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of PubMed using the following terms&#44; without restrictions&#58; &#8220;COVID-19&#8221;&#44; &#8220;SARS-CoV-2&#8221;&#44; &#8220;COVID-19 Vaccines&#8221;&#44; &#8220;human herpesviruses&#8221;&#44; &#8220;human herpes virus&#8221;&#44; &#8220;varicella-zoster virus&#8221;&#44; &#8220;Epstein-Barr virus&#8221;&#44; &#8220;cytomegalovirus&#8221;&#44; &#8220;human herpes virus 1&#8221;&#44; &#8220;human herpes virus 2&#8221;&#44; &#8220;human herpes virus 6&#8221;&#44; &#8220;human herpes virus 7&#8221;&#44; and &#8220;human herpes virus 8&#8221;&#46; Titles and abstracts of all types of studies&#44; from case reports to reviews&#44; were reviewed for relevance&#46; Articles in English or Spanish were accepted&#46; In cases of articles of uncertain relevance&#44; the entire article was reviewed to determine its suitability for inclusion&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Herpes simplex virus 1</span><p id="par0020" class="elsevierStylePara elsevierViewall">An estimated 66&#37; 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as containment of HSV requires intact cellular immunity&#46; However&#44; even in individuals with a vigorous humoral and cellular immune response&#44; HSV-1 evades eradication via multiple immune evasion mechanisms&#46; Human studies have demonstrated the key role of T-cells in immune surveillance and initial containment of HSV-2 reactivation in the mucosa and in ganglia&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Immune compromise can be triggered by any one of a wide range of mechanisms&#44; including infections by other viruses&#44; such as SARS-CoV-2&#44; which causes lymphopenia&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Several articles have described HSV-1 reactivation in patients with COVID-19&#46; Le Balch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> published the first series of 36 cases of HSV-1 reactivation in critically ill COVID patients&#44; and reported higher rates than those described in earlier studies of critically ill patients&#46; Since then&#44; many such cases have been reported&#44; ranging from mild &#40;e&#46;g&#46;&#44; HSV lesions on the lip&#41; to more serious manifestations&#44; including two fatal cases of acute liver failure secondary to HSV-1 and cranial polyneuropathy&#44; respectively&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">HSV-1 has been detected in many different tissues in COVID-19 patients&#46; In May 2020 Hu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> demonstrated the presence of latent HSV-1 in the human anterior segment and the aqueous humor of SARS-CoV-2-infected patients&#44; and speculated that latent HSV-1 infection may have been activated in response to immune compromise caused by COVID-19 infection&#46; This hypothesis was subsequently confirmed in multiple cases of HSV-1 keratitis&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">While several cutaneous and mucosal manifestations were initially directly attributed to SARS-CoV-2&#44; it was later suggested that some&#44; including oral lesions&#44; could be the result of the reactivation of other&#44; more common viruses&#46; K&#228;mmerer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> detected anti-HSV IgM in serum samples from a patient who developed herpetic gingivostomatitis&#44; and Kano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> reported a case of herpetic glossitis related to COVID-19 treatment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The coexistence of HSV-1 and SARS-CoV-2 is also considered in the clinical management of COVID-19 patients&#58; pulmonary HSV-1 reactivation in invasively ventilated patients is a known phenomenon&#44; and tracheal secretions and bronchial lavage samples are screened by Polymerase Chain Reaction &#40;PCR&#41; for HSV-1&#46; This reactivation of HSV-1 coincides with a decrease in the expression of interferon-stimulated genes and an increase in highly activated CD38&#43;HLADR&#43; CD8 T-cells in the later stages of SARS-CoV-2-infection&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">With the development of new vaccines for SARS-CoV-2&#44; reports of HSV-1 reactivation in recently inoculated individuals began to appear&#46; This correlation was observed in the UK&#8217;s yellow card scheme for recording adverse incidents with medicines&#44; and a total of 369 cases of HSV infections associated with COVID-19 vaccines are recorded in the European database of suspected adverse drug reactions &#40;EudraVigilance&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 57 after CX-024414&#59; 305 after Tozinameran&#59; 118 after CHADOX1 NCOV-19&#59; and 7 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Reporting bias is very likely&#44; given that HSV-1 reactivations are likely underdiagnosed due to their innocuous nature&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Herpes simplex virus 2</span><p id="par0060" class="elsevierStylePara elsevierViewall">HSV-2 is a ubiquitous pathogen that primarily causes genital infections&#46; Genital herpes is one of the most common sexually transmitted infections worldwide&#46; Although HSV-2 remains the main cause of recurrent genital herpes infections &#40;70&#37;&#8211;90&#37; overall&#41;&#44; the proportion due to HSV-1 has been increasing&#46; Primary&#44; non-primary initial&#44; and recurrent infections can be symptomatic or asymptomatic&#46; Notably&#44; 81&#37; of those with positive serology have no prior diagnosis of genital HSV infection&#46; Genital HSV-2 infection also increases the risk of acquiring and transmitting HIV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> PCR is increasingly used as a more rapid&#44; sensitive&#44; and specific method to detect HSV DNA in samples from the skin and other organs&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">To date&#44; there is only 1 reported case of SARS-CoV-2 infection and concomitant infection with human immunodeficiency virus&#44; HSV-2&#44; and SARS-CoV-2&#44; with a fulminant clinical course and a false-negative real-time PCR result&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A total of 365 cases of HSV-2 following vaccination against COVID-19 are recorded in the EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 41 after CX-024414&#59; 200 after Tozinameran&#59; 116 after CHADOX1 NCOV-19&#59; and 8 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Varicella-zoster virus</span><p id="par0075" class="elsevierStylePara elsevierViewall">Herpes Zoster &#40;HZ&#41; is associated with high morbidity&#46; It is caused by the reactivation of latent HZV following a decline in cell-mediated immunity&#44; resulting in the appearance of clustered metamerically distributed papules on an erythematous base that rapidly evolves into vesicles&#44; which in turn can progress to pustules&#46; HZ has been associated with advanced age but can occur in individuals with diseases and those treated with immunosuppressant drugs and can even affect immunocompetent individuals&#46; The authors now know that SARS-CoV-2 infection affects T-lymphocytes&#44; especially CD4&#43;T cells&#44; CD8&#43;T cells&#44; and natural killer cells&#44; resulting in an immunocompromised state that may trigger the reactivation of latent viral infections&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This association first came to light when increases in the number of HZ cases were observed during the COVID-19 outbreak relative to the corresponding period in 2019 in several different countries&#44; including Turkey and Brazil&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Case reports and series have described HZ following COVID-19&#44; occurring most frequently within 1&#8211;2 weeks of COVID-19 infection&#44; in the majority of cases with a typical presentation affecting a single dermatome&#46; Atypical HZ presentations have been reported&#44; especially in patients with lymphopenia&#44; giving rise to multimetameric involvement and skin necrosis&#44; and&#44; in the most severe cases&#44; central retinal vein occlusion&#44; meningitis&#44; and encephalomyelitis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Elderly immunocompromised patients are more susceptible to severe and fatal HZ&#46; HZ has been proposed as a clinical biomarker of COVID-19&#58; it has been postulated that ophthalmic involvement may constitute a complication or indicator of COVID-19 infection&#44; particularly in young&#44; immunocompetent patients and in pregnant women&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">This association has been investigated by bioinformatic analyses examining potential genetic crosstalk between HZ and COVID-19&#44; and increases in Th17 cell differentiation and&#44; consequently&#44; IL-17 signaling have been described in both COVID-19 and HZ&#44; suggesting that IL-17 signaling may be one mechanism through which COVID-19 can increase the risk of HZ&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">It is very likely that the prevalence of coinfection is underestimated&#44; as many cases have been diagnosed by telemedicine&#44; and the requisite laboratory testing for HZ was available only in a limited number of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There is more debate regarding COVID-19 with varicella &#40;more commonly known as chickenpox&#41; coinfection&#46; Recalcati et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> first reported that varicella-like vesicles could constitute a cutaneous manifestation of COVID-19&#46; Subsequently&#44; Marzano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> reported that 22 patients with a positive COVID-19 nasopharyngeal test developed varicella-like papulovesicular exanthem&#46; This type of rash was related to typical clinical lesions and symptoms of herpes simplex&#47;zoster&#46; Llamas-Velasco et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> performed herpesvirus microarray PCR in 3 patients with SARS-CoV-2 and vesicular eruption&#44; and detected VZV and other herpesvirus DNA sequences in the vesicle contents&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">There are few cases of chickenpox in the context of a COVID-19 infection in which positive IgM antibodies against VZV have been detected or molecular analysis of the vesicle content has been performed&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Generally&#44; cases have been described in young people with clinical signs typical of chickenpox and SARS-CoV-2 infection&#44; including high fever&#44; myalgia&#44; nasal discharge&#44; and a rash consisting of vesicles&#44; erosions&#44; and crusts associated with petechial enanthem of the palatal mucosa&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> However&#44; cases of more serious involvement with the development of varicella pneumonia have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> This presumptive diagnosis must be established early to begin treatment with acyclovir&#44; which prevents the progression of lung involvement&#44; decreasing the likelihood of a fatal outcome&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Apart from laboratory tests to distinguish varicella-like exanthema from that caused by chickenpox&#44; different pathological anatomical patterns have been described&#46; In varicella-like exanthema&#44; biopsy shows acantholysis and dyskeratosis with a suprabasal&#44; unilocular intraepidermal vesicle&#44; without the large multinucleated cells and ballooning degeneration typical of chickenpox&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; the incidence of varicella and other viral infections has dramatically decreased since the implementation of COVID-19 control measures&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Cases of HZ following the administration of SARS-CoV-2 vaccines have been reported worldwide&#46; The largest series and narrative review include 399 cases&#44; and another systematic review describes 91 cases of VZV reactivation following COVID-19 vaccination&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> counts lower than those who are registered in EudraVigilance &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The number of HZ cases associated with COVID-19 vaccines registered in the EudraVigilance database is 1410 for CX-024414&#44; 9652 for Tozinameran&#44; 3054 for CHADOX1 NCOV-19&#44; and 205 for AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A systematic review by Katsikas Triantafyllidis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> reported that the dermatomal distribution of skin lesions was variable among patients with HZ reactivation following COVID-19 vaccination&#44; although the mammary region was the most frequently affected anatomical site&#46; Most of the lesions and symptoms appeared after the administration of the first vaccine dose&#46; There was a tendency towards greater susceptibility among patients aged &#62; 60 years&#46; Most patients were treated with oral valacyclovir in monotherapy&#46; Furthermore&#44; the majority of affected patients had a concomitant autoimmune disorder and&#47;or were receiving immunosuppressant therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">While causality has not yet been established&#44; increased awareness and early recognition of HZ are crucial to ensure the optimal management of these patients&#46; One of the most recent studies of the clinical and pathologic correlations of cutaneous COVID-19 vaccine reactions collects 4 cases of postvaccine HZ in which biopsies revealed viral cytopathic changes&#44; leading the authors to propose that the immune response induced by vaccination may trigger reactivation of other viruses&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Epstein Barr virus</span><p id="par0135" class="elsevierStylePara elsevierViewall">EBV&#44; human gammaherpesvirus 4&#44; infects B-lymphocytes and epithelial cells&#46; After primary infection EBV persists in a latent state in individual B-cells&#46; Latent EBV is found in approximately 95&#37; of the human population&#46; The presence of EBV in B-lymphocytes has been associated with the appearance of lymphoproliferative diseases and autoimmune diseases such as multiple sclerosis&#44; systemic lupus erythematosus&#44; rheumatoid arthritis&#44; and dermatomyositis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Multiple factors have been implicated in EBV reactivation&#44; in particular psychological stress&#44; including the stress associated with hospitalization for several days&#46; Reactivation is more likely to occur in immunosuppressed patients &#40;e&#46;g&#46;&#44; transplant recipients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Several studies have described increased EBV reactivation in COVID-19 patients&#44; especially those that are critically ill&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Paolucci et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> detected EBV DNA in 95&#46;2&#37; of COVID-19 patients hospitalized in an intensive care unit&#44; as well as significant reductions in CD8&#43; cells and NK counts&#46; This reactivation occurred earlier after admission to an Intensive Care Unit &#40;ICU&#41; and was associated with long-term hospitalization&#46; The course of COVID-19 disease may be aggravated in patients that undergo EBV reactivation&#58; these patients had a higher mortality rate and received more immuno-supportive treatment than SARV-CoV-2 patients without EBV coinfection&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> In fact&#44; Solomay TV et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> reported that severe disease and pneumonitis were more common among patients with EBV coinfection&#46; These patients have a more frequent fever&#44; elevated inflammation markers &#40;C-reactive protein&#41;&#44; and increased liver enzyme levels&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> While mild alterations in liver function tests are common in patients with COVID-19 infection&#44; marked elevation of liver enzymes should raise suspicion of EBV coinfection&#46; These observations highlight the importance of distinguishing between EBV manifestations and COVID-19-associated complications&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">One study reported EBV reactivations in 60&#37; of patients with prolonged COVID-19 symptoms after resolution of acute disease&#44; compared with 10&#37; in a control group&#44; suggesting that some long-term COVID-19 symptoms may be due to EBV reactivation&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Moreover&#44; Verma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> reported that EBV reactivation in nasopharyngeal and oropharyngeal epithelial cells increases expression of Angiotensin-Converting Enzyme 2 &#40;ACE2&#41;&#44; the cellular receptor for SARS-CoV-2&#44; thereby favoring SARS-CoV-2 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The EUDRAvigilance database contains 63 cases of EBV reactivation after COVID-19 vaccination &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 12 for CX-024414&#59; 38 for Tozinameran&#59; 12 for CHADOX1 NCOV-19&#59; and 1 for AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> A single case of EBV-positive diffuse large B-cell lymphoma after the COVID-19 vaccine has been reported in a heart transplant recipient&#46; One study reported no increase in herpesvirus reactivation&#44; including EBV&#44; 1-week after versus 1 week before COVID-19 vaccination &#40;Tozinameran&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Cytomegalovirus</span><p id="par0160" class="elsevierStylePara elsevierViewall">CMV is a member of the Herpesviridae family&#44; and its prevalence increases with age&#46; It typically causes primoinfection in young individuals and subsequently persists in a latent state throughout the life of the host&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In immunocompetent individuals&#44; it remains asymptomatic&#46; However&#44; the increased rate of CMV reactivation among immunosuppressed patients&#44; including solid organ transplant recipients and patients with AIDS or cancer&#44; is a major concern and may require antiviral prophylaxis&#46; This phenomenon has also been described in previously healthy patients admitted to an ICU&#44; who are also at increased risk of reactivation of other herpesviruses&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In fact&#44; these rates appear even higher in critically ill COVID-19 patients&#44; with viral reactivation reported in almost 50&#37; of patients in the series by Le Balc&#39;h et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Explaining this effect&#44; at least in part&#44; both severe lymphopenia and mechanical ventilation are known risk factors for secondary viral infections&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Many cases of CMV reactivation in COVID-19 patients have been reported&#44; some with fatal consequences&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> CMV reactivation can manifest with a wide range of symptoms&#44; including gastrointestinal bleeding and colitis&#44; persistent fever&#44; and secondary pneumonia&#44; all of which are associated with a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Marked and persistent lymphopenia is characteristic of severe COVID-19 infection&#46; Moreover&#44; potent immunosuppressive agents&#44; including high-dose corticosteroids and IL-6 antagonists such as tocilizumab&#44; are more frequently used in these patients&#46; These two factors may contribute to an increased risk of CMV reactivation in critically ill COVID-19 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Studies have investigated the role of CMV in regulating the immune response&#46; CMV appears to contribute to accelerated immune senescence and exacerbate the cytokine storm associated with severe COVID-19 infection&#44; thus negatively altering the host response to COVID-19 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Consequently&#44; patients co-infected with COVID-19 and CMV appear to have a worse prognosis&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> and this immune response dysregulation may also explain why elderly&#44; usually CMV-seropositive&#44; patients develop more severe disease&#46; In line with these findings&#44; areas with a higher prevalence of CMV seropositivity also show higher COVID-19 mortality rates&#46; A total of 56 cases of CMV reactivation after COVID-19 vaccination &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; have been reported in Europe&#58; 10 after CX-024414&#59; 39 after Tozinameran&#59; 6 after CHADOX1 NCOV-19&#59; and 1 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Human herpesvirus 6 and 7</span><p id="par0180" class="elsevierStylePara elsevierViewall">Human Herpesvirus 6 &#40;HHV-6&#41; is a widespread beta-herpesvirus that is genetically related to human CMV&#46; HHV-6 exhibits broad cell tropism in vivo and&#44; like other herpesviruses&#44; induces lifelong latent infection in humans&#46; Many active HHV-6 infections&#44; corresponding to primary infections&#44; reactivations&#44; or exogenous reinfections&#44; are asymptomatic&#46; However&#44; the virus can cause serious diseases&#44; particularly in immunocompromised individuals&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Cutaneous diseases associated with HHV-6 infection include roseola infantum&#44; Pityriasis Rosea &#40;PR&#41;&#44; Gianotti-Crosti syndrome&#44; drug reaction with eosinophilia and systemic symptoms&#44; and thrombocytopenic purpura&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> In the case of PR&#44; several studies have established a causal role of systemic active HHV-6 and&#47;or HHV-7 reactivation&#44; based on the detection of viral DNA in the plasma of PR patients&#44; the expression of mRNA and specific viral antigens&#44; and detection by electron microscopy of HHV virions in PR lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Nonetheless&#44; it is difficult to establish an etiological association between HHV-6 infection and cutaneous disease due to the ubiquity and near-universal prevalence of the virus and the limitations of current research tools&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The association between SARS-CoV-2 and HHV-6 is supported by several reports during the COVID-19 pandemic describing an increased incidence of PR&#44; and in one case HHV-6 reactivation was confirmed by serum PCR&#46; The studied group detected positive IgM serology and&#47;or IgG seroconversion for HHV-6 in 12 patients fulfilling COVID-19 clinical and&#47;or microbiological criteria that presented with different cutaneous manifestations&#44; including PR-like eruption&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> A case of a PR-like eruption in a COVID-19 patient with SARS-CoV-2 spike protein positivity on skin biopsy has also been reported&#44; suggesting a direct pathogenic relationship with this virus&#44; although the HHV-6 status of this patient was not investigated&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">This reactivation has not only been described in association with PR but also in critically ill patients with COVID-19&#46; In their series of 34 COVID-19 patients Simonnet et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> detected HHV-6 viremia in 7 &#40;22&#37;&#41; patients&#44; although HHV-6 status was not associated with morbidity and mortality&#46; This percentage is close to the frequency reported in large studies of septic shock patients&#46; One limitation of Simonnet et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> the study was absent a comparator population&#44; which prevented the authors from determining whether SARS-CoV-2 infection or &#8220;ICU-acquired immunosuppression&#8221; were the main drivers of reactivation&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">One report has described HHV-6 reactivation in the central nervous system of a COVID-19 patient with HHV-6 myelitis and concomitant myelin oligodendrocyte glycoprotein antibody-mediated parainfectious myelitis&#46; Another reported positive detection of SARS-CoV-2&#44; HSV-1&#44; and HHV-6 nucleic acid in tear and conjunctival secretions from a non-conjunctivitis COVID-19 patient with obstruction of common lacrimal ducts&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In both cases&#44; it is speculated that latent HHV-6 infection may have been reactivated in the context of COVID-19-induced immune dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Recently&#44; Biswas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> reported a case of a child with the multisystem inflammatory syndrome &#40;MIS&#41; as a late complication of COVID-19&#46; Initially&#44; a high HHV-6 viral load was detected&#46; Subsequently&#44; the patient was found to have inherited chromosomally integrated HHV-6 &#40;iciHHV-6&#41;&#46; iciHHV-6 is HHV-6 that has been integrated into chromosomal telomeric regions and is transmitted through the germ line&#46; This occurs in &#8764;1&#37; of individuals&#46; The presence of iciHHV-6 has been associated with altered and&#44; in some instances&#44; increased antibody responses to certain viruses and can be reactivated from latency&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Curiously&#44; patients with MIS can show enhanced antibody responses to SARS-CoV-2&#46; Biswas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> concluded that additional research may be warranted to determine whether iciHHV-6 is commonly observed in MIS patients and&#44; if so&#44; whether it may play a part in its pathogenesis&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Finally&#44; since the introduction of SARS-CoV-2 vaccines&#44; multiple cases of Pityriasis Rosea-Like Lesions &#40;PR-LE&#41; have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;44</span></a> Catal&#224; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> noted PR-LE in 4&#46;9&#37; of a cohort of 405 patients&#44; as well as VZV and HSV reactivation in 10&#46;1&#37; and 3&#46;7&#37;&#44; respectively&#46; PR-LE following the administration of other vaccines had been previously described&#46; Some authors distinguish vaccine-induced PR&#44; possibly due to reactivation of HHV-6 and&#47;or -7&#44; from vaccine-induced PR-LE&#44; which may occur as a delayed hypersensitivity response to a vaccine&#44; in the absence of any signs of HHV-6&#47;7 reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Differentiation between &#8220;true&#8221; PR and a PR-like eruption is difficult and virological studies of HHV-6&#47;7 reactivation are performed only in a minority of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> HHV-6 status has not been investigated in most cases of SARS-CoV-2 vaccine-induced PR-like eruption cases reported to date&#44; except in 2 cases related to the Pfizer BioNTech &#40;BNT162b2&#41; vaccine in which high HHV&#8208;6 antibody titers were detected&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Given concerns over an increase in VZV and HSV reactivation after vaccination with Tozinameran&#44; Brosh-Nissimov et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> studied oropharyngeal shedding of herpesviruses&#44; including HHV-6&#44; before and after vaccination&#46; They reported no significant differences in positivity for any herpesvirus between pre-vaccination and post-vaccination samples&#46; The EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; records 9654 cases of HHV-6&#58; 1 after CX-024414&#59; 9652 after Tozinameran&#59; and 1 after CHADOX1 NCOV-19&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Human herpesvirus 8</span><p id="par0220" class="elsevierStylePara elsevierViewall">Kaposi Sarcoma-Associated Herpesvirus &#40;KSHV&#41; is an oncogenic virus of the human &#947;-herpesvirus subfamily and is the etiologic agent of several human cancers&#44; including Kaposi Sarcoma &#40;KS&#41;&#44; primary effusion lymphoma&#44; and multicentric Castleman&#8217;s disease&#46; It is also associated with a hyperinflammatory syndrome named Kaposi sarcoma herpesvirus-associated inflammatory cytokine syndrome&#44; which can be fatal in some patients&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> The seroprevalence of KSHV infection in the general population of North America is less than 10&#37;&#44; but in most of sub-Saharan Africa&#44; the overall seroprevalence exceeds 50&#37;&#46; In the United States and Europe&#44; HHV-8 antibodies are present in &#8764;30&#37; of HIV-1-infected men who have sex with men&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> KSHV can be diagnosed by various methods&#44; including quantification of viral DNA in blood&#44; HHV8-LANA-1 immunostaining in biopsy specimens&#44; and serological testing&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">The KSHV viral life cycle consists of a quiescent latent phase and a replicative lytic phase&#46; While the establishment of latency enables persistent KSHV infection and evasion of the host&#8217;s immune system&#44; lytic replication is essential for the dissemination of the virus between hosts and within the host itself&#46; The transition between these phases&#44; known as lytic reactivation&#44; is controlled by a complex set of environmental&#44; host-related&#44; and viral factors&#46; One such trigger is COVID-19 infection&#44; and SARS-CoV-2-encoded proteins can induce lytic reactivation of KSHV through manipulation of intracellular signaling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> This has been demonstrated in clinical practice in a patient that had been recently hospitalized for COVID-19 infection and developed skin lesions consisting of bluish-red maculopapular&#44; a biopsy of which established a diagnosis of KS&#46; Transmission electron microscopy of the skin biopsy revealed the presence of both COVID-19 and HHV-8&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> It is proposed that SARS-CoV-2 contributes to the development of a hyper inflammatory state&#44; leading to HHV-8 proliferation and consequent recurrence of Kaposi sarcoma&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; records 3 cases of Kaposi sarcoma&#44; all after vaccination with Tozinameran&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0235" class="elsevierStylePara elsevierViewall">Numerous articles have linked COVID-19 infection with coinfection or reactivation of human herpes viruses&#46; Furthermore&#44; evidence suggests that human herpesvirus infection may constitute a prognostic marker of COVID-19 infection and even be responsible for many of the manifestations initially attributed to SARS-CoV-2&#46; Recent reports indicate that in addition to the SARS-CoV-2 virus&#44; all COVID-19 vaccines approved to date in Europe are capable of inducing herpesvirus reactivation&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the main manifestations of herpesvirus infections associated with COVID-19&#46; It is important to take this information into account and to consider all viruses of the Herpesviridae family when managing patients with COVID-19 infection or recently vaccinated against COVID-19&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Financial support</span><p id="par0240" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Authors&#8217; contributions</span><p id="par0245" class="elsevierStylePara elsevierViewall">Alba Navarro-Bielsa&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Tamara Gracia-Caza&#241;a&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Beatriz Aldea-Manrique&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Isabel Abad&#237;as-Granado&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Adri&#225;n Ballano&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Isabel Bernad&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Yolanda Gilaberte&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0280" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Introduction"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Herpes simplex virus 1"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Herpes simplex virus 2"
            ]
            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Varicella-zoster virus"
            ]
            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Epstein Barr virus"
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            4 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Cytomegalovirus"
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            5 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Human herpesvirus 6 and 7"
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            6 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Human herpesvirus 8"
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          "titulo" => "Conclusion"
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          "titulo" => "References"
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            0 => "Coinfection"
            1 => "COVID-19"
            2 => "Herpesvirus 1&#44; human"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Since the onset of the COVID-19 outbreak&#44; numerous articles have highlighted a possible link between COVID-19 vaccination or infection and Herpesviridae co-infection or reactivation&#46; The authors conducted an exhaustive literature review on this topic&#44; the results of which are presented individually for each member of the Herpesviridae family&#58; Herpes Simplex Virus &#40;HSV&#41; types-1 &#40;HSV-1&#41; and 2 &#40;HSV-2&#41;&#59; Varicella-Zoster Virus &#40;VZV&#41;&#59; Epstein-Barr Virus &#40;EBV&#41;&#59; Cytomegalovirus &#40;CMV&#41;&#59; HHV-6&#59; HHV-7&#59; and HHV-8&#46; These human herpesviruses can serve as prognostic markers for the COVID-19 infection and may even underlie some of the clinical manifestations initially attributed to SARS-CoV-2&#46; In addition to SARS-CoV-2 infection&#44; all corresponding vaccines approved to date in Europe appear capable of inducing herpesvirus reactivation&#46; It is important to consider all viruses of the Herpesviridae family when managing patients infected with or recently vaccinated against COVID-19&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Study conducted at the Miguel Servet University Hospital&#44; Zaragoza&#44; Spain&#46;</p>"
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        "tipo" => "MULTIMEDIAFIGURA"
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        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Manifestations of herpesvirus infections associated with COVID-19&#46; VHS-1&#44; Herpes Simplex Virus Type-1&#59; VHS-2&#44; Herpes Simplex Virus Type-2&#59; VVZ&#44; Varicella-Zoster Virus&#59; EBV&#44; Epstein-Barr Virus&#59; CMV&#44; Cytomegalovirus&#59; HHV-6&#44; Herpes Virus-6&#59; HHV-7&#44; Herpes Virus-7&#59; HHV8&#44; Herpes Virus-8&#46;</p>"
        ]
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        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HSV-1&#44; Herpes Simplex Virus type-1&#59; HSV-2&#44; Herpes Simplex Virus type-2&#59; VZV&#44; Varicella-Zoster Virus&#59; EBV&#44; Epstein-Barr Virus&#59; CMV&#44; Cytomegalovirus&#59; HHV-6&#44; Herpes Virus-6&#59; HHV-7&#44; Herpes Virus-7&#59; KSHV&#44; Kaposi Sarcoma-associated Herpesvirus&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Virus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 MRNA vaccine moderna &#40;CX-024414&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 MRNA vaccine Pfizer-Biontech &#40;Tozinameran&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 vaccine Astrazeneca &#40;CHADOX1 NCOV-19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 vaccine Janssen &#40;AD26&#46;COV2&#46;S&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSV-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">305&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">369&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSV-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">200&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">116&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">365&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VZV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1410&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9652&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3054&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">205&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14321&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">EBV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">38&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cases of herpesvirus infections associated with COVID-19 vaccines are recorded in the European database of suspected adverse drug reactions &#40;EudraVigilance&#41;&#46;</p>"
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Review
COVID-19 infection and vaccines: potential triggers of Herpesviridae reactivation
Alba Navarro-Bielsa
Corresponding author
582073@salud.aragon.es

Corresponding author.
, Tamara Gracia-Cazaña, Beatriz Aldea-Manrique, Isabel Abadías-Granado, Adrián Ballano, Isabel Bernad, Yolanda Gilaberte
Department of Dermatology, Miguel Servet University Hospital, IIS Aragón, Zaragoza, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Human Herpesviruses &#40;HHVs&#41;&#44; which include Herpes Simplex Virus &#40;HSV&#41; types-1 &#40;HSV-1&#41; and 2 &#40;HSV-2&#41;&#44; Varicella-Zoster Virus &#40;VZV&#41;&#44; Epstein-Barr Virus &#40;EBV&#41;&#44; Cytomegalovirus &#40;CMV&#41;&#44; HHV-6&#44; HHV-7&#44; and HHV-8&#44; are part of a family of DNA viruses that cause several diseases in humans&#46; Studies of the relationship between these viruses and the recently emerged novel coronaviruses &#40;SARS-CoV-2&#41; have proposed the possibility that SARS-CoV-2 or SARS-CoV-2 vaccines may induce reactivation of different subtypes of these human herpesviruses&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">In this review&#44; the authors examine the available literature and provide an overview of reported cases of reactivation of different HHVs following COVID-19 infection or vaccination and consider the possibility that many manifestations originally attributed to COVID-19 may in fact be due to the reactivation of these viruses&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">The authors conducted a literature search &#40;December 2021&#41; of PubMed using the following terms&#44; without restrictions&#58; &#8220;COVID-19&#8221;&#44; &#8220;SARS-CoV-2&#8221;&#44; &#8220;COVID-19 Vaccines&#8221;&#44; &#8220;human herpesviruses&#8221;&#44; &#8220;human herpes virus&#8221;&#44; &#8220;varicella-zoster virus&#8221;&#44; &#8220;Epstein-Barr virus&#8221;&#44; &#8220;cytomegalovirus&#8221;&#44; &#8220;human herpes virus 1&#8221;&#44; &#8220;human herpes virus 2&#8221;&#44; &#8220;human herpes virus 6&#8221;&#44; &#8220;human herpes virus 7&#8221;&#44; and &#8220;human herpes virus 8&#8221;&#46; Titles and abstracts of all types of studies&#44; from case reports to reviews&#44; were reviewed for relevance&#46; Articles in English or Spanish were accepted&#46; In cases of articles of uncertain relevance&#44; the entire article was reviewed to determine its suitability for inclusion&#46;</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Results</span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Herpes simplex virus 1</span><p id="par0020" class="elsevierStylePara elsevierViewall">An estimated 66&#37; of the world&#8217;s population is infected with HSV-1&#46; HSV-1 is mainly transmitted from person to person via infected oral secretions during close contact&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> After the initial infection&#44; chronic infection is established in the sensory ganglia and reactivated on mucosa and skin&#46; Although infections are frequently asymptomatic&#44; they can produce a range of signs and symptoms&#46; These include recurrent perioral or oral lesions &#40;&#8220;cold sores&#8221;&#41; and skin and mucous lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">During HSV recurrences the reactivated virus switches from latent to lytic replication in trigeminal or sacral ganglia neurons and travels via anterograde axonal transport to epithelial cells&#44; where it replicates and can be shed asymptomatically or give rise to clinically apparent ulceration&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The frequency of reactivation is increased in immunocompromised hosts&#44; as containment of HSV requires intact cellular immunity&#46; However&#44; even in individuals with a vigorous humoral and cellular immune response&#44; HSV-1 evades eradication via multiple immune evasion mechanisms&#46; Human studies have demonstrated the key role of T-cells in immune surveillance and initial containment of HSV-2 reactivation in the mucosa and in ganglia&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Immune compromise can be triggered by any one of a wide range of mechanisms&#44; including infections by other viruses&#44; such as SARS-CoV-2&#44; which causes lymphopenia&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Several articles have described HSV-1 reactivation in patients with COVID-19&#46; Le Balch et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> published the first series of 36 cases of HSV-1 reactivation in critically ill COVID patients&#44; and reported higher rates than those described in earlier studies of critically ill patients&#46; Since then&#44; many such cases have been reported&#44; ranging from mild &#40;e&#46;g&#46;&#44; HSV lesions on the lip&#41; to more serious manifestations&#44; including two fatal cases of acute liver failure secondary to HSV-1 and cranial polyneuropathy&#44; respectively&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">HSV-1 has been detected in many different tissues in COVID-19 patients&#46; In May 2020 Hu et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> demonstrated the presence of latent HSV-1 in the human anterior segment and the aqueous humor of SARS-CoV-2-infected patients&#44; and speculated that latent HSV-1 infection may have been activated in response to immune compromise caused by COVID-19 infection&#46; This hypothesis was subsequently confirmed in multiple cases of HSV-1 keratitis&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">While several cutaneous and mucosal manifestations were initially directly attributed to SARS-CoV-2&#44; it was later suggested that some&#44; including oral lesions&#44; could be the result of the reactivation of other&#44; more common viruses&#46; K&#228;mmerer et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> detected anti-HSV IgM in serum samples from a patient who developed herpetic gingivostomatitis&#44; and Kano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> reported a case of herpetic glossitis related to COVID-19 treatment&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">The coexistence of HSV-1 and SARS-CoV-2 is also considered in the clinical management of COVID-19 patients&#58; pulmonary HSV-1 reactivation in invasively ventilated patients is a known phenomenon&#44; and tracheal secretions and bronchial lavage samples are screened by Polymerase Chain Reaction &#40;PCR&#41; for HSV-1&#46; This reactivation of HSV-1 coincides with a decrease in the expression of interferon-stimulated genes and an increase in highly activated CD38&#43;HLADR&#43; CD8 T-cells in the later stages of SARS-CoV-2-infection&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">With the development of new vaccines for SARS-CoV-2&#44; reports of HSV-1 reactivation in recently inoculated individuals began to appear&#46; This correlation was observed in the UK&#8217;s yellow card scheme for recording adverse incidents with medicines&#44; and a total of 369 cases of HSV infections associated with COVID-19 vaccines are recorded in the European database of suspected adverse drug reactions &#40;EudraVigilance&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 57 after CX-024414&#59; 305 after Tozinameran&#59; 118 after CHADOX1 NCOV-19&#59; and 7 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Reporting bias is very likely&#44; given that HSV-1 reactivations are likely underdiagnosed due to their innocuous nature&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Herpes simplex virus 2</span><p id="par0060" class="elsevierStylePara elsevierViewall">HSV-2 is a ubiquitous pathogen that primarily causes genital infections&#46; Genital herpes is one of the most common sexually transmitted infections worldwide&#46; Although HSV-2 remains the main cause of recurrent genital herpes infections &#40;70&#37;&#8211;90&#37; overall&#41;&#44; the proportion due to HSV-1 has been increasing&#46; Primary&#44; non-primary initial&#44; and recurrent infections can be symptomatic or asymptomatic&#46; Notably&#44; 81&#37; of those with positive serology have no prior diagnosis of genital HSV infection&#46; Genital HSV-2 infection also increases the risk of acquiring and transmitting HIV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> PCR is increasingly used as a more rapid&#44; sensitive&#44; and specific method to detect HSV DNA in samples from the skin and other organs&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">To date&#44; there is only 1 reported case of SARS-CoV-2 infection and concomitant infection with human immunodeficiency virus&#44; HSV-2&#44; and SARS-CoV-2&#44; with a fulminant clinical course and a false-negative real-time PCR result&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">A total of 365 cases of HSV-2 following vaccination against COVID-19 are recorded in the EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 41 after CX-024414&#59; 200 after Tozinameran&#59; 116 after CHADOX1 NCOV-19&#59; and 8 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Varicella-zoster virus</span><p id="par0075" class="elsevierStylePara elsevierViewall">Herpes Zoster &#40;HZ&#41; is associated with high morbidity&#46; It is caused by the reactivation of latent HZV following a decline in cell-mediated immunity&#44; resulting in the appearance of clustered metamerically distributed papules on an erythematous base that rapidly evolves into vesicles&#44; which in turn can progress to pustules&#46; HZ has been associated with advanced age but can occur in individuals with diseases and those treated with immunosuppressant drugs and can even affect immunocompetent individuals&#46; The authors now know that SARS-CoV-2 infection affects T-lymphocytes&#44; especially CD4&#43;T cells&#44; CD8&#43;T cells&#44; and natural killer cells&#44; resulting in an immunocompromised state that may trigger the reactivation of latent viral infections&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> This association first came to light when increases in the number of HZ cases were observed during the COVID-19 outbreak relative to the corresponding period in 2019 in several different countries&#44; including Turkey and Brazil&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Case reports and series have described HZ following COVID-19&#44; occurring most frequently within 1&#8211;2 weeks of COVID-19 infection&#44; in the majority of cases with a typical presentation affecting a single dermatome&#46; Atypical HZ presentations have been reported&#44; especially in patients with lymphopenia&#44; giving rise to multimetameric involvement and skin necrosis&#44; and&#44; in the most severe cases&#44; central retinal vein occlusion&#44; meningitis&#44; and encephalomyelitis&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Elderly immunocompromised patients are more susceptible to severe and fatal HZ&#46; HZ has been proposed as a clinical biomarker of COVID-19&#58; it has been postulated that ophthalmic involvement may constitute a complication or indicator of COVID-19 infection&#44; particularly in young&#44; immunocompetent patients and in pregnant women&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">This association has been investigated by bioinformatic analyses examining potential genetic crosstalk between HZ and COVID-19&#44; and increases in Th17 cell differentiation and&#44; consequently&#44; IL-17 signaling have been described in both COVID-19 and HZ&#44; suggesting that IL-17 signaling may be one mechanism through which COVID-19 can increase the risk of HZ&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">It is very likely that the prevalence of coinfection is underestimated&#44; as many cases have been diagnosed by telemedicine&#44; and the requisite laboratory testing for HZ was available only in a limited number of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">There is more debate regarding COVID-19 with varicella &#40;more commonly known as chickenpox&#41; coinfection&#46; Recalcati et al&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> first reported that varicella-like vesicles could constitute a cutaneous manifestation of COVID-19&#46; Subsequently&#44; Marzano et al&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> reported that 22 patients with a positive COVID-19 nasopharyngeal test developed varicella-like papulovesicular exanthem&#46; This type of rash was related to typical clinical lesions and symptoms of herpes simplex&#47;zoster&#46; Llamas-Velasco et al&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> performed herpesvirus microarray PCR in 3 patients with SARS-CoV-2 and vesicular eruption&#44; and detected VZV and other herpesvirus DNA sequences in the vesicle contents&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">There are few cases of chickenpox in the context of a COVID-19 infection in which positive IgM antibodies against VZV have been detected or molecular analysis of the vesicle content has been performed&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Generally&#44; cases have been described in young people with clinical signs typical of chickenpox and SARS-CoV-2 infection&#44; including high fever&#44; myalgia&#44; nasal discharge&#44; and a rash consisting of vesicles&#44; erosions&#44; and crusts associated with petechial enanthem of the palatal mucosa&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> However&#44; cases of more serious involvement with the development of varicella pneumonia have also been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> This presumptive diagnosis must be established early to begin treatment with acyclovir&#44; which prevents the progression of lung involvement&#44; decreasing the likelihood of a fatal outcome&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Apart from laboratory tests to distinguish varicella-like exanthema from that caused by chickenpox&#44; different pathological anatomical patterns have been described&#46; In varicella-like exanthema&#44; biopsy shows acantholysis and dyskeratosis with a suprabasal&#44; unilocular intraepidermal vesicle&#44; without the large multinucleated cells and ballooning degeneration typical of chickenpox&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> However&#44; the incidence of varicella and other viral infections has dramatically decreased since the implementation of COVID-19 control measures&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Cases of HZ following the administration of SARS-CoV-2 vaccines have been reported worldwide&#46; The largest series and narrative review include 399 cases&#44; and another systematic review describes 91 cases of VZV reactivation following COVID-19 vaccination&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> counts lower than those who are registered in EudraVigilance &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The number of HZ cases associated with COVID-19 vaccines registered in the EudraVigilance database is 1410 for CX-024414&#44; 9652 for Tozinameran&#44; 3054 for CHADOX1 NCOV-19&#44; and 205 for AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">A systematic review by Katsikas Triantafyllidis et al&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> reported that the dermatomal distribution of skin lesions was variable among patients with HZ reactivation following COVID-19 vaccination&#44; although the mammary region was the most frequently affected anatomical site&#46; Most of the lesions and symptoms appeared after the administration of the first vaccine dose&#46; There was a tendency towards greater susceptibility among patients aged &#62; 60 years&#46; Most patients were treated with oral valacyclovir in monotherapy&#46; Furthermore&#44; the majority of affected patients had a concomitant autoimmune disorder and&#47;or were receiving immunosuppressant therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">While causality has not yet been established&#44; increased awareness and early recognition of HZ are crucial to ensure the optimal management of these patients&#46; One of the most recent studies of the clinical and pathologic correlations of cutaneous COVID-19 vaccine reactions collects 4 cases of postvaccine HZ in which biopsies revealed viral cytopathic changes&#44; leading the authors to propose that the immune response induced by vaccination may trigger reactivation of other viruses&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Epstein Barr virus</span><p id="par0135" class="elsevierStylePara elsevierViewall">EBV&#44; human gammaherpesvirus 4&#44; infects B-lymphocytes and epithelial cells&#46; After primary infection EBV persists in a latent state in individual B-cells&#46; Latent EBV is found in approximately 95&#37; of the human population&#46; The presence of EBV in B-lymphocytes has been associated with the appearance of lymphoproliferative diseases and autoimmune diseases such as multiple sclerosis&#44; systemic lupus erythematosus&#44; rheumatoid arthritis&#44; and dermatomyositis&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Multiple factors have been implicated in EBV reactivation&#44; in particular psychological stress&#44; including the stress associated with hospitalization for several days&#46; Reactivation is more likely to occur in immunosuppressed patients &#40;e&#46;g&#46;&#44; transplant recipients&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Several studies have described increased EBV reactivation in COVID-19 patients&#44; especially those that are critically ill&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;27</span></a> Paolucci et al&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> detected EBV DNA in 95&#46;2&#37; of COVID-19 patients hospitalized in an intensive care unit&#44; as well as significant reductions in CD8&#43; cells and NK counts&#46; This reactivation occurred earlier after admission to an Intensive Care Unit &#40;ICU&#41; and was associated with long-term hospitalization&#46; The course of COVID-19 disease may be aggravated in patients that undergo EBV reactivation&#58; these patients had a higher mortality rate and received more immuno-supportive treatment than SARV-CoV-2 patients without EBV coinfection&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a> In fact&#44; Solomay TV et al&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> reported that severe disease and pneumonitis were more common among patients with EBV coinfection&#46; These patients have a more frequent fever&#44; elevated inflammation markers &#40;C-reactive protein&#41;&#44; and increased liver enzyme levels&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> While mild alterations in liver function tests are common in patients with COVID-19 infection&#44; marked elevation of liver enzymes should raise suspicion of EBV coinfection&#46; These observations highlight the importance of distinguishing between EBV manifestations and COVID-19-associated complications&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">One study reported EBV reactivations in 60&#37; of patients with prolonged COVID-19 symptoms after resolution of acute disease&#44; compared with 10&#37; in a control group&#44; suggesting that some long-term COVID-19 symptoms may be due to EBV reactivation&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Moreover&#44; Verma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a> reported that EBV reactivation in nasopharyngeal and oropharyngeal epithelial cells increases expression of Angiotensin-Converting Enzyme 2 &#40;ACE2&#41;&#44; the cellular receptor for SARS-CoV-2&#44; thereby favoring SARS-CoV-2 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">The EUDRAvigilance database contains 63 cases of EBV reactivation after COVID-19 vaccination &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#58; 12 for CX-024414&#59; 38 for Tozinameran&#59; 12 for CHADOX1 NCOV-19&#59; and 1 for AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> A single case of EBV-positive diffuse large B-cell lymphoma after the COVID-19 vaccine has been reported in a heart transplant recipient&#46; One study reported no increase in herpesvirus reactivation&#44; including EBV&#44; 1-week after versus 1 week before COVID-19 vaccination &#40;Tozinameran&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Cytomegalovirus</span><p id="par0160" class="elsevierStylePara elsevierViewall">CMV is a member of the Herpesviridae family&#44; and its prevalence increases with age&#46; It typically causes primoinfection in young individuals and subsequently persists in a latent state throughout the life of the host&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">In immunocompetent individuals&#44; it remains asymptomatic&#46; However&#44; the increased rate of CMV reactivation among immunosuppressed patients&#44; including solid organ transplant recipients and patients with AIDS or cancer&#44; is a major concern and may require antiviral prophylaxis&#46; This phenomenon has also been described in previously healthy patients admitted to an ICU&#44; who are also at increased risk of reactivation of other herpesviruses&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> In fact&#44; these rates appear even higher in critically ill COVID-19 patients&#44; with viral reactivation reported in almost 50&#37; of patients in the series by Le Balc&#39;h et al&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and other authors&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Explaining this effect&#44; at least in part&#44; both severe lymphopenia and mechanical ventilation are known risk factors for secondary viral infections&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">Many cases of CMV reactivation in COVID-19 patients have been reported&#44; some with fatal consequences&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> CMV reactivation can manifest with a wide range of symptoms&#44; including gastrointestinal bleeding and colitis&#44; persistent fever&#44; and secondary pneumonia&#44; all of which are associated with a worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> Marked and persistent lymphopenia is characteristic of severe COVID-19 infection&#46; Moreover&#44; potent immunosuppressive agents&#44; including high-dose corticosteroids and IL-6 antagonists such as tocilizumab&#44; are more frequently used in these patients&#46; These two factors may contribute to an increased risk of CMV reactivation in critically ill COVID-19 patients&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Studies have investigated the role of CMV in regulating the immune response&#46; CMV appears to contribute to accelerated immune senescence and exacerbate the cytokine storm associated with severe COVID-19 infection&#44; thus negatively altering the host response to COVID-19 infection&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Consequently&#44; patients co-infected with COVID-19 and CMV appear to have a worse prognosis&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> and this immune response dysregulation may also explain why elderly&#44; usually CMV-seropositive&#44; patients develop more severe disease&#46; In line with these findings&#44; areas with a higher prevalence of CMV seropositivity also show higher COVID-19 mortality rates&#46; A total of 56 cases of CMV reactivation after COVID-19 vaccination &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; have been reported in Europe&#58; 10 after CX-024414&#59; 39 after Tozinameran&#59; 6 after CHADOX1 NCOV-19&#59; and 1 after AD26&#46;COV2&#46;S&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Human herpesvirus 6 and 7</span><p id="par0180" class="elsevierStylePara elsevierViewall">Human Herpesvirus 6 &#40;HHV-6&#41; is a widespread beta-herpesvirus that is genetically related to human CMV&#46; HHV-6 exhibits broad cell tropism in vivo and&#44; like other herpesviruses&#44; induces lifelong latent infection in humans&#46; Many active HHV-6 infections&#44; corresponding to primary infections&#44; reactivations&#44; or exogenous reinfections&#44; are asymptomatic&#46; However&#44; the virus can cause serious diseases&#44; particularly in immunocompromised individuals&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Cutaneous diseases associated with HHV-6 infection include roseola infantum&#44; Pityriasis Rosea &#40;PR&#41;&#44; Gianotti-Crosti syndrome&#44; drug reaction with eosinophilia and systemic symptoms&#44; and thrombocytopenic purpura&#44; among others&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> In the case of PR&#44; several studies have established a causal role of systemic active HHV-6 and&#47;or HHV-7 reactivation&#44; based on the detection of viral DNA in the plasma of PR patients&#44; the expression of mRNA and specific viral antigens&#44; and detection by electron microscopy of HHV virions in PR lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> Nonetheless&#44; it is difficult to establish an etiological association between HHV-6 infection and cutaneous disease due to the ubiquity and near-universal prevalence of the virus and the limitations of current research tools&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The association between SARS-CoV-2 and HHV-6 is supported by several reports during the COVID-19 pandemic describing an increased incidence of PR&#44; and in one case HHV-6 reactivation was confirmed by serum PCR&#46; The studied group detected positive IgM serology and&#47;or IgG seroconversion for HHV-6 in 12 patients fulfilling COVID-19 clinical and&#47;or microbiological criteria that presented with different cutaneous manifestations&#44; including PR-like eruption&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> A case of a PR-like eruption in a COVID-19 patient with SARS-CoV-2 spike protein positivity on skin biopsy has also been reported&#44; suggesting a direct pathogenic relationship with this virus&#44; although the HHV-6 status of this patient was not investigated&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">This reactivation has not only been described in association with PR but also in critically ill patients with COVID-19&#46; In their series of 34 COVID-19 patients Simonnet et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> detected HHV-6 viremia in 7 &#40;22&#37;&#41; patients&#44; although HHV-6 status was not associated with morbidity and mortality&#46; This percentage is close to the frequency reported in large studies of septic shock patients&#46; One limitation of Simonnet et al&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> the study was absent a comparator population&#44; which prevented the authors from determining whether SARS-CoV-2 infection or &#8220;ICU-acquired immunosuppression&#8221; were the main drivers of reactivation&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">One report has described HHV-6 reactivation in the central nervous system of a COVID-19 patient with HHV-6 myelitis and concomitant myelin oligodendrocyte glycoprotein antibody-mediated parainfectious myelitis&#46; Another reported positive detection of SARS-CoV-2&#44; HSV-1&#44; and HHV-6 nucleic acid in tear and conjunctival secretions from a non-conjunctivitis COVID-19 patient with obstruction of common lacrimal ducts&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> In both cases&#44; it is speculated that latent HHV-6 infection may have been reactivated in the context of COVID-19-induced immune dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Recently&#44; Biswas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> reported a case of a child with the multisystem inflammatory syndrome &#40;MIS&#41; as a late complication of COVID-19&#46; Initially&#44; a high HHV-6 viral load was detected&#46; Subsequently&#44; the patient was found to have inherited chromosomally integrated HHV-6 &#40;iciHHV-6&#41;&#46; iciHHV-6 is HHV-6 that has been integrated into chromosomal telomeric regions and is transmitted through the germ line&#46; This occurs in &#8764;1&#37; of individuals&#46; The presence of iciHHV-6 has been associated with altered and&#44; in some instances&#44; increased antibody responses to certain viruses and can be reactivated from latency&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> Curiously&#44; patients with MIS can show enhanced antibody responses to SARS-CoV-2&#46; Biswas et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> concluded that additional research may be warranted to determine whether iciHHV-6 is commonly observed in MIS patients and&#44; if so&#44; whether it may play a part in its pathogenesis&#46;</p><p id="par0210" class="elsevierStylePara elsevierViewall">Finally&#44; since the introduction of SARS-CoV-2 vaccines&#44; multiple cases of Pityriasis Rosea-Like Lesions &#40;PR-LE&#41; have been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;44</span></a> Catal&#224; et al&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> noted PR-LE in 4&#46;9&#37; of a cohort of 405 patients&#44; as well as VZV and HSV reactivation in 10&#46;1&#37; and 3&#46;7&#37;&#44; respectively&#46; PR-LE following the administration of other vaccines had been previously described&#46; Some authors distinguish vaccine-induced PR&#44; possibly due to reactivation of HHV-6 and&#47;or -7&#44; from vaccine-induced PR-LE&#44; which may occur as a delayed hypersensitivity response to a vaccine&#44; in the absence of any signs of HHV-6&#47;7 reactivation&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Differentiation between &#8220;true&#8221; PR and a PR-like eruption is difficult and virological studies of HHV-6&#47;7 reactivation are performed only in a minority of cases&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> HHV-6 status has not been investigated in most cases of SARS-CoV-2 vaccine-induced PR-like eruption cases reported to date&#44; except in 2 cases related to the Pfizer BioNTech &#40;BNT162b2&#41; vaccine in which high HHV&#8208;6 antibody titers were detected&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">Given concerns over an increase in VZV and HSV reactivation after vaccination with Tozinameran&#44; Brosh-Nissimov et al&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> studied oropharyngeal shedding of herpesviruses&#44; including HHV-6&#44; before and after vaccination&#46; They reported no significant differences in positivity for any herpesvirus between pre-vaccination and post-vaccination samples&#46; The EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; records 9654 cases of HHV-6&#58; 1 after CX-024414&#59; 9652 after Tozinameran&#59; and 1 after CHADOX1 NCOV-19&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Human herpesvirus 8</span><p id="par0220" class="elsevierStylePara elsevierViewall">Kaposi Sarcoma-Associated Herpesvirus &#40;KSHV&#41; is an oncogenic virus of the human &#947;-herpesvirus subfamily and is the etiologic agent of several human cancers&#44; including Kaposi Sarcoma &#40;KS&#41;&#44; primary effusion lymphoma&#44; and multicentric Castleman&#8217;s disease&#46; It is also associated with a hyperinflammatory syndrome named Kaposi sarcoma herpesvirus-associated inflammatory cytokine syndrome&#44; which can be fatal in some patients&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> The seroprevalence of KSHV infection in the general population of North America is less than 10&#37;&#44; but in most of sub-Saharan Africa&#44; the overall seroprevalence exceeds 50&#37;&#46; In the United States and Europe&#44; HHV-8 antibodies are present in &#8764;30&#37; of HIV-1-infected men who have sex with men&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> KSHV can be diagnosed by various methods&#44; including quantification of viral DNA in blood&#44; HHV8-LANA-1 immunostaining in biopsy specimens&#44; and serological testing&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">The KSHV viral life cycle consists of a quiescent latent phase and a replicative lytic phase&#46; While the establishment of latency enables persistent KSHV infection and evasion of the host&#8217;s immune system&#44; lytic replication is essential for the dissemination of the virus between hosts and within the host itself&#46; The transition between these phases&#44; known as lytic reactivation&#44; is controlled by a complex set of environmental&#44; host-related&#44; and viral factors&#46; One such trigger is COVID-19 infection&#44; and SARS-CoV-2-encoded proteins can induce lytic reactivation of KSHV through manipulation of intracellular signaling pathways&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> This has been demonstrated in clinical practice in a patient that had been recently hospitalized for COVID-19 infection and developed skin lesions consisting of bluish-red maculopapular&#44; a biopsy of which established a diagnosis of KS&#46; Transmission electron microscopy of the skin biopsy revealed the presence of both COVID-19 and HHV-8&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> It is proposed that SARS-CoV-2 contributes to the development of a hyper inflammatory state&#44; leading to HHV-8 proliferation and consequent recurrence of Kaposi sarcoma&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">The EUDRAvigilance database &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; records 3 cases of Kaposi sarcoma&#44; all after vaccination with Tozinameran&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Conclusion</span><p id="par0235" class="elsevierStylePara elsevierViewall">Numerous articles have linked COVID-19 infection with coinfection or reactivation of human herpes viruses&#46; Furthermore&#44; evidence suggests that human herpesvirus infection may constitute a prognostic marker of COVID-19 infection and even be responsible for many of the manifestations initially attributed to SARS-CoV-2&#46; Recent reports indicate that in addition to the SARS-CoV-2 virus&#44; all COVID-19 vaccines approved to date in Europe are capable of inducing herpesvirus reactivation&#46; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> shows the main manifestations of herpesvirus infections associated with COVID-19&#46; It is important to take this information into account and to consider all viruses of the Herpesviridae family when managing patients with COVID-19 infection or recently vaccinated against COVID-19&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Financial support</span><p id="par0240" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Authors&#8217; contributions</span><p id="par0245" class="elsevierStylePara elsevierViewall">Alba Navarro-Bielsa&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">Tamara Gracia-Caza&#241;a&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">Beatriz Aldea-Manrique&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Isabel Abad&#237;as-Granado&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0265" class="elsevierStylePara elsevierViewall">Adri&#225;n Ballano&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Isabel Bernad&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Yolanda Gilaberte&#58; Approval of the final version of the manuscript&#44; critical literature review&#44; data collection&#44; analysis and interpretation&#44; effective participation in research orientation&#44; intellectual participation in propaedeutic and&#47;or therapeutic management of studied cases&#44; manuscript critical review&#44; preparation and writing of the manuscript&#44; statistical analysis&#44; study conception&#44; and planning&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0280" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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          "titulo" => "Keywords"
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          "titulo" => "Introduction"
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            0 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Herpes simplex virus 1"
            ]
            1 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Herpes simplex virus 2"
            ]
            2 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Varicella-zoster virus"
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            3 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Epstein Barr virus"
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            4 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Cytomegalovirus"
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            5 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Human herpesvirus 6 and 7"
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            6 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Human herpesvirus 8"
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          "titulo" => "Conclusion"
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            0 => "Coinfection"
            1 => "COVID-19"
            2 => "Herpesvirus 1&#44; human"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Since the onset of the COVID-19 outbreak&#44; numerous articles have highlighted a possible link between COVID-19 vaccination or infection and Herpesviridae co-infection or reactivation&#46; The authors conducted an exhaustive literature review on this topic&#44; the results of which are presented individually for each member of the Herpesviridae family&#58; Herpes Simplex Virus &#40;HSV&#41; types-1 &#40;HSV-1&#41; and 2 &#40;HSV-2&#41;&#59; Varicella-Zoster Virus &#40;VZV&#41;&#59; Epstein-Barr Virus &#40;EBV&#41;&#59; Cytomegalovirus &#40;CMV&#41;&#59; HHV-6&#59; HHV-7&#59; and HHV-8&#46; These human herpesviruses can serve as prognostic markers for the COVID-19 infection and may even underlie some of the clinical manifestations initially attributed to SARS-CoV-2&#46; In addition to SARS-CoV-2 infection&#44; all corresponding vaccines approved to date in Europe appear capable of inducing herpesvirus reactivation&#46; It is important to consider all viruses of the Herpesviridae family when managing patients infected with or recently vaccinated against COVID-19&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Study conducted at the Miguel Servet University Hospital&#44; Zaragoza&#44; Spain&#46;</p>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Manifestations of herpesvirus infections associated with COVID-19&#46; VHS-1&#44; Herpes Simplex Virus Type-1&#59; VHS-2&#44; Herpes Simplex Virus Type-2&#59; VVZ&#44; Varicella-Zoster Virus&#59; EBV&#44; Epstein-Barr Virus&#59; CMV&#44; Cytomegalovirus&#59; HHV-6&#44; Herpes Virus-6&#59; HHV-7&#44; Herpes Virus-7&#59; HHV8&#44; Herpes Virus-8&#46;</p>"
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          "leyenda" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">HSV-1&#44; Herpes Simplex Virus type-1&#59; HSV-2&#44; Herpes Simplex Virus type-2&#59; VZV&#44; Varicella-Zoster Virus&#59; EBV&#44; Epstein-Barr Virus&#59; CMV&#44; Cytomegalovirus&#59; HHV-6&#44; Herpes Virus-6&#59; HHV-7&#44; Herpes Virus-7&#59; KSHV&#44; Kaposi Sarcoma-associated Herpesvirus&#46;</p>"
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Virus&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 MRNA vaccine Pfizer-Biontech &#40;Tozinameran&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 vaccine Astrazeneca &#40;CHADOX1 NCOV-19&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">COVID-19 vaccine Janssen &#40;AD26&#46;COV2&#46;S&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Total&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSV-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">305&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">369&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">HSV-2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">41&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Cases of herpesvirus infections associated with COVID-19 vaccines are recorded in the European database of suspected adverse drug reactions &#40;EudraVigilance&#41;&#46;</p>"
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                      "titulo" => "Global and Regional Estimates of Prevalent and Incident Herpes Simplex Virus Type 1 Infections in 2012"
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ISSN: 03650596
Original language: English
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