# Presentation: 610799

## Post-Vaccinial EncephalitisDiagnostic and Management

- None for specific diagnosis of PVE
- Diagnosis of exclusion – Consider other infectious or toxic etiologies
- 15-25% mortality rate
- 25% varying neurological deficits
- VIG not recommended

**Notes:**
Currently there are no clinical criteria, radiographic findings or laboratory tests that are specific for the diagnosis of PVE.  Post-vaccinial encephalopathy and encephalomyelitis are diagnoses of exclusion, and other infectious or toxic etiologies should be considered before making this diagnosis.  In the past, vaccinees of the NYCBOH strain that developed PVE or PVEM had a 15-25% mortality rate and 25% of survivors were left with varying neurological deficits.  

No study has shown vaccinia immune globulin to be an effective therapeutic for PVE or PVEM and therefore VIG is not recommended for treatment of PVE or PVEM.  Consequently, there is no specific therapy for PVE or PVEM; however, supportive care, anticonvulsants and intensive care may be required.  Since the clinical symptoms of PVE or PVEM are not thought to be a result of replicating vaccinia virus, the role of antivirals have not been elucidated.      

Other reported neurological complications following smallpox vaccination are transverse myelitis, seizures, paralysis, polyneuritis and brachial neuritis.
==========================
Reference:
[i] Spillance JD, Wells CDC:  The neurology of Jennerian vaccination: A clinical account of the Neurologic complications which occurred during the smallpox epidemic in South Wales in 1962.  Brain 1964, 87:1.

## Fetal Vaccinia

**Notes:**
Fetal vaccinia, resulting from vaccinial transmission from mother to fetus, is a very rare, but serious, complication of smallpox vaccination during pregnancy or shortly before conception.  There are fewer than 50 cases reported in the literature.   Fetal vaccinia is manifested by skin lesions, and organ involvement, and often results in fetal or neonatal death.  The skin lesions in the newborn infant are similar to those of generalized vaccinia or progressive vaccinia and can be confluent and extensive.   Few affected pregnancies are maintained until term.  Affected pregnancies have been reported among women vaccinated in all three trimesters, among first-time vaccinees as well as in those being revaccinated, and among non-vaccinated contacts of vaccinees.  Because fetal vaccinia is so rare, the frequency of and risks for fetal vaccinia cannot be reliably determined.  Whether virus infects the fetus through blood or by direct contact with infected amniotic fluid is unknown.  There is no known reliable intrauterine diagnostic test to confirm fetal infection.

Apart from the characteristic pattern of fetal vaccinia, the association of smallpox vaccination of pregnant women with prematurity, low birth weight, and fetal loss has been debated, though not clearly demonstrated, in the literature.  There is no recognizable pattern of congenital malformations associated with smallpox vaccination during pregnancy. 
===========================
References:
[i] Greenberg M, Yankauer A, Krugman S, et al. The effect of smallpox vaccination during pregnancy on the incidence of congenital malformations. Pediatrics 1949; 3:456.
[ii] Green DM, Reid SM, Rhaney K. Generalized vaccinia in the human fetus. Lancet 1966; I:1296.
[iii] Harley JD, Gillespie AM. Complicated congenital vaccinia. Pediatrics 1972; 50:150.
[i] Lane JM, Millar JD, Neff JM. Smallpox and smallpox vaccination policy. Annu Rev Med 1971; 22:251-72:251-272.

[ii] CDC. Smallpox vaccine: recommendations of the Public Health Service Immunization Practices Advisory Committee. MMWR 1978; 27:156-8-163-4.
[iii] CDC. Adverse reactions to smallpox vaccination-1978. MMWR 1979; 28:265-267.

[iv] Levine reference Sheryl Lyss reference here  

================================
Fetal vaccinia in a premature infant, 28 weeks gestation.  Mother received vaccination at 23 weeks gestation.  The infant died at age 8 days and vaccinia was isolated from the placenta.

Source:  J. Michael Lane, Teaching Slide set.  J.M. Lane, M.D.

## Fetal Vaccinia

**Notes:**
Vaccinia immune globulin may be considered for a viable infant born with lesions, although no data exists for dosage or efficacy.  If a pregnant woman is inadvertently vaccinated or if she becomes pregnant within 4 weeks after vaccinia vaccination, she should be counseled regarding the basis of concern for the fetus.  However, given the rarity of fetal vaccinia, vaccination during pregnancy should not ordinarily be a reason to terminate pregnancy. Currently there is no indication for routine, prophylactic use of VIG in an unintentionally vaccinated pregnant woman; VIG should not be withheld, however, if a pregnant woman develops a condition where VIG is needed (e.g., eczema vaccinatum).   

To expand understanding of the risk of fetal vaccinia and to document whether adverse pregnancy outcome may be associated with vaccination, CDC will establish a smallpox vaccination pregnancy registry (see “Requests for clinical consultation or release of VIG and cidofovir”).
============================
Annotation:  Fetal vaccinia scars in an otherwise healthy infant that was born approximately 32 weeks gestation. The child did well and reports indicated normal development.  The mother was vaccinated at 2 months gestation.
Source:  J. Michael Lane, Teaching Slide set.  J.M. Lane, M.D.

## Associating the Condition with the Vaccine

- Know Chronology of immunization and adverse event
- Corresponds to those previously associated
- Biologic plausibility
- Lab result confirms association
- Recurs on re-administration
- Controlled clinical or epi trial shows association

**Notes:**
Less frequently reported adverse events following smallpox vaccination include myocarditis, pericarditis, precipitation of erythema nodosum leprosum or neuritis in leprosy patients, and osteomyelitis (sometimes confirmed by recovery of vaccinia virus).  Reported skin changes at the vaccination scar have included malignant tumors, such as melanoma, discoid lupus, and myxedema as a presenting symptom of Graves’ disease.

It is unclear if the occurrence of these conditions is associated with smallpox vaccination or if other unknown adverse events following smallpox vaccination may yet to be described.   In general, determining causality of reported post-vaccination events associated with a specific vaccine is challenging and requires careful weighing of all the scientific evidence, evaluation of the quality and consistency of the data, and consideration of biologic plausibility of the association between the vaccination and the event

Clinicians should report unexpected and clinically relevant adverse events following vaccination to the Vaccine Adverse Reporting System in conjunction with the local, state and territorial reporting requirements. 
=====================
References: [i] Cangemi VF.  Acute pericarditis after smallpox vaccination. NEJM 1958:258(25).
[ii] Finlay-Jones LR.  Fatal myocarditis after vaccination against smallpox:  Report of a case.  NEJM 1978:1964:270(1).
[iii] Helle EP, Koskenvuo K, Heikkila J, Pikkarainen J, Weckstrom P.  Myocardial complications of immunizations.  Ann Clin Res 1978:10(5). 
[iv] Moschos A, Papioannou AC, Nicolopoulos D., Anagnostakis D.  Cardiac complications after vaccination for smallpox.  Helv Paediatr Acta 1976:31(3).
[v] MacAdam DB, Whitaker W. Cardiac complications after vaccination with smallpox.  British Med Journal 1962: 1099-1100.
[vi] Dalgaard JB. Fatal mayocarditis following smallpox vaccination.  Army Medical Service, Copenhagen, Denmark 1957:54(1).
[vii] Vorst EJ, Gaillard JL.  Vaccinial osteomyelitis in a case of generalized interuterine virus infection.  Pediatr Pathol 1983:1(2)
[viii] Lupton GP.  Discoid lupus erythematosus occurring in a smallpox vaccination scar.  J Am Acad Dermatol 1987:17(4).
[ix] Pujol RM, Monmany J., Bague S., Alomar A.  Graves’ disease presenting as localized myoedematous infiltration in a smallpox vaccination scar.  Clin Exp Dermatol  2000: 25(2).

## Revaccination of Those with History of AE

- In absence of smallpox, do NOT revaccinate
- Defer those not vaccinated from response teams

**Notes:**
Prior to the eradication of smallpox, clinicians were often faced with the decision  of whether or not to revaccinate of individuals who had documented serious adverse events.  Goldstein et al. reported that revaccination of children who have had eczema vaccinatum is not contraindicated, revaccination of children with a history of inadvertent inoculation or erythematous or urticarial rashes presents no known or theoretical risk, and individuals with a history of PV should not be revaccinated.  

In the absence of circulating smallpox virus and smallpox disease, revaccination of individuals with a history of adverse events from smallpox vaccination is not warranted.  Persons with a history of adverse events from smallpox vaccination, who are not vaccinated, should be deferred from participation on smallpox response teams.  This recommendation does not extend to those persons who experienced inadvertent inoculation, or erythematous or urticarial rashes after a previous smallpox vaccination, who can be revaccinated without increased risk of an adverse event.

In the event of an outbreak of smallpox, it is recommended that all persons exposed to a case of smallpox be vaccinated against smallpox regardless of contraindications to vaccination, as the benefits of smallpox vaccination will outweigh the risks of an adverse event from smallpox vaccine.

## Prophlyaxis of High-Risk Groups Accidentally Exposed

- VIG NOT recommended
- Vigilant clinical follow-up
- Do NOT administer VIG with smallpox vaccine
- Exclude those with contraindications

**Notes:**
In the past, VIG has been recommended as a prophylactic treatment for individuals with contraindications who are inappropriately vaccinated, or for persons with contraindications who are exposed to the vaccinia virus through close contact with a recent vaccinee.  For individuals with acquired or inherited immune deficiency, it was recommended to administer therapeutic doses of VIG, and all other high-risk individual were given prophylaxic doses of VIG.  Some experts advocated frequent intervals of revaccination of persons with eczema (also referred to as atopic dermatitis) to maximize the endogenous immunity resulting from prior vaccination.  In these cases, it was common practice to concomitantly administer VIG.   In addition, VIG was sometimes administered to infants less than 12 months of age, pregnant women or individuals with eczema (today referred to as atopic dermatitis) when vaccination was determined to be necessary due to potential exposure to variola.  

However, VIG administration is not without risk, and the efficacy of VIG as a prophylactic against vaccinial infection has not been studied in a controlled setting.  Until VIG is evaluated for such use, VIG is not recommended for prophylaxis when a person with contraindications to smallpox vaccination is inadvertently exposed to vaccinia and has no vaccinia-related complication.  Such persons should have vigilant clinical follow-up so that prompt diagnosis and treatment of an adverse event can occur, should one develop.  Furthermore, in the absence of circulating smallpox virus, VIG is not recommended for concomitant use with smallpox vaccination to vaccinate individuals with contraindications to smallpox vaccination.  Persons with contraindications to smallpox vaccination should not be vaccinated in the pre-outbreak setting.  As recommended by ACIP, careful screening criteria should be used to exclude persons with contraindications to smallpox vaccination from vaccination programs.

In order to better understand the risks of vaccinia exposure in persons with contraindications to smallpox vaccination, CDC will maintain a registry of inadvertent exposures in high-risk groups (e.g., vaccinee or contact with dermatological, pregnancy or immunocompromised contraindications).  Clinicians are encouraged to report these cases to the CDC so that prompt treatment can be initiated when necessary, and patients can be followed in a standardized fashion.  These data will be used to assess risk of developing an adverse event and the potential role for prophylaxis therapy in these patients.

## Laboratory Diagnosis

**Notes:**
Clinical evaluation and a careful patient history of recent smallpox vaccination or contact with a recent vaccinee are the mainstays of diagnosis of smallpox vaccine-related adverse events. 

## Laboratory DiagnosisRule Out Testing

- Varicella
- Herpes Zoster
- Herpes Simplex
- Enteroviruses

**Notes:**
In situations where clinical diagnosis is not straightforward, laboratory diagnostics for vaccinia may be helpful and may prevent inappropriate use of potentially toxic therapies.  However, diagnostics for conditions likely to be confused with vaccinia infection, (varicella, herpes zoster, herpes simplex, and enteroviruses), should be considered first, especially in a non-vaccinee, or someone believed to be a non-contact to a vaccinee.

## Laboratory DiagnosisTests Available

- Electron Microscopy (EM) - Orthopoxvirus
- PCR – Gene Amplification
- Viral Culture – Identify vaccinia
- May be available through LRN
- Consult with CDC for testing advice

**Notes:**
Serologic testing for vaccinia is largely non-informative, as it cannot distinguish between vaccinia immunity and vaccinia infection.  Diagnostic tests for vaccinia include electron microscopy (EM) to look for orthopoxvirus, and gene amplification (polymerase chain reaction, PCR), and viral culture for vaccinia.  Currently these tests are available only for research purposes, but are undergoing multicenter validation studies that may enable FDA to approve the test reagents for diagnostic use.  At that point, testing will be made available through the Laboratory Response Network (LRN), an extensive system of public health and private laboratories, which can be accessed through consultation with state and local health departments.  Until that time, consultation on appropriate use of laboratory testing will be available through CDC.  Results of these tests must be interpreted with caution, as there is more to learn about the clinical implications of positive results.  

## Specimen Collection

- Contact state health department
- CDC Interim Smallpox Response Plan, Guide D
-      www.cdc.gov/smallpox

## Treatments

**Notes:**
Topical ophthalmic antiviral drugs, VIG and cidofovir are some of the therapies used to treat adverse events following smallpox vaccination.  Ophthalmic drugs are discussed in the section on “Ocular Complications”. 

## Vaccinia Immune Globulin

- Immunoglobulin fraction of plasma
- Antibodies to vaccinia from vaccinated donors
- Previously-licensed IM product (Baxter)
- Contains 0.01% thimerosal
- New IV products in production
- Obtain as IND product through CDC and DoD

**Notes:**
VIG is a sterile solution of the immunoglobulin fraction of plasma, containing antibodies to vaccinia virus from individuals who were immunized with vaccinia virus vaccine.  The currently available preparation of VIG is a previously licensed intramuscular product (VIG-IM) produced by Baxter Healthcare Corporation in 1985 and contains 0.01% thimerosal (a mercury derivative) as a preservative. Two new intravenous preparations (VIG-IV) are in production. All preparations of VIG are expected to be available as Investigational New Drug (IND) products through the CDC and DoD.  

## VIG IndicationsIndications

- Eczema vaccinatum
- Progressive vaccinia
- Vaccinia necrosum
- Generalized vaccinia – severe cases

**Notes:**
VIG has demonstrated efficacy in the treatment of smallpox vaccine adverse events that are secondary to continued vaccinia virus replication following vaccination. Such adverse events include eczema vaccinatum, progressive vaccinia or vaccinia necrosum, and severe cases of generalized vaccinia. VIG has no proven effectiveness for the treatment of post-vaccination adverse events such as post-vaccinial encephalitis (PVE) and has a qualified contraindication in keratitis (see ocular vaccinial infections).
==========================
Reference: [i] Sharp JCM, Fletcher W.  Experience of antivaccina immunoglobulin in the United Kingdom. Lancet 1973;(1):656-659.

## Vaccinia Immune GlobulinIndications

| Recommended | Inadvertent Inoculation - severe
Eczema vaccinatum
Generalized vaccinia – severe or underlying illness
Progressive vaccinia |
| --- | --- |
| Not Recommended | Inadvertent Inoculation – Not severe
Generalized vaccinia – mild or limited
Non-specific rashes, EM, SJS
Post-vaccinial encephalitis |
| Consider | Ocular complications |

**Notes:**
VIG is recommended for the treatment of eczema vaccinatum and progressive vaccinia.  As most cases of generalized vaccinia are self-limited, VIG is recommended for the treatment of generalized vaccinia only if the patient is seriously ill or has serious underlying disease that is a risk factor for a complication of vaccination (e.g., immunocompromised condition such as HIV/AIDS).  VIG may also be useful in the treatment of ocular vaccinia resulting from inadvertent implantation.  When ocular vaccinia with keratitis is present, the consideration of VIG should take into account the possibly increased risk of corneal scarring (see Ocular Vaccinia Infections).

Currently, VIG is not recommended for prophylactic use when vaccinating a person with a known contraindication.   A prospective study of prophylactic use of VIG in Danish army recruits demonstrated reduced incidence of developing PVE for individuals vaccinated with a non-NYCBOH strain.  This led to routine administration of VIG in first-time vaccinations of adults in the Netherlands. The incidence of PVE following smallpox vaccination with NYCBOH strain is low, so that concomitant administration of VIG at time of vaccination has never been recommended with the less reactogenic NYCBOH strain. 
=============================
References:[i] Nanning, W. (1962)  Prophylactic effect of antivaccinia gammaglobulin against post-vaccinial encephalitis. Bulletin of the World Health Organization, 27:317-324.
[ii] Polak, MF, Beunders, BJW, Werff, AR, Van der Sanders, EW, Klaveren, JN, Van & Brans, LM (1963).  A comparative study of clinical reactions observed after application of several smallpox vaccines in primary vaccination of young adults.  Bulletin of the World Health Organization, 29:311-322. 

## Vaccinia Immune GlobulinSide Effects - Mild

- Local Pain
- Tenderness
- Swelling
- Erythema
- From few hours to 1 or 2 days

**Notes:**
Vaccinia immune globulin administration has been associated with mild, moderate and severe adverse events.  Mild adverse reactions include local pain and tenderness, swelling, and erythema at the injection site following intramuscular administration of immunoglobulins and can persist from a few hours to 1 or 2 days following administration. 

## Joint Pain
Diarrhea
Dizziness
Hyperkinesis
Drowsiness
Pruritis
Rash
Perspiration
Vasodilation

- Diarrhea
- Dizziness
- Hyperkinesis
- Drowsiness
- Pruritis
- Rash
- Perspiration
- Vasodilation

**Vaccinia Immune Globulin****Side Effects - Moderate**

**Notes:**
Moderate adverse reactions include joint pain, diarrhea, dizziness, hyperkinesis, drowsiness, pruritis, rash, perspiration and vasodilation.   Back and abdominal pain, nausea, and vomiting may occur within the first 10 minutes of injection.   Chills, fever, headache, myalgia and fatigue may begin at the end of infusion and continue for several hours.  More severe reactions of this type may require pretreatment with corticosteroids or acetaminophen, should another dose of VIG be required.  

## Hypotension
Anaphylaxis
Renal Dysfunction
Aseptic Meningitis Syndrome (AMS)

- Anaphylaxis
- Renal Dysfunction
- Aseptic Meningitis Syndrome (AMS)

**Vaccinia Immune Globulin****Side Effects - Serious**

**Notes:**
Serious adverse events associated with administration of VIG can include hypotension, anaphylaxis and anaphylactoid systemic reactions, renal dysfunction and aseptic meningitis syndrome (AMS).  Aseptic meningitis syndrome may begin within several hours to 2 days following treatment, and may occur more frequently in association with high dose (2 g/kg) therapy.   It is characterized by severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting.  Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. 

Anaphylaxis and anaphylactoid systemic reactions have been reported following intramuscular (IM) or intravenous (IV) injection of human immunoglobulin preparations.  The symptoms of classic anaphylactic reactions are: flushing, facial swelling, dyspnea, cyanosis, anxiety, nausea, vomiting, malaise, hypotension, loss of consciousness, and in some cases, death.  Symptoms appear within seconds to several hours after infusion.  The treatment of such reactions is immediate discontinuation of immune globulin and administration of epinephrine, oxygen, antihistamines, intravenous steroids and cardiorespiratory support.

When therapeutic proteins prepared from human blood or plasma are administered, the potential for the transmission of infectious agents cannot be totally excluded.  This also applies to infectious agents that may not have been discovered or characterized when the current preparations of VIG were formulated.  To reduce the risk of transmitting infectious agent(s), stringent controls are applied in the selection of blood and plasma donors, and prescribed standards are used at plasma collection centers, testing laboratories, and fractionation facilities. 

## Vaccinia Immune Globulin Contraindications

- Allergic reaction to thimerosal
- History of severe reaction with IG preparations
- IgA Deficiency
- Vaccinia keratitis, except in some cases
- Pregnancy
- Theoretical risks as with all human plasma

**Notes:**
Contraindications to VIG administration include an acute allergic reaction to thimerosal or history of a severe reaction following administration of human immunoglobulin preparations. .  Persons with selective immunoglobulin A deficiency have the potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA.   Vaccinia keratitis, in the absence of other conditions that require VIG treatment, is a contraindication.

It is not known whether VIG can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity.  Though clinical experience with other preparations containing immunoglobulins suggests there are no fetal adverse events from immunoglobulins, there have been no studies to date evaluating the adverse effects of VIG on the fetus. VIG should be given to a pregnant woman only if clearly needed.  Similarly, it is not known whether this drug is excreted in breast milk, so that caution should be exercised when VIG is administered to a nursing woman.  

Because VIG is made from human plasma, there is a theoretical risk of transmission of viruses and inclusion of adventitious agents that may cause Creutzfeldt-Jacob disease.  The risk that these products contain infectious agents has been reduced by verbal screening of plasma donors for infection risk factors, and by testing for the presence of certain viruses in the plasma.  Furthermore, manufacturing processes have been validated for their ability to inactivate and remove viruses.

## VIG Administration

- VIG-IM 0.6ml/kg
- IM, preferably in buttock or anterolateral aspect of thigh
- Divide doses > 5ml
- Refer to package insert

**Notes:**
Detailed instructions regarding the administration of intramuscular and intravenous vaccinia immune globulin are included in the Investigator’s Brochure portion of the IND materials that will accompany the products. 

For treatment of vaccinial complications, the recommended dose of VIGIM (16.5% solution) is 0.6 ml/kg.   VIGIM is to be administered intramuscularly, preferably in the buttock or the anterolateral aspect of the thigh.  Doses greater than 5 ml should be divided and injected at two or more sites to reduce local pain and discomfort.

Because the concentration of the new VIGIV products differs from that of the IM preparation, clinicians should refer to the manufacturer's package insert for correct dosages.  The dose for intravenous administration of may range from 100mg/kg to 500mg/kg depending upon the VIGIV formulation.  
========================
Reference:[i] American Academy of Pediatrics. [Passive Immunization].  In: Pickering LK, ed. 2000 Red Book:  Report of the Committee on Infectious Diseases.  25th ed. Elk Grove Village, IL:  American Academy of Pediatrics; 2000: [42]

## Cidofovir

- Nucleotide analogue of cytosine
- Some antiviral activity against orthopoxviruses
- Administer under IND protocol, only
- Released by CDC and DoD if:
- No response to VIG
- Patient near death
- All inventories of VIG exhausted

**Notes:**
Cidofovir (VISTIDE®, Gilead Sciences), a nucleotide analogue of cytosine, has shown antiviral activity against some orthopoxviruses in cell-based in vitro and animal model studies.  In addition, cidofovir exhibits antiviral activity against adenovirus and human papillomavirus.  Its effectiveness in the treatment of vaccinia related complications in humans is unknown.  Cidofovir has been shown to be nephrotoxic and carcinogenic even at low doses.  

Cidofovir is approved by FDA for the treatment of CMV retinitis in patients with AIDS.  Its use for the treatment of smallpox vaccination complications is recommended only under an Investigational New Drug protocol (IND) sponsored by the Centers for Disease Control and Prevention (CDC).  This IND is a research protocol to evaluate the effectiveness of cidofovir as a secondary treatment of vaccinia-related complications that do not respond to VIG treatment.  CDC will supply cidofovir at no cost for use under this IND.

Cidofovir will be released for civilian use by CDC and for military use by DOD, if, 1) a patient fails to respond to VIG treatment, or 2) a patient is near death, or 3) all inventories of VIG have been exhausted. This proposed use of cidofovir is investigational and has not been studied in humans, therefore the benefit of cidofovir therapy for vaccinia-related complications is uncertain.  There is no information on dosing, safety, and efficacy of cidofovir to treat smallpox vaccine AEs in the pediatric age group. Dosages for these patients should be determined in consultation with experts at CDC and DoD. Additional information on dosing and administration of cidofovir is included in the Investigator’s Brochure that will accompany the release of this product to the clinician when cidofovir is used under the IND protocol.  
=============================
References:[i] Smee DF, Bailey KW, Wong MH, Sidwell RW.  Effects of Cidofovir on the Pathogenesis of a Lethal Vaccinia Virus Respiratory Infection in Mice. Antiviral Res. 2001 Oct; 52(1):55-62.
[ii] Bray M, Martinez M, Smee D, Kefauver D, Thompson E, Huggins JW. Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge. JID 2000; 181:10-19.
[iii] Gilead Sciences, Inc.  Cidofovir Injection.  Package Insert. September 2000.
[iv] De Clercq E.  Acyclic Nucleoside Phosphonates in the Chemotherapy of DNA Virus and Retrovirus Infections.  Intervirology. 1997;40(5-6):295-303

## Cidofovir Side Effects

- Renal toxicity
- Neutropenia
- Proteinuria
- Decreased intraocular pressure
- Anterior uveitis/iritis
- Metabolic acidosis

**Notes:**
The major complication of cidofovir therapy is renal toxicity, which is sometimes irreversible, resulting in renal failure requiring dialysis or death.  To reduce the renal toxicity of cidofovir it must be administered with careful intravenous hydration and with probenicid, a renal tubular blocking agent.  Cidofovir has also been associated with neutropenia, proteinuria, decreased intraocular pressure/ocular hypotony, anterior uveitis/iritis, and metabolic acidosis.  Cidofovir related carcinogenicity, teratogenicity and hypospermia have been reported in animal studies.  Mammary adenocarcinomas developed in rats exposed to 0.04 times the human exposure at the dose used in clinical practice based on area-under-the-curve comparisons. 

Probenicid has been associated with headache, anorexia, nausea, vomiting, urinary frequency, hypersensitivity reactions, anemia, hemolytic anemia, nephritic syndrome, hepatic necrosis, gout, uric acid stones, and renal colic.  Probenicid should be used with caution in children, pregnant women and persons with sulfa drug allergy.

## Cidofovir Admin

- 5 mg/kg IV over 60 minute period
- Consider 2nd dose one week later if no response
- Adjust dose for renal function
- Assess baseline and post-admin renal function
- IV hydration (1L of 0.9% saline IV)
- 3 doses oral probenicid (25 mg/kg per dose)

**Notes:**
Details for administration of cidofovir® are included with the medication and IND materials that are shipped from CDC.  The proposed dose of cidofovir® for treatment of vaccinia complications is 5 mg/kg administered intravenously, one time, over a 60 minute period.  A second dose one week later may be considered if there is no response to the first.  Dose adjustment may be needed for renal function if a second dose is needed.  Administration procedures include assessment of baseline and post-administration renal function (serum creatinine, calculated creatinine clearance, and microscopic urinalysis), intravenous hydration (1L of 0.9% saline solution IV with each infusion), and 3 doses of oral probenicid (25 mg/kg per dose, maximum dose 2 grams) – 2 doses to be administered prior to cidofovir and 1 dose after.  Patients who receive cidofovir should be followed closely both for drug toxicities and for the outcome of their serious adverse event.  Monitoring for emerging viral resistance to cidofovir is required.   The protocol materials will be supplied to facilitate monitoring and information collection.  Long-term follow-up is required under IND to monitor for carcinogenicity, renal insufficiency, and teratogenicity.

Requests for clinical consultation or release of VIG and cidofovir for civilian providers and registry enrollment for inadvertent vaccinia exposure

## Obtaining VIG and Cidofovir

- Civilian Medical Facilities
- CDC Smallpox Vaccinee Adverse Events Clinical Team
- Military Facilities
- USAMRIID  (301) 619-2257 or 888-USA-RIID

**Notes:**
Physicians at military medical facilities may request VIG or cidofovir by calling the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) at 301-619-2257 or 888-USA-RIID.  

Physicians at civilian medical facilities may request VIG or cidofovir by calling the Centers for Disease Control Smallpox Vaccinee Adverse Events Clinical Team at 1-800-XXXX 

## Consultation

## Consultation

- State and Territories establish program
- Hospitals assign physicians with expertise
- Provide 24/7 access to vaccinees and affected contacts
- CDC Provider Information Line

**Notes:**
In October 2002, the Advisory Committee on Immunization Practices recommended that enhanced bioterrorism preparedness should included vaccination of Smallpox Public Health Response and Health Care Teams.   Implementation for this vaccination program was determined to be the responsibility of the individual States and Territories in conjunction with local pre-designated hospitals.  Prior to participation in the vaccination program, States and Territories must establish a comprehensive program to manage vaccinees and their contacts that experience an adverse event following smallpox vaccination. Hospitals that participate should assign physicians with expertise in infectious diseases, neurology, dermatology, allergy/immunology, or ophthalmology to assess and manage adverse events in vaccinees and their contacts.  Vaccinees and their affected contacts must have 24 hours a day, 7 days a week access to evaluation and medical care for a suspected adverse event.  

The Centers for Disease Control and Prevention will provide expert consultation to State and Territorial public health officials, their surrogate providers, and other requesting physicians on the recognition, evaluation, diagnosis and treatment of adverse events following smallpox vaccination via a 24 hours a day, 7 days a week “Provider Information Line.” For the most difficult cases, the CDC, will obtain expert consultation from the Clinical Immunization Safety Assessment Network (CISA).

In addition, CDC will provide consultation for evaluation and care of persons with contraindications to smallpox vaccination that have an inadvertent exposure vaccinia virus (e.g., vaccination of a pregnant woman or a person with atopic dermatitis).  These individuals will be enrolled in a vaccination registry for prospective follow-up.  
===============================
Reference:[i] The Clinical Immunization Safety Assessment (CISA) Network launched October 2001, is an National Immunization Program (NIP) initiative designed to more closely investigate the occurrence of adverse events (AEs) following immunization through intensive prospective clinical evaluations.  The network strives to improve the understanding of pathophysiology of adverse events following immunization through standardized patient evaluation through the newest medical research technology.  The CISA network is comprised of clinical research-scientists at geographically diverse academic centers of excellence.  The current CISA Centers (Principal Investigator and Co-PIs) are as follows:

        Boston Medical Center in Boston, MA (Marchant, Barnett, Klein, Flemming, Adams)
        New York Presbyterian-Columbia (LaRussa, Gershon, Irgoyen)
        Johns Hopkins University (Halsey) 
        University of Maryland in Baltimore, MD (Rennels)

## ConsultationInformation to Have

- Thorough vaccination history
- Physical Examination of patient
- High-resolution digital photographs of dermatologic manifestations
- Contact state health department, first

**Notes:**
Referring providers should complete a thorough vaccination history and physical examination on all patients with a suspected AE prior to accessing the CDC provider information line.  In addition, high-resolution digital photographs of dermatological manifestations of AEs may aid in the recognition of specific dermatological manifestations of adverse events should be obtained with the patient’s permission and forwarded whenever possible.  Providers seeking assistance should first contact their State Health Department before accessing the CDC consultation service or requesting VIG or cidofovir release.  

## Smallpox Adverse Event Reporting

**Notes:**
Reporting of all clinically significant adverse events following the administration of the smallpox vaccine to the Vaccine Adverse Event Reporting System (VAERS) is strongly encouraged.  States will be mandated to ensure that adverse events that require CDC expert consultation or release of VIG or cidofovir are reported to VAERS in a timely manner.  VAERS is a first-line system for monitoring the safety of all vaccines licensed in the United States, and provides enhanced surveillance of adverse events following administration of the smallpox vaccine.  The Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA) jointly manage VAERS and monitor smallpox vaccine related AE reports daily.  

Conditions requiring administration of VIG or cidofovir must be reported immediately.  Clinically significant adverse events not requiring administration of VIG or cidofovir should be reported within 48 hours of recognition.  All other adverse events should be reported within in one week.

## VAERS Reporting

- Secure web-based reporting
-  https://secure.vaers.org/VaersDateEntryintro.htm
- Downloadable form
- http://www.vaers.org/pdf/vaers_form.pdf
- Fax to:
- 1-877-721-0366

## Additional Information

- CDC Smallpox Website
- www.cdc.gov/smallpox
- Adverse Events Training Module
- www.bt.cdc.gov/training/smallpoxvaccine/reactions

## Infection Control

- Documented rarely in healthcare settings
- Primarily after direct contact with site
- May occur with other infected body sites
- Indirect transmission possible, but never documented

**Notes:**
Unintended transmission of vaccinia virus from recently vaccinated persons to susceptible contacts has been reported, but has been documented rarely in healthcare settings (Neff JAMA 2002; Sepkowitz NEJM 2003). Transmission of vaccinia occurs primarily after direct contact with the vaccination site, but transmission also may occur after direct contact with other vaccinia-infected body sites. Indirect transmission (e.g., airborne transmission) of vaccinia virus has not been well documented, but is theoretically possible when the vaccinee has extensive open lesions with the potential for viral shedding (Sepkowitz).  

## Ocular Vaccinial Infections and Therapy

## Treatment of Ocular Infections

- Previous experience with older antivirals
- Not done by today’s standards
- Currently available topical opthalmic antivirals not studied with vaccinia
- Animal studies

**Notes:**
Ocular vaccinial infections account for 80% of inadvertent inoculation cases.  Unfortunately, data upon which to base treatment recommendations are limited.   Published reports of treatment of human infections are predominantly case series reporting clinical experience with older antiviral drugs (e.g., IDU, interferon) and/or VIG.  These studies did not employ the prospective, randomized, double masked, controlled trials that are the standard today; clinical details and follow-up information are often variable.  None of the currently available topical ophthalmic antiviral agents has been studied in humans with ocular vaccinia disease, except that in one case report vidarabine appeared to be superior to IDU in treating blepharoconjunctivitis.  
=========================
References:[1] Kempe CH, Bowles C, Meiklejohn G, Berge TO, Vincent LST, Sundara Babu BV, Govindarajan S, Ratnakannan NR, Downie AW, Muthy VR.  The use of vaccinia hyperimmune gammaglobulin in the prophylaxis of smallpox.  Bull Wld Hlth Org 1961; 25:41-48.
[2] Hyndiuk R, Okumoto M, Damiano R, Valenton M, Smolin G.: Treatment of vaccinial keratitis with vidarabine. Arch Ophthalmol 1976;94:1363-4.
[3] Hyndiuk R, Seideman S, Leibsohn J: Treatment of vaccinial keratitis with trifluorothymidine. Arch Ophthalmol 1976;94:1785-6.
[4] Pavan-Langston, D.  Ocular Viral Diseases, In: Galasso G, Whitley R. and Merigan T, eds:  Antiviral Agents and Viral Diseases of Man. Lippincott-Raven Press, 1997.
[5] Neuman-Haeflin D, Sundmacher R, Sauter B: Effect of human leukocyte interferon on vaccinia and herpes infected cell culture and monkey corneas. Infect Immun 1975;12:148-55.
[1] Rennie A, Cant J, Foulds W, Pennington T, Timbury M: Ocular vaccinia. Lancet 1974;273-275
[2] Kaufman H, Nesburn A, Maloney E: Cure of vaccinia infection by 5-Iodo-2-Deoxyuridine.Virology 1962;18:567-569.
[3] Jack M, Sorenson R: Vaccinial keratitis treated with IDU. Arch Ophthalmol 1963;68:730-732
[4] Langston D, et al: A double-blind clinical study of adenine arabinoside (vidarabine) therapy of viral conjunctivitis. Am J Ophthal 1972;72(1):81-88

## Animal studies, rabbit model of vaccinial keratitis
Topical vidarabine or trifluridine
Virologic and clinical improvement
Early use might reduce complications
Not approved by FDA for vaccinia disease

- Topical vidarabine or trifluridine
- Virologic and clinical improvement
- Early use might reduce complications
- Not approved by FDA for vaccinia disease

**Treatment of Ocular Infections****Topical Opthalmic Anti-Virals**

**Notes:**
Data from animal models and experience with VIG for treatment of smallpox and vaccinia complications in humans provide some guidance for prevention of ocular complications. In controlled studies using a rabbit model of vaccinial keratitis, animals receiving topical vidarabine or trifluridine had statistically significant virologic and clinical improvement compared to untreated control animals and to animals receiving IDU, suggesting that early use of these antiviral agents may significantly reduce the complications associated with infection. Prophylaxis of the cornea with topical antiviral drugs is common ophthalmologic practice in the treatment of ocular herpes simplex and varicella-zoster infections. In the case of vaccinia, a controlled trial in monkeys found that topical interferon prevented vaccinial keratitis when administered before inoculation and ameliorated disease when begun immediately after vaccination.  Therapeutics that have been considered for treatment of ocular vaccinial infections include topical ophthalmic antiviral drugs [trifluridine (Viroptic®) and vidarabine (Vira-A®) ]† and parenteral vaccinia immunoglobulin (VIG) which is available through an Investigational New Drug (IND) protocol from CDC.   Trifluridine and vidarabine are not approved by FDA for treatment of vaccinia disease, although the product labels for trifluridine and vidarabine state that the drugs have in vitro and in vivo activity against vaccinia virus.
==============================
References:[1] Kempe CH, Bowles C, Meiklejohn G, Berge TO, Vincent LST, Sundara Babu BV, Govindarajan S, Ratnakannan NR, Downie AW, Muthy VR.  The use of vaccinia hyperimmune gammaglobulin in the prophylaxis of smallpox.  Bull Wld Hlth Org 1961; 25:41-48.
[2] Hyndiuk R, Okumoto M, Damiano R, Valenton M, Smolin G.: Treatment of vaccinial keratitis with vidarabine. Arch Ophthalmol 1976;94:1363-4.
[3] Hyndiuk R, Seideman S, Leibsohn J: Treatment of vaccinial keratitis with trifluorothymidine. Arch Ophthalmol 1976;94:1785-6.
[4] Pavan-Langston, D.  Ocular Viral Diseases, In: Galasso G, Whitley R. and Merigan T, eds:  Antiviral Agents and Viral Diseases of Man. Lippincott-Raven Press, 1997.
[5] Neuman-Haeflin D, Sundmacher R, Sauter B: Effect of human leukocyte interferon on vaccinia and herpes infected cell culture and monkey corneas. Infect Immun 1975;12:148-55.
[1] Rennie A, Cant J, Foulds W, Pennington T, Timbury M: Ocular vaccinia. Lancet 1974;273-275
[2] Kaufman H, Nesburn A, Maloney E: Cure of vaccinia infection by 5-Iodo-2-Deoxyuridine.Virology 1962;18:567-569.
[3] Jack M, Sorenson R: Vaccinial keratitis treated with IDU. Arch Ophthalmol 1963;68:730-732
[4] Langston D, et al: A double-blind clinical study of adenine arabinoside (vidarabine) therapy of viral conjunctivitis. Am J Ophthal 1972;72(1):81-88

## No evidence effective
Might increase scarring after vaccinial keratitis
Rabbit studies used increased doses

- Might increase scarring after vaccinial keratitis
- Rabbit studies used increased doses

**Treatment of Ocular Infections****Vaccinia Immune Globulin**

**Notes:**
In humans with generalized vaccinia and eczema vaccinatum, VIG treatment appears to decrease size and limit extension of vaccinial lesions within 24 to 48 hours.  Consequently, VIG has been considered as a means to prevent spread of facial vaccinia to the eye and spread of ocular vaccinia without corneal involvement to the cornea.  There is no evidence that VIG is effective in treating vaccinial infection of the cornea, i.e. vaccinial keratitis, and one study in rabbits (summarized below) suggests that multiple doses of VIG may increase the risk of scarring after vaccinial keratitis. 

The use of VIG for vaccinial keratitis was evaluated in one small controlled study in rabbits.  Rabbits treated with one dose of VIG IM alone or in combination with topical VIG or IDU did not have an altered clinical course compared with rabbits receiving no treatment.  However, rabbits receiving 5 daily intramuscular doses of VIG developed larger corneal scars that rabbits in the other groups.  Viral shedding was similar in all groups.  The authors concluded that VIG did not appear to be beneficial for vaccinial keratitis and that its use in keratitis increased the risk of corneal scarring.  The authors also cited as unpublished data that 4 of their patients had developed persistent corneal clouding with stromal edema after treatment with VIG.  More details of these conditions and the patients’ long-term outcome (e.g., whether they developed corneal scars) are not known.  Based largely on the results of this study, the ACIP concluded that VIG was contraindicated for the treatment of vaccinial keratitis.  

However, the total VIG-IM dose given to the rabbits receiving 5 daily doses was 2.5 to 5 times higher than recommended for human therapy.  Rabbits receiving only one dose of VIG did not develop persistent scarring or prolonged corneal haze.  None of the therapeutic groups demonstrated significant differences in corneal clouding or corneal ulcer development, compared with controls.  Animals receiving VIG-IM for 5 days did not receive topical antivirals, which humans likely would today.

There are uncontrolled case reports of human patients with vaccinial keratitis not treated with VIG who appeared to develop more severe sequelae (including corneal scarring and disciform edema) than described in case reports where VIG therapy was used as well as an uncontrolled case report on the use of VIGIM in treating vaccinial keratitis in which corneal scarring did not develop. There are several published case reports suggesting efficacy of VIGIM in treating vaccinial blepharoconjunctivitis and blepharitis.
=========================
References:
[1] Rennie A, Cant J, Foulds W, Pennington T, Timbury M: Ocular vaccinia. Lancet 1974;273-275
[2] Perera C: Vaccinial disciform keratitis. Arch Ophthalmol 1940;24:352-356
[3] Ellis P, Winograd L: Ocular vaccinia: a specific treatment. Arch Ophthalmol 1962;68:600-9.
[4] Kempe CH. Studies on smallpox and complications of smallpox vaccination. Pediatrics 1960; 26:176-189.
[6] Jones B, Al-Hussaini MK: Therapeutic considerations in ocular vaccinia. Trans Ophthalmol Soc UK 1964;83:613-31.
[7] Ruben F, Lane M: Ocular vaccinia: an epidemiologic analysis of 348 cases. Arch Ophthal 1970;84
[1] Fulginiti V, Winograd L, Jackson M, Ellis P: Therapy of experimental vaccinal keratitis: effect of idoxuridine and VIG. Arch Ophthalmol 1965;74:539-44.
[2] CDC. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR 2001;50(No.RR-10):8.

## Manage in consult with ophthalmologist
Consider off-label use of topical ophthalmic trifluridine or vidarabine
Balance with risk of drug toxicity
Continue until periocular and/or lid lesions heal and scabs fall off

- Consider off-label use of topical ophthalmic trifluridine or vidarabine
- Balance with risk of drug toxicity
- Continue until periocular and/or lid lesions heal and scabs fall off

**Treatment of Ocular Infections****Guidance for Clinicians**

**Notes:**
To discuss treatment options for ocular vaccinia, CDC convened a meeting of ophthalmology and infectious disease consultants in November 2002.  Based on available data and input from these consultants, PHS offers the following guidance for clinicians.  

Suspected ocular vaccinia infections should be managed in consultation with an ophthalmologist whenever possible, to ensure a thorough and accurate eye evaluation, including a slit lamp examination, and the specialized expertise needed to manage potentially vision-threatening disease.  Although it occurs rarely due to the viscosity of smallpox vaccine, vaccine splashes to the eye should be managed by immediate eye washing with water (avoid pressure irrigation, which may cause corneal abrasion), and a baseline evaluation by an ophthalmologist.  Further treatment may not be necessary.  

Off-label use of topical ophthalmic trifluridine or vidarabine should be considered for the treatment of vaccinia infection of the conjunctiva or cornea. Prophylactic therapy with these drugs should also be considered to prevent spread to the conjunctiva and cornea if vaccinia lesions are present on the eyelid, especially if near the lid margin, or adjacent to the eye.  The use of these drugs for prophylaxis should be balanced against the minimal but potential risk of drug toxicity and of introducing virus into the eye by frequent manipulation.  Topical antivirals should be continued until all periocular and/or lid lesions have healed and the scabs have fallen off, except that topical trifluridine generally should not be used for more than 14 days to avoid toxicity. When used for more than 14 days, trifluridine may lead to superficial punctate keratopathy, which resolves on discontinuation of the medication. Topical vidarabine may be preferable for use in children because it can be compounded into an ointment that allows less frequent dosing and is associated with less initial stinging than trifluridine. 

## Consider VIG when keratitis NOT present
Useful with severe blepharitis or blepharoconjunctivitis
Weigh risks and benefits if keratitis present
Use VIG for other severe vaccinia disease, even if keratitis present
Consider prophylaxis against bacterial infection
Enroll in studies

- Useful with severe blepharitis or blepharoconjunctivitis
- Weigh risks and benefits if keratitis present
- Use VIG for other severe vaccinia disease, even if keratitis present
- Consider prophylaxis against bacterial infection
- Enroll in studies

**Treatment of Ocular Infections****Guidance for Clinicians**

**Notes:**
VIG should be considered for use in severe ocular disease when keratitis is not present (e.g. severe blepharitis or blepharoconjunctivitis).  If keratitis accompanies these conditions, consideration of possible VIG use must be weighed against evidence in an animal model for increased risk of corneal scar formation if a large dose is given over several days. VIG need not be withheld if the ocular disease is severe enough to pose a substantial risk of impaired vision as a long-term outcome, e.g. vision-threatening lid malformation. If VIG is given specifically to treat ocular disease in the presence of keratitis, treatment should generally be limited to one dose and patient or guardian should be informed of the possible risks and benefits prior to its use.

The use of VIG as recommended to treat other severe vaccinia disease (e.g. eczema vaccinatum) is indicated even in the presence of keratitis. For treatment of isolated keratitis, VIG has not been clearly shown to offer added benefit when topical antivirals are used and is not recommended.

Topical ophthalmic antibacterials should be considered for the prophylaxis of bacterial infection in the presence of keratitis, particularly if a corneal ulcer is present or steroids are used.  In severe cases of keratitis (e.g., with an ulcer and stromal haze or infiltrate) and in iritis, topical steroids should be considered after the corneal epithelium is healed to decrease immune reaction; mydriatics are also indicated. Topical steroids should not be used without ophthalmologic consultation and should not be used acutely without topical antiviral therapy.  Patients with ocular vaccinia infection, particularly with keratitis or iritis, should receive careful follow-up evaluation by an ophthalmologist to detect and treat possible late onset complications (e.g. scarring and immune reactions).

Additional data from animal and human clinical studies are needed to improve the evidence base used to refine recommendations for ocular vaccinia disease.  Physicians treating patients with ocular vaccinia infection are encouraged to enroll in studies designed to evaluate the safety and efficacy of VIG and current available antiviral preparations for treatment of ocular complications.