Rabies update: They’re biting again

18. April 2013
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Year in year out 55,000 people worldwide die from rabies. In addition to infected dogs or cats, bats in particular play a central role as vectors. Recent pieces of work have been dealing with natural immunity and a daring protocol for therapy.

A patient with unusual symptoms ends up in the emergency department: his symptom history begins with pain in the arm. Finally, a strange anxiety appears: the person affected can no longer shower and drink – so strong is the aversion to water. In contrast, solid food represents no problem. Physicians at Massachusetts General Hospital otherwise find no abnormalities, either in the previous history or in terms of symptoms present. The patient reported only of an assumed insect bite, but cannot recall any animal bites. In the end, after an MRI and a CSF, neurologists establish the fatal diagnosis: rabies. The infected person dies 30 days after admission. In retrospect, the widow recalls an incident. At night, bats strayed into the bedroom – and one of them probably infected the patient.

Time is life

It’s true that since the end of 2008 classic rabies has no longer existed in Germany. Previously, terrestrial wild animals such as foxes, badgers and martens acted as carriers. Bats still trigger individual cases of disease there. In the U.S. meanwhile reports accumulate of infections caused by all kinds of bats. Again and again holiday travellers get infected when patting seemingly tame dogs in the tropics. Anyone who is bitten by an animal must not lose any time. The Robert Koch Institute recommends a rabies vaccination as post-exposure prophylaxis. Rabies immunoglobulin (20 IU/kg body weight) should simultaneously be administered. Otherwise the outlook is not good. After the bite virus particles replicate for several days in the affected tissue.

If the pathogens migrate along the nervous system to the brain or spinal cord, the first symptoms occur – usually after three to eight weeks. Finally, encephalitis or myelitis occurs. According to the older textbook view, all patients die from that during these stages.

Acts of desperation in the clinic

In hopeless situations physicians therefore reach for quite brutal measures. The now eight-year old Precious Reynolds got infected through contact with stray cats. After that, the typical symptoms developed: hydrophobia, cramps, fever – doctors were only actually able to treat their patient with palliative care, the nervous system was already infected. However the attending physicians remembered an older publication: Rodney Willoughby, a paediatrician based in Milwaukee, some time earlier in 2004 found himself facing similar challenges with patient Jeanna Giese. He developed a treatment strategy known as “Milwaukee protocol”: His young patient was put into an artificial coma. In this procedure doctors make use of ketamine and midazolam to reduce brain activity. Ketamine itself according to animal studies is also active against rabies. They also administered the virustatic agents ribavirin and amantadine.

Neurons going crazy

According to Willoughby, pathological effects of rabies are mainly due to temporary disturbances in the brain. In contrast to other viral-origin encephalitis, rabies harms nerve cells via excitotoxicity, in other words overstimulation of too many neurotransmitters, the doctor explains. Other pathogens attack neurons directly. Willoughby worked using this thesis. His hope: If it were possible to give the immune system time by way of reduction in neuronal activity, and taking a course of action against the rabies virus itself, patients would have a chance of survival. Success: Jeanna Giese survived, and after 31 days no more virions were to be found in her body. Rehabilitative treatment was concluded, and over the long term the disease left behind no serious consequences. A couple of years later Giese even went on to do higher education. Precious Reynolds was also lucky: the protocol struck the mark in her case. Some in the media are already talking about a new treatment strategy. Reasons for euphoria are still far from existent, the results vary too much.

Adversary in a white coat

Some numbers here: In the original version of the Milwaukee protocol two out of 25 patients survived. After modification the success rate was two in ten patients: a chance of survival existed for terminally ill people, but results were not really good. Why the Milwaukee protocol sometimes works, but has mostly failed, is discussed by researchers in its various aspects. One reason could be that sometimes there may have only been a few virions in the body of the patient. At the beginning of hospitalisation, doctors identified antibodies from Reynolds but no pathogens. Perhaps patients had been infected with a relatively harmless form of the virus.

The two rabies luminaries Thiravat Hemachudha and Henry Wilde, Bangkok, suspect that doctors had accidentally selected patients who even without treatment would have gotten by. Can the body’s immune system actually render rabies virus harmless? There are in fact other indicators for this.

Is the science wrong?

In the middle of 2012, scientists published an interesting study. They examined various indigenous tribes in Peru. With the Truenococha and Santa Marta they found something surprising: Of 63 subjects, one in ten had blood antibodies against rabies virus. Immunisations definitely stand out as the cause. Consequently, it would seem, indigenous people have come into contact with the pathogen themselves without getting critically ill. Amy Gilbert of the Center for Disease Control and Prevention (CDC) hopes through further research to decipher the mechanisms that lead to immunity. She considers harmless genotypes to also be a possible explanation. The area nonetheless is also rife with rabies pathogen recognised as having high mortality rates.

In the USA the “Texas Wild Child” caused sensation: a street child who survived typical rabies symptoms without treatment. Antibody tests were positive, the patient had received no vaccinations. Earlier case reports also provide information of this possibility, but they have not necessarily been proven beyond shadow of doubt. Thiravat Hemachudha and Henry Wilde tread a similar path with their argumentation, based namely on animals. They report that for instance dogs survive rabies infections in individual cases. The mechanisms are however unknown.

On to new studies

The scientific dilemma regarding the Willoughby Protocol and questions of immunity can ultimately only be sorted out by further research. Globally however, the interest remains within limits, unsurprisingly: over 99 percent of all infections occur in developing countries. Also, the numbers of cases – compared with other medical conditions – are rather low.

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2 comments:

Dr. N Gopalakrishnan
Dr. N Gopalakrishnan

Exciting piece of information.
This write up, yet again reminds us of the complexity of viral immunobiology.
Will we ever be able to unravel it completely?

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jcob george
jcob george

Very Good Information . In india it is worse because of street dogs.

#1 |
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