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Large Injection Site Reactions After a Second Dose of Varicella Vaccine

Walter, Emmanuel B. MD, MPH; Snyder, Martha A. MD; Clements, Dennis A. MD, PhD; Katz, Samuel L. MD

The Pediatric Infectious Disease Journal: August 2008 - Volume 27 - Issue 8 - p 757-759
doi: 10.1097/INF.0b013e31816fc323
Brief Reports

A second dose of varicella vaccine is routinely recommended. We report 2 cases of large local reactions after receipt of a second dose of varicella vaccine administered in the thigh. The reactions resolved with symptomatic therapy. Clinicians should continue to administer the second dose of varicella vaccine, but should use the preferred site in the arm.

From the Department of Pediatrics, Duke University Medical Center, Durham, NC.

Accepted for publication February 21, 2008.

Drs. Walter and Clements are speakers for Merck and members of Advisory Boards for Merck.

Address for correspondence: Emmanuel B. Walter, MD, MPH, Duke Children's Primary Care Clinic, 4020 N. Roxboro Rd., Durham, NC 27704. E-mail:

Live attenuated varicella vaccine (Varivax) was first licensed for use in the United States in 1995. At that time, a single dose of vaccine was recommended for routine vaccination of children aged 12–18 months of age and as catch up vaccination of susceptible children aged 19 months to 12 years. Despite widespread acceptance of varicella vaccine with 2005 national coverage rates as high as 88% among children 19–35 months of age, vaccine effectiveness of 85% after a single dose of varicella vaccine was not sufficient to prevent varicella outbreaks from occurring in highly vaccinated school populations.1,2 Because of the demonstrated superior efficacy of 2 dose regimens, in 2005, a second dose of varicella vaccine was recommended.3,4 Currently, 2 doses of varicella vaccine administered as either monovalent vaccine or as a combination measles, mumps, rubella, and varicella (MMRV) vaccine (ProQuad) are suggested to be given at 12–15 months and again at 4–6 years. In addition, a second dose of varicella vaccine is advised for all persons who received a single dose previously. In the current report, we describe 2 previously vaccinated children who had large local reactions to a second dose of monovalent varicella vaccine. Similar reactions have not previously been reported.

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A 7-year-old boy presented with a chief complaint of a reaction associated with immunizations he had received 2 days previously. Doses of monovalent varicella vaccine and hepatitis A vaccine (Vaqta) had been administered concomitantly. Varicella vaccine was administered subcutaneously in the left thigh and hepatitis A vaccine was administered intramuscularly at a separate site in the left vastus lateralis. Varicella vaccine contains a minimum of 1350 plaque forming units of Oka/Merck varicella virus, sucrose, hydrolyzed gelatin, sodium chloride, monosodium l-glutamate, sodium phosphate dibasic, potassium phosphate monobasic, potassium chloride, residual components of MRC-5 cells; trace quantities of sodium phosphate monobasic, EDTA, neomycin, and fetal bovine serum.

Swelling and redness of the left thigh started the evening after receipt of the vaccinations. At presentation to the clinic the patient was noted to be afebrile and was able to ambulate normally. Erythema, measuring 12 cm in diameter, induration, measuring 4 cm in diameter, and swelling were noted over the left anterior thigh centered about the site where the varicella vaccine had been administered. The area was not tender to palpation and vesicular lesions were not noted. A prior dose of varicella vaccine had been administered when the patient was 12 months of age. This was the primary dose of hepatitis A vaccine. The patient had completed a course of amoxicillin therapy for otitis media within the previous month and his medical history was significant for diagnosis of prematurity being born at 35 weeks gestation. A 10-day course of cephalexin was prescribed to treat a putative bacterial cellulitis at the injection site. By subsequent parental telephone report the redness and induration resolved within a few days of presentation.

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A 10-year-old boy presented to the clinic with a chief complaint of a reaction on his leg 2 days after receiving a single subcutaneous dose of varicella vaccine in the left thigh (different vaccine lot number than first case). An area of redness and purplish discoloration about the vaccination site were noted the day after vaccination and were observed to be increasing in size. Upon presentation to clinic, the patient had an oral temperature of 100.2°F and otherwise appeared well. A swollen, nontender 13 cm by 11 cm area of erythema and induration measuring 7 cm in diameter were noted about the injection site (Fig. 1). Vesicular lesions and inguinal adenopathy were not appreciated and the patient's range of motion in the left lower extremity appeared normal. The patient was able to walk without difficulty. He had received a previous dose of varicella vaccine at 13 months of age. The area of erythema was demarcated with a pen and the parents were instructed to call or return if the swelling or erythema increased. Although cephalexin was prescribed, upon questioning the next day, the parents had not administered any antibiotic and the demarcated area of erythema had decreased by 50%. By subsequent parental report, all signs of the local reaction were resolved within 4 days.



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Within a 7-month period, 2 children presented to our clinic complaining of large areas of nontender, swelling, induration, and erythema at the injection site 24 hours after receiving a second dose of monovalent varicella vaccine. During this same time period, the clinic administered 143 doses of MMRV vaccine and 729 doses of varicella vaccine to children 3 years of age and older, the majority of which given the age of the recipients were likely second doses of varicella vaccine. Although both children in the current report received vaccine in the thigh, it is not common practice for our clinic to administer vaccines in the lower extremity of older children. In both cases vaccine was administered by the same nurse, who noted that in situations when older children are difficult to restrain she administers vaccines in the thigh. According to the package insert for varicella vaccine, the preferred site of administration for varicella vaccine is the outer aspect of the upper arm. It is unclear if the site of administration in these cases was related to the reactions noted. To date, we have not observed similar side effects when vaccine was administered in the arm.

Previous investigations, with both monovalent varicella vaccine and MMRV vaccine, have noted an increased rate of local reactions for those receiving the varicella antigen for a second time. In a study comparing the safety of 1 dose of monovalent varicella vaccine with that of 2 doses administered 3 months apart, children ages 12 months to 12 years were noted to have more frequent local reactions within 3 days of vaccination after dose 2 than after dose 1.5 Similarly, 5- to 6-year-old children receiving MMRV vaccine were more likely to have injection site reactions including pain, redness, and swelling if they had previously received a dose of MMRV as opposed to MMR and the rate of reactions was also observed to be higher after the second dose of MMRV when compared with the first dose.6 However, 12- to 23-month-old children receiving a second dose of MMRV 90 days after receiving a first dose of MMRV did not experience similar increases in the rate of local side effects.7 In another study, 4- to 6-year-old children who had previously received MMR and monovalent varicella vaccine and received MMRV vaccine per protocol had more injection site reactions than children who received either MMR and placebo or MMR and monovalent varicella vaccine.8 Although there seems to be a trend towards greater local reactogenicity after a second dose of varicella vaccine, none of these reports describe reactions of the magnitude noted in the current report.

The mechanism of the large local reactions we observed is unclear. Although it is possible that a bacterial cellulitis occurred after injection, our second patient resolved quickly without antimicrobial therapy. Dramatic presentations of local limb swelling have been described after a 4th and 5th dose of DTaP vaccine.9 The etiology of local reactions to booster doses of DTaP vaccines remains unclear, but it is believed to be related to a cumulative increased response to antigens contained in the vaccine. Unlike reports of limb swelling after DTaP, our cases appeared to have more signs of inflammation. It is possible in the cases we observed that in addition to prior exposure to attenuated varicella virus, the children had also been boosted by exposure to wild-type varicella, thereby increasing their cumulative exposure to varicella antigens. Alternately, the reactions we observed might be explained by a repeat exposure to excipients contained in the vaccine such as hydrolyzed gelatin, neomycin, or fetal bovine serum.

We described the current cases to make providers aware that large local reactions after a second dose of varicella vaccine may occur. These reactions resolve within several days and may not require unnecessary antimicrobial therapy. We suspect that these large reactions may be under-recognized. We do not believe that our observations preclude administration of a second dose of varicella vaccine as the potential benefits far outweigh the risks associated with a self-resolving local reaction. For older children, when possible, doses of vaccine should be given in the outer arm as recommended. Further studies are needed to assess the rate and magnitude of local reactions after a second dose of varicella vaccine when administered at sites other than the deltoid and to also determine whether narrowing the timing of administration might decrease the rate of local reactions after a second dose that was observed in previous reports. Furthermore, current recommendations by the American Academy of Pediatrics and The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices express a preference for a second dose of varicella vaccine to be administered at school entry. It is, however, permissible and perhaps advantageous to administer a second dose within months of the first, rather than leaving some children susceptible after the first dose. If it is determined that large local reactions after varicella vaccine are more common in older children than previously noted, giving 2 doses of vaccine at an earlier age may also be of additional benefit.

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1. Centers for Disease Control and Prevention (CDC). National, state, and urban area vaccination coverage among children aged 19–35 months–United States, 2005. MMWR Morb Mortal Wkly Rep. 2006;55:988–993.
2. Centers for Disease Control and Prevention (CDC). Outbreak of varicella among vaccinated children—Michigan, 2003. MMWR Morb Mortal Wkly Rep. 2004;53:389–392.
3. Kuter B, Matthews J, Shinefield J, et al. Ten year follow-up of healthy children who received on or two injections of varicella vaccine. Pediatr Infect Dis J. 2004;23:132–137.
4. Centers for Disease Control and Prevention (CDC). Prevention of varicella. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2007;56(RR-4):1–40.
5. Ngai AL, Staehle BO, Kuter BJ, et al. Safety and immunogenicity of one vs. two injections of Oka/Merck varicella vaccine in healthy children. Pediatr Infect Dis J. 1996;15:49–54.
6. Vesikari T, Baer M, Willems P. Immunogenicity and safety of a second dose of measles-mumps-rubella-varicella vaccine in healthy children aged 5 to 6 years. Pediatr Infect Dis J. 2007;26:153–158.
7. Shinefield H, Black S, Digilio L, et al. Evaluation of a quadrivalent measles, mumps, rubella and varicella vaccine in healthy children. Pediatr Infect Dis J. 2005;24 665–669.
8. Reisinger KS, Hoffman Brown ML, Xu J, et al. A combination measles, mumps, rubella, and varicella vaccine (ProQuad) given to 4- to 6-year-old healthy children vaccinated previously with M-M-RII and Varivax. Pediatrics. 2006;117:265–272.
9. Rennels MB, Deloria MA, Pichichero ME, et al. Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines. Pediatrics. 2000;105:e12.

varicella; chickenpox; vaccine

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