Ebola: an opportunity for a clinical trial?
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4997 (Published 06 August 2014) Cite this as: BMJ 2014;349:g4997
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Randomized controlled trials (RCTs) offer the fastest and most rigorous assessment of vaccine efficacy. Yet, they are only ethical if there is “clinical equipoise”—genuine uncertainty in the medical community regarding whether the experimental arm will do more good than harm relative to the control arm [1]. We argue that Ebola vaccine RCTs can achieve clinical equipoise without sacrificing scientific rigor by providing enhanced supportive care and access to experimental therapeutics to trial participants who become infected.
Most discussions thus far have analyzed vaccine and treatment RCTs under a single ethical framework. Yet, there is a critical distinction: treatment RCTs investigate whether experimental treatments prevent death and require a relatively high CFR in the control arm to detect clinical efficacy (and we agree with previous arguments that this precludes equipoise [2]), whereas vaccine RCTs investigate whether experimental vaccines prevent infection and can evaluate protective efficacy regardless of the CFR. Thus, scientifically valid vaccine RCTs can and should minimize mortality risk by providing the best standard of care for any trial participant who develops Ebola virus disease, which we argue includes access to experimental therapeutics. Crucially, this would also reduce the difference in mortality risk between arms, thereby facilitating clinical equipoise (Figure).
Although patients treated to date with experimental drugs and convalescent blood products differ from other patients in important ways, there is suggestive evidence linking these treatments to better outcomes, even when compared to hospitalized individuals in West Africa who received intensive supportive care (Table S1). More importantly, the consistent use of experimental treatments in the US and Europe despite limited evidence, implies that the health community expects their benefits to outweigh potential side effects.
Including a “therapeutic safety net” in vaccine RCTs would facilitate clinical equipoise and fulfill the ethical mandate to provide trial participants in developing countries the standard of care in the sponsoring countries [3]. Proposed Ebola vaccine RCTs anticipate only 30 to 60 infections before reaching their stopping criteria [4]. Thus, the supportive care infrastructure and supplies of therapeutic drugs or blood products required to establish a therapeutic safety net should be attainable.
Figure: Example of a therapeutic safety net balancing risk in vaccine trials. Anticipated number of deaths among participants by trial arm in a hypothetical vaccine trial, with and without a therapy that reduces the case fatality rate by 70%. The therapeutic safety net reduces overall mortality and, notably, this substantially bridges the gap between the two arms. Following vaccine trial proposals [5], we assume that 30 participants will become infected before the trial reaches its stopping criteria. Other assumptions are explained in the supplementary code, available at http://ebola.ici3d.org/BMJ/equipoise.R
Steve E Bellan, PhD, MPH
Center for Computational Biology and Bioinformatics, The University of Texas at Austin, Austin, TX, 78712 USA
Juliet RC Pulliam, PhD
Dept. of Biology and Emerging Pathogens Institute, University of Florida, Gainesville, FL, 32611, USA
Prof. Jonathan Dushoff, PhD
Dept. of Biology and Institute of Infectious Disease Research, McMaster University, Hamilton, ON, L8S 4K1, Canada
Prof. Lauren Ancel Meyers, PhD
Dept. of Integrative Biology, The University of Texas at Austin, Austin, TX, 78712 USA
Santa Fe Institute, Santa Fe, NM, 87501, USA
1 Van der Graaf R, van Delden JJM. Equipoise should be amended, not abandoned. Clin Trials 2011;8:408–16. doi:10.1177/1740774511409600
2 Adebamowo C, Bah-Sow O, Binka F, et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet 2014;384:1423–4. doi:10.1016/S0140-6736(14)61734-7
3 Angell M. The ethics of clinical research in the Third World. N Engl J Med 1997;337:847–9. doi:10.1056/NEJM199709183371209
4 Cohen J, Kupferschmidt K. Tough choices ahead in Ebola vaccine trials. ScienceMag 2014;:1–8.
5 GSK. Proposed Phase 2 Program for ChAd3 EBOV Vaccine Candidate. WHO Consultation http://www.who.int/entity/immunization/diseases/ebola/GSK_Phase_2_Progra...
6 Bah EI, Lamah M-C, Fletcher T, et al. Clinical Presentation of Patients with Ebola Virus Disease in Conakry, Guinea. N Engl J Med 2014;:141105140010007. doi:10.1056/NEJMoa1411249
7 Schieffelin JS, Shaffer JG, Goba A, et al. Clinical Illness and Outcomes in Patients with Ebola in Sierra Leone. N Engl J Med 2014;:141029140036007. doi:10.1056/NEJMoa1411680
8 Ebola WHO, Team R, March O, et al. Ebola Virus Disease in West Africa - The First 9 Months of the Epidemic and Forward Projections. N Engl J Med 2014;:1–15. doi:10.1056/NEJMoa1411100
Competing interests: No competing interests
The Ebola epidemic poses an unprecedented threat to the life of millions of West Africa citizens and to global security. Using the Ebola Response modeling tool, the CDC has estimated a range of between 550,000 and 1.4 million cases in only Sierra Leone and Liberia by January 20, 2015 [1]. Classic “outbreak” efforts are no longer sufficient and novel therapeutic interventions are urgently needed.[2] Phase 1 studies on many candidate “magic bullets” (mainly vaccines and the monoclonal antibody compound ZMapp) are on the verge of beginning but, even if adequate safety and efficacy are demonstrated, these treatments will not be available until the first quarter of 2015 at the earliest.[3] A systematic screening of FDA-approved drugs for inhibitors of biological threat agents was published in 2013.[4] The Authors of this paper demonstrated that, in a mouse model of Ebola virus (EBOV) infection, the administration of high-dose chloroquine (CQ) was able to significantly enhance survival rates. They also showed that CQ inhibits endosomal trafficking of virus particles from the early to late endosome, which causes accumulation of virus that does not progress to the late endosome as normal, resulting in an abortive infection.[4] In vitro and/or in vivo anti-viral properties of CQ have been reported against several other types of viral pathogens, including HIV, severe acute respiratory syndrome coronavirus, alphaviruses, Chikungunya virus [5], and H1N1 and H3N2 influenza strains.[6] A randomised, double-blind, placebo-controlled trial performed in Singapore failed to show any efficacy of CQ administration in influenza infection acquisition and clinical course, however the dose of CQ used in this study was low (500 mg/day for 1 week, then once a week for 11 weeks).[6]
The potential use of this drug is particularly intriguing in the Ebola outbreak scenario both because of its pharmacokinetic properties (it is tolerated at relatively high doses and has clinically achievable effective plasma concentrations, it is rapidly absorbed from the gastrointestinal tract and distribute throughout the body [4]), and for logistic reasons (it is FDA-approved, low-cost and widely available in the African continent).
Postexposure prophylaxis is an effective strategy used for preventing development of a number of potentially severe infectious diseases (such as HIV, HBV, meningitis, anthrax, rabies, and many others) and for reducing the risk of secondary transmission to other susceptible persons.[7] For many infectious agents, drugs and doses that are indicated for postexposure prophylaxis would be less effective or ineffective if administered to treat an already established infection from the same agent.
Given the lack of any effective specific agent for the treatment of EBOV infection, a trial investigating the efficacy of a full dose 3-week course of CQ in modifying the clinical course and mortality rates of this infection in suspected contacts of infected patients, could be worthwhile and feasible in a relatively short time.
Another advantage of CQ is that, should any such trial show any benefit, the great availability and low costs of this drug could allow for a mass distribution aimed at dampening the transmission efficiency of this deadly virus (especially in the urban areas where contact tracking and isolation strategies are no longer feasible), while waiting for more effective treatments to become available.
1. Meltzer MI, Atkins CY, Santibanez S, Knust B, Petersen BW, Ervin ED, et al. Estimating the future number of cases in the ebola
epidemic --- liberia and sierra leone, 2014--2015. MMWR Surveill Summ. 2014;26;63:1-14
2. Farrar JJ, Piot P. The Ebola emergency - immediate action, ongoing strategy. N Engl J Med. 2014;371(16):1545-6.
3. Kanapathipillai R, Restrepo AM, Fast P, Wood D, Dye C, Kieny MP, et al. Ebola Vaccine - An Urgent International Priority. N Engl J Med. Epub 2014 Oct 7.
4. Madrid PB, Chopra S, Manger ID, Gilfillan L, Keepers TR, Shurtleff AC, et al. A systematic screen of FDA-approved drugs for inhibitors of biological threat agents. PLoS One. 2013;8(4):e60579.
5. Kaur P, Chu JJ. Chikungunya virus: an update on antiviral development and challenges. Drug Discov Today. 2013;18(19-20):969-83.
6. Paton NI, Lee L, Xu Y, Ooi EE, Cheung YB, Archuleta S, et al. Chloroquine for influenza prevention: a randomised, double-blind, placebo controlled trial. Lancet Infect Dis. 2011;11(9):677-83.
7. Bader MS, McKinsey DS. Postexposure prophylaxis for common infectious diseases. Am Fam Physician. 2013;88(1):25-32.
Competing interests: No competing interests
Ebola virus haemorrhagic fever outbreak – a man-made epidemic?
The first Ebola virus haemorrhaghic fever cases occurred in Zaire in 1976. According to Anonymous (1978. Report of an International Commission: Bull of WHO (56(2): 271-203), “Between 1 September and 24 October 1976, 318 cases of acute haemorrhagic fever occurred in northern Zaire. The outbreak was centred in the one of the Equateur Region and most of the cases were recorded within a radius of 70 km of Yambuku, although a few patients sought medical attention in Bumba, Abumombazi, and the capital city of Kinshasa, where individual secondary and tertiary cases occurred. There were 280 deaths, and only 38 serologically confirmed survivors.
The index case in this outbreak had onset of symptoms on 1 September 1976, five days after receiving an injection of chloroqine for presumptive malaria at the outpatient clinic at Yambuka Mission Hospital (YMH)., He had a clinical remission of his malaria symptoms. Within one week several other persons who had received injections at YMH also suffered from Ebola haemorrhagic fever, and almost all subsequent cases had either received injections at the hospital or had had close contact with another case. Most of these occurred during the first four weeks of the epidemic, after which time the hospital was closed, 11 of the 17 staff members having died of the disease. All, ages and sexes were affected, but women 15 – 29 years of age had the highest incidence of disease, a phenomenon strongly related to the attendance at prenatal and outpatients clinics at the hospital where they received injections. The overall secondary attack rate was about 5%, although it ranged to 20% among close relatives such as spouses, parent or child, and brother and sister.”
There was an interesting reference there as follows “thus it was regarded as quite possible that an infected person had travelled from Sudan to Yambuku and transferred the virus to a needle of the hospital while receiving an injection at the outpatient clinic.” I am particularly in singular tense when referring to a “an injection at the outpatient clinic”. That indicates to me that the hospital very likely used the same (unsterile) needle on many subsequent consecutive patients. Indeed, Baron et al. (1983. Ebola virus disease in southern Sudan: hospital dissemination and intrafamilial spread. Bull of WHO; 61(6): 997-1003) wrote “…while the use of unsterile needles was implicated as a mode of transmission in the Zaire hospital…”).
[The dangerous practice of using unsafe non-disposable unsterile injections in the developing world has been widely researched and publicised in medical journals to this day (Luby et al. 1997. The relationship between therapeutic injections and high prevalence of hepatitis C infection in Hafizabad, Pakistan. Epidemiol Infect; 119: 349-356; Simonsen et al. 1999. Bull WHO; 77 (10): 789-800; Hutin et al. 2003. Use of injections in healthcare settings worldwide, 2000. Literature review and regional estimates. BMJ; 327 (9 November): 1-5)].
Going back to Bull of WHO (1978, as above), “Both the incubation period, and the duration of clinical disease averaged about one week. After 3-4 days of non-specific symptoms and signs, patients typically experienced progressively severe sore throat, developed a maculopapular rash, had an intractable abdominal pain, and began to bleed from multiple sites, principally the gastrointestinal tract. Athough laboratory determinations were limited and not conclusive, it was concluded that pathogenesis of the diseases included non-icteric hepatitis and possibly pancreatitis as well as disseminated intravascular coagulation.”
And, “This syndrome was caused by a virus similar to Marburg virus, but immunologically distinct.. It was named Ebola virus. The agent was isolated from the blood of 8 of 10 suspected cases using vero cell cultures…Ebola virus particles were found in formalin-fixed liver specimens from three cases”.
Importantly, “Virus transmission was interrupted by stopping injections and isolation of patients in their villages. Use of protective clothing and respirators, strict isolation of patients, and careful disposal of potentially contaminated excreta and fomites will almost certainly prevent future major outbreaks. The virus is probably rarely transmitted by infectious aerosols, although infection via large droplets remains a possibility.”
In conclusion, the likelihood of Ebola transmission via unsterile injections is a definite possibility.
Competing interests: No competing interests
Ms Arie is right. Here are a few isolated epidemic areas. Try out vaccines. Not just in case Ebola becomes a pandemic, which does not seem likely: we have had a major exercise in tackling it, the Prime Minister himself watching it. This may well have been preceded by a TEWT.
We have to try it out, in case Ebola is used as an agent by unsocial elements abroad.
We also might remember that in the US, many years ago, a government scientist sent parcels containing pathogenic spores by post. At first foreigners were suspected.
Let us look back at the history. KNOWN outbreaks date back to 1976, hardly likely that the disease did not exist before that. Fruit bats must have been around there and eaten, for thousands of years. Could it be that there have been some changes, for example, in the "balance" between different viruses in the areas, leading to greater pathogenicity in the virus, or diminished resistance in the host?
Secondly, ALL the previous outbreaks, everywhere, were extinguished without the advanced epidemiological expertise residing, inter alia, in the US, UK, France. Is it not very likely that the current outbreaks will also flicker out?
If press reports are to be believed, Heathrow had a very laid back attitude to implementing screening. One journalist had to persuade the Screeners to screen him. Another, a lady, sailed through without being accosted. It has been reported that an immigration officer shook hands with an incomer BEFORE he was screened.
If screening is worth doing at all, it is worth doing well. In the days of small pox, I and my family would always have our smallpox certificates checked at Heathrow. Individuals arriving from infected countries, without a certificate and if symptom-free, were notified to the MOH ( and later his successor, the Proper Officer under the Local Government Act of 1972) for surveillance. Today, I do not even know who the Proper Officer is, for this purpose, in my area. There are numerous other airports, besides, Heathrow, flying to and from Mainland Europe. There are of course, also, numerous yachts sailing to and from our shores. Finally, there is an established "trade" in illegal migration.
The lax controls , ( despite the strident appeals for more money and more action by senior statesmen as well as the WHO) compel me to conclude that:
1. The Illness is not likely to become an epidemic in Europe.
2. A lot of the noise is meant to persuade the public that money is needed for improving health facilities in Africa.
3. That the good ship Argus is doing a worthwhile voyage ( I am already persuaded that our armed forces need to be trained in defensive techniques in biological war;-fare).
Is the virus mutating, becoming more easily transmissible? We do not know and our virologists are silent.
Competing interests: No competing interests
Dear Editor,
In a 1995 outbreak in the Democratic Republic of the Congo, much success was observed when whole blood was administered from patients that had resolved the infection. (Mupapa K, et al., International Scientific and Technical Committee (1999) Treatment of Ebola hemorrhagic fever with blood transfusions from convalescent patients. J Infect Dis 179(suppl 1):S18–S23). Only 1 transfused patient (12.5%) died; this number is significantly lower than the overall case fatality rate (80%) for the EBO epidemic in Kikwit and than the rates for other EBO epidemics. The reason for this low fatality rate remains to be explained. The transfused patients did receive better care than those in the initial phase of the epidemic. Plans should be made to prepare for a more thorough evaluation of passive immune therapy during a new EBO outbreak.
In view of the enormous efforts to treat Ebola infected patients is anyone taking blood samples from patients that have survived the Ebola virus infection? Patients who survive viral infections often have antibodies at the end of the infection that are particularly beneficial in viral resolution in early stages of viral infection. However, there has been a mixed success in the use of post exposure serum treatment for Ebola virus infection and the activity of antibodies against filoviruses is not well understood. It is thought that neutralizing antibodies are produced but at a relatively low frequency. The immune response is weak from serum provided by convalescent patients due to low titres of antibody after recovering from Ebola infection and this possibly explains why the serum therapy or antibody alone is not very successful. Some researchers surmise that the virus takes up the antibodies and few are left after recovery from infection (Borisevich IV, et al. (1995) [Development and study of the properties of immunoglobulin against Ebola fever] Vopr Virusol, 40:270–273).
Perhaps this emphasizes the importance of whole blood therapy assuming that there are other active immune elements other than antibody in the convalescent patient blood? There is some evidence from research that survivors mount a large, broad epitope spectrum of cytotoxic T cells, which require a supportive cytokine environment to accentuate the immune response to Ebola. A late adaptive response has been suggested as being important which will be apparent in convalescent patients (Bradfute SB et al, (2008) Functional CD8+ T Cell Responses in Lethal Ebola Virus Infection,, The Journal of Immunology, vol. 180 no. 6 4058-4066).
Can this cytotoxic cellular response be transferred to recipients and mount a new immune response by transfusion of whole blood?
On the subject of cytokine balance, it was reported that elevated levels of IL-10 are associated with Ebola fatalities, which suggests a that a humoral response is less favourable for resolution of the virus (driven by IL-10), as apposed to a cytotoxic response (McElroy AK et al, (2014) Ebola Hemorrhagic Fever: Novel Biomarker Correlates of Clinical Outcome, J Infect Dis. 210 (4): 558-566).
The logistics of collecting, preparing and storing convalescent bloods seems a daunting task so who can undertake this as an optimistic way forward to treat new cases? After all there are a few thousand survivors so far.
Dr Annwyne Houldsworth BSc MSc PhD FIBMS FHEA MRSC
Competing interests: No competing interests
PAPAYA LEAF EXTRACT FOR EBOLA PATIENTS – WORTH TRYING
Papaya leaf extract is now proven to be effective for dengue fever. (Not merely by increasing the platelet count). The pathology of Ebola virus seems to be similar to that of Dengue fever. Especially when considering the endothelial dysfunction and the hemorrhagic stage. Therefore I strongly feel that Papaya leaf extract will benefit Ebola patients. Researches have shown many beneficial effects of carioca papaya leaf extract on human body which will benefits to fight viral infections. They include:-
1) Stimulation of the hematopoietic system which stimulates Platelet production, White Blood Cell production and Red Blood Cell production (1, 2, 3, 4).
2) In-vitro erythrocyte membrane stabilization properties (5, 6).
3) Stimulates the immune system which enhances the activity against the viral infection (7).
4) Direct anti-viral activity on dengue virus (8).
5) Animal studies have shown that it prevents chemically induced capillary leakage in Mice (9).
6) Preliminary studies conducted by Dr. Sanath Hettige have shown that Carioca papaya leaf extract prevents the drop in serum-Albumin levels in Dengue patients.
Randomize open label case control trial is on going to find out whether Carioca papaya leaf extract can prevent fluid leakage in Dengue fever (10).
7) Many toxicology studies have not shown any significant toxic effects even at higher doses (11).
I have been conducting extensive research with Papaya leaf extract from 2008 and hold the patent rights in Sri Lanka for two processes, willing to collaborate with any researcher or institute to try this on Ebola patients.
It could be given to Ebola patients about 30ml to 20ml 3 times a day as early as possible. For dengue the usual dose used in research settings is 20 ml twice a day.
Many dengue confirmed patients in Sri Lanka and in other Asian countries use this medication on their own accord. I have monitored many patients and they did not have any major side effects except for bitter induced vomiting.
Method of Papaya leaf extract preparation is given below.
PAPAYA LEAVES JUICE EXTRACT PREPERATION – PROTOCOL
Selection of leaf
1. Mature leaf from a fruit bearing tree.
2. The angle of the leaf stalk with the stem should be between 60 to 90 degrees.
3. The leaf should not be wrinkled due to dehydration
4. Leaf should be healthy (free of disease).
5. Whole leaf should be green in colour with no yellowing.
6. Preparation should be made within 6 hour of removing the leaf from the tree.
Method of preparation.
All the necessary equipments should be cleaned and sterilized before starting the procedure. Workers should be in well cleaned uniforms with gloves and masks.
1. Wash the leaves thoroughly, more than five times with running tap water
2. Remove the main stems of the leaves using a scissor
3. Wash the leaves once again with running tap water
4. Weigh the amount of the leaves - 100g
5. Cut the leaves in to pieces and wash it well with boiled cool water
6. Chop it into even smaller pieces
7. Put it in to the grinding machine little by little and grind it very well about 15minutes till you get a uniform pulp
8. Put the pulp in to the juice extractor and squeeze it till you get the pure papaya extract
9. Measure the amount of the juice you got- 50ml
10. Add 50ml cool boiled water with 50g of sugar in to the extracted pure juice and mix it very well
11. Add 30ml of juice extract each in to sterilized bottles and seal it by capping
12. Store it in the refrigerator under 4 ⁰C temperature
13. This preparation should be used within 24 hours. at4 ⁰C temperature.
1. Hettige, S. (2008). Salutary effects of carica papaya leaf extract in dengue fever patients - pilot study. Sri Lankan Family Physician. 29 (1), p17-19.
2. Hettige.S Dengue: an escalating problem /bmj/reply/2011/07/14/fe4b88000f32cb7b.atom.
3. Subenthiran, S., Choon, T.C., Cheong, K.C., Thayan, R., Teck, M.B., Muniandy, P.K., Afzan, A., Abdullah, N.R., Ismail, Z. (2013). Carica papaya leaves Juice significantly accelerates the rate of increase in platelet count among patients with Dengue fever and Dengue haemorrhagic fever. Evidence based complementary and alternative Medicine. 2013 (ID616737), 7pgs
4. Sathasivam, K., Ramanathan, S., Mansor, S. M., Haris, M. R. M. H., Wernsdorfer, W. H. (2009). Thrombocyte counts in mice after the administration of papaya leaf suspension. Wien Klin Wochenschr-The middle European Journal of Medicine. 121 (3), p19-22.
5. Ranasinghe, P., Ranasinghe, P., Abesekara, W.P.K.M., Premakumara, G.A.S., Perera, Y.S., Gurugama, P., Gunathilake, S.B. (2011). In-vitro erythrocyte membrane stabilization properties of carica papaya L. leaf extracts. 3rd international conference on medicinal plants and herbal medicines. Colombo, Sri Lanka.
6. Imaga, N.O.A., Gbenle, G.O., Okochi, V.I., Akanbi, S.O., Edeoghon, S.O., Oigbochie, V., Kehinde, M.O., Bamiro, S.B.. (2009). Anitisicking property of carica papaya leaf extract. African Journal of Biochemistry Research . 3 (4), p102-106.
7. Otsuki, N., Dang, N. H., Kumagai, E., Kondo, A., Iwata, S., Morimoto, C. (2010). Aqueous extract of carica papaya leaves exhibits anti-tumor activity and immunomodulatory effects. Journal of Ethnopharmacology. 127, p760-767.
8. Flavonoid from carica papaya inhibits ns2bnS3 protease and prevents Dengue 2 viral assembly.
Senthilvel P, Lavanya P, Kumar KM, Swetha R, Anitha P, Bag S, Sarveswari S, Vijayakumar
V, Ramaiah S, Anbarasu A.Bioinformation.2013 Nov 11;9(18):889-95. PMID:24307765 PubMed]
9. Hettiarachchi, K., initials Year of publication, Guinea pig rats fed papaya leaf juice concentrate show intriguing results - Tests recording platelet count rise may give hope for dengue patients. Sunday Times, 15/07/2012. In press.
.
10. Controlled trial on effect of Carica papaya leaf extract on patients with Dengue Fever - SLCTR Registration Number SLCTR/2013/005.
11. Halim, S.Z., Abdullah, N.R., Afzan, A., Rashid, B.A.A., Jantan, I., Ismail, Z. (2011). Study of acute toxicity of carica papaya leaf extract in sprague dawley rats. Journal of Medicinal Plants Research. 5 (2), p1867-1872.
Competing interests: No competing interests
Parasitic or tropical diseases do not catch the attention of corporate pharmaceutical firms for reasons of company policy, economic grounds and the need for research. Ebola virus infection, which decimates human health, is one such disease that has attracted the attention of the World Health Organization and the Centers for Disease Control and Prevention (as it involved two US physicians).
The infected US physicians were airlifted (? quarantine), treated with an untested drug (exception is made to save life - which was proved to be effective in treating the infection) and the patients were discharged to be united with their family.
These actions have raised ethical concerns:
Can we airlift people with infection to another country when many are left in the region of infection?
Can we administer untested drugs (bring no harm to the patient)?
Can we discharge the patient without being kept for longer observation?
All these questions and concerns kindle thinking minds, physicians and ethicists to ponder, and after all human life needs to be saved and protected globally.
Competing interests: No competing interests
The current outbreak of Ebola virus in Guinea, Liberia, and Sierra Leone remains an enormous public health concern for the management, treatment and containment of this deadly disease. At the time of this letter, the Ebola virus has been attributed to an outbreak of more than 1300 documented or suspected infections with mortality estimated between 50-75%.1 Ebola is noted to be a type of hemorrhagic fever virus, which frequently results in disseminated intravascular coagulopathy (DIC) through massive overproduction of tissue factor. Active fibrinolysis of cross-linked fibrin has been demonstrated within 24 hours of challenge with viral exposure by measurement of elevated D-dimer.2,3 Treatment is currently aimed at supportive care as new therapies, including humanized monoclonal antibodies, are developed and tested.
It is possible to anticipate that this massive overproduction of tissue factor could initially develop into a prothrombotic state resulting in overproduction of thrombin and subsequent activation of Factors V and VIII. As the coagulopathy progresses through increased thrombin production, factor consumption, and dysregulation of fibrinolysis a bleeding diathesis results. DIC results from dysregulated hemostasis; consumption of coagulation constituents with a loss of appropriate feedback mechanisms further drives the process.
Should we consider initiating treatment with low dose heparin or low-molecular weight heparin in prophylactic doses at time of suspected exposure to counteract or block tissue factor release as a form of post-exposure prophylaxis? While this may not be able to treat the underlying illness, it may potentially result in decreased thrombin production through increasing antithrombin affinity for the overproduced thrombin, partial inhibition of Factor Xa and aid endothelial release of tissue factor pathway inhibitor (TFPI). While it may seem counterintuitive to provide someone at risk for bleeding with anticoagulation, this strategy is already considered in prothrombotic states of DIC prior to development of a bleeding diathesis.4-6 It is possible if dysregulated hemostasis is controlled at the point of the prothrombotic state that the bleeding diathesis may be avoided.7
While clearly there is no single targeted therapy that would resolve DIC induced from Ebola infection currently available, this strategy would be both cost effective and easy to administer. If adequate inhibition of thrombin production did not occur and the affected person progressed to a bleeding diathesis, heparin therapy, with a short half-life, could be stopped. However, administration of heparin during non-prothrombotic states of DIC with global factor consumption occurring could result in significant bleeding morbidity and mortality. For this reason, cautious consideration of treatment would be best warranted as post-exposure or at onset of symptoms and only prior to development of a bleeding diathesis. Other potential treatment options would also be available including recombinant tissue factor pathway inhibitor (rTFPI) or anti-tissue factor monoclonal antibodies. These treatments, however, may be prohibitive from a cost or accessibility standpoint.
While this remains speculative and certainly with significant controversy, it does provide justification for further investigation to all treatments of a disease with up to 90% mortality until more successful ones are available. Blockage of the prothrombotic state could inhibit progression to a bleeding diathesis but aggressive treatment in the form of supportive care would still be needed for other disease-associated symptoms. Opinions on the matter are likely to be strong as well as polarizing. However, at the expense of controversy, ongoing discussion is likely beneficial. Continued treatment strategies that are cost effective and can be made available worldwide should be in foresight of a potential pandemic and not hindsight.
Peter J. Miller, MD
pemiller@wakehealth.edu
References:
1. Outbreak of Ebola in Guinea, Liberia, and Sierra Leone. Vol. 2014: Centers for Disease Control and Prevention; 2014.
2. Geisbert TW, Young HA, Jahrling PB, et al. Pathogenesis of Ebola hemorrhagic fever in primate models: evidence that hemorrhage is not a direct effect of virus-induced cytolysis of endothelial cells. Am J Pathol. 2003;163(6):2371-2382.
3. Geisbert TW, Young HA, Jahrling PB, Davis KJ, Kagan E, Hensley LE. Mechanisms underlying coagulation abnormalities in ebola hemorrhagic fever: overexpression of tissue factor in primate monocytes/macrophages is a key event. J Infect Dis. 2003;188(11):1618-1629.
4. Wada H, Asakura H, Okamoto K, et al. Expert consensus for the treatment of disseminated intravascular coagulation in Japan. Thromb Res. 2010;125(1):6-11.
5. Di Nisio M, Baudo F, Cosmi B, et al. Diagnosis and treatment of disseminated intravascular coagulation: guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res. 2012;129(5):e177-184.
6. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009;145(1):24-33.
7. Pernerstorfer T, Hollenstein U, Hansen J, et al. Heparin blunts endotoxin-induced coagulation activation. Circulation. 1999;100(25):2485-2490.
Competing interests: No competing interests
In the absence of effective treatment and a human vaccine, raising awareness of the risk factors for Ebola infection and the protective measures individuals can take is the only way to reduce human infection and death. But if patients or their family members are willing to have the experimental drugs as treatment for Ebola virus infection we can allow the new and experimental medications FREE of cost.
Competing interests: No competing interests
Ebola: prudence please
Dear Editor,
We highly appreciate this feature article on Ebola, and would like to extend our congratulations to its author Sophie Arie [1]. When there is so much confusion around about Ebola, this article lays down some crucial facts in a straight forward and unambiguous manner and updates our knowledge. As has been pointed out by the author, surely the scientific community and the administrators would like to know more about this neglected disease Ebola, and would also like to undertake clinical trials so as to improve the management and recovery, prevent deaths, and identify a safe and effective vaccine.
Ebola virus disease (EVD) researchers would know and would surely be able to recall a report of an international commission which went into the details of the first outbreak of Ebola in Sudan, the described mortality then was 53% [2]. This outbreak was in the year 1976, and it was the time when the field of medicine was not so advanced as it is now, and still the mortality rates were considerably lower than we get to hear in the present outbreak. Plus the flare up and spread is also very rapid this time. Although it is quite heartening that countries like Nigeria, Congo and Spain have been declared free from Ebola, in some other countries like Sierra Leone, Guinea, Liberia besides the general population, many doctors and health care workers have also succumbed to Ebola this time around despite better protective gear, personal prevention drills, etc. And the numbers are just swelling each day.
While clinical trials may be necessary, these must be carefully planned and executed, without increasing the risks, and with an aim to bring down the morbidity and mortality rates. In a recent clinical review, the case fatality rates have been reported to vary from 30% to 90% [3]. When in 1976, the reported mortality rate was 53%, the aim of all the clinical trials, and all the modern measures and management techniques should be to keep the mortality at or below that lower level [2-3]. It also goes without saying that lessons need to be learnt from the Nigerian, Congo and Spanish experience. It would perhaps be reasonable to assume that whatever had made them succeed against Ebola’s onslaught, may as well be equally relevant for other geo-political and contiguous areas. We also need to catch up on the reasons that were the key behind the success that had put an end to the epidemic quite effectively in a relatively short period way back in the year 1976 [2,4].
Finally we would also like to add that probably it might also be prudent to administer anti-malarials or antibiotics only if actually indicated, and only after getting confirmation by laboratory. Perhaps it would be appropriate to discontinue the practice of empirical therapy in Ebola endemic regions against suspected malaria or a bacterial infection, unless it is a life threatening condition and clinical profile points towards malaria or a bacterial infection. Can’t actually be so positive, but then we would rather be wary of the random and empirical use of anti-malarials and /or antibiotics, as it just might unnecessarily and unwittingly be complicating and aggravating the clinical profile of this viral disease.
Best regards.
Dr (Lt Col) Rajesh Chauhan
Family Healthcare Centre, Agra
Dr. Krishna Mohan Agarwal
Professor, K.D. Dental College, Mathura
Dr. Vinay Mohan
Professor, K.D. Dental College, Mathura
Dr. Shruti Chauhan
Senior Resident, Oral Medicine & Radiology, K.D. Dental College, Mathura
Dr. Neha Garg
Senior Resident, Oral Medicine & Radiology, K.D. Dental College, Mathura
Dr. Ajay Kumar Singh Parihar
Senior Resident, Dept of Medicine, Index Medical College, Indore.
References:
1. Sophie Arie. Ebola: an opportunity for a clinical trial? BMJ 2014; 349: g4997
2. Report of a WHO/International Study Team. Ebola haemorrhagic fever in Sudan, 1976. Bull World Health Organ. 1978; 56(2): 247-270.
3. Report of an International Commission. Ebola haemorrhagic fever in Zaire, 1976. . Bull World Health Organ. 1978; 56(2): 271-293.
4. Beeching NJ, Fenech M, Houlihan CF. Ebola virus disease. BMJ 2014; 349: g7348
Competing interests: The views expressed are those of the authors, and do not reflect any official policy or position of any organization, association, or college. Much of all this is part of the book that is being written on Ebola.