Original Article
Brief Report
Survival after Treatment of Rabies with Induction of Coma
N Engl J Med 2005; 352:2508-2514June 16, 2005
- Abstract
We report the survival of a 15-year-old girl in whom clinical rabies developed one month after she was bitten by a bat. Treatment included induction of coma while a native immune response matured; rabies vaccine was not administered. The patient was treated with ketamine, midazolam, ribavirin, and amantadine. Probable drug-related toxic effects included hemolysis, pancreatitis, acidosis, and hepatotoxicity. Lumbar puncture after eight days showed an increased level of rabies antibody, and sedation was tapered. Paresis and sensory denervation then resolved. The patient was removed from isolation after 31 days and discharged to her home after 76 days. At nearly five months after her initial hospitalization, she was alert and communicative, but with choreoathetosis, dysarthria, and an unsteady gait.
Media in This Article
Video
Cognitive and Verbal Ability, Movement Disorders, and Gait
Figure 1
Relationship between Vital Signs in a Patient with Rabies and the Treatment Regimen.Article Activity
- Article
Video
Cognitive and Verbal Ability, Movement Disorders, and Gait
Rabies in humans is a fatal illness characterized by severe encephalopathy and generalized paresis. When the disease is not treated, death typically occurs within five to seven days after the onset of symptoms. Medical management may prolong survival up to 133 days.1,2 There is scant evidence to indicate that any treatment alters median survival, although five people have survived after receiving immunoprophylaxis before the onset of symptoms.3,4 We report the survival of a patient with rabies who was treated with an intense antiexcitotoxic strategy while the native immune response matured but who received no immune prophylaxis.
Case Report
The patient was a 15-year-old girl who rescued and released a bat that struck an interior window. She sustained a 5-mm laceration to her left index finger from the bat. The wound was washed with peroxide. No medical attention was sought, and no rabies postexposure prophylaxis was administered. The patient continued to excel in school and play sports until one month after exposure, when she experienced generalized fatigue and paresthesia of the left hand. Two days later diplopia developed and she felt unsteady. The next day, she had nausea and vomiting without fever. A neurologist noted partial bilateral sixth-nerve palsy and ataxia. The results of magnetic resonance imaging and angiography of her brain were unremarkable. By the fourth day after the onset of symptoms, blurred vision, weakness of the left leg, and a gait abnormality were present. On the fifth day, fever (38.8°C), slurred speech, nystagmus, and tremors of the left arm developed. With the progression of symptoms and an elicited history of a bat bite, the patient was transferred to our facility.
On the first hospital day, the patient was febrile (temperature, 38.2°C) and semiobtunded but answered simple questions and complied with simple commands during diagnostic maneuvers. She had scanning speech, bilateral sixth-nerve palsies, decreased upward gaze, dysarthria, myoclonus, intention tremor of the left arm, and ataxia. Samples of serum, cerebrospinal fluid, nuchal skin, and saliva were submitted to the Centers for Disease Control and Prevention (CDC) for the diagnosis of rabies. Repeated brain magnetic resonance imaging and angiography showed no abnormalities. The patient began salivating, with uncoordinated swallowing, and was intubated for airway protection. On the second hospital day, the presence of rabies virus–specific antibody in her cerebrospinal fluid and serum was confirmed by the CDC. Attempts to isolate rabies virus, detect viral antigen, and amplify viral nucleic acid from two skin biopsies and nine saliva samples were unsuccessful.
The patient's parents were counseled about her diagnosis and prognosis. We offered both hospice care and an aggressive approach on the basis of an untested strategy that combined antiexcitatory and antiviral drugs with supportive intensive care. We provided information about the probable failure of antiviral therapy and the unknown effect of the proposed therapy, as well as the possibility of severe disability if the patient were to survive. The patient's parents requested that we institute aggressive care on the basis of the principles we had discussed.
We administered ketamine at 2 mg per kilogram of body weight per hour with midazolam at 1 to 3.5 mg per kilogram of body weight per hour to suppress background activity on electroencephalography so that only one to two seconds of cerebral activity were interspersed (Figure 1Figure 1
Relationship between Vital Signs in a Patient with Rabies and the Treatment Regimen.). Oxygen delivery was optimized without inotropic agents by red-cell transfusion to maintain the hemoglobin level at more than 10 g per deciliter, appropriate volume loading, and mechanical ventilation targeting arterial normoxia and mild hypercapnia.5 Adequacy of oxygen delivery to organs was monitored by intermittent assessment of venous saturation, and brain and somatic oxygenation by near-infrared spectroscopy.6 Heparin (10 U per kilogram per hour) was administered prophylactically.7 After the induction of coma and on the basis of discussions with scientists at the CDC, we instituted antiviral therapy. Studies in animals have shown little penetration of ribavirin into the central nervous system, and it has had little effect in animal models, but we administered the drug with the rationale that elevated protein levels in the cerebrospinal fluid indicated permeability of the blood–brain barrier (Table 1Table 1
Evolution of Inflammation and Levels of Rabies Virus–Specific Antibody in Cerebrospinal Fluid, According to Hospital Day.) and that ribavirin might protect against rabies myocarditis.3 Ribavirin was administered on the third hospital day, with a loading dose of 33 mg per kilogram followed by a maintenance dose of 16 mg per kilogram every six hours. Interferon alfa was not used because of its neurotoxicity. Neither rabies vaccine nor rabies immune globulin was administered because of the patient's demonstrated immune response and the potential for harm from a potentiated immune response.8 Amantadine (200 mg per day, administered enterally) was added on the fourth hospital day because of its in vitro activity against rabies virus, as well as its antiexcitotoxic activity, which is distributed more rostrally in the brain than is that of ketamine.9,10 High doses of benzodiazepines with supplemental barbiturates were necessary to maintain burst suppression. Limited availability of preservative-free midazolam necessitated the use of midazolam containing 1 percent benzyl alcohol. Biochemical evidence of hemolysis and acidosis was detected by the fifth hospital day. The hemoglobin level declined from 13.7 to 10.9 g per deciliter, whereas the lactate dehydrogenase level rose from 420 to 1020 U per liter over seven days, a finding that was consistent with hemolysis, probably after a cumulative total of 276 mg per kilogram of ribavirin had been administered. An arterial base excess of 2.7 mmol per liter declined to –3.8 mmol per liter over five days, which was consistent with metabolic acidosis, without a change in the blood lactate level, probably reflecting the cumulative total of 362 mg per kilogram of benzyl alcohol. Ribavirin was reduced to 8 mg per kilogram for nine doses, and midazolam was tapered to 1.5 mg per kilogram per hour, with phenobarbital supplementation to maintain burst suppression.
There were minimal systemic effects of brain-stem and peripheral neuropathy. The patient had transient evidence of both deficiency and excess of antidiuretic hormone on the fifth through seventh hospital days. Clinical autonomic denervation developed on the fifth hospital day, with reduced cardiac variability (Figure 1) and higher central venous pressure.1,11-13 Salivation decreased on the eighth hospital day. The patient's skin became flushed, and ileus developed. Increased levels of liver aminotransferase (52 IU per liter), lipase (1193 U per milliliter), and amylase (288 U per milliliter) were noted. Lipase and amylase peaked on the 15th to 18th hospital days (at 2532 U and 539 U per milliliter, respectively), but without enlargement of the pancreas on sonography. A lumbar puncture on the eighth hospital day showed an increased level of rabies-virus antibody in both the serum and cerebrospinal fluid (Figure 1 and Table 1). Ketamine was tapered over 24 hours, and diazepam was given to replace midazolam.
On the 10th hospital day, the patient responded to suctioning with increases in pulse and blood pressure. A high fever developed on the 12th hospital day, without leukocytosis or culture evidence of infection. The patient's fever did not respond to acetaminophen, ibuprofen, ketorolac, or external cooling. On the 14th day, therapy was intensified with ketamine, high-dose diazepam, and amantadine, without effect on her fever (Figure 1). Studies in both animals and humans describe marked poikilothermia in rabies.1,14 A reduction in the room temperature by 5.5°C on the 15th day was followed by a 3.6°C drop in core body temperature. Ketamine and diazepam were lowered and amantadine continued for one week.
Although the electroencephalographic findings improved after the initial tapering of drugs, the patient had briskly reactive pupils but no other cranial-nerve function on the ninth day. Motor examination showed complete flaccidity, without spontaneous movement or movement in response to pain and the absence of deep-tendon reflexes. Patellar deep-tendon reflexes developed on the 12th day, when the patient also opened her mouth in response to sternal pressure. She blinked when eyedrops were administered and regained eye movements on the 14th day. By the 16th day, she opened her mouth to assist with care and raised her eyebrows in response to speech. On the 19th day, she wiggled her toes and squeezed hands in response to commands, fixed her gaze preferentially on her mother, and had an apneustic breathing pattern associated with dystonic opening of her jaw. Computed tomography of her head was normal.
On the 20th day, patellar and ankle deep-tendon reflexes became hyperreflexic, and deep-tendon reflexes in the biceps and triceps developed. Her attention span was 10 to 30 seconds. On the same day, the patient had respiratory distress associated with diaphoresis, tearing of the eyes, the production of thick secretions, and prolonged episodes of coughing and gagging. This condition responded to applications of lidocaine to her hypopharynx. On the 22nd day, she had episodes of prolonged expiratory phase, responsive to albuterol or suctioning. On the 23rd day, she sat in bed, holding her head erect. On the 26th day, she clearly objected to new staff members, a tremor developed in her jaw, and she showed passive tone when her extremities were moved. She was extubated on the 27th day and later slept for 8 consecutive hours and had 60 seconds of sustained alertness. There was persistent jaw dystonia and limited spontaneous movement. On the 30th day, she cried spontaneously and acknowledged sadness as opposed to fear or pain. Deep-tendon reflexes in her biceps and triceps became hyperreflexic, whereas patellar and ankle reflexes normalized. She reported having no skin hyperesthesia or dysesthesia.
Given her continued neutralizing antibody response to rabies virus in cerebrospinal fluid and blood and our inability to isolate the virus or detect viral nucleic acid in saliva, the patient was considered cleared of transmissible rabies and removed from isolation on the 31st day. After rehabilitation, she was discharged to her home on the 76th day (Figure 2Figure 2
Timeline by Hospital Day from the Time of Inoculation with Rabies Virus until Two Months after Discharge from the Hospital.). In a clinic visit 131 days after her initial hospitalization, she smiled, laughed, and interacted with the examiner; her speech was dysarthric (Video Clip 1, available with the full text of this article at www.nejm.org). The patient was able to dress herself, ate a normal diet, slept well, and attended high school part-time. She had constant buccolingual choreoathetosis with generalized choreoathetosis and intermittent dystonia and ballismus, which produced a lurching gait and fine-motor difficulties (Video Clip 2). She was able to write legibly but slowly and to type with her index fingers. She had normal extremity tone, bilateral upward-going toes, and no clonus. She had decreased dorsiflexion in the left ankle and decreased grip in the left hand. She had intact sense of position and light touch.Discussion
At the time of the patient's transfer to our facility, a search of the recent literature had confirmed the futility of antiviral therapy and immune modulation in the treatment of clinical rabies. This finding was confirmed by experience at the CDC. We noted that the pathology of the human brain in cases of rabies reflected secondary complications rather than any clear primary process and that a normal immune system cleared the virus.2,7,15,16 Clinical reports included the hypothesis that death resulted from “neurotransmitter imbalance” and autonomic failure; supportive care was predicted to succeed.5,7,15,17,18 A search of the literature regarding neurotransmitters in rabies identified ketamine as an N-methyl-D-aspartate (NMDA)–receptor antagonist with specific activity against rabies in animal models.19 We conceived a strategy to try to protect the brain from injury while enabling the immune system to mount a natural response and clear the virus. Hypothermia was ruled out because of its effects on immune function.20 We elected to induce therapeutic coma using γ-aminobutyric acid (GABA)–receptor agonism with benzodiazepines and barbiturates, along with NMDA-receptor antagonism with ketamine and amantadine, to reduce excitotoxicity, brain metabolism, and autonomic reactivity.21-23
This improvised approach was a logical extension of previous efforts to prevent complications through aggressive critical care.5,7,18 The induction of coma was associated with a remarkably uneventful course in the intensive care unit, suggesting that much of the dysautonomia characteristic of rabies can be avoided with therapeutic sedation anesthesia. An alternative hypothesis is that this patient would not have developed substantial dysautonomia. Autonomic hyperreflexia emerged while the drugs were being tapered, which suggests a parallel to the hypersensitivity to environmental stimuli seen in tetanus, with a general preservation of higher cortical function.7,24 Induction of coma through GABA agonism with NMDA antagonism may have conferred specific benefit. Although similar strategies have not shown consistent clinical efficacy for protection against excitotoxicity, our high-dose, multimodal regimen was more aggressive and the insult less cytopathic.
The patient survived, but with neurologic impairment. Although her improvement continued five months after her initial hospitalization, we cannot predict the long-term outcome. In addition to this girl, there are five well-documented survivors of rabies. All of the patients had received either occupationally related preexposure rabies vaccination or postexposure prophylaxis.4 Our patient survived with only naturally acquired immunity, although her exposure to rabies virus consisted of minimal trauma at a distal body site, probably with a limited quantity of inoculum. She was young and athletic. The bat that bit her was not recovered, and we were unable to isolate or detect rabies virus from saliva, cerebrospinal fluid, or nuchal-biopsy specimens. We therefore cannot rule out the possibility that her survival was due to an unusual, more temperate or attenuated variant of the virus or a rare host polymorphism. Therapy may have been more effective than in past cases because of the inferred limited exposure to rabies virus, early recognition of the disease, and aggressive management.
Clearly, our experience with this patient requires replication in other patients and proof-of-concept experiments in animal models. Although our primary therapeutic intent was to provide protection against excitotoxic neuronal injury, the patient may have benefited from the dual action of ketamine and amantadine, drugs with activity against rabies virus. She incurred possible toxic effects associated with ribavirin (hemolysis, pancreatitis, and mitochondrial toxicity) and benzyl alcohol (acidosis). Further review of the literature indicates that rabies virus infection of the heart is infrequent and limited in extent.12,13
Ribavirin is variably toxic to mitochondria, and we measured profoundly depleted serum levels of coenzyme Q10 (0.30 μg per milliliter; range, 0.57 to 3.03) during the second month of her convalescence in association with persistently depressed myocardial contractility.25 Rabies virus is largely restricted to the nervous system, so depletion of coenzyme Q10 was probably associated with her critical illness or administered drugs. For patients whose disease is diagnosed before their immune response to rabies virus can be detected, we suggest considering the use of ribavirin, but at a more limited dose or with concurrent supplementation with coenzyme Q10. Given that manifestations of dysautonomia were easily managed, we recommend a longer-acting benzodiazepine with less preservative for future patients.
Survival of this single patient does not change the overwhelming statistics on rabies, which has the highest case fatality ratio of any infectious disease. Any regimen may be ineffective in cases associated with extremes of age, massive traumatic inoculation, or delayed diagnosis and must be coupled with strategies to reduce the risk of complications from long-term treatment in the intensive care unit.
A related video is available at www.nejm.org.
We are indebted to the following people for their advice, excellent clinical care, laboratory diagnosis, or chart abstraction: S. Connolly, R.N.; A. Church, R.N.; L. Grade, R.N.; C. Hanlon, V.M.D.; J. Kane, M.D.; A. Joseph, M.D.; I. Kuzmin, Ph.D.; K. Larsen, R.N.; B. Ludwig, R.N.; P. Morrill; K. Murkowski, R.R.T.; M. Niezgoda, M.S.; N. Norins, M.D.; L. Orciari, M.S.; L. Quarterman, R.N.; J. Surgis; J. Twanow, M.D.; and P. Yager.
Source Information
From the Departments of Pediatric Infectious Diseases (R.E.W., M.J.C.), Pediatric Critical Care Medicine (K.S.T., N.S.G.), Pediatric Anesthesiology (G.M.H.), and Pediatric Neurology (C.M.A.-L., M.J.S.), Medical College of Wisconsin, Milwaukee; and the Centers for Disease Control and Prevention, Atlanta (C.E.R.).
Address reprint requests to Dr. Willoughby at the Department of Pediatric Infectious Diseases, 8701 Watertown Plank Rd., Midwest Athletes against Childhood Cancer Fund Research Center, Suite 3019, Milwaukee, WI 53226, or at rewillou@mail.mcw.edu.
- References
References
1
Gode GR ,Raju AV ,Jayalakshmi TS ,Kaul HL ,Bhide NK . Intensive care in rabies therapy: clinical observations. Lancet 1976;2:6-8
CrossRef | Web of Science | Medline2
Emmons RW ,Leonard LL ,DeGenaro F Jr , et al. A case of human rabies with prolonged survival. Intervirology 1973;1:60-72
CrossRef | Medline3
Jackson AC ,Warrell MJ ,Rupprecht CE , et al. Management of rabies in humans. Clin Infect Dis 2003;36:60-63
CrossRef | Web of Science | Medline4
Willoughby RE ,Rotar MM ,Dohnau HL , et al. Recovery of a patient from clinical rabies -- Wisconsin, 2004. MMWR Morb Mortal Wkly Rep 2005;53:1171-11735
Hattwick MA ,Weis TT ,Stechschulte CJ ,Baer GM ,Gregg MB . Recovery from rabies: a case report. Ann Intern Med 1972;76:931-942
Web of Science | Medline6
Hoffman GM ,Stuth EA ,Jaquiss RD , et al. Changes in cerebral and somatic oxygenation during stage 1 palliation of hypoplastic left heart syndrome using continuous regional cerebral perfusion. J Thorac Cardiovasc Surg 2004;127:223-233
CrossRef | Web of Science | Medline7
Bhatt DR ,Hattwick MA ,Gerdsen R ,Emmons RW ,Johnson HN . Human rabies: diagnosis, complications, and management. Am J Dis Child 1974;127:862-869
Web of Science | Medline8
Mrak RE ,Young L . Rabies encephalitis in humans: pathology, pathogenesis and pathophysiology. J Neuropathol Exp Neurol 1994;53:1-10
CrossRef | Web of Science | Medline9
Superti F ,Seganti L ,Pana A ,Orsi N . Effect of amantadine on rhabdovirus infection. Drugs Exp Clin Res 1985;11:69-74
Web of Science | Medline10
Porter RH ,Greenamyre JT . Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential. J Neurochem 1995;64:614-623
CrossRef | Web of Science | Medline11
Maton PN ,Pollard JD ,Davis JN . Human rabies encephalomyelitis. Br Med J 1976;1:1038-1040
CrossRef | Web of Science | Medline12
Jogai S ,Radotra BD ,Banerjee AK . Rabies viral antigen in extracranial organs: a post-mortem study. Neuropathol Appl Neurobiol 2002;28:334-338
CrossRef | Web of Science | Medline13
Jackson AC ,Ye H ,Phelan CC , et al. Extraneural organ involvement in human rabies. Lab Invest 1999;79:945-951
Web of Science | Medline14
Bell JF ,Moore GJ . Effects of high ambient temperature on various stages of rabies virus infection in mice. Infect Immun 1974;10:510-515
Web of Science | Medline15
Rubin RH ,Sullivan L ,Summers R ,Gregg MB ,Sikes RK . A case of human rabies in Kansas: epidemiologic, clinical, and laboratory considerations. J Infect Dis 1970;122:318-322
CrossRef | Web of Science | Medline16
Lodmell DL ,Bell JF ,Moore GJ ,Raymond GH . Comparative study of abortive and nonabortive rabies in mice. J Infect Dis 1969;119:569-580
CrossRef | Web of Science | Medline17
Jackson AC . Rabies virus infection: an update. J Neurovirol 2003;9:253-258
Web of Science | Medline18
Gode GR ,Saksena R ,Batra RK ,Kalia PK ,Bhide NK . Treatment of 54 clinically diagnosed rabies patients with two survivals. Indian J Med Res 1988;88:564-566
Web of Science | Medline19
Lockhart BP ,Tordo N ,Tsiang H . Inhibition of rabies virus transcription in rat cortical neurons with the dissociative anesthetic ketamine. Antimicrob Agents Chemother 1992;36:1750-1755
Web of Science | Medline20
Beilin B ,Shavit Y ,Razumovsky J ,Wolloch Y ,Zeidel A ,Bessler H . Effects of mild perioperative hypothermia on cellular immune responses. Anesthesiology 1998;89:1133-1140
CrossRef | Web of Science | Medline21
Reich DL ,Silvay G . Ketamine: an update on the first twenty-five years of clinical experience. Can J Anaesth 1989;36:186-197
CrossRef | Web of Science | Medline22
Wang X ,Shimizu-Sasamata M ,Moskowitz MA ,Newcomb R ,Lo EH . Profiles of glutamate and GABA efflux in core versus peripheral zones of focal cerebral ischemia in mice. Neurosci Lett 2001;313:121-124
CrossRef | Web of Science | Medline23
Nargi-Aizenman JL ,Havert MB ,Zhang M ,Irani DN ,Rothstein JD ,Griffin DE . Glutamate receptor antagonists protect from virus-induced neural degeneration. Ann Neurol 2004;55:541-549
CrossRef | Web of Science | Medline24
Warrell DA ,Davidson NM ,Pope HM , et al. Pathophysiologic studies in human rabies. Am J Med 1976;60:180-190
CrossRef | Web of Science | Medline25
Fleischer R ,Boxwell D ,Sherman KE . Nucleoside analogues and mitochondrial toxicity. Clin Infect Dis 2004;38:e79-e80
CrossRef | Web of Science | Medline
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CrossRef7
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CrossRef11
Yoshihiro Kaku, Akira Noguchi, Kozue Hotta, Akio Yamada, Satoshi Inoue. (2011) Inhibition of rabies virus propagation in mouse neuroblastoma cells by an intrabody against the viral phosphoprotein. Antiviral Research 91:1, 64-71
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Efren M. Dimaano, Stephen J. Scholand, Maria Theresa P. Alera, Domingo B. Belandres. (2011) Clinical and epidemiological features of human rabies cases in the Philippines: a review from 1987 to 2006. International Journal of Infectious Diseases 15:7, e495-e499
CrossRef13
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D Craig Hooper, Anirban Roy, Rhonda B Kean, Timothy W Phares, Darryll A Barkhouse. (2011) Therapeutic immune clearance of rabies virus from the CNS. Future Virology 6:3, 387-397
CrossRef15
Alan C. Jackson. 2011. Therapy of Human Rabies. , 365-375.
CrossRef16
Todd G. Smith, Xianfu Wu, Richard Franka, Charles E. Rupprecht. 2011. Design of Future Rabies Biologics and Antiviral Drugs. , 345-363.
CrossRef17
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CrossRef18
D. Craig Hooper, Anirban Roy, Darryll A. Barkhouse, Jianwei Li, Rhonda B. Kean. 2011. Rabies Virus Clearance from the Central Nervous System. , 55-71.
CrossRef19
Susan A Nadin-Davis. 2010. Rabies: Virus and Disease. .
CrossRef20
Mary Warrell. (2010) Rabies and African bat lyssavirus encephalitis and its prevention. International Journal of Antimicrobial Agents 36, S47-S52
CrossRef21
R. Assenberg, O. Delmas, B. Morin, S.C. Graham, X. De Lamballerie, C. Laubert, B. Coutard, J.M. Grimes, J. Neyts, R.J. Owens, B.W. Brandt, A. Gorbalenya, P. Tucker, D.I. Stuart, B. Canard, H. Bourhy. (2010) Genomics and structure/function studies of Rhabdoviridae proteins involved in replication and transcription. Antiviral Research 87:2, 149-161
CrossRef22
HEATHER D. BARTON, ANDREW J. GREGORY, ROLAN DAVIS, CATHLEEN A. HANLON, SAMANTHA M. WISELY. (2010) Contrasting landscape epidemiology of two sympatric rabies virus strains. Molecular Ecology 19:13, 2725-2738
CrossRef23
M. Hunter, N. Johnson, S. Hedderwick, C. McCaughey, K. Lowry, J. McConville, B. Herron, S. McQuaid, D. Marston, T. Goddard, G. Harkess, H. Goharriz, K. Voller, T. Solomon, R.E. Willoughby, A.R. Fooks. (2010) Immunovirological correlates in human rabies treated with therapeutic coma. Journal of Medical Virology 82:7, 1255-1265
CrossRef24
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CrossRef25
Nicholas Johnson, Adam F. Cunningham, Anthony R. Fooks. (2010) The immune response to rabies virus infection and vaccination. Vaccine 28:23, 3896-3901
CrossRef26
N. Johnson, A. Vos, C. Freuling, N. Tordo, A.R. Fooks, T. Müller. (2010) Human rabies due to lyssavirus infection of bat origin. Veterinary Microbiology 142:3-4, 151-159
CrossRef27
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CrossRef31
S. DURR, R. MINDEKEM, Y. KANINGA, D. DOUMAGOUM MOTO, M. I. MELTZER, P. VOUNATSOU, J. ZINSSTAG. (2009) Effectiveness of dog rabies vaccination programmes: comparison of owner-charged and free vaccination campaigns. Epidemiology and Infection 137:11, 1558
CrossRef32
Rodney E Willoughby. (2009) Are we getting closer to the treatment of rabies?. Future Virology 4:6, 563-570
CrossRef33
John J. Halperin. 2009. Encephalitis and Its Mimics in Critical Care. , 153-163.
CrossRef34
Andrea Julia Nigg, Pamela L Walker. (2009) Overview, Prevention, and Treatment of Rabies. Pharmacotherapy 29:10, 1182-1195
CrossRef35
Dennis J. Cleri, Anthony J. Ricketti, John R Vernaleo. 2009. Bioterrorism Infections in Critical Care. , 432-486.
CrossRef36
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CrossRef37
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CrossRef38
Susan A. Nadin-Davis, Mary Sheen, Alexander I. Wandeler. (2009) Development of real-time reverse transcriptase polymerase chain reaction methods for human rabies diagnosis. Journal of Medical Virology 81:8, 1484-1497
CrossRef39
Alan C. Jackson. (2009) Update on rabies diagnosis and treatment. Current Infectious Disease Reports 11:4, 296-301
CrossRef40
B. Dodet. (2009) Report of the Fifth AREB Meeting. Vaccine 27:18, 2403-2407
CrossRef41
R. E. Willoughby, T. Opladen, T. Maier, W. Rhead, S. Schmiedel, J. Hoyer, C. Drosten, C. E. Rupprecht, K. Hyland, G. F. Hoffmann. (2009) Tetrahydrobiopterin deficiency in human rabies. Journal of Inherited Metabolic Disease 32:1, 65-72
CrossRef42
Jun-Sun Park, Myung-Guk Han. (2009) General Features and Post-Exposure Prophylaxis of Rabies. Infection and Chemotherapy 42:1, 6
CrossRef43
Carl H. Cramer II, Victoria Shieck, Susan E. Thomas, David B. Kershaw, John C. Magee, M. James Lopez. (2008) Immune response to rabies vaccination in pediatric transplant patients. Pediatric Transplantation 12:8, 874-877
CrossRef44
(2008) Update on Emerging Infections: News From the Centers for Disease Control and Prevention. Annals of Emergency Medicine 52:5, 537-539
CrossRef45
AM Geretti, . (2008) British HIV Association guidelines for immunization of HIV-infected adults 2008. HIV Medicine 9:10, 795-848
CrossRef46
Jacob W. Ufberg, David J. Karras. (2008) Commentary. Annals of Emergency Medicine 52:5, 539-540
CrossRef47
Henry Wilde, Thiravat Hemachudha, Alan C. Jackson. (2008) Viewpoint: management of human rabies. Transactions of the Royal Society of Tropical Medicine and Hygiene 102:10, 979-982
CrossRef48
Jesse D. Blanton, Dustyn Palmer, Kira A. Christian, Charles E. Rupprecht. (2008) Rabies surveillance in the United States during 2007. Journal of the American Veterinary Medical Association 233:6, 884-897
CrossRef49
Shungo Yamamoto, Chihiro Iwasaki, Hiroshi Oono, Kiyoshi Ninomiya, Tadashi Matsumura. (2008) The First Imported Case of Rabies Into Japan in 36 Years: A Forgotten Life-Threatening Disease. Journal of Travel Medicine 15:5, 372-374
CrossRef50
Alan C. Jackson. (2008) Rabies. Neurologic Clinics 26:3, 717-726
CrossRef51
Jesse D Blanton, Charles E Rupprecht. (2008) Travel vaccination for rabies. Expert Review of Vaccines 7:5, 613-620
CrossRef52
D. Schiff, L. L. Barton. (2008) Rabies: Beware of Bats!. AAP Grand Rounds 20:1, 5-5
CrossRef53
Diane Twedell. (2008) Rabies in Humans. The Journal of Continuing Education in Nursing 39:7, 294-295
CrossRef54
Mary J Warrell. (2008) Emerging aspects of rabies infection: with a special emphasis on children. Current Opinion in Infectious Diseases 21:3, 251-257
CrossRef55
Gaston De Serres, Frédéric Dallaire, Mathieu Côte, Danuta M. Skowronski. (2008) Bat Rabies in the United States and Canada from 1950 through 2007: Human Cases With and Without Bat Contact. Clinical Infectious Diseases 46:9, 1329-1337
CrossRef56
Nelson Nicolasora, Daniel R. Kaul. (2008) Infectious Disease Emergencies. Medical Clinics of North America 92:2, 427-441
CrossRef57
Naohide Takayama. (2008) Rabies: a preventable but incurable disease. Journal of Infection and Chemotherapy 14:1, 8-14
CrossRef58
Anne M Anglim. (2007) Exotic donor-transmitted infections in solid-organ transplantation: can seemingly random events inform policy?. Current Opinion in Organ Transplantation 12:6, 591-603
CrossRef59
Stephen Toovey. (2007) Preventing rabies with the Verorab® vaccine: 1985–2005. Travel Medicine and Infectious Disease 5:6, 327-348
CrossRef60
Vanessa Müller, Juliana H. Chávez, Flávio H. Reginatto, Silvana M. Zucolotto, Rivaldo Niero, Dionezine Navarro, Rosendo A. Yunes, Eloir P. Schenkel, Célia R. M. Barardi, Carlos R. Zanetti, Cláudia M. O. Simões. (2007) Evaluation of antiviral activity of South American plant extracts against herpes simplex virus type 1 and rabies virus. Phytotherapy Research 21:10, 970-974
CrossRef61
Hu, William T., , Willoughby, Rodney E. Jr., , Dhonau, Howard, , Mack, Kenneth J., . (2007) Long-Term Follow-up after Treatment of Rabies by Induction of Coma. New England Journal of Medicine 357:9, 945-946
Full Text62
Jesse D. Blanton, Cathleen A. Hanlon, Charles E. Rupprecht. (2007) Rabies surveillance in the United States during 2006. Journal of the American Veterinary Medical Association 231:4, 540-556
CrossRef63
Wen-rong Yao, Guo-qiang Pan, Cheng-long Xiong, Qian-fu Zhou, Qi-you Xiao, Ming-hui Li, Yong-zhen Zhang. (2007) Detection and genetic characterization of rabies virus from human patients. Virologica Sinica 22:4, 307-315
CrossRef64
Jan Bronnert, Henry Wilde, Veera Tepsumethanon, Boonlert Lumlertdacha, Thiravat Hemachudha. (2007) Organ Transplantations and Rabies Transmission. Journal of Travel Medicine 14:3, 177-180
CrossRef65
Jacqueline Weyer, Charles E. Rupprecht, Janet Mans, Gerrit J. Viljoen, Louis H. Nel. (2007) Generation and evaluation of a recombinant modified vaccinia virus Ankara vaccine for rabies. Vaccine 25:21, 4213-4222
CrossRef66
Jeff Wyatt. (2007) Rabies???Update on a Global Disease. The Pediatric Infectious Disease Journal 26:4, 351-352
CrossRef67
Samson Wong, Susanna Lau, Patrick Woo, Kwok-Yung Yuen. (2007) Bats as a continuing source of emerging infections in humans. Reviews in Medical Virology 17:2, 67-91
CrossRef68
J.A. Stockman. (2007) Survival After Treatment of Rabies With Induction of Coma. Yearbook of Pediatrics 2007, 256-258
CrossRef69
B. Salzberger. (2006) Antivirale Therapie. Der Internist 47:12, 1245-1250
CrossRef70
Charles E Rupprecht, Rodney Willoughby, Dennis Slate. (2006) Current and future trends in the prevention, treatment and control of rabies. Expert Review of Anti-infective Therapy 4:6, 1021-1038
CrossRef71
Thiravat Hemachudha, Supaporn Wacharapluesadee, Jiraporn Laothamatas, Henry Wilde. (2006) Rabies. Current Neurology and Neuroscience Reports 6:6, 460-468
CrossRef72
Juliana H. Chávez, Paulo C. Leal, Rosendo A. Yunes, Ricardo J. Nunes, Célia R.M. Barardi, Aguinaldo R. Pinto, Cláudia M.O. Simões, Carlos R. Zanetti. (2006) Evaluation of antiviral activity of phenolic compounds and derivatives against rabies virus. Veterinary Microbiology 116:1-3, 53-59
CrossRef73
James J Sejvar. (2006) The evolving epidemiology of viral encephalitis. Current Opinion in Neurology 19:4, 350-357
CrossRef74
R.P.D. Cooke, R. Sharma, R. Burman. (2006) Putting theory into practice – infection control lessons following a delayed diagnosis of paralytic rabies. Journal of Hospital Infection 63:4, 482
CrossRef75
R ISTURIZ. (2006) Global Distribution of Infectious Diseases Requiring Intensive Care. Critical Care Clinics 22:3, 469-488
CrossRef76
Alan C Jackson. (2006) Rabies: new insights into pathogenesis and treatment. Current Opinion in Neurology 19:3, 267-270
CrossRef77
Jennifer N. Post. (2006) Immunizations, neonatal jaundice and animal-induced injuries. Current Opinion in Pediatrics 18:3, 330-335
CrossRef78
Herwig Kollaritsch, Wolfgang Maurer. (2006) Tollwut: Epidemiologie, prä- und postexpositionelle Immunisierung. Wiener klinische Wochenschrift 118:11-12, 312-320
CrossRef79
Thomas R. Howdieshell, Daithi Heffernan, Joseph T. Dipiro. (2006) Surgical Infection Society Guidelines for Vaccination after Traumatic Injury. Surgical Infections 7:3, 275-303
CrossRef80
Rafael Oliveira, Neide Takaoka, Paulo Brandao, Pedro Carnieli, Carla Macedo, Juliana Castilho, Maria Luiza Carrieri, Ivanete Kotait. (2006) Postmortem Confirmation of Human Rabies Source. Emerging Infectious Diseases 12:5, 867-869
CrossRef81
Dan Hurley. (2006) TWO APPROACHES TO KETAMINE MOVE FORWARD FOR COMPLEX REGIONAL PAIN. Neurology Today 6:3, 1
CrossRef82
Rodney E. Willoughby, Anna-Lena Hammarin. (2005) Prophylaxis Against Rabies in Children Exposed to Bats. The Pediatric Infectious Disease Journal 24:12, 1109-1110
CrossRef83
John W. Krebs, Eric J. Mandel, David L. Swerdlow, Charles E. Rupprecht. (2005) Rabies surveillance in the United States during 2004. Journal of the American Veterinary Medical Association 227:12, 1912-1925
CrossRef84
Nina Marano, Paul Arguin, Marguerite Pappaioanou, Lonnie King. (2005) Role of Multisector Partnerships in Controlling Emerging Zoonotic Diseases. Emerging Infectious Diseases 11:12, 1813-1814
CrossRef85
Shimon Kusne, Jerry Smilack. (2005) Transmission of rabies virus from an organ donor to four transplant recipients. Liver Transplantation 11:10, 1295-1297
CrossRef86
(2005) Survival after Treatment of Rabies. New England Journal of Medicine 353:10, 1068-1069
Full Text87
Jackson, Alan C., . (2005) Recovery from Rabies. New England Journal of Medicine 352:24, 2549-2550
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