The Milwaukee protocol – a success or failure?

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The Milwaukee protocol is a medical procedure for the treatment of rabies that was first developed in 2004, by a group of medical professionals, led by Dr Rodney Willoughby. It is a means to prevent death after the onset of symptoms in patients, who have not received the rabies vaccine and have sought out medical attention, too late for the PEP (post exposure prophylaxis) medication to be used. [1]

Rabies itself is an RNA-based zoonotic virus caused by transmission from an infected animal, through a wound or mucous membrane – this can occur as a result of a bite or even a deep scratch. The transference of the virus is most commonly from animal to human, but there have been a few documented cases of human to human contamination as a result of transplants (usually of the cornea). The virus enters the muscles that then allow direct access to the nerves, eventually leading to the brain, where it causes an inflammation. The incubation period of the virus depends on its site of entrance; the further from the head, the longer it takes for symptoms to develop due to the greater distance the virus has to travel to reach the brain. Along with transference to the brain, the virus also finds its way to the saliva, from where it can then be transmitted further. Rabies is considered to be extremely fatal in patients who have not received the vaccine, as a result of its tendency to compromise the brain’s ability to regulate breathing, salivation and heart rate – patients usually drown in their own overproduced saliva, or fail to control their breathing to the point of suffocation. [2] [3]

The Milwaukee protocol was formulated after Willoughby studied prior patients who had suffered and died due to rabies; he discovered that most autopsies showed no signs of brain damage. From this, he suggested that the virus was only interfering with neurochemical communications to temporarily disrupt the brain’s regulation of heart rate and breathing. After eliminating the possibility of permanent harm to nerve and brain cells as a result of the virus, Dr Willoughby and his team hypothesised that inducing a coma in their 15 year old patient, would prevent the rabies virus from entering the brain. This would be a result of the lack of neurotransmission occurring due to suppressed brain activity. Subsequently, the immune system would be given time to produce enough of its own antibodies to clear the infection.

The first patient to receive the Milwaukee protocol, was Jeanna Giese in 2004 – a young girl who had been bitten by a bat a month prior to developing symptoms. She was put in a coma induced by ketamine and midazolam for 7 days. During this period, Giese received a sedative and a ‘cocktail’ of antiviral drugs.  She was then removed from isolation 31 days after administration, with her cognitive abilities largely intact. Following intense rehabilitation, she returned to school and continued her normal life. [4]

Despite the success in the 2004 case, the Milwaukee protocol has been fruitless in several other cases. It was initially trialled in 25 patients but resulted in only 3 survivors, and was subsequently discontinued. Despite further human trials being halted, doctors can still use the procedure as a final resort. A 2017 study reported only 5 out of the 36 treated with the Milwaukee protocol had actually survived. Consequently, it has received lots of backlash by the infectious diseases community; the procedure has low success rates, high costs (16 000 people can be administered the successful vaccine with the money spent on caring for one patient), and has several ethical issues. [5] [6]

Three successful cases all share some common characteristics; none of the girls were bitten by a dog – the carrier for the most fatal strain of rabies to humans – and all three girls tested positive for a rabies antibody – not the actual virus. This suggests that their immune systems had most likely already mounted a defence, and cleared the virus – one that seems to be a weak strain of rabies, unlike the virulent strain produced by dogs. This links in with what researchers have known for years – that some animals in the wild survive rabies independently, due to their own immune systems being strong enough to fight the virus. Dr Craig Hooper and Bernhard Dietzschold’s experiments on mice, show that the blood-brain barrier had allowed immune cells to attack the rabies virus in the brains of the subjects; the immune system can clear the virus from the central nervous system. They hold the view that recovery is possible, even after infection of the brain. [7]

The Thomas Jefferson University researchers have also suggested that the weaker strains can be identified by the immune system, quite quickly, as they are less efficiently cloaked. The weaker strains tend to have glycoproteins on their surfaces to which antibodies bind more easily, thus granting B and T lymphocytes access to the brain.

While most research has shown that the virus affects the release of neurotransmitters (supporting Willoughby’s reasoning), there is still debate due to some autopsies showing widespread neuronal loss and tissue necrosis in rabies victims.

Once symptoms are visible, it is clear the virus has reached the central nervous system and that there is no other treatment (experimental or not); the Milwaukee protocol would be the last possible chance of survival. However, the protocol introduces the risk that doctors may not be able to take the patient out of the coma, or they might suffer from severe neurological problems after waking up, despite successfully battling the virus. Therefore, it is thought that more money should be spent researching better diagnosis techniques, to identify the infection sooner and so allow increased use of PEPs, or even look for alternative treatments. Health officials believe doctors fall back on the Milwaukee protocol, thus impeding efforts to find new treatments. Subsequently, they have ‘blacklisted’ the protocol to encourage experimentation – leading to different treatment options. An example being successful injection of live forms of the weak rabies strains, to already infected mice, to allow the clearing of the infection on their own – an alternative to the Milwaukee protocol for those who do not realise that they have the virus, until symptoms appear. [8]

As a result, I believe the Milwaukee protocol is a success for only a certain subgroup of patients; those infected by a weak strain of rabies that already have an immune system strong enough to produce extremely high levels of antibodies rapidly. The Milwaukee protocol should only be used on patients whose virus has been identified as a weak strain, not virulent, to save money that could instead be spent on developing new ideas to combat the virus, and discovering new treatments.

References

  1. Juliadhomstad, “No Rabies Treatment After All: Failure of the Milwaukee Protocol”, The Pandora Report, May. 1, 2014 https://pandorareport.org/2014/05/01/no-rabies-treatment-after-all-failure-of-the-milwaukee-protocol/
  2. Tara C. Smith, “What Happens When You Get Rabies? An Epidemiologist Explains”, Self, Jan. 24, 2019 https://www.self.com/story/what-happens-when-you-get-rabies
  3. Robert Herriman, “Rabies survivor: Milwaukee protocol saves Brazilian teen”, Outbreak News Today, Jan. 12, 2018 http://outbreaknewstoday.com/rabies-survivor-milwaukee-protocol-saves-brazilian-teen-96855/
  4. “Jeanna Giese”, WikiDoc, Sep. 4, 2012 http://www.wikidoc.org/index.php/Jeanna_Giese
  5. “The Milwaukee Protocol is applied on a human rabies case in the USA”, Esanum, Jan. 22, 2018 https://www.esanum.com/today/posts/the-milwaukee-protocol-is-applied-on-a-human-rabies-case-in-the-usa
  6. Anil Kumar Agarwal, “The ‘Milwaukee protocol’ (MP) hope does not succeeds for rabies victim”, Medical Journal of Dr. D.Y. Patil Vidyapeeth, Mar. 14, 2017 http://www.mjdrdypu.org/article.asp?issn=0975-2870;year=2017;volume=10;issue=2;spage=184;epage=186;aulast=Agarwal
  7. Ferris Jabr, “Rabies may not be the invincible killer we thought”, NewScientist, Jun. 21, 2011 https://www.newscientist.com/article/dn20593-rabies-may-not-be-the-invincible-killer-we-thought/
  8. “Should the Milwaukee protocol be used as a treatment for Rabies?”, A Closer Look at your Health, Sep. 29, 2013 http://cattihall.blogspot.com/2013/09/should-milwaukee-protocol-be-used-as.html

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