most likely to spread infection elsewhere. Moving down to the household level, Ben Adams builds a household-structured model of a population, and shows the importance of larger household sizes in increasing initial growth rates, the basic reproduction number and the household reproduction number (how many within-household infections the average infectious person causes).  If, as seems likely, poorer households are larger households, then the Adams and Fallah papers may be approaching the same issue from different angles.

Patient-level epidemiology

Several papers in December reported on the clinical profile of the epidemic, and how this affected patient outcomes. Oumar Faye and colleagues reviewed viremia data at hospital entry for 699 patients around Conakry up to February 2015, showing that a one-log higher baseline viremia was associated with a 14% reduction in survival probability.  Samuel Crowe and colleagues showed that amongst patients in Bo District, Sierra Leone, time from symptoms to hospital admission was not associated with mortality risk, but viral load at first testing was.  JY Wong and several colleagues reviewed line-list data on all confirmed, probable and suspected Ebola cases in Sierra Leone up to the end of January 2015.  In addition to the typical inverted-u mortality curve associated with age, the authors found no increased mortality risk for women, or for healthcare workers.  Finally, Stefano Petti and colleagues noted, based on a systematic review, that the West African Ebola outbreak showed very different haemorrhagic symptoms to earlier outbreaks – notably a two-thirds drop in bleeding from gums and a tenfold drop in bleeding from the eyes and nose. It is unclear if these changes reflect host, agent or environment (e.g. healthcare) differences.

On the paediatric front, and linked to an earlier suggestion by Benjamin Black and colleagues to focus on maternal health for pregnant women with Ebola ), JM Nelson and colleagues review all published data on live births to Ebola-infected mothers since 1976, showing that all 15 known neonates died with 19 days of birth (although I believe that there is now one longer infant survivor – the last Guinean survivor in the initial outbreak). On a similar topic, Séverine Caluwaerts and colleagues report two cases of pregnant women who recovered from Ebola, but delivered stillborn babies approximately one month post-recovery with EVD in the amniotic fluid. As well as having obstetric implications, these cases suggest yet another reservoir for Ebola post-recovery.

On an operational note, F Vogt and colleagues review MSF’s triage system for admitting suspected Ebola cases in Kailahun to suspect or highly suspect wards in advance of confirmatory tests, based on positive contact history and one other relevant sign/symptom.  They find PPV, NPV, sensitivity and specificity for confirmed cases were all below 76%. Given the high risk of nosocomial infection, the authors recommend single compartments where possible, and the swift implementation of any point-of-care rapid test available. Similarly, Cristina Carias and colleagues evaluated the cost-effectiveness of providing malaria prophylaxis to Ebola case contacts, to avoid malaria and thus false-positive admissions of these contacts to ETUs. Their analysis showed cost savings based just in terms of the cost of admission/bed-stay at the ETUs, although there is also potential benefit of avoiding infection with Ebola, and of sending those with malaria (especially children) to ETUs unable to manage malaria treatment (as highlighted by an article by Gillian McKay on the ethical dilemmas of field triage for malaria/Ebola).

Vaccine and treatment trials

A common message as the West Africa epidemic wanes is that we do not know all that much more about what works in terms of products than we did two years ago. Jon Cohen and Martin Enserink provide two succinct summaries [online article, Magazine version] of the 13 clinical treatment and vaccine trials run to date, noting that only the Guinea Ebola, ca suffit! Ring vaccination trial has shown a clear benefit and had been published by the end of 2015.  Anton Camacho and colleagues provide a model that shows one reason for this dearth of evidence, showing that trials begun in the context of a waning epidemic – in this case Forécariah prefecture in Guinea, beginning in mid-2015 and enrolling 100,000 – are often doomed to failure. One reason for the delay in rolling out trials was uncertainty about the correct way to balance various ethical criteria. Francis Kombe and colleagues discuss the ethical considerations and deliberations that arose in planning a convalescent plasma trial, highlighting the need to provide access even to those typically considered vulnerable and excluded from trials (children; pregnant women), and to provide supportive services to both donors and recipients.

Diagnostics

In contrast to treatments, there appears to have been some progress in developing rapid, point-of-care Ebola tests. Pierre Nouvellet and colleagues review rapid tests for Ebola already available and under development, and use mathematical models to suggest that the earlier isolation they might have allowed could have reduced case numbers by a substantial amount. Meanwhile, Petrus Jansen van Vuren and colleagues, and Benjamin Pinsky and colleagues provide lab evidence of Cepheid’s GeneXpert Ebola PCR test working within 90 minutes. At a conference in late October 2015, Amanda Semper and colleagues showed 100% sensitivity/specificity for the same test in field laboratory setting in West Africa.

Prevention

Less this month on behavioural interventions. Umberto Pellecchia and colleagues used qualitative interviews and discussions to flag the importance of local engagement in epidemic management.  Their work highlighted tensions within communities in Liberia as they negotiated the Ebola outbreak, notably the economic strains of forced quarantines and (bribable) cremation teams, and the effectiveness of local ownership over behavioural interventions and enforcement. On a different tack, Jillian Sacks and colleagues described the process of developing, rolling out and troubleshooting an mHealth solution for electronic data collection by contact tracers in Guinea.

Survivors

As the epidemic splutters out, increasing focus is turning to the health sequelae of infection. In an important piece for planning for possible future outbreaks, Rosalind Eggo and colleagues combined temporal EVD survivor data with evidence that virus can remain in semen for up to nine months for some men, to estimate how the number of potentially-infectious men might evolve over the next few months.  The authors show that the numbers are low and likely to have fallen to a handful by the end of 2015. Malcolm Hugo and colleagues highlighted the need for ongoing psychological assessment and support for Ebola survivors.  Amongst 74 discharged individuals, experiences of death, family member loss and arousal reactions were common; one-third faced stigma in their communities and one-fifth pre-PTSD-type reactions one month post-discharge. John Mattia and colleagues reviewed early data (March/April 2015) from the Port Loko Ebola survivors clinic, finding joint pain (76%) and novel eye symptoms (60%) to be very common; the latter were highly associated with acute Ebola viral load.