Sunday, October 26, 2014

Vaccine for Ebola: will it help?



"Several hundred thousand" doses of Ebola vaccine may be available by mid 2015.

This is a very good development.

But how big will the problem be by June 2015?

Take a look at the useful interactive graph here.

It shows 4,366 cases in total in Liberia, Guinea and Sierra Leone on Sept 7th.
It shows 8,973 cases on Oct 12th - a doubling over 4 weeks.
If we keep to a 4 week doubling rate, by June 2015, when we will have a few hundred vaccines, there will be 4,470,784 cases. That is four and a half (4.5) million cases. Approximately the population of Liberia, the smallest of the three countries. One in five (1:5) of the total population of the three countries.

It may take a month for several hundred thousand health staff to actually become immune from their vaccinations, by which time there will be nearly 9 million cases.

Such is the nature of exponential series.

Of course, it may not be this bad. The virus might miraculously mutate and lose its virulence. Or we could get on top of the epidemic by means of "sensitisation" - education of the people about contact and hygeine. The international community might pull itself together, and start responding with military-level inputs of personnell and materiel, as the generals would say.

Equally, it could get worse. Hysteria and paranoia could spread, resistance to education could become the norm, religious fanaticism could spread, civil war could break out and mass population movements, attempting to flee the infected area, could result.

I am not trying to frighten, only trying to help us understand the nature of doubling series.

If you need a little light relief at this stage, take a look at this video from the excellent Emeritus Professor of Physics, Al Bartlett, who says "The greatest shortcoming of the Human Race is the Inability to understand the Exponential function".



So why am I saying this if not to frighten?

It is to draw attention to this post, which points out that there are several common, cheap drugs available which (if used as part of excellent medical and nursing regime with skilled barrier nursing and a major effort to rehydrate patients) could and should, no, must, be tried in West Africa, in an effort to improve the recovery rate from Ebola. They may or may not work. If they do not work, we have lost nothing. If they do work, alone, or in some kind of combination, we could win the war.

Because the more people recover, the more people will be able to recover, because we can use convalescent serum from survivors to treat patients, and then even more of them will recover. And survivors can work in nursing people and burying bodies safely, because they are to some extent, probably a high extent, immune. Morale will change. Science will be held in esteem. And maybe, just maybe, people will begin to understand what is meant by exponential function.

In other words, it is possible to beat this disease. But to do so we have to try every known trick that presents itself to us. Including looking earnestly at ways of modulating the cytokine storm of Ebola Virus Disease.


Wednesday, October 22, 2014

Non-standard Treatments for the Current Ebola Outbreak

[This is an updated version of this post]
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.
TKM-Ebola
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.
Brincidofovir
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.

Convalescent Serum
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.
[vii] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751082/
[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.

Tuesday, October 21, 2014

Keith Bristow, the NCA, and going for the big paedophiles

Yesterday, Keith Bristow, head of the National Crime Agency (NCA) said that about 50,000 people in the UK are accessing images of children being abused. Present resources are not enough to bring all of these people to court. The NCA will have to prioritise the high-risk offenders, as it is simply not realistic to expect all of these 50,000 to be arrested and tried.

This seems reasonable. 50,000 is a lot of cases. They are breaking the law, but the law does not have the resources to bring them all in. Somehow, police have to screen out the worst cases and arrest them. How do they find the worst cases? Maybe by assessing what they are looking at. For instance, rape and strangulation viewing needs arrest. Simple pictures of nudity maybe just need an educational session on the details of the impact that abuse has on the child, and long-term monitoring of internet activity and behaviour.

However, it looks as if an efficient screen will bring in 12,500 cases who need to be dealt with seriously:
Michael Seto, a research psychologist at the University of Toronto's Centre for Addiction and Mental Health, found in several studies that one in four men arrested for possessing child porn had a history of molesting kids. (Software Tracks Child Porn Traffickers On-Line, USA Today 16th April 2008) Source

Bristow's criterion of going for the high-risk abusers applies also to actual physical (as opposed to virtual) abusers. There has been a pattern in the past of where VIP abusers have been using childrens' homes as a source of boys. The home managers have been arrested, tried and imprisoned, while the VIPs, the MPs and civil servants have escaped. Bristow's principle of going for the high-risk abusers needs to be extended to high-rank abusers too. If there is a public perception that low rank abusers will be punished, but high-rankers can walk free, there will be a public perception also that it is OK to abuse children, so long as you don't get caught.

There is a massive division in the ranks of the police. There are many, a majority probably, of decent coppers who really are opposed to child abuse. There are also some, probably high rankers, probably 1% to 5% of the force, who are paedophiles, who do not want paedophilia to be investigated, who will delay passing on information about paedophiles, and who will actively try to prevent their colleagues from investigating and arresting the group of high ranking paedophiles in Government.

The challenge for Bristow is to overcome the resistance from this enemy withing and nail the big perpetrators. If he does not, or if he fails to go for the big fish, the whole exercise is a waste of police time.

Wednesday, October 15, 2014

Untested Treatments for the Current Ebola Outbreak


Using Untested Treatments

Given that we have no specific treatment for Ebola virus disease (EVD), and given that the doubling rate for incidence in West Africa is about 4 weeks, it is clear that urgent action is required. Much effort is rightly being put into health education and the community response, and the British Government’s input in supplying money has been exemplary.

This paper relates specifically to the medical response. It is very clear that we need to step outside of normal treatment development protocols and test any treatment that offers a reasonable, if at first theoretical, possibility of assisting recovery from the disease. Normal protocols for drug development are rightly detailed, precautionary and protracted, taking months or years before a treatment can be offered to patients. This approach is not appropriate to the current Ebola crisis. The medical profession must be enabled to step outside of the normal system of treatment assessment and deploy untested treatments, “off-license”, but in an orderly way so that the benefit or disbenefit of any treatment can be discovered. Specifically, doctors need to know that they are not at risk of being sued if a patient who has been given an untested treatment dies.

This approach can legitimately be used in the UK on a “Named Patient Basis”, and in the USA under the “Expanded Access Programme”.

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.

Prioritising health care staff
If medications are in short supply, they should be reserved for health care staff who may become infected with EVD.

There are three reasons for this:

First, the staff will be able to give informed consent to the treatment, understanding that it has not been fully tested.

Second, healthcare staff need to feel that they have an improved chance of recovery in case they become infected. Without this job-related bonus, there is a possibility that morale may fall to a point where they simply stop coming to work. If supplies permit, their family may also be offered vaccination, in order to help overcome the fear of contamination from the worker that some families show.

Third, the staff will be able to be followed up and monitored for side effects and for blood tests.

Treatments available

There are two broad categories of treatment: Vaccines (active and passive) directed at the virus itself, and those directed at the cytokine storm that is the cause of the high morbidity and mortality of Ebola.

Vaccines exist for Ebola which have been shown to be effective in animal studies. 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.

The use of ZMapp in these cases sets an important precedent for using untested treatments in this present crisis.


Treating the Cytokine Storm

Cytokine storm can be seen as an over-reaction on the part of the 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 that causes Ebola infection (and, incidentally, other viral infections such as SARS and high-morbidity influenza such as type H5N1) 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. 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.

3. ACE Inhibitors and Angiotensin II receptor blockers are medications in common use against hypertension. They have been shown to reduce the cytokine feedback loop especially in lung conditions.

4. TNF Blockers are medications routinely used in arthritis and other inflammatory conditions. They may 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 that 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 also low-cost. 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 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 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 forbid or delay their use because they have no official license to be used in this condition would be unethical and irrational.




A fully referenced version of this paper will be available shortly