Herpes simplex virus and herpes zoster

They have concluded that SARS-CoV-2 infection could be a risk factor for HHV reactivation and therefore recommend a rapid identification of these co-infections as it may impact the prognosis of infected patients [ 6 ]. Involvement of the central nervous system in COVID infection has been mentioned; however, only 2 cases of encephalitis caused by this infection have been reported.

Marzano et al. They included patients with a COVID—positive nasopharyngeal swab and no medications with varicella-like lesions [ 11 ]. Lamas-Velasco et al. Other complications of HHV in COVID include a fatal case of acute liver failure due to HSV-1 infection [ 14 ] and three patients who have developed a necrotic herpes zoster on the second branch of the trigeminal nerve [ 15 ].

In the present study, the increased OR for COVID with both viruses was diminished when adjusted for respiratory disease and obesity. Similarly, obesity has been linked to HHV infections.

We did not have access to the detailed individual patient information. For example, the patients with COVID may be sicker in general compared to the control hospitalized population, making them in general more likely to get viral reactivation. While there was control for comorbidities, there does not seem to be control for severity of acute illness or use of immune-suppressive medications which are strong risk factors for development of herpes infection.

Nevertheless, we believe that the data is sufficient to establish a strong association between herpes viruses and COVID Although HSV prevalence recorded among non-Hispanic Blacks is significantly higher compared to White non-Hispanic, these findings may represent socioeconomic variables that were not addressed in this study. In conclusion, in the present study we have demonstrated a strong association between herpes virus infection and COVID Although the exact nature of the association is yet to be elucidated, clinicians should be knowledgeable about it.

Keeping in mind that fulminant herpes infection may resemble COVID in some cases, clinicians should include herpes in the differential diagnosis of these cases especially because of the broad availability of anti-herpetic medications, an option still nonexistent for COVID infection. Joseph Katz—conceptualization, writing of manuscript, and data analysis; Sijia Yue—data analysis; Wei Xue—statistical analysis, data interpretation. National Center for Biotechnology Information , U.

Ir J Med Sci. Author information Article notes Copyright and License information Disclaimer. Joseph Katz, Email: ude. Corresponding author. Received Jun 4; Accepted Jul 7. This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source.

This article has been cited by other articles in PMC. Abstract Background Reactivation of herpes family viruses in immunocompromised patients may result in detrimental outcomes for the hosts; therefore, herpes simplex virus-1 and varicella zoster virus infections in the context of COVID may have clinical and prognostic implications.

At the molecular level, the three viruses share most genes and encode similar functions. Given these observations, it is perhaps surprising that HSV and VZV adopt very different modes of pathogenesis in the human host. Each virus has evolved a unique infection pattern and has developed specific abilities to counteract host innate and adaptive immunity.

This review will highlight some remarkable differences in pathogenesis of these viruses, focusing on their interaction with host immunity. We will build on recent developments and previous reviews comparing these two herpesviruses [ 1 , 2 ].

At the outset, the biological differences between VZV and HSV should be stressed, because they greatly affect the ability to study the viruses outside the human host. First, HSV-1 is robust for growth in tissue culture, while VZV is highly cell-associated, and cannot be obtained in titers needed to carry out synchronous VZV infections.

There are numerous small animal models that accurately reflect primary infection, latency, and reactivation of HSV-1 in humans, but no animal model reproduces varicella, latency and zoster. Moreover, VZV is exceedingly difficult to experimentally reactivate from human ganglia.

The lack of animal models has hampered studies of the adaptive immune response to VZV, which is problematic because human studies indicate cellular immune status is a major factor in VZV reactivation. For these reasons, our knowledge of mechanisms of latency and reactivation has advanced more rapidly for HSV than for VZV. The proteomes of the two herpesviruses are quite similar. Genes with homology orthologs are arranged in the same order and direction in the genomes of both viruses i.

All VZV specific ORFs and all those in HSV-1 except gD can be deleted without preventing virus growth in culture, although most influence viral behavior and pathogenicity in animal models, as discussed below. Both virus genomes can be divided into unique long and short regions, with each region being bounded by repeated sequences.

However, the repeats of the HSV short region are 2. The HSV genomes exist in virions as four linear isomers at equimolar ratios involving inversion of the long and short regions with respect to each other , while VZV has two predominant isomers with a fixed orientation of the UL region packaged with two isomers of the short region. This will be discussed in more detail in the section on latency. Most HSV-1 protein functions have been determined by analyses of viral mutants. VZV protein functions that are not well understood are annotated based on knowledge of the HSV-1 counterpart.

This must be taken with caution, as there is clear evolutionary divergence of the two viruses from a presumed common ancestor. While a full review of these differences is beyond the scope of this review, three illustrative examples are provided;.

The biggest difference in genomic organization of the two viruses lies in the short unique region, where VZV has only four proteins and HSV has The obvious question is what mediates VZV cell binding and entry? Both viruses encode many virion tegument proteins. HSV-1 and HSV-2 usually initiate a primary infection at the periphery, and any subsequent recurrent infections following reactivation from latency occur at or near the same sites.

HSV typically infects the oral cavity HSV-1 or vaginal mucosa HSV-2 , but both viruses can infect at the skin, the eye, and other surfaces of the body.

HSV infection rarely involves a systemic component except in infants or immunosuppressed patients. In mice, primary infection is restricted at least in part by type I and type II interferon responses, since abrogation of the respective receptors leads to increased systemic disease [ 24 , 25 ].

HSV replication is typically restricted to the epithelial layer of mucosal surfaces or the epidermal layer of the skin, particularly at sites of dermal abrasion. During the primary infection, virus gains access to the axonal termini of sensory neurons, is transported to neuronal nuclei in sensory ganglia and there establishes latency.

HSV-1 replication at both the periphery and within sensory ganglia is largely controlled by the rapid deployment of an innate immune response, with subsequent involvement of adaptive immunity, as discussed below. Unlike HSV, primary VZV infection involves a viremic phase and systemic delivery, in a manner more characteristic of infection with members of the Beta- and gammaherpesviruses. Elegant studies in the SCID-hu mouse model have contributed to a relatively new paradigm of VZV primary infection, in which inhalation of infectious virus initiates a primary infection at the respiratory lymphoid tissues, such as the tonsils [ 26 , 27 ].

VZV also infects professional antigen presenting cells such as monocytes, dendritic cells and macrophages [ 28 — 30 ], which may then transfer infectious virus to T cells at draining lymph nodes. The T cell associated viremia delivers virus systemically to skin and initiates sites of primary infection in the dermis following migration through the capillary vasculature.

Thus, VZV infection initiates from the basal layer of the skin, whereas HSV initiates infection from the apical surface. HSV and VZV have formed synergistic relationships with their hosts that permit harmonious coexistence. However, recurrent HSV-1 and VZV disease is initiated in the face of a primed adaptive immune response, by a virus that is antigenically identical to that inducing immunity during the primary infection.

The following sections briefly discuss the innate and adaptive immune responses to HSV-1 and VZV and the immune evasion mechanisms they employ to gain footholds in the primed host following reactivation from latency. As our understanding of innate and adaptive immunity develops, the boundaries between the two systems have become increasingly fuzzy. We now know that innate and adaptive immunity cooperate to combat infections.

However during primary infection, a temporal relationship exists in which the cells and molecules comprising the innate immune system have primary responsibility for controlling the virus, while the lymphocytes comprising the adaptive immune system undergo clonal expansion.

A secondary response, orchestrated by lymphocytes of the adaptive immune system, often employs innate immune components as effector cells or molecules that lead to elimination of replicating virus. Upon contact with an epithelial surface, the host recognizes pathogen-associated molecular patterns PAMP on the virus. Notable among these is the toll-like receptor TLR family, with an important role in activating innate immunity.

Although the involvement of TLR in response to VZV is not well characterized, both type I and type II interferons are present in plasma of patients during the early incubation period when viral replication is thought to be mai contained primarily by innate immunity. Plasmacytoid dendritic cells pDC are an important source of type I interferon during HSV-1 infections and are also attracted to VZV lesions, but in the latter case their capacity to produce type I interferon appears to be inhibited by VZV [ 28 ].

The HSV-1 murine model has enabled considerable assessments of the development of cellular immunity to infection. Both mature and immature DCs are susceptible to HSV infection [ 43 — 45 ], but only immature DCs support a productive infection and this leads to apoptosis [ 46 ].

Thus, DCs that are directly infected with either HSV-1 or VZV or those that phagocytose infected cells at the site of infection likely transport viral proteins to the regional lymph nodes. Those, that are directly infected would be inefficient at presenting them to T cells.

Productive infection and immune evasion in DCs might play a role in the VZV viremic phase, either directly or by transfer to T cells in lymph nodes [ 29 ]. Antibodies are directed at viral glycoproteins, tegument or capsid proteins as well as other proteins [ 50 , 51 ].

These antibodies can neutralize the viruses. VZV specific IgG can be used to treat high-risk patients. HSV specific antibodies have been implicated in protection, but patients with lower antibody titers reactivate less, whereas people with higher levels of antibodies tend to reactivate more frequently [ 55 , 56 ].

Both viruses have evolved immune evasion mechanisms capable of blunting protective innate and adaptive immunity, which are thought to facilitate development of recurrent disease in the face of a robust immune response. However the degree to which ICP47 activity contributes to pathogenesis is not clear. This suggests that the effect of ICP47 can easily be overcome at sites of infection. Current knowledge of HSV neuronal latency is derived from multiple animal model systems that reproduce human latency, as well as from direct analyses of human ganglionic tissues.

In contrast, our understanding of VZV latency is restricted by a lack of animal models and further complicated by the lower levels of latent VZV in human cadaver ganglionic tissues. Thus, apparent differences in HSV and VZV latency may, in part, reflect the different settings in which latency is studied. Consistent with the fact that most primary and recurrent HSV-1 infections occur in oral and nasal cavities or on the corneal surface without systemic spread, HSV-1 latency is most commonly observed in trigeminal ganglia TG.

In contrast, VZV DNA is distributed in sensory and autonomic ganglia across the entire neuraxis, consistent with the wide anatomical distribution of primary infection and reactivated disease can occur anywhere on the body.

Quantitative estimates of viral genome copy numbers indicate VZV DNA is higher in the TG than in any single dorsal root ganglion [ 68 ] but is an order of magnitude lower than the HSV-1 latent load [ 69 ]. Both viruses access the ganglia by rretrograde axonal transport from the skin to neuronal nuclei, but VZV may also access nerve cell bodies by the hematogenous route during the viremic phase of infection. Thus, VZV has been found in ganglia such as the enteric ganglia that do not infiltrate the periphery [ 70 ].

The reduced latent VZV load could reflect factors such as age at primary infection, levels of HSV-1 and VZV exposure during primary infection, and the increased frequency of HSV-1 reactivation and shedding with increased genomic load at each recurrence. In human ganglia, both the VZV and HSV genomes appear as endless circular episomal structures that are associated with chromatin [ 1 , 68 , 71 , 72 ].

The heterochromatin state of the genomes is suspected to be responsible for the repression of gene expression and the productive cycle. However the limited transcription of both viruses during latency occurs in very different patterns. HSV latency is relatively well characterized.

Other conditions that can present with similar symptoms include traumatic lesions mechanical, thermal, or chemical , aphthous ulcers, chicken pox, shingles, syphilis, Bechet syndrome, Stevens-Johnson syndrome, human immunodeficiency virus HIV , and inflammatory bowel disease Table 2. Routine treatment for healthy individuals with mild-to-moderate recurrent episodes of HSV-1 is not recommended.

Most episodes of herpes labialis are self-limiting, the evidence on the benefits of oral antivirals is limited, and oral treatment needs to be initiated at the onset of prodromal symptoms which might be challenging to do. This is relying on patients reporting symptoms in a timely fashion, prompt access to prescribed antivirals, and patient adherence to treatment.

Antiviral drugs inhibit viral replication. These guanine nucleoside analogues are converted into their active drug component within an infected cell by the action of viral thymidine kinase. Most viral replication occurs within the first 24 hours of infection. Prompt treatment at prodromal stage, prior to lesions erupting is recommended to limit epithelial damage and possible secondary complications. Oral agents available in the United Kingdom and the United States include aciclovir and valaciclovir.

In the United States, valociclovir is more readily available covered by the majority of insurance providers. Valaciclovir is a prodrug of acyclovir and has greater bioavailability and absorption, but it is more expensive. Oral acyclovir is a safe drug with a minimal side effect profile and does not require monitoring. While side effects can occur, they are rare.

For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium or the British National Formulary. Resistance to aciclovir is very rare in immunocompetent people. If symptoms worsen or do not improve significantly in 5 to 7 days, then an alternative diagnosis should be considered.

Patients should be referred for medical review and investigation of systemic causes of ulcers, such as HIV, inflammatory bowel disease, Bechet, complex apthosis, and systemic lupus erythematosus SLE. Oral antivirals taken early before the lesion appears in a recurrent episode might be more effective than a placebo at reducing symptom duration and healing time. Treatment is not a cure and will only prevent lesions if administered at the prodromal stage.

Once the lesions have appeared, symptoms might be lessened in duration by one day. In immunocompromised individuals with an episode of primary or recurrent oral herpes simplex infection, use of oral antiviral medications should be based on best clinical judgement. When an oral antiviral drug is indicated, clinicians should advise their patients to take the medication from the time of onset of prodromal symptoms, before vesicles appear, if possible, until lesions have healed, for a minimum of five days.

When a patient reports a cold sore eruption following a low-risk procedure, clinicians should educate patients on management of symptoms and prevention of spread and further reinfection and should continue to monitor and document the eruption until resolved. Patients might present with concurrent or subsequent superimposed bacterial infection with impetigo surrounding crusted lesions.

Bacterial infections are often responsible for symptoms worsening rather than failure of antiviral treatment, and following clinical assessment antibiotics should be considered.

In immunocompromised patients or those with poor absorption, mg Aciclovir PO five times a day is recommended. Clinical decision making and risk assessment should consider the patient-specific history and assessment. While there is no definitive evidence base on the actual risk of reactivation following minimally invasive procedures or in the actual benefit of prophylactic regimes, CMAC advocates anti-HSV prophylaxis for patients who have previously had a herpetic outbreak following an aesthetic procedure,,14 when the procedure breaches the integrity of the skin, such as medical needling, chemical peels, dermabrasion and microdermabrasion, dermal filler injections to the lips or nasal labial folds, and routinely for CO 2 laser resurfacing procedures.

If previous history of failure on aciclovir prophylaxis with good adherence or deemed to be high risk of reactivation including immunosuppression:.

There are no randomized controlled trials to indicate optimum time to commence episodic prophylaxis. Based on a review of the literature, a reasonable protocol would not be before two days prior to treatment and no later than the day of treatment and continue for five days, or until skin post procedure has healed.

Oral antivirals do not prevent progression of latent infection. If the patient suffers a recurrence despite prophylaxis, revert to treatment of active infection protocol.

Provide self-help advice on the management of symptoms and the prevention of autoinoculation and transmission to others. All patients presenting with a herpetic eruption postprocedure should be supported to manage their condition, as per patient advice sheet, and carefully monitored. Photographs should be taken to objectively assess over time. Refer to primary care for further investigation, if symptoms do not improve after seven days or if they worsen.

The patient should be offered appropriate prophylactic treatment for subsequent treatments in the future. Identifying and communicating potential risks with the patient as part of the assessment and consent process, good record keeping, and good follow-up and support all play their part in preventing a complication from becoming a complaint.

Members of the organization are part of a collaboration that aims to capture data to help improve patient safety. For more details, please see www. National Center for Biotechnology Information , U. J Clin Aesthet Dermatol. Author information Copyright and License information Disclaimer. Corresponding author. Matrix Medical Communications.