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Ocular complications of smallpox vaccination
PERSPECTIVE Ocular Complications of Smallpox Vaccination JAY S. PEPOSE, MD, PHD, TODD P. MARGOLIS, MD, PHD, PHILLIP LARUSSA, MD, AND DEBORAH PAVAN-LANGSTON, MD
● PURPOSE: To describe the ocular complications of smallpox vaccination and to discuss potential therapeutic options. ● DESIGN: Review of pertinent medical literature and recent treatment recommendations of the Centers for Disease Control and Prevention. ● RESULTS: After immunization against smallpox, vaccinia infection of the eyelid, conjunctiva, or ocular surface can result from accidental autoinoculation from a vaccination site before scab formation or from contact with a recently vaccinated individual. While uncommon, corneal involvement can lead to stromal opacification and scarring. Clinical findings of ocular and periocular vaccinia must be differentiated from those produced by other pathogens such as molluscum contagiosum, herpes simplex, varicella zoster, and acanthamoeba infections. Clinical diagnosis can be confirmed by electron microscopy to identify the presence of orthopoxvirus, as well as by virologic culture, polymerase chain reaction, and/or restriction endonuclease analysis of viral isolates. ● CONCLUSIONS: While the majority of ocular complications of smallpox vaccination in immunocompetent patients are self-limiting, selective cases may require treatment with trifluridine drops, topical corticosteroids and vaccinia immune globulin (VIG). Vaccinia virus does not appear to be sensitive to acyclovir. Specific treatment recommendations are outlined for the spectrum of ocular manifestations. (Am J Ophthalmol 2003;136:343–352. © 2003 by Elsevier Inc. All rights reserved.) Accepted for publication March 5, 2003. InternetAdvance publication at ajo.com March 18, 2003. From the Pepose Vision Institute, Chesterfield, Missouri (J.S.P.), and the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri (J.S.P.); The Francis I. Proctor Foundation and Department of Ophthalmology, University of California San Francisco, San Francisco, California (T.P.M.); Department of Pediatrics, Columbia University, New York, New York (P.L.); Department of Ophthalmology, Harvard Medical School, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts (D.P.L.). This study was supported, in part, by a grant from the Midwest Cornea Research Foundation, Chesterfield, Missouri. Inquiries to Jay S. Pepose, MD, PhD, Pepose Vision Institute 16216 Baxter Road, Suite 205, Chesterfield, MO 63017 0002-9394/03/$30.00 doi:10.1016/S0002-9394(03)00293-9
©
2003 BY
R
OUTINE SMALLPOX VACCINATIONS HAVE NOT BEEN
performed in the general population of the United States in 30 years. Because of growing concerns about the use of the smallpox (variola) virus as an agent of bioterrorism,1,2 vaccinia inoculations of the military, bioterrorism first responder groups, and healthcare personnel have been recently recommended.3 Ocular complications of smallpox vaccination can arise from accidental autoinoculation of the eye or eyelid with virus from the vaccination site or from close physical contact with a vaccinee shedding virus.4 In this Perspective, we review the clinical and laboratory diagnosis of ocular vaccinia, and discuss potential therapeutic options for specific ocular manifestations using topical antivirals, topical corticosteroids and vaccinia immune globulin.
History of Smallpox Vaccination and Eradication SMALLPOX, A POTENTIALLY DEVASTATING DISEASE WITH
up to 30% mortality, was eradicated from nature in 1979.5 This fantastic feat was accomplished using a strategy of surveillance and containment vaccination, under the auspices of the World Health Organization. The vaccine against smallpox currently licensed in the United States is a lyophilized, live-virus preparation of infectious vaccinia virus, a related orthopox virus, administered by using a multiple puncture technique on the upper arm with a bifurcated needle. The vaccine does not contain the smallpox (variola) virus itself. By the late 1960s, the risk of importing smallpox into the United States had greatly diminished. The last reported case of smallpox in the United States was in 1949.6 The recommendation of smallpox vaccination for the general public was officially rescinded in 1971 and was discontinued for healthcare workers in 1976. In January 1982, smallpox vaccination was no longer required for international travelers, and routine vaccination of military personnel ceased in 1990.7 With the exception of military personnel who served in the 1980s, certain laboratory workers and healthcare workers using orthopox viruses or
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involved in clinical trials with recombinant vaccinia vaccines, the entire United States population younger than age 30 has no immunity to smallpox. Most of those age 30 and older have only had a single vaccination in childhood and would be expected to both shed virus from a repeat vaccination site and be susceptible to contact infection from other recently vaccinated individuals. Because of growing concerns about the potential use of smallpox as an agent of bioterrorism,1,2 the United States Department of Health and Human Services has recommended that smallpox vaccination be reinstated for United States military personnel and bioterrorism first responder units, followed by primary and ancillary healthcare personnel.3 These two phases of immunization will probably involve administering around 1 million vaccinations. It is possible that a larger-scale volunteer smallpox vaccination program for the general public could follow at some time in the future. While smallpox (vaccinia) vaccination is considered a relatively safe and effective preventative against smallpox with a complication rate of 0.004%,8 severe reactions are more common than following any other vaccine. While the majority of complications occur in the person who has been vaccinated, the virus can be inadvertently transmitted from the vaccinee to others, as the inoculation site can shed infectious virus up to 21 days, until the scab detaches. The most serious complications8 –10 that can follow vaccination or contact with a vaccinated person include: (1) vaccinia necrosum (progressive vaccinia)—the primary vaccination site does not heal, and the infection spreads locally and by viremia producing necrotic lesions—this occurs primarily in immunocompromised individuals with T-cell deficiency/dysfunction (for example, those with HIV infection, AIDS, cancer, congenital T-cell deficiency, or on immunosuppressive agents); (2) eczema vaccinatum—produces fever, lymphadenopathy, and generalized, often confluent, lesions in areas other than the vaccination site (frequently the face and limbs) in individuals with eczema (atopic dermatitis) or a history of eczema; (3) accidental infection—vaccinial lesions resulting from unintentional implantation of vaccinia virus in the eye, lids, mouth, or elsewhere in individuals without eczema or other preexisting skin lesions; (4) postvaccinial encephalitis—the most serious complication after vaccination of healthy individuals. This most often affects primary vaccinees aged ⬍ 1 year or adolescents and adults receiving primary vaccination, but it has not been reported in secondary acquired vaccinia. Approximately 15% to 25% of primary vaccinees with encephalitis die, and 25% have permanent neurological sequelae;8 –11 and (5) fetal vaccinia—which is a rare condition resulting from transmission of vaccinia from a vaccinated pregnant woman to her fetus. Less than 50 cases have been reported, but the resulting skin and organ involvement often leads to fetal or neonatal death. 344
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It is difficult to predict with certainty the number of adverse events that may be associated with current day smallpox vaccination, because a number of pertinent factors have changed since 30 years ago.9,12 In the 21st century, the number of immunocompromised individuals (many of whom are in a hospital setting) has increased dramatically secondary to organ transplants, cancer, use of chemotherapy, corticosteroids and immunosuppressive drugs, HIV infection, and the expansion of intensive care units and neonatal nurseries.11 Many contemporary hospital and healthcare workers (some of whom are themselves immunocompromised) have either never been vaccinated or received one vaccination 30 or more years ago. Such hospital and healthcare workers now have little or no vaccinia immunity, may shed virus longer after vaccination, and may be in more frequent contact with immunocompromised individuals than their counterparts would have 3 decades ago.9,12,13 In the early 1960s, many hospital staff vaccination programs strategically performed smallpox vaccinations immediately before a holiday and did not permit clinical duty during the period in which healthcare workers might shed virus.9 This may not be uniformly or even frequently practiced today, as the Advisory Committee on Immunization Practices has stated that it is not necessary to furlough vaccinated healthcare workers.3 To counterbalance this, the use of precautions that were not routinely employed 30 years ago, such as the use of semipermeable polyurethane dressings over the vaccination site,7 are likely to limit spread to other individuals if closely adhered to. Another smallpox vaccination risk not present in the 1960s is highlighted by the estimate of the Centers for Disease Control and Prevention that 300,000 individuals in the United States are unaware that they are currently infected with HIV13 and that more than 23,000 healthcare workers have AIDS.14 As an unfortunate example of the potential consequence of unknowingly vaccinating a highrisk individual, an apparently healthy United States military recruit developed progressive vaccinia soon after receiving a smallpox vaccination in 1984 and was only later diagnosed as having HIV infection.15 Cutaneous manifestations of HIV infection may also serve as a portal for secondary vaccinia infection.9 Finally, the prevalence of atopic dermatitis in children has increased between two to threefold over the past 30 years and is now estimated to be between 6% and 22% in the United States.16 This group may be more susceptible to acquiring contact vaccinia, manifesting as eczema vaccinatum. Other skin conditions that may predspose to secondary contact acquisition of vaccinia include seborrheic dermatitis, impetigo, scabies, burns, and pemphigus foliaceus.17 The purpose of this Perspective is to review the ocular complications of smallpox vaccination, their clinical and laboratory diagnoses, and potential treatment options. As will be discussed, some of the ocular antiviral therapies OF
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were not available in the previous era of smallpox vaccination, and none of the treatment options have been evaluated or statistically validated in prospective, masked, randomized trials.
Ocular Complications of Smallpox Vaccination OF THE NINE POXVIRUSES THAT CAUSE DISEASE IN HU-
mans, four are associated with ocular or eyelid infections: vaccinia virus, variola virus, orf virus, and molluscum contagiosum.4 During the period of routine smallpox vaccination, ocular vaccinia sometimes occurred by transmission from the vaccination “take” of another individual or by autoinoculation from the vaccinee’s own lesion. Spread of vaccinia virus to the eye was mainly by digital contact after rubbing the vaccination site. Signs and symptoms of primary accidental self inoculation may appear between 5 and 11 days after vaccination. Secondary cases generally manifest between 8 and 18 days after exposure. The incidence of ocular vaccinia was approximately one per 40,000 primary vaccinations,8,18 and the clinical manifestations of ocular vaccinia varied depending upon the specific immune status of the host. In previously vaccinated individuals, accidental autoinoculation into the eye after close contact with a recent vaccinee was often limited to mucopurulent blepharoconjunctivitis.19 More severe ocular complications were far more common in primary vaccinees than in revacinees,18 and in accidental primary autoinoculation. Primary vaccinee and primary autoinoculation refer to patients not previously vaccinated or exposed to the vaccinia virus, who are, therefore, without previous immunity. A revaccinee has had some previous immune response after previous deliberate or accidental inoculation. ● VACCINIA BLEPHARITIS: Vaccinia infection of the eyelid or ocular surface may lead to the formation of vesicles that progress to pustules that umbilicate and indurate, sometimes followed by a scab that detaches (Figures 1 to 3). This is similar to the transformation on the arm seen after a successful vaccine “take” (Figure 4). One differentiating factor between herpes simplex and vaccinia lesions is that herpetic vesicles of the eyelid or ocular surface do not go through a pustular phase (Figure 5). A differentiating feature between herpes zoster and vaccinia dermatitis is that vaccinia lesions do not respect a dermatomal distribution. Single or multiple vaccinia lesions can produce profound eyelid swelling and periorbital erythema, resembling orbital cellulitis (Figures 1, 6, and 7). This is commonly accompanied by preauricular and/or submandibular lymphadenopathy.18,20 Eyelid lesions can progress to scarring and madarosis. The differential diagnosis of vaccinia lesions of the eyelid includes
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FIGURE 1. Vaccinia lesions of the eyelid are seen in various stages of evolution from vesicles to umbilicated pustules.
FIGURE 2. Multiple periocular vaccinial lesions in a 22-yearold military recruit produce lid ulceration, madarosis, and hemorrhage, accompanied by chemosis and conjunctival injection.
molluscum contagiosum, staphylococcal blepharitis, and herpes simplex or varicella zoster virus blepharitis. ● VACCINIA CONJUNCTIVITIS:
In the majority of cases, ocular vaccinia is limited to the eyelid and conjunctiva. Vaccinia conjunctivitis is characterized by an acute papillary reaction and serous or mucopurulent discharge. Multifocal ulceration of the papillary and bulbar conjunctiva occurs commonly. Conjunctival ulcers have a whitish center with surrounding injection and edema; may be covered by a thick, yellowish-gray membrane; and may lead to symblepharon formation. Preauricular adenopathy commonly accompanies vaccinial conjunctivitis, but the presence of follicles is rare.
● VACCINIA KERATITIS: Corneal involvement after autoinoculation is uncommon, with reports of approximately 1.2 cases per million primary vaccinations.4,8 Other studies
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FIGURE 3. The same eye as in Figure 2, shows resolution of blepharoconjunctivitis at 14 days after treatment with vaccinia immune globulin.
FIGURE 5. Herpes simplex vesicles of the eyelid do not go through the pustular phase commonly seen with vaccinia.
FIGURE 4. Limbal vesicle (arrow) and inferior corneal epithelial defect. FIGURE 6. Multiple vaccinia lesions producing severe periorbital edema and erythema, mimicking orbital cellulitis.
indicate postvaccinial keratitis in 6% to 37% of vaccinia cases with ocular involvement.18 –20 Keratitis appears more frequently in primary vaccinees than revaccinees. This would appear to be a reflection of the immune status of the previously vaccinated patient. Corneal manifestations of ocular vaccinia range from mild superficial punctate keratitis to interstitial or stromal keratitis (Figure 8), to disciform keratitis with keratic precipitates (Figure 9), to necrosis with perforation. As with epithelial herpes simplex or varicella zoster keratitis, corneal epithelial vaccinia lesions stain with rose bengal early in the course of the disease and with fluorescein as an epithelial defect evolves. Direct infection of the corneal epithelium with vaccinia may present as multiple punctate lesions, dendritiform lesions, or in a geographic pattern. All forms of vaccinia epithelial keratitis may closely resemble that seen with herpes simplex (Figure 10). Stromal keratitis due to vaccinia may initially appear as scattered subepithelial opacities similar to that seen in epidemic keratoconjunctivitis. This pattern may evolve to 346
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ring infiltrates, ulceration (Figure 11), and/or stromal necrosis, or scarring (Figure 12), which must be differentiated from acanthamoeba, herpes zoster, and herpes simplex stromal keratitis. Long-term sequelae, such as madarosis, punctal stenosis, and cicatricial lid changes are more common in cases with corneal manifestations (18%) than in ocular vaccinia without keratitis (2%). However, reexamination of seven of the 22 patients with corneal vaccinia after 5 years revealed either no ocular residua or only minor corneal changes, including mild corneal scarring, ghost vessels, and subepithelial opacity with chronic conjunctivitis.18
Laboratory Diagnosis of Ocular Vaccinia A HISTORY OF RECENT SMALLPOX VACCINATION OR EXPO-
sure to a recent vaccinee is essential supporting informaOF
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FIGURE 9. Granulomatous appearing keratic precipitates (arrow) are localized in the inferior paracentral and midperipheral corneal endothelium underlying a zone of disciform keratitis. FIGURE 7. The same eye as in Figure 6, shows healing vaccinial blepharitis 10 days later, after treatment with vaccinia immune globulin and topical vidarabine.
FIGURE 8. Vaccinia keratitis with scattered nummular anterior stromal infiltrates in the paracentral cornea.
tion in the diagnosis of ocular vaccinia. In cases where the clinical diagnosis is not clear, the history of exposure is difficult to obtain, or where the patient may be unaware of having been inadvertently exposed, ancillary laboratory testing may be helpful. Laboratory findings include numerous polymorphonuclear cells in smears of the mucopurulent discharge and eosinophilic cytoplasmic inclusion bodies known as Guarneri bodies in direct scrapings of vaccinia lesions. Cotton or polyester swabs of vaccinial lesions can be placed in standard viral transport medium, and the virus can be propagated in a wide variety of tissue cultures, including HeLa cells, rabbit or monkey kidney cells, MRC-5 human embryonic lung fibroblasts, and human embryonic kidney cells.21 The differentiation of vaccinia virus from other poxvirus isolates can be confirmed by restriction endonuclease VOL. 136, NO. 2
FIGURE 10. Vaccinia keratitis produces a large epithelial defect that stains with fluorescein, resembling geographic herpes simplex keratitis.
analysis of infected-cell-DNA extracts. Rapid laboratory diagnosis of vaccinia infection using real time polymerase chain reaction may allow rapid processing of autoclaved suspensions, thereby inactivating the infectivity of the virus.22 Electron microscopic studies of thin sections of infected cells reveals the characteristic 300 ⫻ 200-nm, brick shaped vaccinia virus particles, generally restricted to the cell cytoplasm (Figure 13), as seen in this isolate from the base of a conjunctival pustule taken with a swab. Local and state health departments will be coordinating laboratory testing of swabs and tissue specimens for infection with vaccinia, and inquiries about proper collection, storage, and shipping of these specimens should be directed to those agencies. Specific specimen collection guidelines are also available at: http://www.bt.cdc.gov/agent/smallpox/ vaccination/vacciniaspecimen-collection.asp. Currently, electron microscopy to identify the presence of orthopoxvirus, polymerase chain reaction gene amplifi-
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FIGURE 11. Acute vaccinia keratitis with signs of corneal ulceration, stromal thinning, and mucus formation.
FIGURE 13. Ultrastructural examination reveals cross-sections of multiple vaccinia viral particles, with characteristic dumbbell-shaped cores, in the cytoplasm of an infected human embryonic kidney cell in tissue culture (uranyl acetate and lead citrate, ⴛ86,000).
Treatment of Ocular Vaccinia DURING THE PREVIOUS ERA OF ROUTINE SMALLPOX VACCI-
nation, the treatment of ocular vaccinia was based predominantly on anectodal reports and case series describing the use of vaccinia immune globulin alone or in combination with idoxuridine or topical interferon. Many of these isolated case reports were written before the availability of more effective topical antivirals, such as trifluridine and vidarabine. In the absence of masked, controlled clinical trials, a meaningful meta-analysis of the literature is not possible. Because of this limitation, some of the following recommendations which depart from the previous policy designed in the mid 1960s, were made by the CDC after consultation with an outside panel of corneal and external disease and infectious disease specialists.23 They are based on principles routinely employed in the treatment of other viral diseases of the ocular surface; treat active viral replication with antivirals followed by cautious use of topical corticosteroids (when appropriate) to prevent inflammatory damage of the cornea and anterior segment. For vaccinia, there is an additional therapeutic agent, vaccinia immune globulin (VIG), which is used as indicated below. Because ocular vaccinia virus infections are generally self-limited, treatment should be directed toward shortening the course and limiting the severity of the disease. The evaluation and treatment of ocular complications of vaccinia virus should be performed by an ophthalmologist in a timely manner. Treatment recommendations are summarized in Table 1. The only product currently licensed for the treatment of complications of vaccinia vaccination is vaccinia immune
FIGURE 12. Residual dense, central disciform corneal scar, and low-grade immune keratitis.
cation of vaccinial DNA, and viral culture for vaccinia are available only for research purposes. These tests are currently undergoing multicenter validation studies that might enable the FDA to approve the test reagents for diagnostic use. After that approval, testing will be made available through the Laboratory Response Network, an extensive system of private and public health laboratories that can be accessed through consultation with state and local health departments. Consultation regarding specialized laboratory testing will be available through the Centers for Disease Control and Prevention (CDC). A suspected case of an adverse event after smallpox vaccination should be reported promptly to the appropriate local, state, or territorial health department and to the Vaccine Adverse Event Reporting System at https://secure.vaers. org/VaersDataEntryintro.htmor 1-800-822-7967. 348
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TABLE 1. Recommendations for the Treatment of Ocular Vaccinia
TABLE 1. Continued KERATITIS WITH SEVERE BLEPHARITIS AND/OR CONJUNCTIVITIS
BLEPHARITIS
Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic: 4 times a day for 10 days VIG: Consider VIG IM 100 mg/kg one dose, consider repeat in 48 hours if no improvement. Topical corticosteroid: After epithelium is healed (at about 7 days) add moderate-low-dose steroid to decrease immune reaction, if present (for example, prednisone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1%, or similar potency topical corticosteroid) and taper slowly. Topical antiviral cover should accompany corticosteroid use for treatment of acute disease. Mydriatic
Mild (few pustules, mild edema, no fever) Topical antiviral: Consider prophylaxis of the conjunctiva and cornea: Adults: Trifluridine 1% drops 9x/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic ointment Severe (pustules, edema, hyperemia, lymphadenopathy, cellulitis, fever) Topical antiviral: Adults: Trifluridine 1% drops 9x/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: 100 mg/kg intramuscularly; repeat in 48 hours if not improved Topical antibiotic ointment
IRITIS
Treat as for other accompanying eye conditions mentioned above Topical corticosteroid: Add moderate-low dose steroid to decrease immune reaction (e.g., prednisolone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1% or similar topical corticosteroid) if corneal epithelium is intact. Taper slowly. Mydriatic
CONJUNCTIVITIS WITH OR WITHOUT BLEPHARITIS BUT WITHOUT KERATITIS
Mild (mild hyperemia and edema, no membranes or focal lesions) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: The majority of ophthalmic consultants recommended VIG 100 mg/kg intramuscularly Severe: (marked hyperemia, edema, membranes, focal lesions, lymphadenopathy, fever) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: VIG 100 mg/kg; repeat in 48 hours if not improved Topical antibiotic ointment
VIG ⫽ vaccinia immune globulin. *If vidarabine is not available, use trifluridine in children in the recommended adult dose.
KERATITIS WITH MILD OR MODERATE BLEPHARITIS OR CONJUNCTIVITIS
Mild (grey epitheliitis, no ulcer, no stromal haze, or infiltrate) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks; Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic ointment: once daily for 10 days Moderate (epithelial defect, but no stromal haze or infiltrate) Same treatment as mild, but use topical antibiotic four times a day for 10 days or until ulcer healed Severe (ulcer, stromal haze, or infiltrate) Same treatment as for moderate, but after epithelium is healed (at about 7 days) add moderate-low-dose corticosteroid to decrease immune reaction (for example, prednisolone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1%, or similar potency topical corticosteroid) and taper slowly. Topical antiviral cover should accompany corticosteroid use for treatment of acute disease. Mydriatic
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globulin, referred to as VIG.7 This is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons recently vaccinated with the smallpox vaccine; VIG is currently administered intramuscularly, but future formulations should allow intravenous administration. It is effective for the treatment of eczema vaccinatum, certain cases of progressive vaccinia, and some cases of ocular vaccinia resulting from inadvertent implantation; VIG is available only via an Investigational New Drug protocol through the CDC. Physicians at civilian medical facilities may request VIG by calling CDC’s Smallpox Vaccinee Adverse Events Clinician Information line at 877-5544625. Physicians at military medical facilities may request VIG by calling the United States Army Medical Research Institute of Infectious Diseases (USAMRID) at 301-6192257 or 888-USA-RIID. No controlled clinical trials of antiviral or VIG therapy for ocular vaccinia disease in humans have been published.24,25 However, the use of VIG for vaccinial keratitis was evaluated in one controlled study in rabbits.26 Rabbits receiving one dose of VIG did not demonstrate any difference in clinical course or corneal scarring compared with rabbits receiving no treatment. Rabbits receiving five
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when topical antivirals are used and is not recommended. If VIG is administered to a patient who has keratitis, informed consent should be obtained after discussion of potential risks and benefits. While no Food and Drug Administration-licensed topical antiviral has an approved indication for the treatment of ocular vaccinia, topical trifluridine drops or vidarabine ointment can be used off-label for this purpose, and are likely to be more effective and less toxic than topical idoxuridine or cytosine arabinoside.33–38 Topical vidarabine may be preferable for use in children, because it has been available in an ointment preparation that allows less frequent dosing and is associated with less initial stinging than trifluridine. Vidarabine ointment is currently not commercially available, but it may be obtained through compounding pharmacists. If, however, vidarabine cannot be obtained or the patient would better tolerate drops, trifluridine may be used in children just as it is in ocular herpes simplex in the doses indicated in Table 1. Topical antiviral drugs should be considered for prophylaxis of the conjunctiva and cornea if vaccinia lesions are present on the eyelid, especially if near the lid margin. The use of these drugs for prophylaxis should be balanced against the possible risk of drug toxicity and of introducing virus into the eye by frequent manipulation. Topical trifluridine may possibly have an increased risk of toxicity if used for longer than 14 days. Toxic changes to the ocular surface are almost invariably reversible with discontinuation of the drug. Acyclovir has not been shown to be effective against vaccinia by in vitro antiviral screening.38 Uncontrolled studies have suggested that topical leukocyte interferon (monkey or human) may be of benefit in the treatment or prophylaxis of vaccinia infection of the ocular surface.39,40 For end-stage disease with a visually disabling scar or leukoma, lamellar or penetrating keratoplasty has a generally favorable prognosis in the absence of corneal neovascularization or active inflammation.41
daily intramuscular doses of VIG, 2.5 to 5 times the recommended human dose, developed stellate corneal scars persisting until study termination at day 67. For these rabbits, daily treatment with VIG for 5 days may have presented an overwhelming immunologic challenge to the infected corneas. 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. Based largely on the results of this animal study, VIG has been considered contraindicated for the treatment of vaccinial keratitis. It should be noted, however, that there are at least five case reports of notable coneal scarring reported in patients who did not receive intramuscular VIG.27–30 The question has been recently raised whether VIG should continue to be contraindicated for keratitis and, in particular, whether VIG should be withheld from patients with keratitis who also have extensive ocular or extraocular disease and might benefit from its use. There are uncontrolled human data on the usefulness of VIG in vaccinial complications. Jones and associates31 reported four cases of severe orbital cellulitis to intramuscular VIG responding within 24 hours. Ellis and colleagues27 reported six ocular cases, three with keratitis, all treated successfully with intramuscular VIG, two receiving three doses and one receiving seven doses. There were no residua except minimal stromal edema and 20/40 vision in the latter patient. Ruben and Lane18 reported their accumulated experience of 348 cases of ocular vaccinia, 22 with keratitis, of which 336 were treated with intramuscular VIG and 28 with idoxuridine with or without VIG. Only 2% of noncornea cases had residua, none considered severe, comprised of eyelid scarring, madarosis, and punctal stenosis with epiphora. Of the 22 patients with keratitis, 4 (18%) had some residual findings (only 1 had a residual corneal scar). Seven of the 22 patients who originally presented with keratitis were re-examined 5 years later; 3 of the 7 had no corneal residua, and 4 had only mild findings not involving the visual axis. Other case reports suggest a therapeutic effect of VIG on vaccinia keratitis, as illustrated in brothers with similar ocular corneal vaccinia where the one with VIG healed without scarring in 24 hours and the untreated brother had 4 weeks of active disease with residual corneal scarring.27 Vaccinia immune globulin should be considered for use in severe ocular disease when keratitis is not present (for example, severe blepharitis or blepharoconjunctivitis).23 If keratitis accompanies these conditions, VIG need not necessarily be withheld but should be used cautiously (and generally in a single dose) due to a possible increased risk of corneal scar formation. Similarly, if VIG is indicated based on other criteria (for example, eczema vaccinatum, progressive vaccinia), its use or dosing need not be withheld if keratitis is also present. For treatment of isolated keratitis, VIG has not been shown to offer added benefit 350
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Prevention of Ocular Vaccinia BECAUSE AUTOINOCULATION IS THOUGHT TO BE THE
most common means of developing ocular vaccinia, every effort should be made to keep the inoculation site covered until the scab has dried up and fallen off (⬃21 days). Vaccinees will also be warned by public health officials to avoid touching the site when it is uncovered for bathing. Healthcare professionals who are caring for patients with recent vaccinations or vaccine-related complications should engage in routine precautions for dealing with infectious agents, including gloves, proper hand washing, and disinfection of contaminated equipment. Disinfection with 70% alcohol or diluted bleach solution (10%) should be effective for this purpose. Healthcare providers who are OF
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pregnant, have active atopic dermatitis, or are immune compromised in any way (for example, HIV infected, history of leukemia or lymphoma, on immunosuppresants or chemotherapy) should not be evaluating or caring for recent vaccinees or those with vaccine-related adverse events. The CDC has not yet recommended that all healthcare professionals who care for these patients need to be vaccinated. Instead it is simply recommending that strict precautions be taken, similar to those appropriate for blood-borne pathogens.
Smallpox Vaccine Exclusionary Criteria for Eye Banking THE EYE BANK ASSOCIATION OF AMERICA ADDED A NEW
contraindication to its Medical Standards for potential cornea donors, effective January 10, 2003. The smallpox vaccine exclusionary criteria are as follows: (1) potential donors who received the smallpox vaccine without complications shall be deferred until after the vaccination scab has separated and the vaccination site appears to be healed and not inflamed, or for 21 days after vaccination, whichever is the later date; (2) potential donors who received the smallpox vaccine and developed complications that have resolved shall be deferred for 14 days after all vaccine complications have completely resolved, or for 21 days after vaccination, whichever is the later date; (3) potential donors who received the smallpox vaccine and developed complications that have not resolved shall be deferred; and (4) potential donors who have had contact with someone who has received the smallpox vaccine shall be deferred in cases where the donors have had recognizable signs or symptoms attributable to the virus within 14 days before donation.
Summary WITH THE REINITIATION OF SMALLPOX VACCINATION IN
selected groups in the United States, healthcare workers are likely to see cases of ocular vaccinia present as a result of autoinoculation or contact with a recent vaccinee. Ophthalmologists should familiarize themselves with the ocular manifestations of vaccinia and seek consultation with local and state health department as well as with the CDC for guidance in treatment options and laboratory confirmation. A need exists for masked, controlled trials of VIG in patients with vaccinia keratitis and in the development of animal models that mimic the features of ocular vaccinia in humans and for in vivo assessment of therapeutics. VOL. 136, NO. 2
REFERENCES 1. Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management (consensus statement). JAMA 1999;281:2127–2137. 2. Bozzette SA, Boer R, Bhatnagar V, et al. A model for a smallpox-vaccination policy. N Engl J Med 2003;348:416 – 425. 3. Centers for Disease Control and Prevention. Recommendations for using smallpox vaccine in a pre-event vaccination program. MMWR 2003;52(RR07):1–16. 4. Pepose JS, Esposito JJ. Molluscum contagiosum, orf and vaccinia. In: Pepose JS, Holland GN, Wilhelmus KR, editors. Ocular infection and immunity. St. Louis: Mosby; 1996: 846 –856. 5. World Health Organization Study Group. Declaration of global eradication of smallpox. Wkly Epidemiol Rec 1980; 55:145–152. 6. Centers for Disease Control and Prevention. Smallpox fact sheet, smallpox overview, 2002. 7. Centers for Disease Control and Prevention. Vaccinia (smallpox) vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2001. MMWR 2001;50:1–22. 8. Lane JM, Ruben FL, Neff JM, Millar JD. Complications of smallpox vaccination, 1968: national survey in the United States. N Engl J Med 1969;281:1201–1208. 9. Neff JM, Lane JM, Fulginiti V, Henderson DA. Contact vaccinia: Transmission of vaccinia from smallpox vaccination. JAMA 2002;288:1901–1905. 10. Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions: guidance for clinicians. MMWR Dispatch 2003;52:1–29. 11. Goldstein JA, Neff JM, Lane JM, Koplan JP. Smallpox vaccination reactions, prophylaxis and therapy of complications. Pediatrics 1975;55:342–347. 12. Sepkowitz KA. How contagious is vaccinia? N Engl J Med 2003;348:439 –446. 13. Walensky RP, Losina E, Steger-Craven KA, et al. Identifying undiagnosed human immunodeficiency virus. Arch Intern Med 2002;162:887–892. 14. Centers for Disease Control and Prevention. Surveillance of health care workers with HIV/AIDS. Available at: http:// www.cdc.gov/hiv/pubs/facts/hchsurv.htm. Accessed Sept 13, 2002. 15. Redfield RR, Wright DC, James WD, et al. Disseminated vaccinia in a military recruit with a human immunodeficiency virus (HIV) disease. N Engl J Med 1987;316:673–676. 16. Engler RJ, Kenner J, Leung DY. Smallpox vaccination: risk considerations for patients with atopic dermatitis. J Allergy Clin Immunol 2002;110:357–365. 17. Sommerville J, Napier W, Dick A. Kaposi’s varicelliform eruption: record of an outbreak. Br J Dermatol 1951;63:203– 214. 18. Ruben F, Lane J. Ocular vaccinia: epidemiologic analysis of 348 cases. Arch Ophthalmol 1970;84:45–48. 19. Sedan J, Ourgaud AG, Guillot P. Les accidents oculaires d’origine vaccinale observe´s dans le De´partment des Bouches-du-Rhone au cours de I’e´pidemie´ variolique de I’hiver 1952. Ann Oculist 1953;186:34 –61. 20. Ellis PP, Winograd LA. Current concepts of ocular vaccinia. Trans Proc Coast Ophthalmol Soc 1963;44:141–148. 21. Lee SF, Butler R, Chansue E, et al. Vaccinia keratouveitis manifesting as a masquerade syndrome. Am J Ophthalmol 1994;117:480 –487. 22. Espy MJ, Uhl JR, Sloan LM, Rosenblatt JE, Cockerill FR, III,
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23. 24. 25. 26. 27. 28. 29. 30. 31. 32.
Smith TF. Detection of vaccinia virus, herpes simplex virus, varicella-zoster virus, and Bacillus anthracis DNA by LightCycler polymerase chain reaction after autoclaving: implications for biosafety of bioterrorism agents. Mayo Clin Proc 2002;77:624 –628. Centers for Disease Control and Prevention. Smallpox vaccination and adverse reactions: guidance for clinicians. MMWR Dispatch 2003;52:1–29. Sharp JCM, Fletcher W. Experience of anti-vaccina immunoglobulin in the United Kingdom. Lancet 1973;i:656 –659. Franc¸ois J, Molder ED, Gildemyn H. Ocular vaccinia. Acta Ophthalmologica 1967;45:25–31. Fulginiti VA, Winograd LA, Jackson M, Ellis P. Therapy of experimental vaccinial keratitis. Arch Ophthal 1965;74: 539 –544. Ellis P, Winograd L. Ocular vaccinia: a specific treatment. Arch Ophthalmol 1962;68:600 –609. Kempe C. Studies on smallpox and complications of smallpox vaccination. Pediatrics 1960;26:176 –189. Perera C. Vaccinial disciform keratitis. Arch Ophthalmol 1940;24:352–356. Rennie A, Cant JS, Foulds WS, Pennington TH, Timbury MC. Ocular vaccinia. Lancet 1974;213–215. Jones BR, Al-Hussaini MK. Therapeutic considerations in ocular vaccinia. Trans Ophthalmol Soc U K 1964;83:613– 631. Hyndiuk RA, Seideman S, Leibsohn J. Treatment of vaccin-
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33. 34. 35. 36. 37. 38. 39. 40.
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ial kevatitis with trifluorothymidine. Arch Ophthalmol 1976;94:1785–1786. Hyndiuk R, Okumoto M, Damiano R, Valenton M, Smolin G. Treatment of vaccinial keratitis with vidarabine. Arch Ophthalmol 1976;94:1363–1364. Pavan-Langston D, Dohlman CH. A double-blind clinical study of adenine arabinoside (vidarabine) therapy of viral conjunctivitis. Am J Ophthalmol 1972;74:81–88. Kaufman HE, Nesburn AB, Maloney ED. Cure of vaccinia infection by 5-iodo-2⬘- deoxyuridine. Virology 1962;18:567– 569. Gordon D. Vaccinial blepharoconjunctivitis treated with cytosine arabinoside. Am J Ophthalmol 1965;59:480 –482. Jack MK, Sorenson RW. Vaccinial keratitis treated with IDU. Arch Ophthalmol 1963;69:730 –732. Elion GB, Rideout JL, de Miranda P, et al. Biological activities of some purine arabinosides. Ann N Y Acad Sci 1975;255:468 –480. Jones BR, Galbraith JEK, Al-Hussaini MK. Vaccinial keratitis treated with interferon. Lancet 1962;1:875–879. 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 –155. Sugar A, Meyer RF. Smallpox and vaccinia. In: Darell RW, editor. Viral diseases of the eye. Philadelphia: Lea and Febiger, 1985: 121–127.
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● PURPOSE: To describe the ocular complications of smallpox vaccination and to discuss potential therapeutic options. ● DESIGN: Review of pertinent medical literature and recent treatment recommendations of the Centers for Disease Control and Prevention. ● RESULTS: After immunization against smallpox, vaccinia infection of the eyelid, conjunctiva, or ocular surface can result from accidental autoinoculation from a vaccination site before scab formation or from contact with a recently vaccinated individual. While uncommon, corneal involvement can lead to stromal opacification and scarring. Clinical findings of ocular and periocular vaccinia must be differentiated from those produced by other pathogens such as molluscum contagiosum, herpes simplex, varicella zoster, and acanthamoeba infections. Clinical diagnosis can be confirmed by electron microscopy to identify the presence of orthopoxvirus, as well as by virologic culture, polymerase chain reaction, and/or restriction endonuclease analysis of viral isolates. ● CONCLUSIONS: While the majority of ocular complications of smallpox vaccination in immunocompetent patients are self-limiting, selective cases may require treatment with trifluridine drops, topical corticosteroids and vaccinia immune globulin (VIG). Vaccinia virus does not appear to be sensitive to acyclovir. Specific treatment recommendations are outlined for the spectrum of ocular manifestations. (Am J Ophthalmol 2003;136:343–352. © 2003 by Elsevier Inc. All rights reserved.) Accepted for publication March 5, 2003. InternetAdvance publication at ajo.com March 18, 2003. From the Pepose Vision Institute, Chesterfield, Missouri (J.S.P.), and the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri (J.S.P.); The Francis I. Proctor Foundation and Department of Ophthalmology, University of California San Francisco, San Francisco, California (T.P.M.); Department of Pediatrics, Columbia University, New York, New York (P.L.); Department of Ophthalmology, Harvard Medical School, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts (D.P.L.). This study was supported, in part, by a grant from the Midwest Cornea Research Foundation, Chesterfield, Missouri. Inquiries to Jay S. Pepose, MD, PhD, Pepose Vision Institute 16216 Baxter Road, Suite 205, Chesterfield, MO 63017 0002-9394/03/$30.00 doi:10.1016/S0002-9394(03)00293-9
©
2003 BY
R
OUTINE SMALLPOX VACCINATIONS HAVE NOT BEEN
performed in the general population of the United States in 30 years. Because of growing concerns about the use of the smallpox (variola) virus as an agent of bioterrorism,1,2 vaccinia inoculations of the military, bioterrorism first responder groups, and healthcare personnel have been recently recommended.3 Ocular complications of smallpox vaccination can arise from accidental autoinoculation of the eye or eyelid with virus from the vaccination site or from close physical contact with a vaccinee shedding virus.4 In this Perspective, we review the clinical and laboratory diagnosis of ocular vaccinia, and discuss potential therapeutic options for specific ocular manifestations using topical antivirals, topical corticosteroids and vaccinia immune globulin.
History of Smallpox Vaccination and Eradication SMALLPOX, A POTENTIALLY DEVASTATING DISEASE WITH
up to 30% mortality, was eradicated from nature in 1979.5 This fantastic feat was accomplished using a strategy of surveillance and containment vaccination, under the auspices of the World Health Organization. The vaccine against smallpox currently licensed in the United States is a lyophilized, live-virus preparation of infectious vaccinia virus, a related orthopox virus, administered by using a multiple puncture technique on the upper arm with a bifurcated needle. The vaccine does not contain the smallpox (variola) virus itself. By the late 1960s, the risk of importing smallpox into the United States had greatly diminished. The last reported case of smallpox in the United States was in 1949.6 The recommendation of smallpox vaccination for the general public was officially rescinded in 1971 and was discontinued for healthcare workers in 1976. In January 1982, smallpox vaccination was no longer required for international travelers, and routine vaccination of military personnel ceased in 1990.7 With the exception of military personnel who served in the 1980s, certain laboratory workers and healthcare workers using orthopox viruses or
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involved in clinical trials with recombinant vaccinia vaccines, the entire United States population younger than age 30 has no immunity to smallpox. Most of those age 30 and older have only had a single vaccination in childhood and would be expected to both shed virus from a repeat vaccination site and be susceptible to contact infection from other recently vaccinated individuals. Because of growing concerns about the potential use of smallpox as an agent of bioterrorism,1,2 the United States Department of Health and Human Services has recommended that smallpox vaccination be reinstated for United States military personnel and bioterrorism first responder units, followed by primary and ancillary healthcare personnel.3 These two phases of immunization will probably involve administering around 1 million vaccinations. It is possible that a larger-scale volunteer smallpox vaccination program for the general public could follow at some time in the future. While smallpox (vaccinia) vaccination is considered a relatively safe and effective preventative against smallpox with a complication rate of 0.004%,8 severe reactions are more common than following any other vaccine. While the majority of complications occur in the person who has been vaccinated, the virus can be inadvertently transmitted from the vaccinee to others, as the inoculation site can shed infectious virus up to 21 days, until the scab detaches. The most serious complications8 –10 that can follow vaccination or contact with a vaccinated person include: (1) vaccinia necrosum (progressive vaccinia)—the primary vaccination site does not heal, and the infection spreads locally and by viremia producing necrotic lesions—this occurs primarily in immunocompromised individuals with T-cell deficiency/dysfunction (for example, those with HIV infection, AIDS, cancer, congenital T-cell deficiency, or on immunosuppressive agents); (2) eczema vaccinatum—produces fever, lymphadenopathy, and generalized, often confluent, lesions in areas other than the vaccination site (frequently the face and limbs) in individuals with eczema (atopic dermatitis) or a history of eczema; (3) accidental infection—vaccinial lesions resulting from unintentional implantation of vaccinia virus in the eye, lids, mouth, or elsewhere in individuals without eczema or other preexisting skin lesions; (4) postvaccinial encephalitis—the most serious complication after vaccination of healthy individuals. This most often affects primary vaccinees aged ⬍ 1 year or adolescents and adults receiving primary vaccination, but it has not been reported in secondary acquired vaccinia. Approximately 15% to 25% of primary vaccinees with encephalitis die, and 25% have permanent neurological sequelae;8 –11 and (5) fetal vaccinia—which is a rare condition resulting from transmission of vaccinia from a vaccinated pregnant woman to her fetus. Less than 50 cases have been reported, but the resulting skin and organ involvement often leads to fetal or neonatal death. 344
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It is difficult to predict with certainty the number of adverse events that may be associated with current day smallpox vaccination, because a number of pertinent factors have changed since 30 years ago.9,12 In the 21st century, the number of immunocompromised individuals (many of whom are in a hospital setting) has increased dramatically secondary to organ transplants, cancer, use of chemotherapy, corticosteroids and immunosuppressive drugs, HIV infection, and the expansion of intensive care units and neonatal nurseries.11 Many contemporary hospital and healthcare workers (some of whom are themselves immunocompromised) have either never been vaccinated or received one vaccination 30 or more years ago. Such hospital and healthcare workers now have little or no vaccinia immunity, may shed virus longer after vaccination, and may be in more frequent contact with immunocompromised individuals than their counterparts would have 3 decades ago.9,12,13 In the early 1960s, many hospital staff vaccination programs strategically performed smallpox vaccinations immediately before a holiday and did not permit clinical duty during the period in which healthcare workers might shed virus.9 This may not be uniformly or even frequently practiced today, as the Advisory Committee on Immunization Practices has stated that it is not necessary to furlough vaccinated healthcare workers.3 To counterbalance this, the use of precautions that were not routinely employed 30 years ago, such as the use of semipermeable polyurethane dressings over the vaccination site,7 are likely to limit spread to other individuals if closely adhered to. Another smallpox vaccination risk not present in the 1960s is highlighted by the estimate of the Centers for Disease Control and Prevention that 300,000 individuals in the United States are unaware that they are currently infected with HIV13 and that more than 23,000 healthcare workers have AIDS.14 As an unfortunate example of the potential consequence of unknowingly vaccinating a highrisk individual, an apparently healthy United States military recruit developed progressive vaccinia soon after receiving a smallpox vaccination in 1984 and was only later diagnosed as having HIV infection.15 Cutaneous manifestations of HIV infection may also serve as a portal for secondary vaccinia infection.9 Finally, the prevalence of atopic dermatitis in children has increased between two to threefold over the past 30 years and is now estimated to be between 6% and 22% in the United States.16 This group may be more susceptible to acquiring contact vaccinia, manifesting as eczema vaccinatum. Other skin conditions that may predspose to secondary contact acquisition of vaccinia include seborrheic dermatitis, impetigo, scabies, burns, and pemphigus foliaceus.17 The purpose of this Perspective is to review the ocular complications of smallpox vaccination, their clinical and laboratory diagnoses, and potential treatment options. As will be discussed, some of the ocular antiviral therapies OF
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were not available in the previous era of smallpox vaccination, and none of the treatment options have been evaluated or statistically validated in prospective, masked, randomized trials.
Ocular Complications of Smallpox Vaccination OF THE NINE POXVIRUSES THAT CAUSE DISEASE IN HU-
mans, four are associated with ocular or eyelid infections: vaccinia virus, variola virus, orf virus, and molluscum contagiosum.4 During the period of routine smallpox vaccination, ocular vaccinia sometimes occurred by transmission from the vaccination “take” of another individual or by autoinoculation from the vaccinee’s own lesion. Spread of vaccinia virus to the eye was mainly by digital contact after rubbing the vaccination site. Signs and symptoms of primary accidental self inoculation may appear between 5 and 11 days after vaccination. Secondary cases generally manifest between 8 and 18 days after exposure. The incidence of ocular vaccinia was approximately one per 40,000 primary vaccinations,8,18 and the clinical manifestations of ocular vaccinia varied depending upon the specific immune status of the host. In previously vaccinated individuals, accidental autoinoculation into the eye after close contact with a recent vaccinee was often limited to mucopurulent blepharoconjunctivitis.19 More severe ocular complications were far more common in primary vaccinees than in revacinees,18 and in accidental primary autoinoculation. Primary vaccinee and primary autoinoculation refer to patients not previously vaccinated or exposed to the vaccinia virus, who are, therefore, without previous immunity. A revaccinee has had some previous immune response after previous deliberate or accidental inoculation. ● VACCINIA BLEPHARITIS: Vaccinia infection of the eyelid or ocular surface may lead to the formation of vesicles that progress to pustules that umbilicate and indurate, sometimes followed by a scab that detaches (Figures 1 to 3). This is similar to the transformation on the arm seen after a successful vaccine “take” (Figure 4). One differentiating factor between herpes simplex and vaccinia lesions is that herpetic vesicles of the eyelid or ocular surface do not go through a pustular phase (Figure 5). A differentiating feature between herpes zoster and vaccinia dermatitis is that vaccinia lesions do not respect a dermatomal distribution. Single or multiple vaccinia lesions can produce profound eyelid swelling and periorbital erythema, resembling orbital cellulitis (Figures 1, 6, and 7). This is commonly accompanied by preauricular and/or submandibular lymphadenopathy.18,20 Eyelid lesions can progress to scarring and madarosis. The differential diagnosis of vaccinia lesions of the eyelid includes
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FIGURE 1. Vaccinia lesions of the eyelid are seen in various stages of evolution from vesicles to umbilicated pustules.
FIGURE 2. Multiple periocular vaccinial lesions in a 22-yearold military recruit produce lid ulceration, madarosis, and hemorrhage, accompanied by chemosis and conjunctival injection.
molluscum contagiosum, staphylococcal blepharitis, and herpes simplex or varicella zoster virus blepharitis. ● VACCINIA CONJUNCTIVITIS:
In the majority of cases, ocular vaccinia is limited to the eyelid and conjunctiva. Vaccinia conjunctivitis is characterized by an acute papillary reaction and serous or mucopurulent discharge. Multifocal ulceration of the papillary and bulbar conjunctiva occurs commonly. Conjunctival ulcers have a whitish center with surrounding injection and edema; may be covered by a thick, yellowish-gray membrane; and may lead to symblepharon formation. Preauricular adenopathy commonly accompanies vaccinial conjunctivitis, but the presence of follicles is rare.
● VACCINIA KERATITIS: Corneal involvement after autoinoculation is uncommon, with reports of approximately 1.2 cases per million primary vaccinations.4,8 Other studies
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FIGURE 3. The same eye as in Figure 2, shows resolution of blepharoconjunctivitis at 14 days after treatment with vaccinia immune globulin.
FIGURE 5. Herpes simplex vesicles of the eyelid do not go through the pustular phase commonly seen with vaccinia.
FIGURE 4. Limbal vesicle (arrow) and inferior corneal epithelial defect. FIGURE 6. Multiple vaccinia lesions producing severe periorbital edema and erythema, mimicking orbital cellulitis.
indicate postvaccinial keratitis in 6% to 37% of vaccinia cases with ocular involvement.18 –20 Keratitis appears more frequently in primary vaccinees than revaccinees. This would appear to be a reflection of the immune status of the previously vaccinated patient. Corneal manifestations of ocular vaccinia range from mild superficial punctate keratitis to interstitial or stromal keratitis (Figure 8), to disciform keratitis with keratic precipitates (Figure 9), to necrosis with perforation. As with epithelial herpes simplex or varicella zoster keratitis, corneal epithelial vaccinia lesions stain with rose bengal early in the course of the disease and with fluorescein as an epithelial defect evolves. Direct infection of the corneal epithelium with vaccinia may present as multiple punctate lesions, dendritiform lesions, or in a geographic pattern. All forms of vaccinia epithelial keratitis may closely resemble that seen with herpes simplex (Figure 10). Stromal keratitis due to vaccinia may initially appear as scattered subepithelial opacities similar to that seen in epidemic keratoconjunctivitis. This pattern may evolve to 346
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ring infiltrates, ulceration (Figure 11), and/or stromal necrosis, or scarring (Figure 12), which must be differentiated from acanthamoeba, herpes zoster, and herpes simplex stromal keratitis. Long-term sequelae, such as madarosis, punctal stenosis, and cicatricial lid changes are more common in cases with corneal manifestations (18%) than in ocular vaccinia without keratitis (2%). However, reexamination of seven of the 22 patients with corneal vaccinia after 5 years revealed either no ocular residua or only minor corneal changes, including mild corneal scarring, ghost vessels, and subepithelial opacity with chronic conjunctivitis.18
Laboratory Diagnosis of Ocular Vaccinia A HISTORY OF RECENT SMALLPOX VACCINATION OR EXPO-
sure to a recent vaccinee is essential supporting informaOF
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FIGURE 9. Granulomatous appearing keratic precipitates (arrow) are localized in the inferior paracentral and midperipheral corneal endothelium underlying a zone of disciform keratitis. FIGURE 7. The same eye as in Figure 6, shows healing vaccinial blepharitis 10 days later, after treatment with vaccinia immune globulin and topical vidarabine.
FIGURE 8. Vaccinia keratitis with scattered nummular anterior stromal infiltrates in the paracentral cornea.
tion in the diagnosis of ocular vaccinia. In cases where the clinical diagnosis is not clear, the history of exposure is difficult to obtain, or where the patient may be unaware of having been inadvertently exposed, ancillary laboratory testing may be helpful. Laboratory findings include numerous polymorphonuclear cells in smears of the mucopurulent discharge and eosinophilic cytoplasmic inclusion bodies known as Guarneri bodies in direct scrapings of vaccinia lesions. Cotton or polyester swabs of vaccinial lesions can be placed in standard viral transport medium, and the virus can be propagated in a wide variety of tissue cultures, including HeLa cells, rabbit or monkey kidney cells, MRC-5 human embryonic lung fibroblasts, and human embryonic kidney cells.21 The differentiation of vaccinia virus from other poxvirus isolates can be confirmed by restriction endonuclease VOL. 136, NO. 2
FIGURE 10. Vaccinia keratitis produces a large epithelial defect that stains with fluorescein, resembling geographic herpes simplex keratitis.
analysis of infected-cell-DNA extracts. Rapid laboratory diagnosis of vaccinia infection using real time polymerase chain reaction may allow rapid processing of autoclaved suspensions, thereby inactivating the infectivity of the virus.22 Electron microscopic studies of thin sections of infected cells reveals the characteristic 300 ⫻ 200-nm, brick shaped vaccinia virus particles, generally restricted to the cell cytoplasm (Figure 13), as seen in this isolate from the base of a conjunctival pustule taken with a swab. Local and state health departments will be coordinating laboratory testing of swabs and tissue specimens for infection with vaccinia, and inquiries about proper collection, storage, and shipping of these specimens should be directed to those agencies. Specific specimen collection guidelines are also available at: http://www.bt.cdc.gov/agent/smallpox/ vaccination/vacciniaspecimen-collection.asp. Currently, electron microscopy to identify the presence of orthopoxvirus, polymerase chain reaction gene amplifi-
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FIGURE 11. Acute vaccinia keratitis with signs of corneal ulceration, stromal thinning, and mucus formation.
FIGURE 13. Ultrastructural examination reveals cross-sections of multiple vaccinia viral particles, with characteristic dumbbell-shaped cores, in the cytoplasm of an infected human embryonic kidney cell in tissue culture (uranyl acetate and lead citrate, ⴛ86,000).
Treatment of Ocular Vaccinia DURING THE PREVIOUS ERA OF ROUTINE SMALLPOX VACCI-
nation, the treatment of ocular vaccinia was based predominantly on anectodal reports and case series describing the use of vaccinia immune globulin alone or in combination with idoxuridine or topical interferon. Many of these isolated case reports were written before the availability of more effective topical antivirals, such as trifluridine and vidarabine. In the absence of masked, controlled clinical trials, a meaningful meta-analysis of the literature is not possible. Because of this limitation, some of the following recommendations which depart from the previous policy designed in the mid 1960s, were made by the CDC after consultation with an outside panel of corneal and external disease and infectious disease specialists.23 They are based on principles routinely employed in the treatment of other viral diseases of the ocular surface; treat active viral replication with antivirals followed by cautious use of topical corticosteroids (when appropriate) to prevent inflammatory damage of the cornea and anterior segment. For vaccinia, there is an additional therapeutic agent, vaccinia immune globulin (VIG), which is used as indicated below. Because ocular vaccinia virus infections are generally self-limited, treatment should be directed toward shortening the course and limiting the severity of the disease. The evaluation and treatment of ocular complications of vaccinia virus should be performed by an ophthalmologist in a timely manner. Treatment recommendations are summarized in Table 1. The only product currently licensed for the treatment of complications of vaccinia vaccination is vaccinia immune
FIGURE 12. Residual dense, central disciform corneal scar, and low-grade immune keratitis.
cation of vaccinial DNA, and viral culture for vaccinia are available only for research purposes. These tests are currently undergoing multicenter validation studies that might enable the FDA to approve the test reagents for diagnostic use. After that approval, testing will be made available through the Laboratory Response Network, an extensive system of private and public health laboratories that can be accessed through consultation with state and local health departments. Consultation regarding specialized laboratory testing will be available through the Centers for Disease Control and Prevention (CDC). A suspected case of an adverse event after smallpox vaccination should be reported promptly to the appropriate local, state, or territorial health department and to the Vaccine Adverse Event Reporting System at https://secure.vaers. org/VaersDataEntryintro.htmor 1-800-822-7967. 348
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TABLE 1. Recommendations for the Treatment of Ocular Vaccinia
TABLE 1. Continued KERATITIS WITH SEVERE BLEPHARITIS AND/OR CONJUNCTIVITIS
BLEPHARITIS
Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic: 4 times a day for 10 days VIG: Consider VIG IM 100 mg/kg one dose, consider repeat in 48 hours if no improvement. Topical corticosteroid: After epithelium is healed (at about 7 days) add moderate-low-dose steroid to decrease immune reaction, if present (for example, prednisone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1%, or similar potency topical corticosteroid) and taper slowly. Topical antiviral cover should accompany corticosteroid use for treatment of acute disease. Mydriatic
Mild (few pustules, mild edema, no fever) Topical antiviral: Consider prophylaxis of the conjunctiva and cornea: Adults: Trifluridine 1% drops 9x/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic ointment Severe (pustules, edema, hyperemia, lymphadenopathy, cellulitis, fever) Topical antiviral: Adults: Trifluridine 1% drops 9x/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: 100 mg/kg intramuscularly; repeat in 48 hours if not improved Topical antibiotic ointment
IRITIS
Treat as for other accompanying eye conditions mentioned above Topical corticosteroid: Add moderate-low dose steroid to decrease immune reaction (e.g., prednisolone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1% or similar topical corticosteroid) if corneal epithelium is intact. Taper slowly. Mydriatic
CONJUNCTIVITIS WITH OR WITHOUT BLEPHARITIS BUT WITHOUT KERATITIS
Mild (mild hyperemia and edema, no membranes or focal lesions) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: The majority of ophthalmic consultants recommended VIG 100 mg/kg intramuscularly Severe: (marked hyperemia, edema, membranes, focal lesions, lymphadenopathy, fever) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* VIG: VIG 100 mg/kg; repeat in 48 hours if not improved Topical antibiotic ointment
VIG ⫽ vaccinia immune globulin. *If vidarabine is not available, use trifluridine in children in the recommended adult dose.
KERATITIS WITH MILD OR MODERATE BLEPHARITIS OR CONJUNCTIVITIS
Mild (grey epitheliitis, no ulcer, no stromal haze, or infiltrate) Topical antiviral: Adults: Trifluridine 1% drops 9⫻/day for 2 weeks; Children: Vidarabine 3% ointment twice a day for 2 weeks may be substituted for trifluridine* Topical antibiotic ointment: once daily for 10 days Moderate (epithelial defect, but no stromal haze or infiltrate) Same treatment as mild, but use topical antibiotic four times a day for 10 days or until ulcer healed Severe (ulcer, stromal haze, or infiltrate) Same treatment as for moderate, but after epithelium is healed (at about 7 days) add moderate-low-dose corticosteroid to decrease immune reaction (for example, prednisolone acetate 1/8%, lotoprednol 0.2–0.5%, or rimexolone 1%, or similar potency topical corticosteroid) and taper slowly. Topical antiviral cover should accompany corticosteroid use for treatment of acute disease. Mydriatic
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globulin, referred to as VIG.7 This is an isotonic sterile solution of the immunoglobulin fraction of plasma from persons recently vaccinated with the smallpox vaccine; VIG is currently administered intramuscularly, but future formulations should allow intravenous administration. It is effective for the treatment of eczema vaccinatum, certain cases of progressive vaccinia, and some cases of ocular vaccinia resulting from inadvertent implantation; VIG is available only via an Investigational New Drug protocol through the CDC. Physicians at civilian medical facilities may request VIG by calling CDC’s Smallpox Vaccinee Adverse Events Clinician Information line at 877-5544625. Physicians at military medical facilities may request VIG by calling the United States Army Medical Research Institute of Infectious Diseases (USAMRID) at 301-6192257 or 888-USA-RIID. No controlled clinical trials of antiviral or VIG therapy for ocular vaccinia disease in humans have been published.24,25 However, the use of VIG for vaccinial keratitis was evaluated in one controlled study in rabbits.26 Rabbits receiving one dose of VIG did not demonstrate any difference in clinical course or corneal scarring compared with rabbits receiving no treatment. Rabbits receiving five
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when topical antivirals are used and is not recommended. If VIG is administered to a patient who has keratitis, informed consent should be obtained after discussion of potential risks and benefits. While no Food and Drug Administration-licensed topical antiviral has an approved indication for the treatment of ocular vaccinia, topical trifluridine drops or vidarabine ointment can be used off-label for this purpose, and are likely to be more effective and less toxic than topical idoxuridine or cytosine arabinoside.33–38 Topical vidarabine may be preferable for use in children, because it has been available in an ointment preparation that allows less frequent dosing and is associated with less initial stinging than trifluridine. Vidarabine ointment is currently not commercially available, but it may be obtained through compounding pharmacists. If, however, vidarabine cannot be obtained or the patient would better tolerate drops, trifluridine may be used in children just as it is in ocular herpes simplex in the doses indicated in Table 1. Topical antiviral drugs should be considered for prophylaxis of the conjunctiva and cornea if vaccinia lesions are present on the eyelid, especially if near the lid margin. The use of these drugs for prophylaxis should be balanced against the possible risk of drug toxicity and of introducing virus into the eye by frequent manipulation. Topical trifluridine may possibly have an increased risk of toxicity if used for longer than 14 days. Toxic changes to the ocular surface are almost invariably reversible with discontinuation of the drug. Acyclovir has not been shown to be effective against vaccinia by in vitro antiviral screening.38 Uncontrolled studies have suggested that topical leukocyte interferon (monkey or human) may be of benefit in the treatment or prophylaxis of vaccinia infection of the ocular surface.39,40 For end-stage disease with a visually disabling scar or leukoma, lamellar or penetrating keratoplasty has a generally favorable prognosis in the absence of corneal neovascularization or active inflammation.41
daily intramuscular doses of VIG, 2.5 to 5 times the recommended human dose, developed stellate corneal scars persisting until study termination at day 67. For these rabbits, daily treatment with VIG for 5 days may have presented an overwhelming immunologic challenge to the infected corneas. 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. Based largely on the results of this animal study, VIG has been considered contraindicated for the treatment of vaccinial keratitis. It should be noted, however, that there are at least five case reports of notable coneal scarring reported in patients who did not receive intramuscular VIG.27–30 The question has been recently raised whether VIG should continue to be contraindicated for keratitis and, in particular, whether VIG should be withheld from patients with keratitis who also have extensive ocular or extraocular disease and might benefit from its use. There are uncontrolled human data on the usefulness of VIG in vaccinial complications. Jones and associates31 reported four cases of severe orbital cellulitis to intramuscular VIG responding within 24 hours. Ellis and colleagues27 reported six ocular cases, three with keratitis, all treated successfully with intramuscular VIG, two receiving three doses and one receiving seven doses. There were no residua except minimal stromal edema and 20/40 vision in the latter patient. Ruben and Lane18 reported their accumulated experience of 348 cases of ocular vaccinia, 22 with keratitis, of which 336 were treated with intramuscular VIG and 28 with idoxuridine with or without VIG. Only 2% of noncornea cases had residua, none considered severe, comprised of eyelid scarring, madarosis, and punctal stenosis with epiphora. Of the 22 patients with keratitis, 4 (18%) had some residual findings (only 1 had a residual corneal scar). Seven of the 22 patients who originally presented with keratitis were re-examined 5 years later; 3 of the 7 had no corneal residua, and 4 had only mild findings not involving the visual axis. Other case reports suggest a therapeutic effect of VIG on vaccinia keratitis, as illustrated in brothers with similar ocular corneal vaccinia where the one with VIG healed without scarring in 24 hours and the untreated brother had 4 weeks of active disease with residual corneal scarring.27 Vaccinia immune globulin should be considered for use in severe ocular disease when keratitis is not present (for example, severe blepharitis or blepharoconjunctivitis).23 If keratitis accompanies these conditions, VIG need not necessarily be withheld but should be used cautiously (and generally in a single dose) due to a possible increased risk of corneal scar formation. Similarly, if VIG is indicated based on other criteria (for example, eczema vaccinatum, progressive vaccinia), its use or dosing need not be withheld if keratitis is also present. For treatment of isolated keratitis, VIG has not been shown to offer added benefit 350
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Prevention of Ocular Vaccinia BECAUSE AUTOINOCULATION IS THOUGHT TO BE THE
most common means of developing ocular vaccinia, every effort should be made to keep the inoculation site covered until the scab has dried up and fallen off (⬃21 days). Vaccinees will also be warned by public health officials to avoid touching the site when it is uncovered for bathing. Healthcare professionals who are caring for patients with recent vaccinations or vaccine-related complications should engage in routine precautions for dealing with infectious agents, including gloves, proper hand washing, and disinfection of contaminated equipment. Disinfection with 70% alcohol or diluted bleach solution (10%) should be effective for this purpose. Healthcare providers who are OF
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pregnant, have active atopic dermatitis, or are immune compromised in any way (for example, HIV infected, history of leukemia or lymphoma, on immunosuppresants or chemotherapy) should not be evaluating or caring for recent vaccinees or those with vaccine-related adverse events. The CDC has not yet recommended that all healthcare professionals who care for these patients need to be vaccinated. Instead it is simply recommending that strict precautions be taken, similar to those appropriate for blood-borne pathogens.
Smallpox Vaccine Exclusionary Criteria for Eye Banking THE EYE BANK ASSOCIATION OF AMERICA ADDED A NEW
contraindication to its Medical Standards for potential cornea donors, effective January 10, 2003. The smallpox vaccine exclusionary criteria are as follows: (1) potential donors who received the smallpox vaccine without complications shall be deferred until after the vaccination scab has separated and the vaccination site appears to be healed and not inflamed, or for 21 days after vaccination, whichever is the later date; (2) potential donors who received the smallpox vaccine and developed complications that have resolved shall be deferred for 14 days after all vaccine complications have completely resolved, or for 21 days after vaccination, whichever is the later date; (3) potential donors who received the smallpox vaccine and developed complications that have not resolved shall be deferred; and (4) potential donors who have had contact with someone who has received the smallpox vaccine shall be deferred in cases where the donors have had recognizable signs or symptoms attributable to the virus within 14 days before donation.
Summary WITH THE REINITIATION OF SMALLPOX VACCINATION IN
selected groups in the United States, healthcare workers are likely to see cases of ocular vaccinia present as a result of autoinoculation or contact with a recent vaccinee. Ophthalmologists should familiarize themselves with the ocular manifestations of vaccinia and seek consultation with local and state health department as well as with the CDC for guidance in treatment options and laboratory confirmation. A need exists for masked, controlled trials of VIG in patients with vaccinia keratitis and in the development of animal models that mimic the features of ocular vaccinia in humans and for in vivo assessment of therapeutics. VOL. 136, NO. 2
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