COMPLICATIONS OF SMALLPOX VACCINATION (VACCINIA)

1. COMPLICATIONS OF SMALLPOX VACCINATION (VACCINIA) Vincent A. Fulginiti, M.D. Professor Emeritus, Pediatrics University of Arizona & University of Colorado

2. (Classic cartoon lampooning smallpox vaccination)

3. VACCINATIONNORMALSEQUENCE Dixon

4. VACCINATION COMPLICATIONS • Non-infectious rashes-E.multiforme, variety of others • Bacterial superinfection:Staph, strep,tetanus, +++ • Accidental inoculation:self or from vaccinee, eczema vaccinatum • Congenital vaccinia: rare • Generalized vaccinia: often benign; can progress • Progressive vaccinia: vaccinia necrosum, vaccinia gangrenosa, primarily in immunodeficient • Post-vaccination encephalitis: rare • Miscellaneous: hemolytic anemia, arthritis, osteo, pericarditis, myocarditis

5. Non-specific rashes • Erythema multiforme : most common @ 7-14 days post primary; sooner after revaccination-pruritic-? Allergic vs toxic Macular rash; intense perivaccinia Maculopapular Occasionally vesicular (differentiate from generalized vaccinia) Urticaria Rarely, Stevens-Johnson Syndrome

6. ERYTHEMA MULTIFORME COMMON, IMPRESSIVE, BUT BENIGN; RARELY CAN SEE STEVENS-JOHNSON SYNDROME

7. Diagnosis by clinical appearance Temporal association with vaccinia Rarely need consulatation to r/o other skin conditions Treatment is totally symptomatic Usually antihistamines suffice for most of these rashes With SJS, may need steroids. Locally (eye) and systemically DIAGNOSIS AND TREATMENT

8. Bacterial superinfection • At one time, tetanus, syphilis, enteric were major complicating infections, especially with ritualistic poultices • In recent times, staph and strep have predominated • Can be accentuated by occlusive dressings • Responds rapidly and completely to prompt, appropriate antimicrobial therapy

9. STAPH ………...AND STREP Vesicular border with clearing central area -pure staphylococcal (Heaped up streptococcal infection -red color is artifact of topical drug)

10. ACCIDENTAL ADMINISTRATION • Two major types of accidents Inadvertent I.M. Injection Oral ingestion • To my knowledge, no adverse consequences from either accident, unless oral injury occurs from vaccine instrument during ingestion

11. Accidental inoculation • Autoinoculation or from a vaccinee • Any part of body affected • Serious: keratitis, burns, and eczema vaccinatum (in last untreated may result in 30% mortality;with VIG, virtually zero) • Traumatic/surgical woulds predispose • Dermal infection/ disease may predispose • Mucosal inoculation possible; dental extraction sites, tonsillar lesions, rectal, laryngeal, esophageal

12. Factors in Accidental Inoculation • Common in very young infants/children • Caretakers at risk • Transfer often by hand to skin/mucosa • Inflammatory eye disease predisposes to periorbital/corneal lesions (eye-rubbing) • Bathing can result in autoinoculation

13. EXAMPLES INOCULATION INTO DIAPER RASH FROM VACCINATED SIBLING AND PARENT (VACCINIA KERATITIS)

14. ECZEMA VACCINATUM

15. ANOTHER EXAMPLE

16. ACNE AND VACCINIA

17. DIAGNOSIS • Diagnosis usually obvious as lesions are identical to original vaccination • Ocular lesions may be confused with herpes and other eye infections; look for adjacent lesions, timing and hx of appropriate contact • Wound/post surgical lesions may be confusing; look for contact history • Viral dx tests occasionally indicated

18. TREATMENT • For most lesions; 0.6 ml/kg VIG sufficed • Occasionally need up to 1-2 mg/kg • Eczema vaccinatum, 1-5 ml/kg; start with 1 and add to it if new lesions appear. The largest used was 10 ml/kg with massive lesions. • Eye: AVOID VIG; use topical antivirals (human experience and animal work suggest that an Ag/Ab reaction occurs in the eye with VIG rx • Thiosemicarbazone used occasionally; not enough experience to judge efficacy

19. Congenital vaccinia • Rare event • Greatest danger for pregnant susceptible is third trimester • No congenital anomalies have been linked to maternal vaccination

20. GENERALIZED VACCINIA • Despite appearance, is generally benign • Differs from eczema vaccinatum and progressive vaccinia • Lesions “normal” and multiple, presumably bloodborne, and occur in healthy individual (as far as could be determined by prevailing immunologic methods at the time). Primary normal. • Usually self-limited; rarely recurrent every 4-6 weeks up to one year

21. Note that all lesions are “normal” and non-progressive GENERALIZED VACCINIA - BENIGN

22. DIAGNOSIS & TREATMENT • Clinical picture characteristic; verify with viral isolation or identification, p.r.n. • Immunologic studies warranted with today’s knowledge of range of defects • Rx: 0.6 ml/kg VIG (although most episodes self-limited, with repeat episodes may wish to give more or repeat course of rx • Consider antivirals

23. Progressive Vaccinia • In immunolgically deficient; primarily in cell-mediated immune deficiencies, but a few cases in hypogammaglobulinemia have been seen (immunologic studies not as sophisticated then as now) • Progressive enlargement of primary, viremic spread to other parts of the body, each lesion expanding without limitation • Fatal in most cases, a few survived

24. PROGRESSIVE VACCINIA Note that the lesions have no inflammation, and progress in size without limitation. Child had severe combined immunodeficiency (SCID) and despite rigorous and extensive antibody and antiviral chemotherapy, died with overwhelming viremia.

25. PROGRESSIVE VACCINIA Primary lesion in child with absent cell-mediated immunity. Note vesicular edge of advancing viral infection in the absence of any inflammatory reaction

26. PROGRESSIVE VACCINIA(Hypogammaglobulinemia with concurrent viral infection shortly after vaccination applied resulting in progressive lesion) This child underwent extensive antibody and antiviral treatment without effect. When viral load was reduced by amputation, therapy resulted in cure and he is alive and well today.

27. EMPIRIC THERAPY

28. ADDITIONAL EXAMPLES

29. ADDITIONAL EXAMPLES

30. ANTIBODY +; CMI ABSENT RX: VIG, ISTC, SURGERY-Excision followed by grafting, ANTIBIOTICS

31. ADULT VACCINIA

32. VIROLOGIC DX IMMUNOLOGIC ASSESSMENT CRITICAL GENETIC TESTING FAMILY HISTORY VIG (ALSO PLASMA, EXCHANGE TRANSFUSION ANTIVIRAL RX IUDR INEFFECTIVE THEN THIOSEMICARBAZONES ? NOW (CIDOFOVIR?) CELL TRANSFER GVH RESULTED ? GENE THERAPY DIAGNOSIS & TREATMENT

33. Post-vaccination encephalitis • Rare: 1 in 100,000 -500,000 vaccinations • Sudden onset of headache,vomiting in second week after vaccination • Convulsions, lethargy progressing to coma, paralysis, focal neurologic signs • Cerebral edema evident with massive increased intracranial pressure • Varies in severity and prognosis; can be mild and self limited, or progressive and fatal. ? Autoimmune (anti virus-neural cell component)

34. DIAGNOSIS & TREATMENT • Clinical diagnosis plus temporal association- usually in 2nd week after vaccination. Sxs include convulsions, lethargy, coma, paralysis, increased intracranial pressure & focal neurologic signs in any combination. • Compatible CSF findings • Supportive care only

35. REFERENCES-I • BEST OVERALL SOURCES: • Dixon CW, SMALLPOX, 1962, J & A Churchill LTD, London: This text is the classic in smallpox and vaccinia. The author did • many of the original clinical studies of this disease and his text is authoritative and beautifully illustrated. • Henderson DA, Inglesby TV, Bartlett JG, et al: Smallpox as a Biological Weapon, JAMA 1999, 281:2128-2136 A concise summary • of the disease and medical and public health aspects of management in the event of a bioterrorist attack • Kempe CH: Studies on Smallpox and Complications of Smallpox Vaccination: E Mead Johnson Award Address, Pediatrics 1960, 26: • 177-189. A definitive report of the state of the art of the time. • Kempe CH, St Vincent L: Variola and Vaccinia Viruses: WHO Expert Committee on Smallpox, WHO Tech Report Series, 1964, #283, • 665-692. Definitive information of the viruses • www.cdc.gov: definitive website for up-to-date information on smallpox • GENERAL: • Anthony RL, Douglass LT, Daniel RW, et al: Studies of Variola Virus and Immunity in Smallpox, J Infect Dis 1970: 121: 295-302; • 1971, 123:485-89 • Angulo JJ, Rodrgues-DA-Silva G, Rabello SI: Spread of Variola Minor in Households, Amer J Epidemiol 1967, 86:479-87 • Bauer DJ, St Vincent L, Kempe CH: Prophylaxis of Smallpox with Methisazone, Amer J Epidemiol 1969, 96:130-145 • Breman JG, Arita I: The Confirmation and Maintenance of Smallpox Eradication, NEJM 1980, 303:1263-73 • Cohen J, Marshall E: Vaccines for Biodefense: A System in Distress, Science 2001, 294:498 • Cruickshank JG, Bedson HS, Watson, DH: Electron Microscopy in the Rapid Diagnosis of Smallpox, Lancet 1966, 2:527-530 • Dekking F, Rao AR, St Vincent L, Kempe CH: The Weeping Mother, an unusal source of variola virus, Arch Fur Die Ges Virusforsch • 1967, 22:215-18 • Den nis DT, Doberstyn EB, Awoke S: Failure of cytosine arabinoside in treating smallpox, Lancet 1974, 2:377-379 • Downie AW, St Vincent L, Meiklejohn G, Ratnakannan NR, Rao AR, Krishnan, Kempe CH; Studies on the Virus Content of Mouth • Washings in the Acute Phase of Smallpox, Bull WHO 1961, 25:41-71 • Downie AW, Hobday TL, St Vincent L, Kempe CH: Studies of Smallpox Antibody Levels of Sera from Samples of the • Vaccinated Adult Population of Madras, Ibid • Fenner F: Global Eradication of Smallpox, Rev Infect Dis 1982, 4:916-930 • Fulginiti V, Kempe CH: Poxvirus Diseases, in Brenneman-Kelley Practice of Pediatrics, Vol II, Chap 25, 1968; • Fulginiti VA, Vol II, Chapter 39, 1972 • Fulginiti VA, Kempe CH, Hathaway WE, et al: Progressive Vaccinia in Immunologically Defieicient Individuals, in Immunologic • Deficiency Diseases in Man, Birth Defects Original Article Series, 1968, The National Foundation March of Dimes, IV:129-151 • Fulginiti VA, Winograd LA, Jackson, M and Ellis P: Therapy of Experimental Vaccinal Keratitis, Arch Ophtal 1965, 74:539-44 • Fulginiti, VA: Variola (smallpox). In Clinical Dermatology. Demis, DJ et al, eds. Vol. 3, revised edition, Unit 14:8, pp. 1-8. Harper & • Row, 1974. (Revised for 2002 publication)

36. REFERENCES II Hobday TL, Rao AR, Kempe CH, Downie AW: Compariason of Dired Vaccine With Fresh Indian Buffalo-Calf Lymph in Revaccination Against Smallpox, 1961 Bull WHO 25:41-71 Hathaway WE, Fulginiti VA, Pierce CW, Githens JH, Pearlman DS, Muschenheim F, Kempe CH: Graft-vs-Host Reaction following a Single Blood Transfusion, JAMA 1967, 201: 1015-1020 Hopkins DR, Smallpox:Ten Years Gone, AJPH 1988, 78:1589-95 Henderson RH, Yepke M: Smallpox Transmission in Southern Dahomey, Amer J Epidemiol 1969, 90:423-28 Kempe CH,Bowles G, Meikeljohn G, et al: The Use of Vaccinia Hyperimmune Gamma-Globulin in the Prophylaxis of Smallpox, Bull WHO 1961: 25:41-71 Kempe CH, Fulginiti VA, Minamitani M, Shinefeld H: Smallpox Vaccination of Eczema Patients with a Strain of Attenuated Live Vaccinia (CVI-78), Pediatrics 1968, 42:980-985 Ker FL: Variola Minor, Clin Pediatr 1967, 6;533-39 Lane JM, Millar JD, Neff JM: Smallpox and Smallpox Vaccination Policy,Ann Rev Med 1971, 251-272 Lane JM, Ruben FL, Abrutyn E, Millar JD: Deaths Attributable to Smallpox Vaccination, 1959 to 1966, and 1968, JAMA 1970, 212:441-444 Lane JM, Ruben FL, Neff JM, Millar JD: Complications of Smallpox Vaccination-1968, NEJM 1969, 281:1201-08 Lane JM, Millar JD, Risks of Smallpox Vaccination Complications in the United States, Amer J Epidemiol 1971, 93:238-240 Meiklejohn G, Kempe CH, Downie AW, Berge TO, St Vincent L, Rao AR: Air Sampling to Recover Smallpox Virus in the Environment of a Smallpox Hospital, Bull WHO, 1961 25:41-71 Meikeljohn G: Smallpox: Is the End in Sight? Maxwell Finland Lecture, J Infect Dis1976, 133:347-353 Mc Kenzie PJ, Githens JH, Harwood ME, Roberts JF, Rao AR, Kempe CH: Haemorrhagic Smallpox, Bull WHO 1965, 33:773-782 Mack TM: Smallpox in Europe, 1950-1971, J Infect Dis 1972, 125:161-169 Ministry of Health: Smallpox 1961-62, Reports on Public Health and Medical Subjects #109, Her Majresy’s Stationary Office, London 1963 Murray HGS: The Diagnosis of Smallpox by Immunofluorescence, Lancet 1963, 1:847-848 Rao AR, Prahlad I, Swaminathan M: A Study of 1000 Cases of Smallpox, J Indian Med Assoc 1960, 35:296-307 Roberts JF, Coffee G, Creel SM, Gaal A, Githens JH, Rao AR, Babu VS, Kempe CH: Haemorrhagic Smallpox, Bull WHO 1965, 33:607-613 Ritzinger FR: Disease Transmission by Aircraft, Miitary Med 1965 130:643-47 WHO Expert Committee on Smallpox First Report , WHO Tech Report Series , #283, 1964, WHO, Geneva

37. TECHNICAL REFERENCES TECHNICAL REFERENCES Bedson S, Downie AW, MacCallum FO, Stuart-Harris CH, VIRUS AND RICKETTSIAL DISEASES OF MAN, Edward Arnold Ltd, London Lennette, EH, Schmidt NJ, DIAGNOSTIC PROCEDURES FOR VIRAL, RICKETTSIAL AND CHLAMYDIAL INFECTIONS, 5TH ED., 1979, American Public Health Association, Washington, D.C. Swain RHA, Dodds TC: CLINICAL VIROLOGY, 1967, Williams and Wilkins Co, Baltimore, MD. Galasso GJ, Merigan T, Buchanan RA: ANTIVIRAL AGENTS AND VIRAL DISEASES OF MAN, 1979Raven Press, New York, New York