Sex: F
Vaccine: VARCEL
Symptoms: Polymerase chain reaction positive, Rash erythematous, Rash generalised, Rash maculo-papular, Rash vesicular
Clinical narrative: This literature marketed report was received from the authors of the published article, and refers to a 25 days old, female patient. The authors documented the first case of vOka varicella in a newborn associated with postpartum maternal vaccination and in the absence of post-vaccination rash. A previously healthy term infant developed a rash, which began on the forehead and progressed to her face, chest, abdomen and extremities. On presentation to the clinic the next day, physical examination showed an alert, interactive and afebrile infant with a generalized rash consisting of 50-60 maculopapular and vesicular lesions in different stages of development. A clinical diagnosis of varicella was made and fluid from several vesicles was collected for varicella zoster virus (VZV) polymerase chain reaction (PCR) testing. The infant was afebrile, did not require hospitalization, and was treated with oral acyclovir at 60 mg/kg/day divided in four doses. She recovered completely over the next week. The mother, who had no prior history of varicella and VZV seronegative during prenatal testing, received the varicella virus vaccine live (Oka/Merck) on her third postpartum day. The infant was in the room with the mother when the vaccine was drawn into the syringe, cleared of air bubbles, and administered in the mother's left upper arm. The mother denied any post-vaccination fever or erythema, pruritus or rash at the vaccination site or elsewhere. The infant was primarily formula-fed, but received expressed breastmilk four times a day. She had no recognized exposure to any person with any kind of rash and none of the infant's contacts except the mother had been vaccinated in the 90 days before the infant presented with varicella. PCR-based sequence analysis confirmed presence of vOka deoxyribonucleic acid (DNA) in the lesion sample from the infant. Specifically, four vaccine-associated single nucleotide polymorphisms at open reading frame (ORF) 38, ORF54, and ORF62 were evaluated using real-time PCR methods as previously described, and carried the vaccine-strain profile. In addition, three-amplicon genotypic analysis of the isolate confirmed that it was a Clade 2 virus, the genotype of the vaccine. This was the first report of laboratory-confirmed vOka varicella in the absence of contact with an individual with post-vaccination rash. Infection was contracted by an unrecognized mechanism as the case-patient had no contact with any individual with a rash and only her mother had been recently vaccinated. This case was mild, which was consistent with the previous reports of vOka varicella, and in contrast to wild type varicella, which was usually severe in susceptible infants. The patient developed vOka varicella 22 days following maternal vaccination. Although there was no evidence of a post-vaccination rash in the mother, the timing of varicella presentation after maternal vaccination in this case was such that transmission from an unrecognized post-vaccination rash could have been plausible. The earliest presentation of post-vaccine rash was thought to be 5 days with the earliest possible secondary transmission generally occurring 14 days after exposure, for likely minimal interval of 19 days between primary vaccination and a secondary case. The authors suggested that the most plausible transmission mechanism in this case, with the absence of maternal post-vaccination rash, was direct exposure of the infant to vOka during vaccination of the mother. As the infant was present in the room when her mother was vaccinated, and the vaccine-filled syringe was cleared of air bubbles prior to injection, aerosolization of the vaccine could have resulted in a direct transmission of vOka to the infant. Direct inoculation of vaccine from the mother's injection site onto the infant's mucosa or conjunctiva could also have occurred. Injection was in the mother's left arm, which was used to hold the infant during feedings; the loosely covered injection site could have been scratched, with subsequent transfer of vaccine fluid to the infant. Transmission through this route would have had to occur soon after vaccination, as the virus does not survive long at room temperature. The authors considered three other possible transmission mechanisms. Based on limited data, the authors concluded that transmission through breast milk was unlikely. Although possible, based on thorough investigation, transmission from contact with other individuals with vOka zoster also seemed unlikely in this case. The only varicella-vaccinated individuals the infant was in contact with during the incubation period had received the varicella vaccine more than a year prior to the infant's birth and none of these vaccinated individuals had any rashes. Another putative mechanism of vOka transmission could be via maternal respiration secretions of saliva. The extent to which vaccination with VZV-containing vaccines resulted in viral excretion in saliva is poorly understood. Vaccine VZV DNA was detected in the saliva as early as one week after vaccination with zoster vaccine in a small study of zoster vaccine recipients. However, zoster vaccine had 13 times the potency of the varicella vaccine and the viability or transmissibility of the VZV detected in saliva was not evaluated. These routes of transmission seemed less likely since postpartum varicella vaccination of seronegative mothers was part of routine care since 2007, and transmission via these routes was not observed previously. Thus, there were several theoretical modes of transmission: direct mucosal contact with vOka as a result of aerosolization of vaccine at the time of administration to the mother seemed most likely, but transmission via breast milk, saliva or respiratory droplets in the first seven to 10 days after maternal vaccination could not be eliminated. Upon completion of their pregnancies, women who did not have evidence of varicella immunity should receive the first dose of varicella vaccine before discharge. Delay in postpartum vaccination of susceptible women based on this isolated case report would prolong the period of vulnerability for both mother and infant and, as such, was not advisable. Infants born to VZV-seronegative mothers lack maternal antibody protection against varicella, which could be severe in infancy. Vaccinating household members, including post-partum women, was critical for protecting infants, for whom varicella vaccination was not recommended until age 12 months. The very low risk of vOka transmission following postpartum vaccination was greatly exceeded by the risk of severe consequences from wild-type varicella disease in susceptible mothers and their newborns. While the exact mechanism of infection with the vaccine virus could not be determined, this case suggested that it may be prudent to avoid preparation and administration of varicella vaccine to post partum women when their infants were in the room. Normal, close mother-infant contact should continue for women vaccinated postpartum as the risk of transmission of vaccine virus after vaccination was extremely low. Providers should continue to follow appropriate immunization practices, and report side effects of immunization when they occurred. Follow-up information has been received on 25-JUN-2012 via medical records and from a physician concerning a twenty six days old female patient. The patient had no pre-existing physician-diagnosed allergies, birth defects or medical conditions and was reported as "previously health". There were no adverse events following prior vaccination in the patient and her sibling. The patient's brother had received two doses of varicella virus vaccine live (Oka/Merck), the second in June 2007. The patient was born at term via repeat caesarian delivery with birth weight 2420 grams (also reported as 5 pounds, 9 ounces and 2513 grams) after an uncomplicated pregnancy. She was initially bottle-fed with expressed breastmilk feedings added on the third day and continued four times a day until age 2 months. The patient did not take any other medications. On 25-JAN-2010, the patient, aged 3 days was present in the hospital room when the VARIVAX injection, lot#665421/1163Y was reconstituted and her mother was vaccinated with the first dose of VARIVAX subcutaneously in her left arm at about 14:00 (dose and expiration date was not reported) at hospital. The patient's mother (36 years old) had no history of varicella infection and was seronegative for varicella antibody during prenatal testing (ELISA AtheNa multi-lyte system), it was unknown if she had pre-existing physician-diagnosed allergies, birth defects or medical conditions but she was reported as "healthy overall"). She had no illness at the time of vaccination. The mother had no skin changes, rash, itching, pain or redness at the site of vaccination or elsewhere (also reported as she denied having any macular rash, pink papules or vesicular lesions on her arm or elsewhere) the day of vaccination or afterwards. The infant was kept in the room during the daytime and was present during vaccination. On 17-FEB-2010 at 04:15, the patient developed a erythematous, papular and vesicular rash that began on her forehead and spread to her face, chest, abdomen and extremities. Lesions appeared initially pink papules which developed central vesicles "filled with water". The number of lesions increased gradually in a descending pattern, eventually reaching her extremities. The physician reported that "rash was classic for varicella". Rash peaked at 36 degrees Celsius. On 17-FEB-2010 (reported as Day 1 of illness) cell blood count (CBC) was normal. The patient was afebrile, mildly symptomatic only and did not require hospitalization. She was breastfed four times a day (reported as QID) (also reported as the patient's mother was partially breastfeeding). The patient was alert, interactive and afebrile when she presented to the clinic (date was not reported) and exam was normal except for a papulo-vesicular eruption. Maximum temperature was 98.2 (units not provided), complete blood count was normal and her weight was 3.44 kg. A clinical diagnosis of varicella was made and a swab of vesicular fluid was sent for PCR testing for Varicella Zoster Virus (VZV). Laboratory testing for signs of bacterial disease (white count, C-reactive protein (CRP) and blood culture) were normal and the infant was discharged from the clinic to home with daily follow-up. On 18-FEB-2010 (reported as one day later), the rash increased to 60 lesions (also reported as 50-60 papular and vesicular lesions with a few crusted lesions) and original swab was varicella positive. The patient had decreased oral intake, mild irritability (onset date was not reported) but no fever. On an unknown date, treatment with acyclovir was started at 60 mg/kg/day orally, divided every 6 hours (also reported as 50-60 mg/kg/day and 15 mg/kg orally, four times a day). The patient's mother reported that feeding fussiness began improving about 12 hours after acyclovir was started and no new lesions appeared. By follow up 72 hours after the rash started many lesions had formed crusts. By the fourth day (48 hours after acyclovir therapy started), the patient was feeding well, most lesions scabbed over and photographs were obtained. She continued to improve and recovered completely (date of recovery was reported by the physician as 24-FEB-2010, also reported as "rash was improving in 24 degrees, resolved 72 degrees") and had no complications or sequelae (also reported as with two small scars on forehead). No other family members had rash. VZV DNA detection result was positive in two swabs (also reported as "10-050") and VZV genotype was reported as vaccine on 02-MAR-2010. On 18-FEB-2010, polymerase chain reaction (PCR) based sequence analysis confirmed the presence of vOka DNA in the lesion sample collected from the patient on 17-FEB-2010. Specifically, 4 vaccine-associated nucleotide polymorphisms at open reading frame (ORF) 38, ORF54 and ORF62 were evaluated using real-time PCR methods and carried the vaccine-strain profile. In addition, 3 amplicon genotypic analysis of the isolate confirmed that it was clade 2 virus, the genotype of vaccine. On 22-FEB-2010, culture positive for VZV was confirmed, varicella was detected by PCR, herpes simplex virus was not detected by PCR, both in specimen from lesion collected on 17-FEB-2010. On 22-FEB-2010, CRP was < 0.5 (also reported as <0.8 mg/dl), herpes simplex immunoglobulin M (IgM) antibody was 0.198 (units not reported, also reported as OD ratio, negative), from the specimen collected on 17-FEB-2010. On 17-FEB-2010, white blood count (WBC) was 6.9 K/microlitre, red blood count (RBC) was 4.02 m//microlitre, hemoglobin was 13.9 g/dl, hematocrit was 38.8% (decreased), mean cell volume (MCV) was 96.5 fL, mean cell hemoglobin (MCH) was 34.5 pg, mean corpuscular hemoglobin concentration (MCHC) was 35.8 g/dl, red blood cell distribution width (RDW) was 15.6%, platelets were 163 K/microlitre, mean platelet volume (MPV) was 10.3 fL (increased), nucleated RBC's automated was 0.0/100 WBC's, varicella zoster Ab immunoglobulin G (IgG) was 0.06 (unit IV, negative), varicella zoster Ab IgM was 0.11 (unit: ISR, negative). The relatedness between the events and VARIVAX was not reported. The patient was vaccinated herself with varicella virus vaccine live (Oka/Merck) (manufacturer unknown) (dose, route and site of administration, lot # and expiration date not reported) at the age of 15 months and had no side effects from the vaccination. All available medical records will be provided upon request. Additional information has been requested. Upon internal review, it has been determined that case # US-009507513-1206USA04371 and case # US-009507513-1205USA04456 are duplicates of case # US-009507513-1004USA03844. Therefore, cases # US-009507513-1206USA04371 and case # US-009507513-1205YSA04456 are being deleted from our files and the cases are consolidated into case # US-009507513-1004USA03844 on VARIVAX.