Herpes zoster after COVID vaccination

COVID-19 presents in various ways, but mainly as a pulmonary disease (Marzano, 2020). Skin manifestations have been reported, including reactivation of the varicella-zoster virus (Marzano, 2020). Our case report describes two adults developing herpes zoster after vaccination with tozinameran (the Pfizer-BioNTech COVID-19 mRNA vaccine). A possible cause for this reaction is a transient lymphocytopenia that occurs after the vaccination — similar to that in COVID-19 disease (Mulligan, 2020; Wang, 2020; Qin, 2020; Brabilla, 2020; Wang, 2020; Wei, 2017). In the context of vaccinating older and/or immunocompromised adults, our observations can be the starting point for further evaluation of a possible relationship between COVID-19, COVID vaccines, and herpes zoster.


Case presentation
Case 1 was a 29-year-old female healthcare professional with no noteworthy medical history, except for chicken pox three times as a child, and once during adolescence. In spite of this, she never had HZ. On January 8, 2021, she received the first dose of tozinameran, with no adverse reactions until January 23, when she noticed painful grouped vesicles on the left lateral of the ox coccyges (dermatome S3), clinically diagnosed as being HZ ( Figure 1 A). On January 29, she received the second dose of the vaccine. At that time, there was still some ulceration left, but there was no relapse of HZ after the second dose. After 2 weeks, the lesions had resolved without medical intervention.
Case 2 was a 34-year-old male healthcare professional with a medical history of ulcerative colitis, for which he had been using infliximab and, for 4 years without infectious complications. He had chicken pox as a child, but never HZ. He received his first dose of tozinameran on January 12, 2021, with no adverse reactions over the following days. On January 25, he noticed painful and swollen inguinal lymph nodes, after which he saw a rash on his right leg. He visited the ER, where a papulovesicular rash was identified in dermatome S2 ( Figure 1 B). Blood analysis was normal. A PCR test performed on vesical fluid was positive for VZV. He was prescribed valacyclovir, 1 gram thrice daily, for 10 days, and recovered completely. On February 2, he received the second dose of the vaccine without any complications.

Discussion
Herpes zoster is characterized by multiple, painful, and/or itching unilateral vesicles and ulcerations, typically occurring in a single dermatome ( Dayan, 2017 ;Gershon, 2015). The average duration of the rash ranges from 7 to 10 days, and is a self-limiting condition ( Van Oorschot, 2021 ). Although usually a limited disease, it can progress to disseminated cutaneous eruptions, encephalomyelitis, and pneumonia, especially in immunocompromised individuals (Gershon 2015 HZ is caused by reactivation of VZV, which tends to remain in a latent state in the dorsal root ganglia of cutaneous nerve endings following a primary episode of chicken pox (Wei, 2017;Gershon, 2015). Reactivation occurs when the immunological mechanisms that suppress VZV replication fail to contain the virus (Wei, 2017). Classic risk factors include advanced age, use of immunosuppressant medication, immunocompromising conditions (e.g. HIV, autoimmune disease), and psychological stress ( Gershon, 2015 ;Marra, 2020 ). Both cases presented here had chicken pox in childhood, yet never suffered from HZ. While subject 2 had other risk factors for HZ (use of immunosuppressive agents), subject 1 did not. Both subjects received the vaccination as healthcare professionals, and were completely free of any symptoms at the time of vaccination. The occurrence of HZ after vaccination could be a simple coincidence. However, recent reports have described similar cases, mostly involving known risk factors for HZ reactivation ( Bostan, 2021 ;Furer, 2021 ;Arora, 2021 ;Tessas, 2021 ;Eid, 2021 ). Rodriguez et al. described five young, healthy adults without risk factors who developed HZ reactivation ( Rodríguez-Jiménez et al., 2021 ). Furthermore, several case reports have described a link between COVID-19 and HZ reactivation in the absence of any of the classical risk factors ( Marzano, 2020 ;Brambilla, 2020 ;Ferreira, 2020 ;Tartari, 2020 ;Elsaie, 2020 ;Márcia et al., 2020 ;Nofal, 2020 ;Pona, 2020 ;Saati, 2020 ). This led to the hypothesis that illness, with physi-cal and psychological stress, might trigger HZ. Additionally, lymphopenia occurs in over 70% of patients with COVID-19, especially in those with a more severe clinical course Qin, 2020 ). While all subsets seem to decrease, the most marked depletion and exhaustion occur in CD4 + and CD8 + lymphocytes Qin, 2020 ;Marra, 2020 ). Since cell-mediated immunity is considered to be of great importance in protection against herpes zoster reactivation, such a functional impairment of Tlymphocytes could reactivate VZV ( Brambilla, 2020 ;Wei 2017 ). Interestingly, as with COVID-19 infection, the phase-I/II trial with BNT162b1 (now called tozinameran) showed a dosedependent decrease in lymphocytes in the first days following injection ( Mulligan, 2020 ). With the dosage now used worldwide, which is 30 micrograms, 45.5% of the recipients had lymphocyte counts below 1 × 10 9 , with one subject (9.1%) having grade-3 lymphopenia (0.2-0.5 × 10 9 ). These decreases were transient, with lymphocyte levels returning to normal 6-8 days after vaccination. The phase-I/II trial with ChAdOx1 nCoV-19 showed transient lymphopenia in 46% of the participants ( Folegatti, 2020 ). It is conceivable that this short period of lymphopenia -after COVID-19 infection or vaccination -can trigger a VZV reactivation. Although a full discussion regarding the role of T-regulatory cells is beyond the scope of this report, Sahin et al. speculate that the lymphopenia might be caused by an increase in type 1 interferons ( Sahin, 2020 ). This would cause rolling and adhesion of lymphocytes to the endothelium, and consequently fewer T-cells available to be measured in blood samples (Kamphuis, 2006). However, functionality would not be decreased, and type 1 interferons would normally inhibit varicella zoster replication ( Kamphuis, 2006 ;Ku, 2016 ). It would be interesting to ascertain whether patients developing VZV after vaccination have altered interferon responses.
In conclusion, we report two cases who developed herpes zoster after vaccination with tozinameran. While frequently a harmless condition, disseminated zoster can have fatal consequences. In the context of vaccinating older and/or immunocompromised adults, our observations require further evaluation of the possible relationship between COVID-19 and herpes zoster.

Other information
None of the above-listed authors have conflicts of interest to report. There was no funding or other financial support of any organization. Written informed consent was obtained from the participants in this case report.