Diagnostic Considerations

Conditions to consider in the differential diagnosis of rabies include the following:

Other infectious causes of encephalitis
Guillain-Barré syndrome
Botulism
Tetanus
Transverse myelitis
Cerebrovascular accident
Psychosis
Intracranial mass
Epilepsy
Atropine poisoning
Creutzfeldt-Jacob disease
Poisoning with atropinelike compounds
Pseudohydrophobia (hysterical reaction to animal bites due to fear of rabies)

Differential Diagnoses

Workup

Zandi F, Goshadrou F, Meyfour A, Vaziri B. Rabies Infection: An Overview of Lyssavirus-Host Protein Interactions. Iran Biomed J. 2021 Jul 1. 25 (4):226-42. [QxMD MEDLINE Link].
Conceição P, Abreu C. [Human Rabies: Optimization of Prevention and Paths Towards the Cure]. Acta Med Port. 2021 Nov 2. 34 (11):767-773. [QxMD MEDLINE Link]. [Full Text].
WHO. Rabies. World Health Organization. Available at http://www.who.int/mediacentre/factsheets/fs099/en/. 21 May 2019; Accessed: 1 Jun 2019.
Zhao H, Zhang J, Cheng C, Zhou YH. Rabies Acquired through Mucosal Exposure, China, 2013. Emerg Infect Dis. 2019 May. 25 (5):1028-1029. [QxMD MEDLINE Link]. [Full Text].
Liu C, Cahill JD. Epidemiology of Rabies and Current US Vaccine Guidelines. R I Med J (2013). 2020 Aug 3. 103 (6):51-53. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. Investigation of rabies infections in organ donor and transplant recipients--Alabama, Arkansas, Oklahoma, and Texas, 2004. MMWR Morb Mortal Wkly Rep. 2004 Jul 9. 53(26):586-9. [QxMD MEDLINE Link].
Srinivasan A, Burton EC, Kuehnert MJ, et al. Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med. 2005 Mar 17. 352(11):1103-11. [QxMD MEDLINE Link].
Centers for Disease Control and Prevention. CDC confirms rabies death in organ transplant recipient. CDC Newsroom. March 15, 2013. Available at https://www.cdc.gov/media/releases/2013/s0315_rabies_organs.html.
Zhu JY, Pan J, Lu YQ. A case report on indirect transmission of human rabies. J Zhejiang Univ Sci B. 2015 Nov. 16 (11):969-70. [QxMD MEDLINE Link]. [Full Text].
Kunkel A, Minhaj FS, Whitehill F, Austin C, Hahn C, Kieffer AJ, et al. Notes from the Field: Three Human Rabies Deaths Attributed to Bat Exposures - United States, August 2021. MMWR Morb Mortal Wkly Rep. 2022 Jan 7. 71(1):31-32. [QxMD MEDLINE Link]. [Full Text].
CDC. Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings (2007). Centers for Disease Control and Prevention. Available at https://www.cdc.gov/infectioncontrol/guidelines/isolation/precautions.html#IIIa. Nov 25, 2015; Accessed: May 28, 2019.
Shankar SK, Mahadevan A, Sapico SD, Ghodkirekar MS, Pinto RG, Madhusudana SN. Rabies viral encephalitis with probable 25 year incubation period!. Ann Indian Acad Neurol. 2012 Jul. 15 (3):221-3. [QxMD MEDLINE Link]. [Full Text].
Blanton JD, Palmer D, Christian KA, Rupprecht CE. Rabies surveillance in the United States during 2007. J Am Vet Med Assoc. 2008 Sep 15. 233(6):884-97. [QxMD MEDLINE Link].
Kim BI, Blanton JD, Gilbert A, et al. A Conceptual Model for the Impact of Climate Change on Fox Rabies in Alaska, 1980-2010. Zoonoses Public Health. 2013 Mar 4. [QxMD MEDLINE Link].
Messenger SL, Smith JS, Rupprecht CE. Emerging epidemiology of bat-associated cryptic cases of rabies in humans in the United States. Clin Infect Dis. 2002 Sep 15. 35(6):738-47. [QxMD MEDLINE Link].
Willoughby RE Jr, Hammarin AL. Prophylaxis against rabies in children exposed to bats. Pediatr Infect Dis J. 2005 Dec. 24(12):1109-10. [QxMD MEDLINE Link].
McLean RG. Rabies in raccoons in the Southeastern United States. J Infect Dis. 1971 Jun. 123(6):680-1. [QxMD MEDLINE Link].
National Association of State Public Health Veterinarians. Compendium of animal rabies prevention and control, 2016: National Association of State Public Health Veterinarians, Inc. (NASPHV). J Am Vet Med Assoc. March 1, 2016. 248:505-517. [Full Text].
Moore DA, Sischo WM, Hunter A, Miles T. Animal bite epidemiology and surveillance for rabies postexposure prophylaxis. J Am Vet Med Assoc. 2000 Jul 15. 217(2):190-4. [QxMD MEDLINE Link].
Doyle TJ, Bryan RT. Infectious disease morbidity in the US region bordering Mexico, 1990-1998. J Infect Dis. 2000 Nov. 182(5):1503-10. [QxMD MEDLINE Link].
Cliquet F, Guiot AL, Aubert M, Robardet E, Rupprecht CE, Meslin FX. Oral vaccination of dogs: a well-studied and undervalued tool for achieving human and dog rabies elimination. Vet Res. 2018 Jul 13. 49 (1):61. [QxMD MEDLINE Link].
Rupprecht CE, Blass L, Smith K, et al. Human infection due to recombinant vaccinia-rabies glycoprotein virus. N Engl J Med. 2001 Aug 23. 345(8):582-6. [QxMD MEDLINE Link].
Jackson AC. Screening of organ and tissue donors for rabies. Lancet. 2004 Dec 11-17. 364(9451):2094-5. [QxMD MEDLINE Link].
WHO. WHO expert consultation on rabies. First Report. WHO technical report series. 2004. 931:1-121.
[Guideline] WHO. Rabies vaccines and immunoglobulins: WHO position. World Health Organization. Available at https://apps.who.int/iris/bitstream/handle/10665/259855/WHO-CDS-NTD-NZD-2018.04-eng.pdf?sequence=1. 2017; Accessed: 1 Jun 2019.
Hemachudha T, Ugolini G, Wacharapluesadee S, Sungkarat W, Shuangshoti S, Laothamatas J. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol. 2013 May. 12 (5):498-513. [QxMD MEDLINE Link]. [Full Text].
Ugolini G. Rabies virus as a transneuronal tracer of neuronal connections. Adv Virus Res. 2011. 79:165-202. [QxMD MEDLINE Link]. [Full Text].
Smith JS, Fishbein DB, Rupprecht CE, Clark K. Unexplained rabies in three immigrants in the United States. A virologic investigation. N Engl J Med. 1991 Jan 24. 324 (4):205-11. [QxMD MEDLINE Link]. [Full Text].
Grattan-Smith PJ, O'Regan WJ, Ellis PS, O'Flaherty SJ, McIntyre PB, Barnes CJ. Rabies. A second Australian case, with a long incubation period. Med J Aust. 1992 May 4. 156 (9):651-4. [QxMD MEDLINE Link]. [Full Text].
Johnson N, Fooks AR, McColl K. Reexamination of Human Rabies Case with Long Incubation, Australia. Emerg Infect Dis. 2008. 14:950-1951. [Full Text].
Boland TA, McGuone D, Jindal J, Rocha M, Cumming M, Rupprecht CE, et al. Phylogenetic and epidemiologic evidence of multiyear incubation in human rabies. Ann Neurol. 2014 Jan. 75 (1):155-60. [QxMD MEDLINE Link]. [Full Text].
Kumar N, Gupta P, Meena MK. Paralytic rabies: a Guillain-Barre syndrome mimic. QJM. 2019 May 1. 112 (5):365-366. [QxMD MEDLINE Link]. [Full Text].
Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention--United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008 May 23. 57:1-28. [QxMD MEDLINE Link].
Goldstein EJ. Current concepts on animal bites: bacteriology and therapy. Curr Clin Top Infect Dis. 1999. 19:99-111. [QxMD MEDLINE Link].
Baer GM. The Natural History of Rabies. Boston, MA: CRC Press; 1991.
Willoughby RE Jr, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. 2005 Jun 16. 352(24):2508-14. [QxMD MEDLINE Link]. [Full Text].
Hantson P, Guérit JM, de Tourtchaninoff M, et al. Rabies encephalitis mimicking the electrophysiological pattern of brain death. A case report. Eur Neurol. 1993. 33(3):212-7. [QxMD MEDLINE Link].
Hemachudha T. Human rabies: clinical aspects, pathogenesis, and potential therapy. Curr Top Microbiol Immunol. 1994. 187:121-43. [QxMD MEDLINE Link].
Willoughby RE, Roy-Burman A, Martin KW, et al. Generalised cranial artery spasm in human rabies. Dev Biol (Basel). 2008. 131:367-75. [QxMD MEDLINE Link].
Wacharapluesadee S, Hemachudha T. Nucleic-acid sequence based amplification in the rapid diagnosis of rabies. Lancet. 2001 Sep 15. 358(9285):892-3. [QxMD MEDLINE Link].
Wacharapluesadee S, Hemachudha T. Urine samples for rabies RNA detection in the diagnosis of rabies in humans. Clin Infect Dis. 2002 Mar 15. 34(6):874-5. [QxMD MEDLINE Link].
WHO. Guide for post-exposure prophylaxis. World Health Organization. Available at http://www.who.int/rabies/human/postexp/en/. Accessed: October 18, 2010.
World Health Organization. Rabnet Database. Department of Communicable Diseases Surveillance and Response. Animal and Food related Public Health Risks. Geneva, Switzerland: World Health Organization; 2001. [Full Text].
Rupprecht CE, Gibbons RV. Clinical practice. Prophylaxis against rabies. N Engl J Med. 2004 Dec 16. 351(25):2626-35. [QxMD MEDLINE Link].
Linlin Fan, Li Zhang, Jingxin Li & Fengcai Zhu. Advances in the progress of monoclonal antibodies for rabies. Human Vaccines & Immunotherapeutics. 16 Feb 2022. 1-8. [Full Text].
Fisher DJ. Resurgence of rabies. A historical perspective on rabies in children. Arch Pediatr Adolesc Med. 1995 Mar. 149(3):306-12. [QxMD MEDLINE Link].
Rupprecht CE, Briggs D, Brown CE, et al. Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices. MMWR. 2010 March 19. 59:1-9. [QxMD MEDLINE Link]. [Full Text].
Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence. MMWR. 1993. 42:1-18. [QxMD MEDLINE Link]. [Full Text].
Parize P, Poujol P, Morineau Le Houssine P, et al. Immune response to rabies post-exposure prophylaxis in patients with non-HIV secondary immunodeficiencies. Vaccine. 2020. 38:5091-5094. [QxMD MEDLINE Link]. [Full Text].
Committee on Infectious Diseases, American Academy of Pediatrics. 2006 Red Book - Report of the Committee on Infectious Diseases. 27. Elk Grove, IL: American Academy of Pediatrics; 2006. 552-9.
WHO. Rabies vaccines: WHO position paper – April 2018. WEEKLY EPIDEMIOLOGICAL RECORD. 20 April 2018. 32:201-220. [Full Text].
Arya SC, Agarwal N. Assessing the safety of post-exposure rabies immunization in pregnancy. Hum Vaccin. 2007 Sep-Oct. 3(5):155; author reply 155. [QxMD MEDLINE Link].
Abazeed ME, Cinti S. Rabies prophylaxis for pregnant women. Emerg Infect Dis. 2007 Dec. 13(12):1966-7. [QxMD MEDLINE Link]. [Full Text].
Complete List of Vaccines Licensed for Immunization and Distribution in the U.S. Food and Drug Administration. Available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm.
Willoughby RE Jr. "Early death" and the contraindication of vaccine during treatment of rabies. Vaccine. 2009 Nov 27. 27(51):7173-7. [QxMD MEDLINE Link].
de Melo GD, Hellert J, Gupta R, Corti D, Bourhy H. Monoclonal antibodies against rabies: current uses in prophylaxis and in therapy. Curr Opin Virol. 2022 Feb 9. 53:101204. [QxMD MEDLINE Link]. [Full Text].
Alan C. Jackson, Mary J. Warrell, Charles E. Rupprecht, Hildegund C. J. Ertl, Bernhard Dietzschold, Michael O'Reilly, et al. Management of Rabies in Humans. Clinical Infectious Diseases. 1 January 2003. 36:60-63. [Full Text].
Centers for Disease Control and Prevention. Recovery of a patient from clinical rabies--Wisconsin, 2004. MMWR Morb Mortal Wkly Rep. 2004 Dec 24. 53(50):1171-3. [QxMD MEDLINE Link]. [Full Text].
Zeiler FA, Jackson AC. Critical Appraisal of the Milwaukee Protocol for Rabies: This Failed Approach Should Be Abandoned. Can J Neurol Sci. 2016 Jan. 43 (1):44-51. [QxMD MEDLINE Link]. [Full Text].
Dandoy S, Scanlon F. Teaching kids about rabies. Am J Public Health. 1999 Mar. 89(3):413-4. [QxMD MEDLINE Link].
Murray KO, Arguin PM. Decision-based evaluation of recommendations for preexposure rabies vaccination. J Am Vet Med Assoc. 2000 Jan 15. 216(2):188-91. [QxMD MEDLINE Link].
Moran GJ, Talan DA, Mower W, et al. Appropriateness of rabies postexposure prophylaxis treatment for animal exposures. Emergency ID Net Study Group. JAMA. 2000 Aug 23-30. 284(8):1001-7. [QxMD MEDLINE Link].
Prosniak M, Faber M, Hanlon CA, Rupprecht CE, Hooper DC, Dietzschold B. Development of a cocktail of recombinant-expressed human rabies virus-neutralizing monoclonal antibodies for postexposure prophylaxis of rabies. J Infect Dis. 2003 Jul 1. 188(1):53-6. [QxMD MEDLINE Link].
Wilson JM, Hettiarachchi J, Wijesuriya LM. Presenting features and diagnosis of rabies. Lancet. 1975 Dec 6. 2(7945):1139-40. [QxMD MEDLINE Link].
A Human Monoclonal Antibody to Rabies Virus Provides Protective Neutralizing Activity: Results of a Phase 1 Study, 50th Annual Meeting, Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Boston, MA, 2010:
Senthilkumaran S, Jena NN, Gore SB, Manikam R, Thirumalaikolundusubramanian P. Factors for early death in rabies- the bitter truth. Indian J Crit Care Med. 2015 Sep. 19 (9):566-7. [QxMD MEDLINE Link].
Taylor E, Banyard AC, Bourhy H, Cliquet F, Ertl H, Fehlner-Gardiner C, et al. Avoiding preventable deaths: The scourge of counterfeit rabies vaccines. Vaccine. 2019 Apr 17. 37 (17):2285-2287. [QxMD MEDLINE Link]. [Full Text].
Quiambao BP, Ambas C, Diego S, Bosch Castells V, Korejwo J, Petit C, et al. Intradermal post-exposure rabies vaccination with purified Vero cell rabies vaccine: Comparison of a one-week, 4-site regimen versus updated Thai Red Cross regimen in a randomized non-inferiority trial in the Philippines. Vaccine. 2019 Apr 10. 37 (16):2268-2277. [QxMD MEDLINE Link]. [Full Text].
Guo Y, Duan M, Wang X, Gao J, Guan Z, Zhang M. Early events in rabies virus infection-Attachment, entry, and intracellular trafficking. Virus Res. 2019 Apr 2. 263:217-225. [QxMD MEDLINE Link]. [Full Text].
Garcés-Ayala F, Aguilar-Setién Á, Almazán-Marín C, Cuautle-Zavala C, Chávez-López S, Martínez-Solís D, et al. Rabies Virus Variants Detected from Cougar (Puma concolor) in Mexico 2000-2021. Pathogens. 2022 Feb 18. 11(2):265. [QxMD MEDLINE Link]. [Full Text].
Iso T, Yuan F, Rizk E, Tran AT, Saldana RB, Boyareddigari PR, et al. Avoidable emergency department visits for rabies vaccination. Am J Emerg Med. 2022 Feb 7. 54:242-248. [QxMD MEDLINE Link]. [Full Text].
Cárdenas G, Salgado P, Laura-Foronda E, Popoca-Rodriguez I, Delgado-Hernández RD, Rojas R, et al. Neglected and (re-)emergent infections of the CNS i n low-/middle-income countries. Infez Med. 2021 Dec 10. 29(4):513-525. [QxMD MEDLINE Link]. [Full Text].
de Melo GD, Sonthonnax F, Lepousez G, Jouvion G, Minola A, Zatta F, et al. A combination of two human monoclonal antibodies cures symptomatic rabies. EMBO Mol Med. 2020 Nov 6. 12:e12628. [QxMD MEDLINE Link]. [Full Text].
Agam K Rao, Deborah Briggs, Susan M Moore, et al. Use of a Modified Preexposure Prophylaxis Vaccination Schedule to Prevent Human Rabies: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022. MMWR. 2022 May 6. 71:619-627. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Hematoxylin and eosin stain of Negri body in a rabies-infected neuron. Courtesy of the US Centers for Disease Control and Prevention.
Distribution of the 5 strains of rabies virus and the associated wildlife in the United States.

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Table 1. Risk Categories for Active Preexposure Immunization and Rabies Titer Monitoring, ACIP 2022

Table 1. Risk Categories for Active Preexposure Immunization and Rabies Titer Monitoring, ACIP 2022

Category	Nature of exposure	Target Population	Relevant biogeography	Immunization Regimen	Serologic Testing
1. Elevated risk for unrecognized and recognized exposures including unusual or high-risk exposures	High concentration exposure is possible, might be recognized or unrecognized, or might be unusual (eg, aerosolized virus)	Rabies research laboratory workers, vaccine production workers, or diagnostic laboratory workers who may work with live rabies virus	Laboratories	Primary series: IM rabies vaccine on days 0 and 7	Rapid Fluorescent Foci Inhibition Test (RFFIT) titer every 6 months; booster if titer < 0.5 IU/mL
2. Elevated risk for unrecognized and recognized exposures	Exposure typically recognized but could be unrecognized; unusual exposures are unlikely	Persons who frequently 1) handle bats, 2) have contact with bats, 3) enter high-density bat environments, or 4) perform animal necropsies (eg, biologists who frequently enter bat roosts or who collect suspected rabies samples).	All geographic regions where any rabies reservoir is present, US domestic and international	Primary series: IM rabies vaccine on days 0 and 7	RFFIT titer every 2 years; booster if titer < 0.5 IU/mL
3. Elevated risk for recognized exposures, sustained risk	Exposure nearly always recognized; risk for recognized exposures higher than that for the general population and duration exceeds 3 years after the primary vaccination	Persons who interact with animals that could be rabid; occupational or recreational activities that typically involve contact with animals include 1) veterinarians, technicians, animal control officers, and their students or trainees; 2) persons who handle wildlife reservoir species (eg, wildlife biologists, rehabilitators, and trappers); and 3) spelunkers	All US domestic and international geographic regions where any rabies reservoir is present	Primary series: IM rabies vaccine on days 0 and 7	1) One-time RRFIT titer at years 1–3 after primary series; booster if titer < 0.5 IU/mL, OR 2) Booster at at point between day 21 and year 3 after primary series
4. Elevated risk for recognized exposures, but not sustained or continuous	Exposure nearly always recognized; risk for exposure higher than for general population but expected to be time-limited (≤3 years from the 2-dose primary vaccination series)	Same as for risk category 3, but risk duration ≤3 years (eg, short-term volunteer providing hands-on animal care or infrequent traveler with no expected high-risk travel >3 years after PrEP administration)	Same as for risk category 3	IM rabies vaccine on days 0 and 7	None
5. Low risk for exposure	Uncommon exposure.	Typical person living in the United States. General population.	None	None	None

Back to List

Author

Sandra G Gompf, MD, FACP, FIDSA Professor of Infectious Disease and International Medicine, University of South Florida Morsani College of Medicine; Chief, Infectious Diseases Section, Director, Occupational Health and Infection Control Programs, James A Haley Veterans Hospital

Sandra G Gompf, MD, FACP, FIDSA is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Tri M Pham, MD Consulting Physician, Division of Infectious Diseases, Watson Clinic, Lakeland

Tri M Pham, MD is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Charurut Somboonwit, MD, FACP Associate Professor of Internal Medicine, Division of Infectious Disease and International Medicine, University of South Florida College of Medicine; Clinical Research and Communicable Diseases Director, USF Health and Hillsborough Health Department

Charurut Somboonwit, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Albert L Vincent, PhD Associate Professor, Division of Infectious Diseases and International Health, Department of Internal Medicine, University of South Florida College of Medicine; Scientific and Research Advisor to the Division of Epidemiology, Hillsborough County Health Department

Disclosure: Partner received none from none for none.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, Association of Professors of Medicine, Infectious Diseases Society of America, Oklahoma State Medical Association, Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Acknowledgements

Leslie L Barton, MD Professor Emerita of Pediatrics, University of Arizona College of Medicine

Leslie L Barton, MD is a member of the following medical societies: American Academy of Pediatrics, Association of Pediatric Program Directors, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society