Subject: Brazilian Rabies Survivor 2008
Archive Number 20081122.3689
Published Date 22-NOV-2008
Subject PRO/AH/EDR Rabies, human survival, bat - Brazil
(02): (Pernambuco)
RABIES, HUMAN SURVIVAL, BAT - BRAZIL (02): (PERNAMBUCO)
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A ProMED-mail post <http://www.promedmail.org<http://www.promedmail.org/
ProMED-mail is a program of the International Society for Infectious Diseases
<http://www.isid.org<http://www.isid.org/
In this posting:
[1] Brazilian case
[2] Thailand comparison and comment
[3] Thailand additional comments
******
[1] Brazilian case
Date: Thu 21 Nov 2008
From: Dr. Gustavo Trinidade Henriques Filho
<gustavothf@uol.com.br<mailto:gustavothf@uol.com.br
[ProMED received questions and comments from several subscribers. The questions were combined
and Dr. Gustavo Henriques, the physician in charge of the surviving rabies case, kindly replied. Mod.TY]
1). Did the patient develop anti-rabies antibody in blood and CSF? If so, at what stage of his infection
were antibodies 1st detected?
Yes, neutralizing antibodies were detected in thelaboratory of Dr. Ivanete Koteit at the Pasteur
Institute, São Paulo, Brasil. The titers increased dramatically over the treatment period,
exceeding 100 IU/mL in both serum and CSF.
2). Was rabies virus RNA detected in CSF?
No. Virus RNA was detected in skin (hair follicle).
3). Was the virus isolated and sequenced?
Yes.
4). Was rabies-immune globulin administered to the patient at any time?
No, unfortunately the patient only received tissue culture-based vaccine. Full prophylaxis was not given.
5). How long after the vampire bat bite was the 1st dose of rabies vaccine administered?4 days.
6). Was a 5th dose of vaccine administered (after Symptoms appeared)?
Unfortunately yes.
7). Since the patient received 4 doses of rabies vaccine before the 1st symptoms appeared, do you
consider this to be a case of vaccine failure?
Immunoglobulin was not given, which explains the failure of the prophylaxis.
8). Was the Wisconsin protocol followed exactly, or were changes made?
We followed the "Milwaukee protocol" as closely as we could. We used ketamine, midazolan and
amantadine. We did not use ribavirin, which is the recommendation of version 2 of the protocol.
We did not use an EEG due to limited availability.
9). Did the patient have cerebral edema? A neurologist in Thailand wrote to say that of the
several rabies patients that he has attended, cerebral edema was not a problem.
MRI findings included edema of the deep gray matter.
There was no need to treat cerebral edema clinically.
We are delighted to report our survivor, and will follow up with submission of a detailed
manuscript very quickly, so that others can achieve similar successes. Please send me copies
of the articles that you [ProMED subscribers and others] discuss our case, at the following address
and e-mail.
-Gustavo Trindade Henriques Filho
Critical Care Unit of Infectious Disease
Oswaldo Cruz University Hospital
Recife-Pernambuco, Brasil.
Adress: Rua do Futuro, 1200/3301 - Gracas
Recife-Pernambuco, Brasil
CEP: 52.050-010
gustavothf@uol.com.br<mailto:gustavothf@uol.com.br
[ProMED is grateful to Dr. Henriques for his prompt response. Questions above were provided by
Drs. Henry Wilde, Bangkok, Thailand, Allen Lenoir, Miami, Florida, USA, Nancy N. Bermal, Muntinlupa
City, Philippines, and Mod.TY]
******
[2] Thailand comparison and comment
Date: Mon 17 Nov 2008
From: Thiravat Hemachudha
<fmedthm@gmail.com<mailto:fmedthm@gmail.com
It is interesting to see the eventual outcome of this Brazilian case. Approximately 5 weeks after
onset, he became clinically stable, could open his eyes. He received therapeutic coma and
antiviral 7 days after the onset. Viral RNA could be demonstrated in hair follicles and saliva,
however, status of antibodies in the serum and CSF were not reported.
Several factors responsible for survival may include:
1. Nature of virus variant. As seen in cases with good recovery, all were associated with bat
variants; 1972 and 2004 US cases and (hopefully) 2008 Brazilian case
2. Absence of classic manifestations. 1972 US case had unsteady gait, dysarthria and hemiparesis 4
days after onset; 1976 dog variant case had quadriparesis, myoclonus, ataxia, dysmetria,
dysdiadokokinesia, frontal lobe dysfunctions, bi-brachial weakness; the remaining (1977 laboratory
accident case, one 1994 and 2 1995 Mexican cases related to dog variants and one Indian related to dog
variant in 2003) also had no typical features of rabies. This may also include 2004 US and 2008 Brazilian.
It is understandable that bat related cases may have atypical presentations since at least some
bat variants have different tissue tropism (skin and dermis cells rather than nicotinic acetylcholine
receptor at the muscle), thus, may use different neural pathways. However, in the remaining dog
related cases, this is still intriguing. Having atypical clinical signs in dog cases may reflect interaction
between host factors and virus spread, resulting to a more favorable outcome.
3. Early development of serum and CSF neutralizing antibody. This may best explain the
1972 and 2004 US cases. These 2 also did not have virus recovered or RNA demonstrated.
Nevertheless, this may not be the sole determinant since 2002 Indian case had CSF appeared in both
compartments as early as day 8 after onset (2004 US had antibody on day 6). Whether or not presence
of virus or viral RNA in the secretions is a bad prognostic factor remains to be determined (depending on
the outcome of this Brazilian case).
4. Postexposure treatment after symptoms developed may not be a contraindication. 1972 and
1976 bat cases, and the remaining cases (lab accident and dog related) either had pre- or post
exposure treatment. What previously believed as immune accelerated deaths may not be true. We have
shown that furious rabies patients who died faster had more cell mediated immune (CMI) response to
rabies antigen as well as more cytokine responses (as determined in the blood) when compared to
paralytic rabies. We proposed this as evidence of bad immune effect. However, our recent study in
furious and paralytic rabies infected dogs revealed that furious dogs had more viral load in the brain but
less cytokine response (RNA transcripts) and less brain MRI disturbances than paralytic dogs. Virus in the
brain then would be drained into the cervical lymph nodes, explaining more CMI response in the blood
of furious rabies. The only concern about immune hazard may be the use of rabies immune globulin. We
have treated a furious rabies patient with large dose of intravenous rabies immune globulin. This caused
paralytic complications, probably by immune attack against virus in the axon.
5. Therapeutic coma induction. At present, it is still inconclusive whether survival is due to the
effect of treatment. Longer survival in treated cases may also be a misunderstanding. Generally,
treatment with intensive care support was withheld once there were no signs of brain functions. In
cases with therapeutic coma, this supportive care was prolonged. Autopsy in our case treated with such
protocol revealed liquefied brain tissue at autopsy (similar to others with same treatment).
Finally, it has been known that virus enters the brain and spinal cord long before the symptoms
developed. This is based on MRI and electrophysiologic evidence in rabies patients at various stages.
Once the death cascade starts, it may not be possible to stop the progression unless counteractive
mechanisms have been developed more or less at the same stage (such as development of antibody)
which may depend in part of the nature of virus variant. To date, there has been no experimental or
animal evidence supporting the role of excitotoxicity in rabies. Antiviral, ribavirin, cannot penetrate the
blood brain barrier, however, it may help fighting against virus in the peripheral tissue. Regarding brain
edema, we have never seen brain edema at autopsy except in our case who was treated with massive
dose of rabies antibody.
References:
----------1. Hemachudha T, Phanuphak P, Sriwanthana B, Manutsathit S, Phanthumchinda K, Siriprasomsup W,
Ukachoke C, Rasameechan S, Kaoroptham S. Immunologic study of human encephalitic and paralytic
rabies. A preliminary study of 16 patients. Am J Med 1988;84:673-6.
2. Hemachudha T. Chapter on Rabies. In: Vinken PJ, Bruyn GW, Klawans HL, eds Handbook of
clinical neurology. Viral Disease. Amsterdam: Elsevier Science Publishers, 1989:383-404.
3. Hemachudha T, Panpanich T, Manatsathit S, Phanuphak P. Immune activation in human rabies.
Trans Royal Soc Trop Med Hyg 1993;87:106-8.
4. Hemachudha T. Human Rabies: Clinical aspects, pathogenesis and potential therapy. In: Rupprecht
CE, Koprowski H, eds. Current Topics in Microbiology and Immunology. Lyssavirus. Springer
Verlag 1994:121-43.
5. Hemachudha T, Laothamathas J, Rupprecht CE. Rabies. Lancet Neurology 2002; 1:101-9.
6. Laothamatas J, Hemachudha T, Mitrabhakdi E, Tulyadaechanont S,. MR imaging in human
encephalitic and paralytic rabies. Am Neuroradiology 2003; 24:1102-9.
7. Hemachudha T , Sunsaneewitayakul B, Mitrabhakdi E, Suankratay C, Laothamathas J,
Wacharapluesadee S, Khawplod P, Wilde H. Paralytic complications following intravenous
rabies immune globulin treatment in a patient with furious rabies. Int J Infect Dis 2003:7:76-7.
8. Hemachudha T, Wacharapluesadee S, Lumlertdaecha B, Orciari LA, Rupprecht CE,
La-ongpant M, Juntrakul S, Denduangboripant J . Sequence analysis of rabies virus in humans
exhibiting furious or paralytic rabies. J Infect Dis 2003; 188:960-6
9. Hemachudha T, Wacharapluesadee S, Mitrabhakdi E, Wilde H, Morimoto K, Lewis RA.
Pathophysiology of human paralytic rabies. J Neurovirol 2005;11:93-100.
10. Mitrabhakdi E, Shungshoti S, Wannakrairot P, Susuki S, Laothamatas J, Lewis RA Hemachudha
T. Difference in neuropathogenetic mechanisms in human encephalitic and paralytic rabies. J Neurol
Sci. 2005;238(1-2):3-10. Epub 2005 Oct 14.
11. Hemachudha T. Rabies. Current Neurology and Neuroscience Reports. Brust JCM, Fahn F, Jubelt B
(eds), Current Science, Inc. 2006;6:460-8.
12. Hemachudha T, Sunsaneewitayskul B, Desudchit T, Suankratay, C, Sittipunt C, Wacharapluesadee
S, Khawplod P, Wilde H, Jackson AC. Failure to treat a rabies patient with coma induction therapy. J
Neurovirol 2006:12:407-9.
13. Laothamatas J, Wacharapluesadee S, Lumlertdacha B, Ampawong S, Vera Tepsumethanon V,
Phumesin P, Asavaphatiboon S, Worapruekjaru L, Hemachudha T. Canine furious and paralytic
rabies: virological, cytokines, and neuroimaging studies. J Neurovirol 2008;14:119-129..
14. Wilde H, Hemachudha T, Jackson AC. Viewpoint: management of human rabies. Trans R Soc
Trop Med Hyg 2008 May 15 [Professor Thiravat Hemachudha added the followng, after receiving the
answers to the questions in part [1] above]:
Therefore, this is what we expected. Rabies antibody was developed very early in the disease
course, if I understand correctly as what Dr.Gustavo mentioned. This may be a critical factor. RNA was
demonstrated only in hair follicles, unlike our case (and others) where RNA was found with an increasing
number at all sites, CSF, urine, saliva. Viruses at other sites might have been eradicated since the
beginning in this Brazilian case. There was no EEG monitoring. This means that coma induction to "burst
suppression" as in Milwaukee protocol may not be that necessary and usually it is dangerous. To achieve
such a coma stage, dosage of medications would be large and this requires careful monitoring to avoid
complications it may induce, especially to the cardiovascular system. Monitoring of cardiac
output, peripheral vascular resistance, wedge pressure, etc. is necessary as in Thai case and
others (with treatment failure) once large dose of these sedatives is used.
Using such sedatives as in the Brazilian case is relevant and this has been done to rabies patients
elsewhere in dog rabies endemic countries for decades with the aim to control agitated symptoms but
not to combat excitotoxic mechanisms. Vaccine use in this case more or less suggests that it is not
contraindicated. The 1st survivor and others had post-exposure prophylaxis. It is hoped that this boy will
not have major sequele which then supports that just routine intensive care support is sufficient and
what has been expressed in "viewpoint of management of human rabies (2008)" holds true that
intensive care support should be applied to a patient who has antibody in the serum and in
CSF at admission. To prolong death in patients who do not have antibody since the beginning may not
be beneficial. As in our study in rabies infected dogs (J Neurovirol 2008), cytokine mRNA transcripts is
only a transient phenomenon in the brain. It appears during the early stage (not very prominent) and
disappears thereafter.
R Thiravat Hemachudha, MD
Professor of Neurology
Department of Medicine (Neurology) and
Molecular Biology Center for
Neurological Diseases
Chulalongkorn University Hospital
Bangkok, Thailand
<fmedthm@gmail.com<mailto:fmedthm@gmail.com
******
[3] Thailand additional comments
Date: Sat 22 Nov 2008
From: Henry Wilde
<wildehenry@yahoo.com<mailto:wildehenry@yahoo.com
It is great to know that there was another survivor of rabies but keep in mind that this may
not at all be due to the chemicals or deep anesthesia which was provided but due to good
nursing and ICU care. This case is virtually identical to that of the 6-year-old Ohio boy who
had neither antiviral chemicals nor even intubation; only good nursing care. The Brazilian
patient had significant CNS antibodies early in the course of his illness which is something we
have not seen in the over 100 rabies patients that we followed in Bangkok. We infused HRIG
intravenously (900 mL total) into one patient and found that the antibody did not appear in CNS
fluid, indicating that the BB [blood-brain] barrier remains intact in most if not all cases.
Thus, I would assume that the antibody in the Brazil, Wisconsin and Ohio patients were produced
in the CNS and may have played a significant role in recovery.
I stand by our recommendation, made in the referenced paper above [Wilde H, Hemachudha T,
Jackson AC. Viewpoint: management of human rabies. Trans R Soc Trop Med Hyg 2008 May 15],
that we would treat any patient who is still reasonably intact and has antibody in CNS on or
shortly after admission with high quality standard ICU care without the Wisconsin regimen
which only adds to risks and is unlikely to contribute to recovery or could be carried out in
most locations where rabies is common. The real issues in rabies for today are not related to
these rare recoveries but to how we manage to control the vector: the huge numbers of free
roaming dogs in most rabies endemic countries. We still do not have an answer for this nor do
governments have the will to tackle it.
-Henry Wilde, MD, FACP
Professor of Medicine
Division of Research Affairs
Faculty of Medicine
Chulalongkorn University
Rama IV Road, Bangkok, Thailand 10330
<wildehenry@yahoo.com<mailto:wildehenry@yahoo.com
[See also:
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20041126.3163<http://www.promedmail.org/pls/otn/f?p=2400:1001:3052112656363119::::F2400_P1001_BACK_PAGE,F2400_P1001_ARCHIV
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Rabies, human, bat - USA (WI)(02): partial recovery
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E_NUMBER,F2400_P1001_USE_ARCHIVE:1001,20041021.2853,Y]