After the initial herpes virus infection, the virus remains dormant in the peripheral autonomic ganglia [20]. Herpes zoster results from reactivation of the virus presenting as pain, itching, dysesthesia, and malaise, followed by unilateral skin vesicles that ulcerate and crust over [21]. Herpes zoster can also manifest as vision change, headache, ear pain and dysgeusia when it involves the face. It rarely leads to encephalitis, pneumonia and bacterial skin infection [21]. In addition, it can be accompanied by different neurological syndromes, including postherpetic neuralgia (PHN), the main complication of shingles [21].
The present study reported a herpetic infection after the first injection of cosmetic botulinum toxin type A (BTX-A) in a young, healthy woman who responded well to acyclovir. Similar to our case, Graber et al. [14] reported two cases of herpes zoster infection following cosmetic Botox injections. Their patients were older than ours and developed lesions almost one week after injection, whereas in our case vesicles appeared one day after injection. In another study by de Souza et al. [15], a 43-year-old woman developed shingles after a Botox injection. The patient initially developed inflammation and erythematous papules, which misled doctors into diagnosing the condition as cellulitis. However, after development of vesicles and no response to antibiotic therapy, a diagnosis of herpes zoster was made. Reactivation of VZV after Botox injection for medical treatment is also reported in conditions such as migraine and hyperhidrosis (Table 1) [22,23,24].
BTX-A is the most potent member of botulism neurotoxins [25]. It is approved by the Food and Drug Administration (FDA) for different therapeutic and cosmetic purposes, including the treatment of blepharospasm, hemifacial spasm, muscle relaxation and wrinkles. [13, 25]. It also reduces specific chemicals that sensitize pain receptors to reduce neuroinflammation [25].
Botulism neurotoxins consist of a core neurotoxin and complexing clostridial accessory proteins. However, due to the purification process, the complexity of these proteins has been reduced [18]. Such complex proteins have been considered potential stimulators of immune cells. Thus, as antigens, botulism toxin proteins can trigger an immune response by promoting the production of antibodies and cytokines, which sometimes leads to Botox treatment failure [18, 26, 27].
According to previous reports, complications resulting from Botox injections have been associated with reactivation of herpes simplex virus (HSV) and varicella-zoster virus (VZV). A comprehensive review of the patient’s medical history, including site of viral reactivation, types and stages of vesicular lesions, severity of recurrent disease, and Tzanck test results, led to consideration of herpes zoster as a possible diagnosis, given the absence periodic subclinical reactivation.
The pathophysiology of herpes reactivation is not yet fully understood [14]. However, it is hypothesized to be associated with a decrease in VZV-specific cellular immunity [28]. Immunodeficiency, systemic diseases and cancers, along with old age, are shown to be risk factors for developing shingles [15]. In addition, several factors can cause VZV reactivation, including radiation therapy, skin grafting, eye laser procedures, dental procedures, and surgery [23].
It appears that the relationship between Botox injection and herpes reactivation can be attributed to the alteration of the cellular immune system through T cells. T cells exposed to prolonged or high doses of antigen (including Botox complex proteins) lose their ability to function effectively. This phenomenon, known as T cell exhaustion, is attributed to the atypical expression of the immune checkpoint protein (Fig. 3). [29,30,31].
Schematic illustration of the immune process during simultaneous Botox injection and varicella-zoster virus reactivation. The amount of protein picked up by dendritic cells from a botulinum toxin preparation and presented to T cells via their specific receptor (TCR) determines antigenicity. Conversely, once T cells experience prolonged exposure to antigen, the production of CD4 + and CD8 + T cells decreases and T cell exhaustion occurs due to certain epigenetic variables. VZV initiates reactivation after depletion of CD4 + and CD8 + T. (VZV, varicella zoster virus, DC, dendritic cells, TCR, T-cell receptor)
A key element in the process of T cell exhaustion is a transcription factor known as HMG BOX (TOX) that is associated with thymocyte selection. Prolonged TOX expression alters certain epigenetic factors, inhibits cell differentiation and enters a state of T cell exhaustion [32]. TOX expression causes down-regulation of CD4 + and CD8 + T cells [33]. With TOX overexpression and subsequent T cell exhaustion, the production of Tumor Necrosis Factor α (TNF-α), interleukin 6 (IL-6) and interferon a (IFN-α) decreases [32, 34, 35]resulting in reactivation of the virus [36, 37]. In contrast, in latently infected individuals, T-cell responses were induced by the expression of T-cell cytokines such as tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interferon a (IFN-α) in both CD4 and CD8 subsets.
[28, 36]. These cytokines are associated with mild varicella, while cell-mediated immunodeficiency (low and depleted VZV-specific CD4 and CD8 T-cell responses) may also be associated with severe herpes zoster (Fig. 3). [38].
Limitations and future proposals
In the current study, we presented a rare case report of herpes reactivation after Botox injection. However, we recognize several limitations that should be taken into account. First, the study is based on a case report of a 33-year-old woman who developed shingles after a Botox injection. Therefore, caution should be exercised when trying to generalize these findings to a larger population, as individual variations may exist. Furthermore, establishing a definitive causal relationship between Botox injections and the development of shingles may prove challenging due to the limited reports on it. Further cross-sectional and meta-analysis studies are needed to evaluate this relationship.
Another limitation is the lack of long-term patient follow-up. After resolution of symptoms and improved skin lesions, the patient was discharged, leaving us uncertain of any lifetime risk of herpes reactivation. Recognizing this knowledge gap and further investigating the potential long-term effects of VZV reactivation after Botox injections is necessary.
Furthermore, while ocular edema showed gradual improvement after initiation of treatment, we inadvertently neglected to have an ophthalmologist evaluate the patients. It is important to ensure proper evaluation by a specialist in future cases.
We lacked specific information about the brand and quality of injectable botox. Variations in Botox formulations or administration techniques could affect the results, making it vital for future studies to address this aspect for a more complete understanding.
Furthermore, it is important to recognize that genetic factors can significantly influence the immune system’s response to viral reactivations. The interplay between genetic predispositions and immune system functionality varies between individuals, leading to different outcomes when dealing with infections such as herpes zoster.
