[This is an updated version of this post]
21 October 2014
21 October 2014
Using Untested Treatments
Given that the doubling rate for incidence of Ebola in West Africa in October 2014 is about 4 weeks, it is clear that urgent action is required. This short paper relates specifically to the medical response. The World Health Organisation confirmed on 12th August in Geneva that using untested drugs on Ebola patients would be ethical[i].
Ideally, experimental treatments should be assessed in Randomised Controlled Trials (RCTs), but in the situation on the ground in Africa, this may not be possible. In this case, simple audits of treatments may be used instead. Any treatment centre will know the recovery rate that it is experiencing. If an agent is introduced, whether in comparison with placebo or not, if the recovery rate rises, we would have an indication that the agent may be effective, and deserves more precise assessment.
There are two broad categories of treatment: Vaccines (active and passive) and drugs directed at the virus itself, and those directed at the cytokine storm that is the cause of the high morbidity and mortality of Ebola.
Medications directed at the virus
Vaccines exist for Ebola which have been shown to be effective in animal studies[ii]. Some take 6 months to produce immunity, but others produce antibodies within 28 days. Health care staff (and if possible, their families) should be offered vaccination on a voluntary basis as and when they become available.
ZMapp is a monoclonal antibody that provides passive immunity by attacking the Ebola virus. It has been effective in rhesus macaque monkey trials, but has not been in human trials. It is produced by a genetically modified tobacco plant, and supplies ran out in August 2014, after 7 patients had been treated. Of those seven, 5 recovered, 2 died. This compares favourably with 2 recoveries and 5 deaths that would be expected from the untreated population, although of course the number of cases treated is far too small to be of any statistical significance. Icon Genetics are working on producing more, but production is slow and quantities will be limited.
This targets the RNA of the Ebola virus. Studies are limited[iii] to a small animal test and one human patient who recovered. A trial is planned, but generating large amounts of TKM will be difficult.
An antiviral that prevents viral replication. Effective in vitro against Ebolavirus. The manufacturer, Chimerix, has enough for trials.
All of the above pharmaceuticals are limited by the amount that is already available, or can be prepared in a short time. These limitations are significant in terms of the sheer numbers of people affected. They may have a role to play in the treatment of health care staff who are at risk of infection (in the case of limited vaccines), and those who fall ill, but they are unlikely to play a large part in controlling the present epidemic.
Transfusions of serum from patients who have recovered from the infection may be beneficial[iv]. The limitation is that the patient should have recovered for 28 days, and should not have any serum-transmissible diseases like HIV and Hepatitis. It does require skilled work to prepare and administer the serum.
This approach has the clear advantage that the supply is provided by grateful recovered patients, and will therefore be commensurate with the demand. It is promising, and is under development.
Medications directed at the Cytokine Storm
Cytokine storm is an exaggerated reaction on the part of the cellular immune system. A positive feedback loop forms between cytokines released at the site of infection, which attract more defence cells, which produce more cytokines. It is this vicious circle that causes Ebola infection to have such high mortality.
Several approaches have been put forward for reducing cytokine storm:
1. OX40 is a protein secreted by T-cells that keeps them from dying, and therefore perpetuates the feedback loop. OX40 IG is a synthetic immunoglobulin that neutralises this protein. It has been shown to be effective in mice[v]. It was tested in 2003, but its present availability is uncertain, and its cost is likely to be high.
2. Simvastatin and Gemfibrozil, both lipid-lowering drugs in common use, have been shown to have an effect in reducing the cytokine response. In the case of Simvastatin, an effect has been shown in humans, albeit not in acute infection. Simvastatin also has an effect on the replication of some viruses. It decreases OX40[vi]. Terblanche has reviewed the properties of simvastatin[vii].
3. ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. The Renin-angiotensin system is involved in the cytokine storm[viii]. ACE is involved in pulmonary inflammation[ix],[x]. They have been shown to reduce the cytokine feedback loop[xi].
4. TNF Blockers are medications routinely used in arthritis and other inflammatory conditions, and work by inhibiting Tumour Necrosis Factor (TNF) which is implicated in cytokine storm. They may possibly have a role to play, but are relatively costly.
5. Naltrexone, an established opioid receptor antagonist, may inhibit cytokine storm. There is evidence from animal studies[xii],[xiii],[xiv],[xv] that shows it may be clinically effective. It is inexpensive.
6. Antioxidants such as Ascorbic acid may have a role to play in reducing the adverse effects of cytokine storm.
Note that the latter five groups of medicines are already in use, and therefore have been tested for human acceptability. They are relatively inexpensive. Their side effects are known. It is true that we do not know what happens when they are used in patients infected with the Ebola virus, but the only way to find out in good time is to test them. They may have adverse effects in the given situation, they may have no benefit, but equally, one or more of them, alone or in combination, may prove helpful, and the exercise will be worthwhile – even, possibly, game-changing.
In conclusion, there are several modalities of treatment for Ebola that must be tried in the present outbreak. Their deployment will be “off-licence” and their effectiveness must be monitored, but to test their effectiveness in the Ebola situation that we are currently in would be ethical and rational.
[v] Humphreys I R, Walzl G, Edwards L, Rae A, Hill S, Hussell T. A Critical Role for OX40 in T Cell-mediated Immunopathology during Lung Viral Infection. The Journal of Experimental Medicine 2003;198:1237-1242
[vi] Liu B, Yu G, Yang Z, Sun L, Song R, Liu F, et al. Simvastatin Reduces OX40 and OX40 Ligand Expression in Human Peripheral Blood Mononuclear Cells and in Patients with Atherosclerotic Cerebral Infarction. The Journal of International Medical Research. 2009;37:601-10.
[viii] Genctoy, G; B Altun et al. (February 2005). "TNF alpha-308 genotype and renin-angiotensin system in hemodialysis patients: an effect on inflammatory cytokine levels?". Artif Organs 29 (2): 174–178.
[ix] Marshall, RP; P Gohlke et al. (January 2004). "Angiotensin II and the fibroproliferative response to acute lung injury". Am J Physiol Lung Cell Mol Physiol (Royal Free and University College London Medical School) 286 (1): 156–164. PMID 12754187.
[x] Moldobaeva, A; EM Wagner (December 2003). "Angiotensin-converting enzyme activity in ovine bronchial vasculature". J Appl Physiol (Department of Medicine, Johns Hopkins University) 95 (6): 2278–2284.
[xi] Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, et al. Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int. 2002;62(S82):S12-S22.
[xii] Peng X, Mosser DM, Adler M, et al. Morphine enhances interleukin-12 and the production of other pro-inflammatory cytokines in mouse peritoneal macrophages, Journal of Leukocyte Biology. 2000;68:723-728.
[xiii] Hola N V, Zaji Cova A, Krulova M, Blahoutova V, Wilczek H. Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clinical & Experimental Immunology 2003;132:40-45.
[xiv] Lin S L, Lee Y M, Chang H Y, Cheng Y W and Yen M H. Effects of naltrexone on lipopolysaccharide-induced sepsis in rats. J Biomed Sci. 2005;12:431-40.
[xv] Greeneltch KM, Haudenschild CC, Keegan AD, Shi Y. The opioid antagonist naltrexone blocks acute endotoxic shock by inhibiting tumor necrosis factor-alpha production. Brain Behav Immun. 2004;18:476-84.