clinical presentation of herpes simplex virus type 1

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Epidemiology, Clinical Presentation, and Antibody Response to Primary Infection With Herpes Simplex Virus Type 1 and Type 2 in Young Women

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David I. Bernstein, Abbie R. Bellamy, Edward W. Hook, Myron J. Levin, Anna Wald, Marian G. Ewell, Peter A. Wolff, Carolyn D. Deal, Thomas C. Heineman, Gary Dubin, Robert B. Belshe, Epidemiology, Clinical Presentation, and Antibody Response to Primary Infection With Herpes Simplex Virus Type 1 and Type 2 in Young Women, Clinical Infectious Diseases , Volume 56, Issue 3, 1 February 2013, Pages 344–351, https://doi.org/10.1093/cid/cis891

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Background.  Herpes simplex virus infections type 1 (HSV-1) and type 2 (HSV-2) are common, but the epidemiology of HSV disease is changing.

Methods.  HSV-seronegative women, aged 18–30 years, who were in the control arm of the HERPEVAC Trial for Women were followed for 20 months for primary HSV infections.

Results.  Of the 3438 evaluable participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. The rate of infection for HSV-1 (2.5 per 100 person-years) was more than twice that for HSV-2 (1.1 per 100 person-years). Most infections (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease. The HSV-2 infection rate was 2.6 times higher in non-Hispanic black participants than in Hispanics and 5.5 times higher than in non-Hispanic whites ( P < .001), while the HSV-1 infection rate was 1.7 times higher in non-Hispanic whites than non-Hispanic blacks. Younger participants (18–22 years) were more likely to acquire HSV-1 infections and less likely to develop recognized disease than older participants. Overall, 84% of recognized disease cases were genital. No differences were noted in the clinical manifestations of genital HSV-1 vs genital HSV-2 disease. The clinicians’ assessment that cases were caused by HSV was good when they assessed cases as clinically confirmed or unlikely (validated in 83% and 100% of cases, respectively).

Conclusions.  HSV-1 is now more common than HSV-2 as a cause of oral and genital mucosal infections in young women, but there are important age and race differences.

(See the Editorial Commentary by Whitley on pages 352–3.)

Herpes simplex virus (HSV) is a common cause of both genital and oral disease. HSV type 2 (HSV-2), a sexually transmitted pathogen, infects >500 million people worldwide and causes an estimated 23 million new infections each year [ 1 ]. HSV type 1 (HSV-1) is even more common, with an estimated seroprevalence of >90% in many nations [ 2 ]. HSV-1 is frequently acquired during early childhood, primarily through oral secretions [ 3 ]. However, the epidemiology of HSV-1 is changing, such that the frequency of sexual transmission of HSV-1 has increased in many countries, including the United States [ 4 , 5 ].

The control arm of an investigational HSV-2 vaccine study, the HERPEVAC Trial for Women [ 6 ], provided the opportunity to prospectively follow a large cohort of HSV-seronegative women in order to characterize the epidemiology, clinical manifestations, and antibody response to primary HSV infections. Thus, all infections identified in these women were primary infections in which the etiology (HSV-1 or HSV-2) could be confirmed by Western blot analysis and the identification of symptomatic vs unrecognized primary infections categorized with a high degree of certainty. This obviated limitations present in past studies where primary and recurrent infections might be misclassified, and where the ability to serologically distinguish HSV-1 from HSV-2, was suboptimal.

Study Population

A subset of participants enrolled in the HERPEVAC Trial for Women, a phase 3 herpes vaccine study [ 6 ] at 50 sites in the United States and Canada from 2003 to 2007, were included in this analysis. Women aged 18–30 years who were seronegative for HSV-1 and HSV-2, absent of significant health problems, not pregnant, and willing to use effective methods of birth control, were enrolled. The analysis presented here includes the 3438 women who only received the control hepatitis A vaccine (Havrix) in this trial, and had at least 1 follow-up visit. Race and ethnicity were self-described by participants and classified as non-Hispanic white, non-Hispanic black, or Hispanic (any race) for analysis. Women with missing data or not fitting into one of these categories were classified as “other.”

Study Design

Participants were followed for 20 months after study entry. They were educated regarding the signs and symptoms of genital and nongenital herpes disease and requested to attend clinic within 48 hours, or as soon as possible thereafter, if they noted possible signs or symptoms. Active surveillance for suspected HSV disease was conducted monthly by telephone call, e-mail, text message, or social media communication. Serum for evaluation of infection (seroconversion) was obtained prior to vaccination (month 0) and at months 2, 6, 7, 12, 16, and 20. At clinic visits for suspected genital or nongenital herpes disease, participants were examined, viral cultures were obtained, and treatment was initiated at the discretion of the local investigator. The protocol was approved by the institutional review boards/ethics committees at all sites, and participants gave written informed consent.

An HSV infection was defined as unrecognized if a woman seroconverted to HSV-1 or HSV-2 and did not present with any signs or symptoms of disease within the previous 6 months. HSV disease was defined by the presence of compatible signs and/or symptoms with confirmation by virus culture and/or seroconversion within 6 months after onset of symptoms. Cases were determined centrally by an independent blinded endpoint review committee.

Laboratory Methods

Serum samples were evaluated for antibodies to HSV-2 with HerpeSelect-2 (Focus Technologies, Cypress, CA) after each blood draw. Samples testing positive, using the manufacturer's criteria, were then tested for HSV-1 and HSV-2 antibody using Western blot (WB) at the University of Washington [ 7 ]. For each participant, the first and last serum samples were also tested by WB. Seroconversion was defined as a positive HSV-1 and/or HSV-2 WB in a participant with a previously negative result for the corresponding HSV type. If seroconversion was detected using the first and last sample, all samples were tested to determine the time of seroconversion.

Statistical Analysis

Categorical variables were compared by Fisher exact test, and continuous variables were compared by Student t test. Cox proportional hazards models were used to compare rates of HSV-1 and HSV-2 infection by age group and race/ethnicity.

The association between genital HSV disease and participants’ reported signs and symptoms was assessed by fitting separate univariate logistic regression models for each sign or symptom (lesion location [genital or perianal/buttocks], papules, vesicles, ulcers, crusts, fissures, pain, painful urination, redness, vaginal discharge, swelling, headache, malaise, muscle ache, fever). Then, any sign or symptom found to be significant ( P < .05) in the univariate models was considered for inclusion in a multivariate logistic regression model. Signs and symptoms were chosen for inclusion in the multivariate model using a forward selection algorithm; where at each step the variable that most reduced Akaike information criterion was selected. The variables selected by the model were used to define classification rules for genital HSV disease, and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of each rule compared with the participant's true HSV genital disease status was calculated. The logistic regression modeling analyses included 165 participants who presented with at least 1 suspected genital herpes episode and provided complete diary card data; 17 participants without completed diary cards were excluded.

Of the 3438 subjects included in the natural history analysis, 98 (3%) did not have any samples tested by WB, 2 (<1%) had only baseline WB results, and 3338 (97%) had first and last samples tested by WB. Of these 3438 participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. Of the 242 women who presented for evaluation of signs and/or symptoms that the participant felt were compatible with HSV infection, as they had been instructed, 54 (22%) had confirmed HSV disease (Figure 1 ). Irrespective of virus type, most (84%) recognized disease was genital. Of the 54 participants with symptomatic HSV, 33 had HSV-1 disease (5 oral, 24 genital, 4 both genital and oral), and 21 had HSV-2 disease (all genital). Two additional participants from this group who were not infected at the time of their clinical evaluation later developed unrecognized HSV-1 infections, while 6 developed unrecognized HSV-2 infections (Figure 1 ). An additional 92 participants who did not present with suspected disease became infected with HSV-1, while 29 who did not present with suspected disease became infected with HSV-2. Thus, most infections in this study (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease despite frequent reminders to return to the clinics with any sign or symptom compatible with HSV disease. The rate of infection for HSV-1 was 2.5 cases per 100 person-years (py) and for HSV-2, 1.1 cases per 100 py (Table 1 ). Among non-Hispanic black participants, 74% (20 of 27) of those who acquired HSV were found to have HSV-2 (rate of infection, 4.4 per 100 py). In comparison, HSV-2 accounted for 23% (31 of 135) of HSV infections in non-Hispanic white participants (rate of infection, 0.8 per 100 py; P < .0001 vs non-Hispanic black participants). In Hispanic participants with HSV infections, 40% (4 of 10) were HSV-2 (attack rate, 1.7 per 100 py), while 9% (1 of 11) of HSV infections in participants of other race/ethnicity were HSV-2. In contrast, the rate of infection for HSV-1 was 1.5 per 100 py in non-Hispanic blacks, and 2.6 per 100 py in both non-Hispanic whites and in Hispanics. Participants 18–22 years of age were significantly more likely than older participants to acquire HSV-1 infections and significantly more likely to develop asymptomatic or unrecognized disease. This trend was similar for HSV-2 infections, although the differences were not significant.

Rate and Frequency of Herpes Simplex Virus Infection in Healthy Young Women

Abbreviations: HSV, herpes simplex virus; py, person-years.

a P = .001 for comparison with 18–22-year-olds.

b P = .03 for comparison with 18–22-year-olds.

c P = .002 for comparison with 18–22-year-olds.

d P ≤ .0001 for comparison with non-Hispanic white participants.

Natural history of herpes simplex virus (HSV) infections in herpes simplex virus (HSV)–seronegative women aged 18–30 years. The analysis presented here includes the 3438 women who only received the control hepatitis A vaccine (Havrix) in the HERPEVAC trial, were not infected with HSV at baseline, and had at least 1 follow-up visit. Abbreviation: HSV, herpes simplex virus.

Genital HSV Disease

We compared the clinical manifestations of genital disease caused by HSV-1 (n = 28) to those caused by HSV-2 (n = 21) in the 49 women who developed genital symptoms and lesions (Table 2 ). Lesions were reported by 93% of participants with HSV-1 and 81% of participants with HSV-2 genital disease ( P = .38). Similarly, lesions were documented by the clinician in 71% of participants with either HSV-1 or HSV-2 genital disease. The most frequent lesion types reported by participants were similar for HSV-1 and HSV-2: ulcers (HSV-1, 75%; HSV-2, 52%), vesicles (HSV-1, 64%; HSV-2, 48%), and papules (HSV-1, 61%; HSV-2, 57%). Approximately 50% of women with genital HSV disease had systemic symptoms, most commonly malaise, regardless of the HSV type (Table 2 ). Fever was noted in 18% of those infected with HSV-1 and 33% of those infected with HSV-2 ( P = .32). Muscle aches were reported by 36% of participants with HSV-1 and 38% of participants with HSV-2 ( P = 1.0). Additionally, local symptoms of genital HSV-1 or HSV-2 disease were similar, with about 90% reporting pain, burning, or itching, and about 50% reporting a vaginal discharge.

Local Manifestations of Primary Symptomatic Genital and Oral Herpes Disease

Abbreviation: HSV, herpex simplex virus.

a P = .0003 for comparison between HSV-1 and HSV-2 for symptoms collected on subject diary card.

b A subject may have had >1 location of lesions recorded.

c “Other” locations specified by clinician for 3 subjects included (1) internal genital, (2) cervix and mons pubis, (3) cervicovaginal.

d Local and systemic symptoms were only recorded on the subjects’ diary cards.

Oral HSV Disease

All oral HSV disease (n = 9) was caused by HSV-1. Systemic symptoms were reported by 56% of the participants. Local symptoms included pain/burning/itching (100%), redness (44%), and swelling (22%).

Accuracy of Clinical Assessment for Genital HSV Disease

When clinicians assessed the participants presenting for possible genital herpes as clinically confirmed herpes, their assessments were validated by HSV culture and/or serological test results 83% of the time (Table 3 ). When their assessment was that genital herpes was possible, 30% were validated. No cases that the investigator felt were not genital herpes were confirmed as genital herpes by laboratory testing.

Accuracy of Clinician Assessment

Thirteen subjects with missing investigator assessment or clinical exam date were excluded.

Univariate logistic regression analysis of participants reporting signs and symptoms of genital herpes demonstrated significant associations between the diagnosis of genital HSV disease and the presence of vesicles, ulcers, pain, painful urination, redness, swelling, malaise, and muscle aches. These 8 variables were considered for inclusion in a multivariate logistic regression model. A forward selection algorithm resulted in a model with 4 predictors (in order of selection): ulcers, vesicles, painful urination, and pain, which were used to define 8 classification rules: classify with HSV disease if woman has (1) ulcers; (2) ulcers or vesicles; (3) ulcers or vesicles or painful urination; (4) ulcers or vesicles or painful urination or pain; (5) at least 1 of the 4 signs/symptoms; (6) at least 2 of the 4 signs/symptoms; (7) at least 3 of the 4 signs/symptoms; (8) all 4 of the 4 signs/symptoms. The predictive ability of each classification rule is summarized in Table 4 . Specificity, positive predictive value, and accuracy for the diagnosis of genital herpes were all highest when ulcers were present.

Signs and Symptoms Predictive of Laboratory-Confirmed Genital Herpes Disease

Abbreviations: NPV, negative predictive value; PPV, positive predictive value.

HSV Antibody Response

When the 28 participants with HSV-1 genital disease (23 culture confirmed) and the 21 participants with HSV-2 genital disease (16 culture confirmed) were evaluated by WB, all but 3 women with HSV-1 infection seroconverted after developing genital herpes. Of these, 1 did not return for follow-up and 2 had not developed antibodies at 8 and 13 months, after culture-confirmed HSV-1 genital infection. Of the 5 participants who developed oral disease without genital disease, 3 had disease confirmed by culture and all seroconverted to HSV-1. Of particular interest, 6 participants (1 genital HSV-1, 4 genital HSV-2, and 1 oral HSV-1) seroconverted prior to developing recognized symptoms of herpes disease (data not shown). Their first recognized symptoms occurred from 176 to 319 days after they were first infected.

During the study, 32 participants developed an indeterminate WB (14 for HSV-1, 13 for HSV-2, and 5 for both HSV-1 and HSV-2). A designation of indeterminate is assigned when the test does not meet the definition for a positive but has some evidence indicating the presence of HSV antibody. Of these participants, 25 later developed a positive WB response (average, 184 days after the first indeterminate result [range, 30–434 days]). Seven participants with an indeterminate WB did not develop a positive WB during study follow-up, 3 did not have any further samples tested after the indeterminate result was obtained, and 4 remained indeterminate throughout study follow-up (range, 23–421 days).

This is the largest prospective study of HSV acquisition in HSV-seronegative women ever performed. It confirms and extends several observations of primary HSV infections. The rate of infection for HSV-1 (2.5 per 100 py) was more than twice that for HSV-2 (1.1 per 100 py) in young women. This is quite different from the rate of 1.0 case per 100 py for HSV-1 and 6.8 per 100 py for HSV-2 in women in another prospective study evaluating participants in an HSV vaccine study conducted from 1993 to 1995 [ 8 ]. However, that study was enriched for women with a high risk of exposure to HSV-2 (HSV-discordant couples and sexually transmitted infection [STI] clinic attendees). Further, women with and without previous HSV-1 infections were included and only women with ≥4 sexual partners in the prior year prior were enrolled. In a previous prospective study of women recruited from STI clinics from 1992 to 1995, the HSV-2 infection rate was also considerably higher, 20.5 per 100 py [ 9 ], whereas in a study of young adolescents conducted in early 2000, the rate was 4.4 and 3.2 per 100 py for HSV-2 and HSV-1, respectively [ 10 ]. The higher HSV-2 rate of infection in this study may reflect the predominance of non-Hispanic black participants in this trial.

In the young adult women studied here, clinically recognized HSV-1 infections presented 3 times more commonly as genital than oral disease. Thus, while HSV-1 acquired in childhood occurs as oral infections, in young adults the majority may be acquired as genital infection. This finding must be tempered by the fact that while participants were instructed to report any oral or genital HSV disease, the emphasis for the study was genital disease. Furthermore, the majority (74%) of HSV-1 infections did not produce recognizable disease and thus the site of infection is unknown.

Infection rates for HSV-1 and HSV-2 differed markedly between racial groups. HSV-2 infections accounted for 74% of HSV infections in non-Hispanic blacks (the rate of infection was 2.6 times higher than in Hispanics and 5.5 times higher than in non-Hispanic whites). In contrast, the rate of HSV-1 infection was 1.7 times higher in non-Hispanic whites than in non-Hispanic blacks, and it was identical in Hispanics and non-Hispanic whites. In a previous study, [ 8 ] the HSV-2 acquisition rate was similarly nearly double for non-white women (11.2 per 100 py) compared with white women (5.8 per 100 py). This suggests that there are differences in the prevalence of HSV types in the source partners of the study participants as documented in large sero-surveys [ 11 , 12 ]. Alternatively, the variability in type-specific HSV rates of infection may be in part attributable to race-based differences in sexual practices or other behaviors.

The rates of infection and the development of recognized HSV disease also differed by age. Younger participants were more likely to acquire HSV-1 infections compared with older participants and less likely to develop recognized disease. Differences in HSV type may reflect differences in sexual practices by age, with younger participants more likely to engage in oral than vaginal sex [ 13 ]. Differences in the development of recognized signs and symptoms of HSV disease may reflect a maturing ability to recognize changes in sexual health or a real difference in the development of the signs and symptoms.

As noted in previous studies, [ 8 , 13–15 ] most primary infections with HSV do not produce recognized signs or symptoms. In the study reported here, 74% of HSV-1 and 63% of HSV-2 infections did not produce participant-recognized disease (or at least did not bring them to the study clinics). Thus, despite educational efforts, most participants were unaware of their infections and would therefore not undertake efforts to prevent transmission .

The manifestations of HSV-1 were compared to HSV-2 and, as previously noted [ 16 ], the infections produced indistinguishable disease.

As reported previously [ 17 , 18 ], the first clinical presentation of genital HSV can occur long after the primary infection. In the study reported here, 6 participants were infected and developed HSV antibody responses 176–319 days before developing the first oral (n = 1) or genital (n = 5) symptoms of HSV. In a previous study, 8% of participants developed their first clinical episode of genital HSV-2 after developing HSV-2 antibodies [ 8 ].

Western blots are often obtained to determine if a patient has been infected with HSV. Physicians may receive a report of indeterminate results either because the infection is recent or for other unexplained reasons. Of the 32 WBs reported as indeterminate, 25, became positive and 7 remained indeterminate Thus, the majority were infected with HSV.

Finally, it is difficult to distinguish genital HSV infections from other diseases that cause similar signs and symptoms by clinical exam, and thus culture (or polymerase chain reaction) and/or serology is recommended as an aid to the clinician. [ 14 , 15 , 19 ]. We developed a multivariate logistic regression model using a forward selection algorithm of 8 signs or symptoms that were associated with genital HSV by univariate analysis. This resulted in a model with 4 predictors, which were used to define rules for identifying genital HSV infections. Use of only 1 of these signs/symptoms to identify genital HSV infections had the highest sensitivity (98%), whereas the rule that required all 4 to be present had the best specificity (100%) and accuracy (83%).

There are several factors that might influence our findings and their generalizability. The population evaluated was a diverse group of women, 18–30 years of age. However, they represent a self-selected sample that volunteered to be in a study of a herpes vaccine and therefore could conceivable be more at risk for acquiring an HSV infection. Thus, it is possible our estimates of rates of infection could be somewhat higher than the general population of young women.

In summary, this is the largest prospective study of documented primary HSV infections in which the identification of symptomatic vs unrecognized primary infections could be categorized with a high degree of certainty. We found that, overall, the rate of infection for HSV-1 was higher than for HSV-2, but that there were significant age and racial differences. Infections by either type were most often not recognized by the participants, despite the efforts to educate them regarding possible signs and symptoms of HSV disease. These findings have important implications for the design and implementation of treatment and prevention strategies.

Author contributions.  D. I. B. and R. B. B. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Financial support.  This work was supported by the National Institute of Allergy and Infectious Diseases (N01-AI-45250) and GlaxoSmithKline.

Potential conflicts of interest.  D. I. B. has received lecture fees and royalties from GlaxoSmithKline. R. B. B. has served as a board member of Vivaldi Biosciences, has received consulting fees from GlaxoSmithKline, has received consulting fees and lecture fees from MedImmune, and has received lecture fees from Merck. G. D. is an employee of and has received stock and travel, accommodations, and meeting expenses from GlaxoSmithKline and royalties from Pfizer. T. C. H. is an employee of GlaxoSmithKline and has received travel, accommodations, meeting expenses, and stock equity from GlaxoSmithKline. M. J. L. has received consulting fees and grants from GlaxoSmithKline. A. W. has received consulting fees from AiCuris, Agenus, and ViruLite, and grant support from Genocea, Gilead, GlaxoSmithKline, and the Washington Vaccine Alliance. E. W. H. has received consulting fees from Cempra, grants from Becton Dickinson and GlaxoSmithKline, honoraria from Becton Dickinson, and royalties from McGraw-Hill. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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• simplexvirus
• epidemiology
• antibody formation
• human herpesvirus 1
• human herpesvirus 2
• hispanics or latinos
• genital system
• herpes simplex infection
• racial differences

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Reducing Transmission of Herpes Simplex Virus Type 1 In Clinical Practice

Understanding the clinical presentations, distinguishing features, and treatment protocols of herpes simplex virus type 1 will help reduce the risk of transmission in dental settings.

EDUCATIONAL OBJECTIVES

After reading this course, the participant should be able to:

• Define herpes simplex virus type 1 and known risk factors for this infection.
• Discuss the clinical presentation, diagnosis, and treatment of this virus.
• Describe the role of oral health professionals in preventing the spread of herpetic infections among patients and dental team members.

There are more than 100 known herpes viruses, and herpes simplex virus type 1 (HSV-1) is among the eight known to infect humans. 1 Herpes is a Greek word meaning to “creep or crawl” and its use is in reference to the spreading nature of the symptomatic lesions. The HSV-1 strain causes infections in the mucocutaneous areas of the orofacial region, such as the lips, known as herpes labialis (but commonly referred to as cold sores or fever blisters). 2 Intraoral herpetic lesions may be confused with other ulcerative conditions. Further, uncertainty may exist concerning when to treat patients who present with viral infections such as HSV-1. Therefore, this paper will describe the pathogenesis, diagnosis, clinical presentation and treatment of HSV-1, as oral health professionals will most likely encounter patients seeking treatment who present with this condition.

Infection with HSV-1 is common and most often acquired during childhood. 3–5 Among U.S. adults, almost 90% are exposed to HSV-1 by the time they are 50. 6 Between 2005 and 2010, the percentage of HSV-1 seroprevalence in the U.S. was 53.9, which is more than three times higher than the seroprevalence of HSV-2. 7 By gender, HSV-1 prevalence is higher among women (50.9%) than men (45.2%). 8

An inverse relationship exists between seroprevalence of HSV-1 infections and an individual’s socioeconomic background. 9 Lower socioeconomic populations tend to have HSV-1 infections occurring early in life, before the age of 5. In addition, HSV-1 infections are generally higher among immunocompromised individuals due to reduced systemic resistance. 10

While HSV-1 infections are often thought of as “above the belt,” genital herpes may also be caused by HSV-1. 11,12 The known risk factor for initial infection of HSV-1 is generally contact with saliva and oral lesion secretions from an infected individual. The primary transmission mode is asymptomatic shedding of the virus, as opposed to lesion shedding. Risk factors for recurrent HSV-1 include trauma, such as diffuse axonal injury, stress (physical or emotional), reduced cellular immunity, fever, sunlight and ultraviolet radiation exposure. 4,5,11,13

Pathogenicity

Taxonomically, HSV-1 belongs to the alpha (α) herpes virus subfamily, which includes other neurotropic viruses, such as HSV-2 or genital herpes, and the varicella-zoster virus, which causes chickenpox and shingles (Figure 1). 1,14

The HSV-1 strain uses the human host for survival and replication. Its typical cellular-level life cycle involves adsorption, penetration, uncoating, replication, assembly and release. Worth noting is that HSV-1 stages can vary among infected cells; meaning, the virus can be in latency in some cells and in the replication stage in other infected cells. 15

Characterized by several unique properties, including neurovirulence, latency and reactivation, HSV-1 has the capacity to invade and replicate in the nervous system (neurovirulence). 16,17 In latency, the replicated virions travel in an anterograde fashion in nerve cell ganglion, and remain in a nonreplicative state until they are reactivated. The trigeminal ganglia are most commonly involved in HSV-1. Reactivation and replication of latent HSV result in overt or covert recurrent infection and shedding of the virus. 15 Once an individual is infected, HSV-1 remains a lifelong condition in approximately one-third of affected patients. 18

Clinical Presentation  

Clinically, HSV-1 can cause either primary or reactivation infections. The course of this oral infection depends on age, immune status of the host, and anatomic site of involvement. 11,16 Primary HSV-1 is manifested in children usually between the ages of 6 months and 5 years as acute (or primary) herpetic gingivostomatitis. Adolescents and adults may also develop acute gingivostomatitis, but it can be less severe and is more often associated with posterior pharyngitis. Infections (primary and recurrent) occurring in immunocompromised individuals tend to be more severe, prolonged and widespread, and are more likely to recur. 11,16,19

Features of primary herpetic gingivostomatitis include, but are not limited to, fever, anorexia, malaise, lymphadenopathy, headache, nausea, vomiting, gingivitis (with markedly swollen, erythematous and friable tissue), and vesicular lesions. Vesicles can occur on the oral mucosa, palate, tongue and lips, which rupture and coalesce into painful ulcers. 10,11,16,20,21 Oral lesions tend to occur within one to two days of systemic symptoms. Acute herpetic gingivostomatitis lasts approximately five to seven days, and symptoms resolve within two weeks. However, viral shedding from the saliva may continue for three weeks or longer. 11,16

In adults, primary HSV-1 causes pharyngitis and tonsillitis more often than herpetic gingivostomatitis, and is referred to as acute herpetic pharyngotonsillitis. This condition is accompanied by fever, headache, malaise, and a sore throat with pharyngeal erythema or exudate. Herpetic oral and labial lesions occur in less than 10% of patients who experience acute herpetic pharyngotonsillitis. 16,22

Reactivation of HSV-1 usually manifests as recurrent herpes labialis. 23 Prodromal symptoms of tingling, pain, itching and burning are common at the affected site, followed by the development of vesicles that become pustular, ulcerate and form a crust. Reactivated herpes infection can also occur intraorally on the hard palate and gingiva, beginning as a cluster of vesicles that coalesce into ulcerations. 21,24,25 Recurrence is estimated to affect 33% to 40% of these patients. 19,26 The number of recurrences can range from once per year to once per month. 25 Compared to the initial presentation, the duration of recurrent symptoms tends to be shorter and the symptoms are often less severe. Further, recurrences can be subclinical or clinically unrecognizable; therefore, transmission to susceptible individuals can occur in the absence of overt lesions. 16,21,26

Differential Diagnosis

The diagnosis of oral HSV-1 is typically made by the appearance and location of lesions and patient history. 21,25,27 However, not all lesions are readily apparent. The differential diagnosis for primary symptoms includes impetigo, streptococcal pharyngitis, erythema multiforme, acute necrotizing ulcerative gingivitis, Behcet syndrome, herpangina, pemphigus vulgaris, candidiasis, hand-foot-and-mouth disease, herpes zoster and syphilis. 10,11,16,19,21,24,25 The differential diagnosis for intraoral recurrent herpes is aphthous ulcers. Herpetic lesions tend to have prodromal symptoms and multiple lesions; additionally, vesicles precede ulcers, and lesion locations include the palate and gingiva. Aphthous stomatitis, in contrast, tends to be single versus coalescing, larger, and almost exclusively on nonkeratinized mucosa, such as the buccal mucosa, alveolar mucosa or floor of the mouth. 24,25

Adjunctive diagnostic testing is available to confirm HSV infection and is required to diagnose atypical presentations. Examples of laboratory studies include tissue culture, Tzank smear, polymerase chain reaction, direct fluorescent antigen, and antibody testing. 16,20,25 Detection of HSV DNA through polymerase chain reaction techniques is the preferred testing modality and can be used to detect asymptomatic viral shedding. 16

Treatment and Prognosis

Most HSV-1 infections are self-limiting and resolve within seven to 14 days. 24 Treatment consists of over-the-counter products and prescription antiviral medications (Table 1), and these therapies are most beneficial if provided during the prodromal stage within 24 to 48 hours of lesion onset. 20 These medications shorten the duration and severity of the infection, but do not eliminate the virus from the body. Supportive therapy, including fluids, rest and analgesics, serves as an important adjunct for individuals experiencing primary HSV-1.

In addition, patients should be counseled to use a lip balm with sunscreen of at least SPF 15 and to avoid known triggers for outbreaks. When lesions are present and patients are applying creams or ointments, instruct them to use a cotton applicator or rubber glove to prevent autoinoculation or transmission of the virus to other areas or individuals. 24,25

Oral Health Considerations

Most dental histories include a section that asks about a history of sores or ulcers in the mouth. If a patient answers positively to this question or presents with lesions that appear to be herpetic in nature, oral health professionals should document:  

• The location, frequency and duration of lesions  
• Symptoms associated with the lesions  
• Known triggers  
• Disease course  
• Treatment rendered  
• Complications associated with the lesions and/or treatment  
• Overall medical history that might correlate with the oral condition  

If atypical lesions are found or recurrent intraoral herpes is present in an immunocompromised patient, further diagnostic investigation is warranted using laboratory analysis, and the patient should be referred to an appropriate dental or medical specialist with expertise in this area. 27

In some cases, individuals who are unfamiliar with the contagious nature of HSV-1 present with a primary or recurrent lesion and expect oral healthcare services. This presents an opportunity to provide education regarding the nature of this viral condition. Patients should understand they are contagious and pose a risk to themselves and the dental team. Advise patients their appointment can be rescheduled once the lesion is completely healed. 27,28 During the time of an active lesion, individuals should limit personal contact, as there is shedding of the virus in their saliva. 27 Meticulous hygiene is important, and individuals must use caution, as they can spread the virus through autoinoculation. Oral health professionals should advise patients not to share utensils and food, limit touching the lesions, and to wash their hands frequently with soap and water to prevent the risk of cross-infection.

Elective dental and dental hygiene treatment should be deferred for patients who present with active herpetic lesions. 16,24,27,28 Therapy may be uncomfortable and the patient is at risk for the spread of infection or reinfection. Treatment should be postponed until the lesions are completely healed. Oral health professionals are at risk of infection through aerosolization of the virus during dental procedures. 24,27 Examples of occupational herpetic infections among oral health professionals include herpetic whitlow and herpes keratitis. 28  

For patients with an active HSV-1 infection who present for urgent or emergency dental care, Browning and McCarthy 28 recommend:

• Using extreme caution and extra personal protective equipment that fully covers the body, eyes and face  
• Wearing a National Institute for Occupational Safety and Health N95-rated or higher mask to protect against aerosols
• Avoiding instruments and hands touching the lesion (to the extent possible)
• Changing gloves frequently if the procedure is lengthy
• Washing hands with soap and water between glove changes
• Providing eye protection for the patient
• Recommending the patient wash his or her hands and face after treatment
• Educating the patient about the nature of the herpes virus  

If a member of the dental team has an orofacial herpes infection, limit treatment to those patients who are immunocompetent; cover the lesion with a suitable mask and use a facial shield; change gloves frequently if the hand is brought anywhere near the team member’s mouth; and inform the patient of the clinician’s condition and seek consent for treatment. 28

Herpetic whitlow is highly infectious; therefore, providers with this condition should not work until the lesions are healed. In the case of herpes keratitis, viral shedding is high. Protect patients by washing hands with soap and water between glove changes and following the protocol described above.

Some oral health professionals and patients may consider these recommendations disruptive to the office schedule, all for a simple “cold sore.” However, negative effects in proceeding with elective treatment must be considered. Browning and McCarthy 28 note the patient-provider relationship could be compromised if the patient later develops active herpetic lesions or worsening of symptoms — all of which could have been avoided by postponing treatment during periods of active infection. Further, employers have an obligation to follow guidelines and take precautions to protect employees. 29 The risk of infection of a dental team member is likely greater than the temporary inconvenience of delaying elective treatment for a patient with an active infection from a herpetic lesion.

Lastly, laser treatment has been used to manage recurrent herpes labialis. A review of the literature examining the efficacy of lasers revealed that laser phototherapy appears to decrease pain and the interval of recurrences. High-power lasers may also be beneficial in draining vesicles. Other advantages include the absence of drug interactions and side effects. However, none of the laser therapies completely eliminate the virus or recurrence. Most of the literature involves case reports; thus, additional studies are needed that address efficacy of laser therapy in terms of duration of viral shedding, viral inactivation, and interval of recurrence. 30 Oral health professionals should recognize that while the lip lesion may have been lased, the nature of the virus is such that active virus may be present in the saliva, leaving the patient vulnerable to intraoral infection if elective treatment is rendered.  

As an ubiquitous viral condition with oral implications, primary and secondary HSV-1 infections may occur — although most lesions are self-limiting and will resolve within one to two weeks. Oral health professionals should be cognizant of the clinical presentations, distinguishing features, and treatment protocols to prevent the spread of infection among patients and providers.  

• Whitley RJ. Herpesviruses. In: Baron S, ed. Medical Microbiology . Galveston, Texas: University of Texas Medical Branch at Galveston; 1996.
• Baltimore D, Lodish H. Molecular Cell Biology . 7th ed. New York: WH Freeman and Co; 2012:248.
• U.S. Centers for Disease Control and Prevention. Sexually Transmitted Disease Surveillance 2017. Available at: https:/​​/​​www.cdc.gov/​​std/​​stats17/​​2017-STD-Surveillance-Report_​​CDC-clearance-9.10.18.pdf. Accessed September 9, 2021.
• Carroll KC, Butel JS, Morse SA. Jawetz Melnick & Adelbergs Medical Microbiology . 27th ed. New York: McGraw-Hill Education; 2015:864.
• Mertz GJ. Asymptomatic shedding of herpes simplex virus 1 and 2: implications for prevention of transmission. J Infect Dis . 2008;198:1098–1100.  
• Johns Hopkins Medicine. Oral Herpes. Available at: https:/​​/​​www.hopkinsmedicine.org/​​health/​​conditions-and-diseases/​​herpes-hsv1-and-hsv2/​​oral-herpes. Accessed September 9, 2021.
• Bradley H, Markowitz LE, Gibson T, McQuillan GM. Seroprevalence of herpes simplex virus types 1 and 2 — United States, 1999–2010. J Infect Dis . 2014;209:325–333.  
• U.S. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey. Available at: https:/​​/​​www.cdc.gov/​​nchs/​​nhanes/​​index.htm. Accessed September 9, 2021.
• Arduino PG, Porter SR. Herpes simplex virus type 1 infection: overview on relevant clinico-pathological features. J Oral Pathol Med . 2008;37:107–121.  
• Roizman B, Knipe DM, Whitley RJ. Herpes simplex viruses. In: Knipe DM, Howley P, eds. Fields Virology . Philadelphia: Lippincott Williams & Wilkins; 2013:1823–1897.
• Brown DN, Kollipara R, Tyring S. Oral signs of viral disease. In: Fazel N, ed. Oral Signs of Systemic Disease . Cham, Switzerland: Springer Nature; 2019:145–167.
• Cunningham A, Griffiths P, Leone P, et al. Current management and recommendations for access to antiviral therapy of herpes labialis. J Clin Virol . 2012;53:6–11.  
• Kolokotronis A, Doumas S. Herpes simplex virus infection, with particular reference to the progression and complications of primary herpetic gingivostomatitis. Clin Microbiol Infect . 2006;12:202–211.
• Ananthanarayan R, Paniker CK. Ananthanarayan and Paniker’s Textbook of Microbiology . 7th ed. Hyderabad, India: Orient Longman; 2006.
• Pellett PE, Roizman B. Herpesviridae. In: Knipe DM, Howley P, eds. Fields Virology . Philadelphia: Lippincott Williams & Wilkins; 2013:802–822.
• Medscape. Herpes Simplex. Available at: https:/​​/​​emedicine.medscape.com/​​article/​​218580-overview. Accessed September 9, 2021.
• Schiffer JT, Corey L. Herpes simplex virus. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases . Philadelphia: Elsevier/​​Saunders; 2015:1713–1730.
• Li Z, Fang C, Su Y, et al. Visualizing the replicating HSV-1 virus using STED super-resolution microscopy. Virol J . 2016;13:1–13.  
• Amir J. Primary herpes simplex gingivostomatitis and recurrent orolabial infection. In: Studahl M, Cinque C, Bergström T, eds. Herpes Simplex Viruses . Boca Raton, Florida: CRC Press; 2006.
• Stoopler ET, Sollecito TP. Oral mucosal diseases: evaluation and management. Med Clin North Am . 2014;198:1323–1352.  
• Usatine RP, Tinitigan R. Nongenital herpes simplex virus. Am Fam Physician . 2010;82:1075–1082.
• McMillan JA, Weiner LB, Higgins AM, Lamparella VJ. Pharyngitis associated with herpes simplex virus in college students. Pediatr Infect Dis J . 1993;12:280–284.  
• Ramchandani M, Kong M, Tronstein E, et al. Herpes simplex virus type 1 shedding in tears and nasal and oral mucosa of healthy adults. Sex Transm Dis . 2016;43:756–760.  
• DeLong L, Burkhart NW. General and Oral Pathology for the Dental Hygienist . 3rd ed. Philadelphia: Wolters Kluwer; 2019.
• Regezi JA, Sciubba J, Jordan RC. Oral Pathology: Clinical Pathologic Correlations . 7th ed. St. Louis: Elsevier; 2017.
• Opstelten W, Neven AK, Eekhof J. Treatment and prevention of herpes labialis. Can Fam Physician . 2008;54:1683–1687.
• Stoopler ET, Kuperstein AS, Sollecito TP. How do I manage a patient with recurrent herpes simplex? J Can Dent Assoc . 2012;78:154.
• Browning WD, McCarthy JP. A case series: herpes simplex virus as an occupational hazard. J Esthet Restor Dent . 2012;24:61–66.  
• U.S. Department of Labor. Occupational Safety and Health Standards. United States Code of Federal Regulations; CFR 1910.1030 Bloodborne Pathogens. Available at: https:/​​/​​www.osha.gov/​​laws-regs/​​regulations/​​standardnumber/​​1910/​​1910.1030. Accessed September 9, 2021.
• de Paula Eduardo C, Aranha AC, Simões A, et al. Laser treatment of recurrent herpes labialis: a literature review. Lasers Med Sci . 2014;29:1517–1529.  

From  Decisions in Dentistry. October 2021;7(10):40-43.

Selvi M. Das Purkayastha, BDS, RDH, is a licensed dental hygienist in Illinois. She has a background in general dentistry and endodontics, and is currently a graduate dental hygiene student at Idaho State University in Pocatello. She can be reached at [email protected]

JoAnn R. Gurenlian, RDH, MS, PhD, AFAAOM, is the director of education and research at the American Dental Hygienists’ Association and professor emerita in the Department of Dental Hygiene at ISU.

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• HIV Clinical Guidelines: Pediatric Opportunistic Infections

Herpes Simplex Virus

Guidelines for the prevention and treatment of opportunistic infections in children with and exposed to hiv, search guidelines.

• Archived Guidelines (1)
• Guidance for COVID-19 and People with HIV (2)
• Guidelines for Caring for Persons with HIV in Disaster Areas (4)
• HIV Clinical Guidelines: Adult and Adolescent ARV (19)
• HIV Clinical Guidelines: Adult and Adolescent Opportunistic Infections (34)
• HIV Clinical Guidelines: Pediatric ARV (19)
• HIV Clinical Guidelines: Pediatric Opportunistic Infections (28)
• Perinatal HIV Clinical Guidelines (18)

Epidemiology

Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) can cause disease at any age. It is generally regarded that HSV-1 is transmitted primarily through contact with infected oral secretions and that HSV-2 is acquired primarily through contact with infected genital secretions. However, among some populations of older adolescents and young adults, HSV-1 is the cause of a large proportion of first episodes of genital HSV infection. 1-4 In the United States, HSV-1 seroprevalence reaches 30% by adolescence. 5-7 Seroprevalence is higher among children who live below the poverty level and in non-Hispanic black children and children born in Mexico or of Mexican heritage. 5,6 The seroprevalence of HSV-1 approaches 60% in older adults. HSV-2 seroprevalence before reported onset of sexual activity is low (approximately 2%); rises to 20% to 26% in adults 30 to 49 years, and is higher in non-Hispanic blacks, individuals with multiple sex partners and early age of onset of sexual activity, females, and in those living below the poverty level. 6,7 Among young adolescent girls, a longer history of sexual activity and another sexually transmitted disease in the past 6 months was associated with HSV-2 seropositivity. 8 These epidemiologic data indicate that children are at significant risk for primary infection or reactivation with HSV 1 and/or HSV-2 throughout childhood and adolescence. The age-specific seroprevalence of both HSV types is higher in many developing countries. 9-11

Young children generally acquire HSV-1 from the oral secretions of caretakers or playmates. Rarely is this the result of contact with active herpetic lesions; infection most often results from exposure to HSV shed asymptomatically in the saliva of the contact. Salivary shedding of HSV detected by polymerase chain reaction (PCR) in adults who are HSV-1-seropositive is frequent (9% to 30% of days). 12-14 Older individuals who avoided infection during childhood or adolescence also acquire HSV-1 (oral or genital) from exposure to infected saliva. HSV-2 is more likely to be acquired during adulthood or adolescence than in childhood as it is typically sexually transmitted. Genital shedding of HSV-2 by women who do not have HIV, as detected by PCR, is frequent (19% of days). 12 Either HSV type can be transmitted by oral-oral, oral-genital, and genital-genital contact. In general, shedding of oral HSV persists longer in young children. Oral and genital HSV shedding is more common in close proximity to the first episode of infection and in patients with HIV (30% of days in individuals who are HSV seropositive and not on antiretroviral therapy [ART]). 15,16

HSV infection can be acquired as a neonatal infection, primarily through exposure to HSV-infected maternal fluids during vaginal delivery; less commonly, infection may occur in utero . 17,18 Newborns are infected infrequently from oral secretions of an adult caretaker. The risk of transmitting HSV during delivery is approximately 1% in pregnant women with remote primary HSV infection, whereas the risk is much higher for infants born to women with recent HSV infection (range: 30% to 50%). 18 Maternal HSV antibody status before delivery appears to reduce the probability of transmission to infants and the severity of neonatal infection. 19,20 Genital shedding of HSV at delivery and presence of a fetal scalp monitor electrode increase the risk of transmission, as does prolonged rupture of membranes (>6 hours), probably because of ascending HSV infection from the cervix. Importantly, mothers of neonates with active HSV disease often do not have a clinical history of either past genital HSV infection or incident genital lesions, as maternal infection is frequently asymptomatic. 21,22

HSV co-infection in pregnant women with HIV is not uncommon because both viral infections share risk factors (race, socioeconomic status, and number of sexual partners). Genital HSV-2 was detected by PCR in 23% to 31% of HSV-seropositive women with HIV at the time of delivery, compared with 9% to 12% of HSV-seropositive pregnant women without HIV. 16,23 Shedding is greatest when the CD4 T lymphocyte (CD4) count is low and/or the patient is not receiving ART. 15,24 However, there is no evidence that in utero HSV infection of the fetus occurs more frequently in pregnant women with HIV/HSV-2 co-infection, or that infants born to these women are at increased risk of perinatal (intrapartum) HSV infection. In the general population, the neonatal HSV infection rate is 1 case per 2,000 to 10,000 deliveries, indicating that neonatal HSV will be observed rarely at clinics caring for co-infected pregnant women. 17,25 Numerous studies have shown that co-infection with genital HSV-2 in adults is associated with higher titers of HIV RNA in plasma and genital secretions; HSV-2-seropositivity increases the risk of HIV transmission to sexual partners, even in the absence of genital ulcer disease. 26,27 Three studies suggest that maternal HSV-2 co-infection increases the risk of intrapartum HIV transmission. 28-30

Clinical Manifestations

In most immunologically competent children outside of the neonatal period, HSV infection causes minimal signs and symptoms and is often unrecognized as a distinct illness. Up to one third of all immunocompetent children may develop a characteristic orolabial syndrome (primary gingivostomatitis), usually from HSV-1 infection, which leads to fever, irritability, tender submandibular lymphadenopathy, and superficial, painful ulcers on the gingival and oral mucosa and perioral skin. 31,32 HSV viremia occurs in approximately one-third of patients with primary herpetic gingivostomatitis. 33 In addition, HSV is a common cause of severe posterior pharyngitis in older children and adolescents. 34,35 Children with advanced HIV infection may have primary infection with multiple lesions that are atypical in appearance and delayed in healing. 36 Very rarely, disseminated HSV with visceral involvement (including liver, adrenals, lung, and brain) and generalized skin lesions occurs in individuals with HIV. 37 A small number of recurrent perioral or perinasal vesicles (“cold sores” or “fever blisters”) that heal quickly can occur intermittently in both healthy children and children with HIV throughout their lives, but those with AIDS are at risk of frequent recurrences, which can be associated with severe ulcerative disease and symptoms similar to primary HSV infection. 36,38 Children with HIV also may have prolonged shedding of HSV after both primary and reactivation infection. HSV esophagitis can occur in severely immunocompromised children. A study in adults found that patients with HIV who have HSV esophagitis often lack evidence of oral HSV infection. 39 Prolonged cutaneous HSV infection and organ involvement are AIDS-indicator conditions. However, these illnesses are uncommon in children with HIV in the era of ART, with a documented incidence rate of systemic HSV of only 0.30 per 100 child-years. 40,41

Genital infection is the most common manifestation of HSV-2 infection in sexually active adolescents. Most primary infections are asymptomatic or subclinical in adolescents who are not HIV infected. Symptomatic disease is characterized by painful, ulcerative lesions on the perineum, penis, labia, and vaginal/urethral mucosae. Mucosal disease often is accompanied by dysuria and/or vaginal or urethral discharge. Inguinal lymphadenopathy is common with perineal disease during primary infection. 42 Frequent recurrences and delayed healing are more likely in severely immunosuppressed patients. Severe HSV proctitis and perianal infections occur in, but are not limited to, patients who practice receptive anal intercourse. 43,44

HSV keratitis and herpetic whitlow in patients with HIV are similar in presentation to these diseases in individuals without HIV, but may be more severe. Acute retinal necrosis and progressive outer retinal necrosis are rare sight-threatening complications that occur more frequently in immunocompromised individuals. 45,46 HSV encephalitis occurs in patients with HIV, but is not more frequent or more severe than in individuals without HIV and has similar signs and symptoms. 47,48

Neonatal HSV infection in infants born to mothers with HIV and HSV is similar in presentation to that seen in infants of mothers with HSV alone. Neonatal HSV can appear as disseminated multiorgan disease, localized disease of the central nervous system (CNS), or disease localized to the skin, eyes, and mouth. 49 Vesicular rash occurs in only approximately 60% of infants with CNS or disseminated disease. 17,49,50

The clinical diagnosis of HSV infection is based on the typical location and appearance of vesicles and ulcers. The virus is readily isolated in tissue culture within 1 to 3 days, especially when samples are from first episode infections or are obtained early after the appearance of recurrent lesions (especially when vesicles are present). Speed and sensitivity of diagnosis are maximized with the shell vial method, which combines centrifugation onto coverslips and staining with fluorescein-conjugated monoclonal antibodies after 24 hours to detect synthesis of early-appearing HSV proteins. Detection of HSV DNA by PCR is very sensitive and specific and is the gold-standard method for diagnosis of HSV infection. 51,52 DNA PCR may be especially useful when assessing skin lesions that are recurrent or are being evaluated long after their appearance. In these cases, the HSV DNA remains in the healing lesions and scabs, even though HSV can no longer be cultured. PCR of mucosal and cutaneous sites in neonatal HSV disease has not been evaluated systematically, and culture of those sites in this population remains the standard of care until such comparative studies are completed. Direct immunofluorescence for HSV antigen can be performed on cells scraped from skin, conjunctiva, or mucosal lesions. 53 The sensitivity of this method may be less than 75%, often because it is difficult to obtain evaluable specimens, but the results are usually available the same day.

The preferred diagnostic method for evaluation of children with suspected HSV meningoencephalitis is detection of HSV DNA in the cerebrospinal fluid (CSF), because cultures of CSF are usually negative. Sensitivity of HSV PCR is generally considered to be ≥95% for CSF samples, especially if the samples are obtained more than 3 days after onset of herpes encephalitis. 48,54 In one study of participants with brain biopsy-proven HSV encephalitis, the sensitivity of HSV PCR was 98%. 55 In a report of 15 patients being treated for proven HSV encephalitis, the CSF HSV PCR remained positive for a mean of 10 days after neurologic symptom onset. 56 In neonatal CNS HSV disease, CSF PCR has been reported to have a sensitivity of 75% to 100% and a specificity of 71% to 100%. 48,57 HSV PCR of blood may be used adjunctively in the diagnosis of HSV infection in neonates and other at-risk populations, but its sensitivity remains to be fully defined. 20,58 Definitive diagnosis of HSV esophagitis requires endoscopy with biopsy. Histologic evidence of HSV includes multinucleated giant cells with intranuclear viral inclusions, but diagnosis is established by staining the biopsy with HSV-specific monoclonal antibodies and/or culture or PCR of the tissue.

The rapid onset of poor vision, eye pain, and/or red eye (especially if red eye is associated with decreased vision or pain) should prompt a referral to an ophthalmologist, because these symptoms may be caused by herpesviruses or other pathogens that require specialized diagnostic testing (including fluorescein staining to detect characteristic dendritic corneal ulceration, advanced fundoscopic examination, and sampling of vitreous humor for PCR) and treatment approaches.

Typing of HSV isolates (or genotyping of amplicons) can provide prognostic information. For example, the frequency of recurrence after genital HSV-1 infection in patients without HIV is significantly less than after HSV-2 infection. 59,60

Prevention Recommendations

Preventing exposure.

Exposure to HSV-1 is frequent in childhood. Although avoiding direct contact with secretions from adult caretakers, siblings, or other close contacts with active herpes labialis is intuitive, it is likely that most infections result from unrecognized exposure to the frequent asymptomatic shedding of HSV by individuals with prior infection.

Male condoms are effective in preventing many sexually transmitted diseases, including HIV. 61,62 When used consistently and correctly, male latex condoms reduce the risk of type 2 genital herpes. 63 An early study in participants in an HSV vaccine trial demonstrated some protection against HSV infection with condom use, which varied with gender and frequency of sexual activity. 64 A similar, but larger trial demonstrated a 26% reduction in HSV-2 genital infection, but not in HSV-1 infection, with condom use. 65 Protection was related to the proportion of sex acts that were protected with a condom. In a pooled analysis of 6 studies, condom use reduced the risk of HSV-2 acquisition by 30%, and the risk of HSV-2 acquisition increased steadily with each unprotected sex act. 63 A separate analysis of the pooled data estimated that the odds of HSV-2 acquisition with each sexual act were 3.6%, 2.7%, and 0% when condoms were never used, sometimes used, or always used, respectively. 66

Individuals with HIV should use latex condoms consistently and correctly during sexual intercourse to protect sexual partners and reduce (not eliminate) the risk of acquiring HSV and other sexually transmitted pathogens. They should specifically avoid sexual contact when herpetic lesions (genital or orolabial) are evident. However, most genital herpes infections are transmitted by genital-genital or oral-genital contact from asymptomatic shedding of HSV when their partners are not experiencing a clinical recurrence or are unaware that they are infected. Condoms will not protect against orogenital transmission and infection transmitted prior to penetration.

Administration of chronic suppressive therapy to individuals with HIV and HSV to reduce clinical recurrences also reduces HSV-2 transmission to susceptible HSV-discordant partners without HIV by 25% to 75% and can reduce HSV shedding in patients with HIV/HSV co-infection. 67-71 Although these reductions in transmission and shedding are less than reductions in clinical disease observed with suppressive therapy, when administered to prevent clinical recurrences, suppressive therapy may thus limit spread to sexual partners. All HSV-active antivirals are equally effective in reducing transmission, but twice-daily dosing may be superior to a larger once-daily dose. 69 ART also reduces the frequency of asymptomatic HSV shedding. 15

Transmission of HSV to fetuses and neonates born to pregnant women with HSV/HIV coinfection can occur, but the likelihood is low. Effective ART regimens may decrease, but not prevent, maternal genital HSV shedding and recurrence of genital lesions. 15 Use of acyclovir or valacyclovir near term suppresses genital HSV outbreaks and shedding in late pregnancy in women with recurrent genital herpes who do not have HIV and reduces the need for cesarean delivery for recurrent HSV. 72 Although the study demonstrating these results had insufficient sample size to determine the effect of prophylaxis on neonatal infection, the American Congress of Obstetricians and Gynecologists (ACOG) recommends that pregnant women with recurrent genital herpes who do not have HIV be offered suppressive antiviral therapy at or beyond 36 weeks of gestation. 73 The safety and efficacy of this strategy have not been evaluated in women with HIV/HSV-2 coinfection, who may have less HSV-2-specific antibody and/or T-cell function and are more likely to have both symptomatic and asymptomatic reactivation of genital HSV. Currently, there is not sufficient data in this population on which to base a specific recommendation regarding this strategy. Importantly, neonatal HSV disease can occur following delivery among women on suppressive antiviral therapy 74  illustrating that protective effects of maternal suppression are not absolute. Elective cesarean delivery, preferably before rupture of membranes, is recommended for all women, both those with and without HIV, who have active genital HSV lesions at the onset of labor. 75-77

Preventing Disease

Antiviral prophylaxis before or after potential sexual exposure to HSV has been used successfully to prevent HSV acquisition but has not been studied in patients with HIV and is not recommended . 78

Treatment Recommendations

Treating disease.

Acyclovir is the drug of choice for treatment of local and disseminated HSV in infants and children, regardless of HIV-infection status. Neonatal HSV disease should be treated with intravenous (IV) acyclovir (20 mg/kg body weight three times a day) administered for at least 21 days for CNS and disseminated disease and for 14 days for disease localized to the skin, eyes, and mouth. 79 IV acyclovir therapy should not be discontinued in neonates with CNS disease unless a repeat CSF HSV DNA PCR assay at or after 21 days of treatment is negative.

Treatment of HSV encephalitis or disseminated HSV is the same for children and adolescents with and without HIV. IV acyclovir is the drug of choice. Beyond the neonatal period, HSV encephalitis should be treated for 21 days (10–15 mg/kg body weight three times a day, with dose determined by age and body size). 47,48

Children and adolescents with severe mucocutaneous HSV lesions or organ involvement (e.g., esophagitis) should receive IV acyclovir (5–10 mg/kg per dose every 8 hours). 80-82 Patients with severe mucocutaneous lesions can be changed to oral antiviral therapy after their lesions have begun to regress. Duration of therapy will depend on the rate and character of healing, but therapy should be continued until all lesions have completely healed. Failure to heal, or a marked delay or change in rate of healing, should raise concern for acyclovir resistance. 83,84

Oral acyclovir, valacyclovir, or famciclovir are used to treat genital HSV episodes, generally for periods of 5 to 14 days. First-episode genital (or orolabial) lesions in HIV-infected children or adolescents can be treated with oral acyclovir for 7 to 10 days as indicated by the response to therapy. 82,85,86 Patients with recurrent mucocutaneous lesions, if treated, generally receive oral acyclovir for 5 days.

Sufficient information exists to support the use of valacyclovir in children, especially given its 2- to 3-fold improved bioavailability as compared to acyclovir, at a dose of 20 to 25 mg/kg body weight administered 2 to 3 times a day. 87 Lower doses may be insufficient for children weighing less than 20 kg. 88-90 No pediatric formulation is available and valacyclovir can generally only be used for children old enough to swallow the large tablets, although crushed valacyclovir tablets can be used to make an extemporaneous suspension with reliable bioavailability and shelf life following instructions that are included in the U.S. Food and Drug Administration (FDA) Package Insert. 89,91 A sprinkle formulation of famciclovir is available for children who are unable to swallow the available pill formulation or who are too small for available pills. A schedule for weight-adjusted dosing is available to inform dosing of small children. 92 Because of their improved bioavailability, valacyclovir and famciclovir administered at higher doses for only 1 to 3 days often is sufficient to manage recurrent genital HSV infection in HIV-uninfected adults, and these regimens have been used safely in HIV-uninfected children. 93,94 However, these short regimens have not been recommended for HIV-infected adolescents and adults. 82

Treatment for acute retinal disease caused by HSV should be guided by an ophthalmologist. HIV-infected patients with acute retinal necrosis should be on ART and receive IV acyclovir (10–15 mg/kg body weight IV every 8 hours for 10–14 days), followed by prolonged (i.e., 4–6 weeks) oral therapy, such as with valacyclovir or acyclovir. 95 HSV keratoconjunctivitis is usually treated with topical trifluridine or ganciclovir, although many experts recommend adding oral therapy. 96 Because of potential corneal toxicity of topical therapy, close follow-up by an ophthalmologist is recommended and duration of therapy should be individualized.

Monitoring and Adverse Events

Primary toxicities of acyclovir are phlebitis (when administered IV), renal toxicity, nausea, vomiting, and rash. Toxicities are similar for valacyclovir and famciclovir, except for phlebitis. In infants receiving high-dose acyclovir for neonatal disease, neutropenia (defined as absolute neutrophil count <1,000/mm 3 ) occurs in approximately 20% of treated neonates. 79 Among severely ill children who were HIV-uninfected and received high-dose IV acyclovir, renal injury or failure was observed in >10% of patients. 97 It is recommended that renal function be determined at initiation of IV acyclovir treatment and at least once weekly for the duration of treatment, particularly in those who have underlying renal dysfunction and are receiving prolonged therapy. If possible, avoid other nephrotoxic drugs. IV acyclovir must be diluted adequately and administered slowly over 1 to 2 hours. Since acyclovir is excreted primarily by the kidney, dose adjustment based on creatinine clearance is needed in patients with renal insufficiency or renal failure.

Managing Treatment Failure

Resistance of HSV to acyclovir occurs in 5% to 10% of immunocompromised patients. 98 This results from the mutation frequency of HSV, the virostatic nature of acyclovir, and the inadequacy of HSV-specific cell-mediated immunity to rapidly clear the HSV infection. Resistance to antiviral drugs should be suspected if systemic involvement and skin lesions do not begin to resolve within 5 to 7 days after initiation of therapy, skin lesions are atypical in appearance, or satellite lesions appear after 3 to 4 days of therapy. If possible, a lesion culture should be obtained and if virus is isolated, susceptibility testing performed to confirm resistance. This may be difficult to arrange, and results may not be readily available. Thus, the decision to change therapy is often based on clinical observations. All acyclovir-resistant HSV strains are resistant to valacyclovir, and it is very rare that they are sensitive to famciclovir. The therapeutic choice for acyclovir-resistant herpes is foscarnet. 82,83,99,100 Foscarnet has significant nephrotoxic potential; up to 30% of patients experience increases in serum creatinine levels. It also causes serious electrolyte imbalances (including abnormalities in calcium, phosphorus, magnesium, and potassium levels) in many patients, and secondary seizures or cardiac dysrhythmias can occur. For patients receiving foscarnet, complete blood count, serum electrolytes, and renal function should be monitored twice weekly during induction therapy and once weekly thereafter. Infusing foscarnet after saline fluid loading can minimize renal toxicity. Doses should be modified in patients with renal insufficiency.

IV cidofovir is recommended for patients with HSV resistant to acyclovir and foscarnet. 82,83 For disease limited to a small number of indolent, non-healing lesions, topical formulations of trifluridine, foscarnet, and cidofovir have been used successfully, although this will require local preparation of the topical formulations and may require prolonged application for 21 to 28 days or longer. 101

Preventing Recurrence

Administration of oral acyclovir prophylaxis (suppressive therapy) for 6 months can prevent cutaneous recurrences of HSV after neonatal disease of the CNS or skin, eyes, and mouth in infants without HIV and is associated with better neurodevelopmental outcome in those with CNS disease. 102

Because recurrent episodes of mucocutaneous HSV disease can be treated successfully, chronic prophylaxis with acyclovir or other available antivirals against HSV is not required for patients who develop HSV infection beyond the neonatal period. Effective ART may decrease recurrences. Children who have frequent, severe, or troubling recurrences (i.e., 4 to 6 severe episodes a year) can be given daily prophylaxis with oral acyclovir; daily valacyclovir or famciclovir also are options for prophylaxis in adolescents. 69,82 Prophylaxis may be desired not only because recurrences may be especially problematic in patients with severe immune suppression, but also for cosmetic or psychosocial reasons. Use of suppressive antiviral drugs against HSV in adults reduces recurrences by 30% to 60%, and in adults with HIV receiving ART, symptomatic recurrences are reduced by 60% to 75%. 67,68,103

Because corneal clouding can occur due to the stromal reaction of recurrent keratoconjunctivitis, many ophthalmologists use acyclovir prophylaxis to reduce the frequency of ocular recurrences. However, resistance to acyclovir has been reported in this circumstance in patients without HIV. 104

Discontinuing Secondary Prophylaxis

Patients receiving prophylactic therapy should be evaluated annually for the need to continue prophylaxis. Cessation of secondary prophylaxis will be determined by the level of immune reconstitution, frequency and severity of recurrences, individual tolerance of recurrent episodes, and location of recurrence (e.g., recurrent keratitis may require longer prophylaxis because of risk of vision-impairing disease).

Recommendations

Primary prevention.

I. Will using condoms, compared to not using condoms, prevent HSV infection in sexually active adolescents and young adults with HIV?

• Condoms should be used to prevent HSV (and other sexually transmitted diseases) in adolescents and young adults with HIV ( strong; low ). The data regarding the level of protection provided by condoms are very limited for individuals with HIV in general, and for youth specifically.
• Male condoms are effective in preventing many sexually transmitted diseases, including HIV. A large observational trial on condom use and HSV acquisition demonstrated a 26% reduction in HSV-2 genital infection, but not in HSV-1 infection. 65 A pooled analysis of 6 similar studies concluded that condom usage resulted in a 30% lower risk of HSV-2 acquisition as compared to no condom use. 63,66 Patients with HIV should use latex condoms consistently and correctly during sexual intercourse to reduce the risk of acquiring HSV and other sexually transmitted pathogens and to protect sexual partners.

Secondary Prevention

II. Will adolescents and young adults with HIV who have recurrent genital HSV infection benefit from suppressive anti-HSV antiviral therapy as compared to not using suppressive therapy?

• Adolescents and young adults with HIV who suffer severe, frequent, and/or troubling recurrent genital HSV infection will benefit from anti-HSV suppression therapy ( strong; moderate ).
• Placebo-controlled trials demonstrated that antiviral drugs against HSV, administered for recurrent HSV disease in adults with HIV who are receiving ART, reduced symptomatic recurrences by 60% to 75%. This is an option for patients with frequent, severe, or troubling HSV recurrences. Chronic suppressive therapy in individuals with HSV also reduced HSV-2 transmission to susceptible partners without HIV by 25% to 75%. 67-69

III. Should children and adolescents with HIV with severe primary or recurrent HSV (genital or orolabial) infection receive IV acyclovir as compared to not receiving IV antiviral therapy?

• Children and youth with HIV who have severe mucocutaneous HSV infections should be treated with IV acyclovir. When improvement is noted, they can be switched to oral therapy until healing is complete ( strong; moderate ).
• Placebo-controlled trials in children and youth with immunocompromising conditions (other than HIV infection) indicate that those with severe mucocutaneous HSV lesions or organ involvement benefitted from IV acyclovir. 80,81 Patients with severe mucocutaneous lesions can be switched to oral antiviral therapy after their lesions have begun to regress. Duration of therapy will depend on the rate and character of healing, but therapy should be continued until lesions have completely healed. Failure to heal, or a marked delay or change in rate of healing, should raise concern for acyclovir resistance.

IV. Should children and adolescents with HIV be treated with oral acyclovir, valacyclovir, or famciclovir for non-severe primary episodes or recurrent episodes of orolabial or genital HSV (compared with no antiviral therapy)?

• Oral anti-HSV drugs will shorten the duration and reduce the severity of non-severe HSV infections in children and adolescents with HIV. Valacyclovir and famciclovir have superior pharmacokinetics ( strong; moderate ).
• Controlled trials in children without HIV and adults with HIV indicate that treatment of first-episode orolabial or genital HSV lesions results in reduction in duration and severity of lesions. 85,86 Recurrent mucocutaneous lesions also benefit from treatment. Because of their improved bioavailability, valacyclovir and famciclovir can be administered less frequently and will achieve higher serum antiviral levels when compared with acyclovir. Both alternatives have been safely used in children without HIV. 92,93

V. Is foscarnet the best choice for anti-HSV therapy for children and adolescents with HIV in whom therapy is failing because of acyclovir-resistant HSV?

• Foscarnet is the therapy of choice for acyclovir-resistant HSV ( strong, very low ). Ideally, the viral isolate should be tested to determine the antiviral resistance pattern. Resistance of HSV to acyclovir occurs in 5% to 10% of immunocompromised patients. Resistance to antiviral drugs should be suspected if systemic involvement and skin lesions do not begin to resolve within 5 to 7 days after initiation of therapy. The decision to change therapy often is based on clinical observations because virus isolation and testing for resistance take many days. The therapeutic choice for acyclovir-resistant herpes is foscarnet, based primarily on the sensitivity pattern of HSV isolates from HSV infections unresponsive to acyclovir in immunocompromised patients 99,100 and expert opinion. Patients receiving foscarnet should have electrolytes and renal function monitored twice weekly during induction therapy and once weekly thereafter. The package insert contains an algorithm for drug infusion and dose modification for patients with renal insufficiency.
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• Saez-Llorens X, Yogev R, Arguedas A, et al. Pharmacokinetics and safety of famciclovir in children with herpes simplex or varicella-zoster virus infection. Antimicrob Agents Chemother . 2009;53(5):1912-1920. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19273678 .
• Block SL, Yogev R, Waldmeier F, Hamed K. Safety and pharmacokinetics of a single 1500-mg dose of famciclovir in adolescents with recurrent herpes labialis. Pediatr Infect Dis J . 2011;30(6):525-528. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21178655 .
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• Dworkin RH, Johnson RW, Breuer J, et al. Recommendations for the management of herpes zoster. Clin Infect Dis . 2007;44 (Suppl 1):S1-26. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17143845 .
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Common Viruses of the mouth: Herpes Simplex Viruses 1 and 2

Common viruses that can be present in the oral cavity are Herpes Simplex 1 and 2. Herpes Simplex Virus Type 1 (HSV-1) is spread predominantly through infected saliva or active perioral lesions. HSV-1 is adapted best and performs more efficiently in the oral, facial, and ocular areas. The pharynx, intraoral sites, lips, eyes, and skin above the waist are involved most frequently [1[.

Like what you’re learning?  Download a brochure for our online, postgraduate  Oral Pathology and Radiology  degree program.

Herpes Simplex Virus Type 2 (HSV-2) is adapted best to the genital area, is transmitted predominantly through sexual contact, and typically involves the genitalia and skin below the waist. Exceptions to these rules occur, however, and HSV-1 can be seen in a pattern similar to HSV-2 and vice-versa. The clinical lesions produced by both types are identical, producing the same changes in the tissue [1].

Who is at risk?

It is estimated that almost 90% of the world’s population is seropositive for HSV-1 by 35 years of age, and half of the individuals carrying the virus will experience reactivation in the form of herpes labialis. Herpetic gingivostomatitis is equally distributed amongst gender and race groups and is not found to have a particular seasonal or geographic distribution [2].

What is the Clinical Presentation?

HSV-1 symptoms may include a prodrome of fever, followed by mouth lesions with submandibular and cervical lymphadenopathy. The mouth lesions (Figure 1.) consist of painful blisters on a red, swollen base that occur on the lips, gingiva, oral palate, or tongue. The lesions ulcerate, and the pain can be severe. Refusal to eat or drink may be a clue to the presence of oral HSV. The lesions usually heal within 10 to 14 days.

HSV-2 may present as a primary infection with painful genital ulcers, sores, crusts, tender lymphadenopathy, and dysuria. The classical features are macular or papular skin and mucous membrane lesions progressing to vesicles and pustules that often last up to 3 weeks. Genital lesions can be especially painful, leading to swelling of the vulva in women, burning pain, and dysuria [3].

Figure 1. A and B show herpetiform presentation of HSV 1. Photo credits Usatine RP et al. [4]

How can it be transmitted?

Both HSV-1 and HSV-2 are highly contagious and can be transmitted through direct contact with an infected person’s sores or through oral, genital, or anal mucous membranes [5].

What are the treatment options?

While there is no cure for herpes, antiviral medications can help manage and reduce the severity and frequency of outbreaks. These medications may also reduce the risk of transmission. Additionally, topical anesthetics may be incorporated into the treatment for pain management. Some of the treatment options are listed below:

• Xylocaine 2% Viscous
• Magic Mouth Wash (1 part viscous lidocaine 2%, 1 part diphenhydramine 12.5mg/5ml, 1 part Maalox)
• Acyclovir 200mg; Disp 50 to 60 capsules. Take 1 capsule 5 times per day for 7 days.
• Valacyclovir 1000mg; Disp 20 tablets. Take 1 tablet 2 times per day for 7 days (not indicated for HIV patients due to the risk of thrombocytopenia).
• Famciclovir 250mg; Disp 30 tablets. Take 1 tablet 3 times per day for 7 days.

Reactivation of the Virus: Recurrence?

During their first infection, people may experience fever, body aches, sore throat (oral herpes), headache, and swollen lymph nodes near the infection, and the HSV can enter the terminal axons of neurons that innervate tissue at the initial site of infection. Although viral genomes are most frequently detected in sensory ganglia, particularly the trigeminal ganglia (HSV-1) and lumbar-sacral ganglia (HSV-2) [6].

Reactivation of HSV 1 can establish latency in the trigeminal ganglion and cause clinical signs and symptoms associated with several cranial nerves. Reactivation of HSV 2 in adults can remain dormant in sacral nerve root ganglia infection, and lesions can affect many organs in the body (6). People can have repeated outbreaks over time (‘recurrences’). These are usually shorter and less severe than the first outbreak [5].

What are the complications?

• Ocular Infections, such as scarring of the cornea that may lead to blindness
• Oropharyngeal infections
• Eczema herpetic
• Herpetic whitlow
• Visceral infections resulting from viremia
• Encephalitis
• Bell’s palsy
• Neuritis, among others

If viral infections are left untreated, they could progress to complications such as coma and death.

The transmission of HSV can be reduced by avoiding contact with potential virus-shedding lesions, safe sexual practices, and antiviral therapy before complications. Significant research for a potential vaccine is ongoing and offers hope for the future.

Postgraduate Oral Pathology and Radiology Degree

Learn more about the clinical and didactic skills necessary to evaluate and manage patients with oral diseases by enrolling in Herman Ostrow School of USC’s online, competency-based certificate or master’s program in  Oral Pathology and Radiology .

References:

• Neville B.W, Damm D.D, Allen C.M, Bouquot, J.E Oral and Maxillofacial Pathology, 3rd ed. St Louis: Elsevier-Saunders. 2009; St Louis: Elsevier.
• Minira Aslanova; Rimsha Ali; Patrick M. Zito. (2023). Herpetic Gingivostomatitis. Herpetic Gingivostomatitis.
• Mathew Jr J, Sapra A. Herpes Simplex Type 2. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-
• Usatine RP, Tinitigan R. Nongenital herpes simplex virus. American Family Physician. 2010 Nov 1;82(9):1075-82. PMID: 21121552
• World Health Organization. (2023, April 5). Herpes Simplex Virus . Retrieved from World Health Organization.
• Jon B. Suzich, A. R. (2018). Strength in diversity: Understanding the pathways to herpes simplex virus. Virology, 11.

Dr. Andrea Santacruz graduated from dental school in El Salvador, and she is currently obtaining her post-doctorate certificate program in Oral Pathology and Radiology at Herman Ostrow School of Dentistry. She has worked for non-profit organizations and has a strong passion for working with underserved populations. Her dream is to become a part of academia and teach future generations.

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Dr. Vistoso Monreal received her DDS from Universidad de Chile, an Advanced Program Certificate in Prosthodontics from Universidad del Desarrollo, earned a Master of Science degree in Orofacial Pain and Oral Medicine with an Advanced Program Certificat in Orofacial Pain from USC, and did an additional Advanced Clinical Training in Oral Medicine at UCSF. She is an Orofacial Pain Board-Certified specialist and Assistant Professor of Clinical Dentistry at the University of Southern California. Her research is focused on precision orofacial sciences with the application of Artificial intelligence in the subdisciplines of orofacial pain and oral medicine. 

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• Review Article
• Published: 27 March 2024

Herpes zoster in neuro-ophthalmology: a practical approach

• Brendan Ka-Lok Tao   ORCID: orcid.org/0000-0001-7069-3162 1 ,
• Deep Soor 2 &
• Jonathan A Micieli   ORCID: orcid.org/0000-0003-4911-9152 2 , 3 , 4 , 5 , 6  

Eye ( 2024 ) Cite this article

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• Antiviral agents
• Ocular motility disorders
• Optic nerve diseases
• Pupil disorders
• Viral infection

Herpes Zoster (HZ) or shingles is the reactivation of the Varicella Zoster Virus (VZV), usually along a single sensory nerve, but can affect both sensory and motor cranial nerves. Major risk factors for HZ include immunosuppressed status and age older than 60 years. In the United States, the lifetime risk of HZ is approximately 30%. Worldwide, the median incidence of HZ is 4–4.5 per 1000 person-years across the Americas, Eurasia, and Australia. HZ ophthalmicus, occurring in 10–20% of patients, is an ophthalmic emergency characterized by VZV reactivation along the V 1 branch of the trigeminal nerve. Approximately half of this patient subgroup will go on to develop ocular manifestations, requiring prompt diagnosis and management. While anterior segment complications are more common, neuro-ophthalmic manifestations are rarer and can also occur outside the context of overt HZ ophthalmicus. Neuro-ophthalmic manifestations include optic neuropathy, acute retinal necrosis or progressive outer retinal necrosis, cranial neuropathy (isolated or multiple), orbitopathy, and CNS manifestations. Although typically a clinical diagnosis, diagnosis may be aided by neuroimaging and laboratory (e.g., PCR and serology) studies. Early antiviral therapy is indicated as soon as a presumptive diagnosis of VZV is made and the role of corticosteroids remains debated. Generally, there is wide variation of prognosis with neuro-ophthalmic involvement. Vaccine-mediated prevention is recommended. In this review, we summarize neuro-ophthalmic manifestations of VZV.

带状疱疹 (Herpes Zoster, HZ) 或带状疱疹 (shingles) 是再次激活的水痘带状疱疹病毒 (VZV), 沿着单个感觉神经影响感觉神经和运动脑神经的一种神经性疾病。HZ的主要危险因素包括免疫抑制状态和年龄60岁以上的老年人。在美国, HZ的终生风险约为30%。在全球范围内, 美洲、欧亚大陆和澳大利亚的HZ发病率中位数为每年每1000人4-4.5例。发生眼内炎的几率为10-20%。HZ也是一种眼科急症, 其特征是沿三叉神经V1分支的VZV病毒激活后产生的 (病变) 。患者中约有一半会出现眼部表现, 需要及时诊断和治疗。眼前段并发症更为常见, 神经眼科较为罕见, 也可能发生眼部不受累的情况。神经眼科的临床表现包括视神经病变、急性视网膜坏死或进行性视网膜外层坏死、脑神经病变 (孤立性或多发性) 、眼眶病和中枢神经系统表现。尽管可根据典型的临床表现进行诊断, 神经影像学和实验室 (如聚合酶链式反应和血清学) 结果可提供重要的辅助性临床诊断资料。一旦待确诊VZV, 需及早的抗病毒治疗, 但目前皮质类固醇的作用仍有争议。一般来说, 神经眼科病变者的预后差异很大。建议通过疫苗进行预防。在这篇综述中, 我们总结了VZV的神经眼科表现。

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Florid pustular eruption in an adult man

A healthy man, aged 44 years, presented to a tertiary hospital with a one-week history of a painful eruption involving the right shoulder. The patient believed that the rash was a result of a burn injury caused by applying a hot water bottle to relieve neck pain, which preceded the development of the rash. He was assessed by his general practitioner who provided analgesia and silver sulfadiazine cream. However, the cutaneous involvement progressed. Four days later, the affected area evolved into a pustular eruption (Figure 1, 2) associated with severe pain. The patient remained systemically well. He was immunocompetent with no significant medical history, medication use or known allergies. Routine investigations were within normal limits except for an elevated C-reactive protein of 66 mg/L.

Figure 1. Posterior view of the pustular eruption of the right shoulder.

Figure 2. Anterior view of the pustular eruption of the right shoulder.

Describe the lesion in Figures 1 and 2.

What is the most likely diagnosis? What are the other differentials to consider?

Both figures demonstrate confluent and coalescing pustules with associated crusting on an erythematous base in a dermatomal distribution involving the right posterior base of the neck, right shoulder and anterior chest.

A painful vesiculopustular eruption might occur in herpes zoster, commonly known as shingles, a viral syndrome due to reactivation of dormant varicella zoster virus (VZV). The rash appears over 3–5 days after a prodrome of fever and burning pain. The lesions are unilateral and distributed within a single dermatome. 1 A major differential is herpes simplex virus type 1 (HSV-1) infection, which characteristically manifests as a painful vesicular rash in the same dermatome where it was inoculated into the skin. It commonly affects the face and mucosa but can become disseminated in immunocompromised individuals and in those with underlying dermatological conditions such as atopic dermatitis (eczema herpeticum) and Darier’s disease. Other differential diagnoses to consider are acute localised exanthematous pustulosis (ALEP) and evolving acute generalised exanthematous pustulosis (AGEP). These are cutaneous adverse drug reactions characterised by an eruption of sterile pustules typically following drug administration. 2,3 Both ALEP and AGEP highlight the importance of obtaining a medication history, as antibiotics and non-steroidal anti-inflammatories, for instance, have been commonly implicated in these cases. It is also essential to consider secondary bacterial infection as a differential diagnosis, especially when a history of skin injury or trauma is elicited. Finally, an atypical presentation of pustular psoriasis, localised or koebnerised, is also important to consider in a pustular eruption, albeit in this case, the striking dermatomal distribution makes this less likely.

What investigations would you perform?

What is the treatment of choice for this condition?

An accurate diagnosis of herpes zoster can be made from history and clinical examination due to its distinctive presentation. However, laboratory testing can be useful to confirm diagnosis and to identify the responsible virus. This is necessary, as advice to avoid pregnant women is essential for individuals with herpes zoster virus, and the dosing of antiviral therapy is higher for herpes zoster than for HSV-1. Polymerase chain reaction (PCR) is most useful for confirming a clinical suspicion of herpes zoster due to its high sensitivity and rapid turnaround time. Bacterial swabs for microscopy, culture and sensitivity (MCS) are important to exclude bacterial infection and secondary bacterial infection, which are common in herpes zoster infection. Additionally, skin biopsy might be needed to exclude other differential diagnoses of an inflammatory aetiology, such as a drug eruption and pustular psoriasis.

Antiviral therapy is used to reduce the severity of illness and accelerate the resolution of pain and skin lesions. It is most effective when initiated within 72 hours of rash onset. Additionally, early treatment reduces the risk of developing complications such as postherpetic neuralgia (PHN) and is especially important in elderly people, who have a higher risk of PHN. Current Australian guidelines recommend famciclovir and valaciclovir, as they have greater bioavailability and simpler dosing regimens compared to aciclovir. The dose for valaciclovir is 1 g three times daily for seven days. 4

Case continued

Viral and bacterial swabs for PCR and MCS were performed, and the patient was commenced on valaciclovir 1 g three times daily for seven days. Advice on the natural course of VZV infection was given, including on potential complications such as postherpetic neuralgia. Education on transmission prevention of the virus was provided, and the patient was advised to minimise exposure to family members, vulnerable individuals such as pregnant women and those who are immunocompromised or with no previous varicella immunisation.

What is the most frequent complication of herpes zoster? How should it be treated?

How can this condition be prevented?

PHN is defined as pain persistent for more than four months after the onset of the rash. This differs from usual herpes zoster pain, which lasts two to four weeks. Current guidelines recommend oral therapies such as tricyclic antidepressants, gabapentin, pregabalin and opioids as well as topical lidocaine and capsaicin patches for the treatment of PHN. 5 While both have been shown to provide effective analgesia, oral therapies are associated with systemic adverse effects. 5 Additionally, 2% of pregnant women exposed to herpes zoster virus in the first 20 weeks will develop foetal varicella syndrome. 6 VZV immunoglobulin is a possible treatment, and consultation with foetal medicine or infectious diseases should be considered, preferably within 72 hours of exposure. 6

It is important to vaccinate susceptible individuals to prevent shingles. There have been recent changes to the National Immunisation Program that have made available a two-dose course of Shingrix for people aged 65 years or older, First Nations people over 50 years of age and immunocompromised patients over 18 years of age. Shingrix does not contain live virus and has been found to be more effective than older vaccines (eg Zostavax). 7 This is significant because it can be safely given to immunocompromised people. 7 Specialist advice is recommended according to individual circumstances.

• Pustular eruptions have a wide differential diagnosis.
• Herpes zoster (shingles) can be diagnosed clinically; however, a VZV PCR swab is prudent to confirm infectious aetiology.
• Oral valaciclovir 1 g three times daily for seven days is usually the treatment of choice.
• The new Shingrix vaccine is more effective than Zostavax, and it should be offered to people aged 65 years or older, First Nations people over 50 years of age and immunocompromised patients over 18 years of age.

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• Patil A, Goldust M, Wollina U. Herpes zoster: A review of clinical manifestations and management. Viruses 2022;14(2):192. doi: 10.3390/v14020192. Search PubMed
• Safa I, Ines L, Noureddine L, et al. Acute localized exanthematous pustulosis: Clinical features, pathophysiology, and therapy. Dermatol Ther 2021;34(5):e15087. doi: 10.1111/dth.15087. Search PubMed
• Parisi R, Shah H, Navarini AA, et al. Acute generalized exanthematous pustulosis: Clinical features, differential diagnosis, and management. Am J Clin Dermatol 2023;24(4):557–75. doi: 10.1007/s40257-023-00779-3. Search PubMed
• Ormrod D, Goa K. Valaciclovir: A review of its use in the management of herpes zoster. Drugs 2000;59(6):1317–40. doi: 10.2165/00003495-200059060-00009. Search PubMed
• Hadley GR, Gayle JA, Ripoll J, et al. Post-herpetic neuralgia: A review. Curr Pain Headache Rep 2016;20(3):17. doi: 10.1007/s11916-016-0548-x. Search PubMed
• Heuchan AM, Isaacs D; Australasian Subgroup in Paediatric Infectious Diseases of the Australasian Society for Infectious Diseases. The management of varicella-zoster virus exposure and infection in pregnancy and the newborn period. Med J Aust 2001;174(6):288–92. doi: 10.5694/j.1326-5377.2001.tb143273.x. Search PubMed
• Boutry C, Hastie A, Diez-Domingo J, et al; Zoster-049 Study Group. The adjuvanted recombinant zoster vaccine confers long-term protection against herpes zoster: Interim results of an extension study of the pivotal phase 3 clinical trials ZOE-50 and ZOE-70. Clin Infect Dis 2022;74(8):1459–67. doi: 10.1093/cid/ciab629. Search PubMed

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StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

StatPearls [Internet].

Herpetic gingivostomatitis.

Minira Aslanova ; Rimsha Ali ; Patrick M. Zito .

Affiliations

Last Update: June 12, 2023 .

• Continuing Education Activity

Herpetic gingivostomatitis is a manifestation of herpes simplex virus type 1 (HSV-1) and is characterized by high-grade fever and painful oral lesions. While herpetic gingivostomatitis is the most common cause of gingivostomatitis in children before the age of 5, it can also occur in adults. The condition is characterized by a prodrome of fever followed by an eruption of painful, ulcerative lesions of the gingiva and mucosa, and often, yellow, perioral, vesicular lesions. HSV-1 is usually spread from direct contact or via droplets of oral secretions or lesions from an asymptomatic or symptomatic individual. Once a patient is infected with the herpes simplex virus, the infection can recur in the form of herpes labialis with intermittent re-activation occurring throughout life. This activity reviews the presentation, evaluation, and management of herpes gingivostomatitis and emphasizes the role of the interprofessional team in the care of affected patients.

• Identify the epidemiology of herpes gingivostomatitis.
• Describe the presentation of a patient with herpes gingivostomatitis.
• Outline the management options available for herpes gingivostomatitis.
• Review interprofessional team strategies for improving care coordination and communication to advance the treatment of herpes gingivostomatitis and improve outcomes.
• Introduction

Herpetic gingivostomatitis is a manifestation of herpes simplex virus type 1 (HSV-1) and is characterized by high-grade fever and painful oral lesions. While herpetic gingivostomatitis most commonly occurs in children from ages 6 months to 5 years, it may also occur in adults. [1] HSV-1 is usually spread from direct contact or via droplets of oral secretions or lesions from an asymptomatic or symptomatic individual. Once a patient is infected with the herpes simplex virus, the infection can recur in the form of herpes labialis (cold sores) with intermittent re-activation occurring throughout life. [2]

The causative agent is Herpes simplex virus type 1 (HSV-1), which belongs to the alphaherpesvirus group.  The virus is enveloped and has a linear double-stranded DNA genome. HSV-1 is mostly responsible for oral, ocular, and facial infections as it has a tropism for oral epithelium. While most cases of herpetic gingivostomatitis are associated with HSV-1 infection, some adult cases have been reported where HSV-2 was isolated from the oral lesions. Oral infection with HSV-2 is probably transmitted through orogenital contact and has also been observed in HIV-positive patients and patients undergoing immunosuppressive therapy. [3]

• Epidemiology

Primary herpetic gingivostomatitis typically occurs in children younger than the age of 5 years, but can also occur in adolescents and adults. HSV-1 is usually acquired in childhood by coming into contact with oral secretions. It is estimated that almost 90% of the world’s population is seropositive for HSV-1 by 35 years of age, and half of the individuals carrying the virus will experience reactivation in the form of herpes labialis. Herpetic gingivostomatitis is equally distributed amongst gender and race groups and is not found to have a particular seasonal or geographic distribution. [4] [5]

• Pathophysiology

Both HSV-1 and HSV-2 have three major biological properties that play an important role in disease pathogenesis. These include neurovirulence, latency, and reactivation. Neurovirulence is the ability to invade and replicate in the nervous system, and latency is the ability to maintain the latent infection in the nerve cell. Reactivation is the ability to replicate and cause the disease process again, once induced by specific stimuli. HSV-1 causes herpes gingivostomatitis and eventually herpes labialis using the same biological properties. The pathogenesis of herpes gingivostomatitis involves the replication of the herpes simplex virus, cell lysis, and eventual destruction of mucosal tissue. Exposure to HSV-1 of the abraded surfaces allows the virus to enter and rapidly replicate in epidermal and dermal cells. This results in the clinical manifestation of perioral blisters, erosions of the lips and mucosa, and eventual hemorrhagic crusting. Sufficient viral inoculation and replication allow the virus to enter sensory and autonomic ganglia, where it travels intra-axonally to the ganglionic nerve bodies. HSV-1 most commonly infects the trigeminal ganglia, where the virus remains latent until reactivation, most commonly in the form of herpes labialis. [2]

• Histopathology

Histological appearance of a mucosal herpetic infection includes degeneration of stratified squamous epithelial cells, acantholysis, and formation of an inflammatory infiltrate around the capillaries of the dermis. The characteristic intranuclear inclusion bodies known as Cowdry type A are found on light microscopy showing arrays of viral capsids and electron-dense glycoproteins. [6]  Cowdry type A bodies are eosinophilic inclusion bodies that are also found in varicella-zoster, making the histologic lesions of herpetic gingivostomatitis and varicella indistinguishable. Direct immunohistochemistry using fluorescent antibodies can be used to further distinguish between the herpes virus and the varicella virus. [7]

• History and Physical

Primary herpes gingivostomatitis usually occurs in children who have not been previously exposed to the virus. It may be asymptomatic in some cases, but most cases develop a prodrome of fever, anorexia, irritability, and the development of painful oral lesions. Associated symptoms include malaise, lethargy, and cervical or submandibular lymphadenopathy. [8]

The initial sign of herpetic gingivostomatitis is hyperemia of the oral and perioral mucosa, followed by rapidly spreading vesicular lesions on the gingiva, palate, buccal, and labial mucosa. The lesions may ulcerate and then eventually rupture. On physical examination, they may appear flat, yellowish in color, and approximately 2 to 5 mm in size. The ulcers are quick to bleed and typically heal without scarring in 2 to 3 weeks.

Recurrent herpes lesions commonly develop in one-third of the patients who have experienced primary herpetic gingivostomatitis. The patient’s symptoms include burning and itching, followed by the formation of vesicular lesions in a localized area. The lesions mostly develop on keratinized skin such as the vermillion border of the lips, perioral skin, or the hard palate. The lesions may develop when the patient is under physical or emotional stress or systemic illness. Other triggers include sunlight exposure and trauma. The lesions occur in the same area during every episode of recurrence, and systemic manifestations such as malaise and lymphadenopathy are mild. [9]

The diagnosis of herpetic gingivostomatitis is usually clinical, based on the patient’s history and physical examination. The appearance of the oral vesicular and ulcerative lesions is sufficient for the diagnosis. However, if additional testing is required, herpetic gingivostomatitis can be confirmed using a direct immunofluorescent examination of ulcer scrapings or blister fluid. Another test that can be used but is not entirely reliable for diagnosis is the Tzanck smear, which shows the cytologic changes induced by the herpes virus. The Tzanck smear will confirm the presence of a virus in the active lesions but fails to distinguish between HSV-1, HSV-2, and varicella-zoster virus. [10] The gold standard for diagnosis is the isolation of the virus in tissue culture. Antibody testing can help demonstrate seroconversion but does not yield a diagnosis.

• Treatment / Management

Herpes gingivostomatitis is generally a mild and self-limited condition, and supportive care is generally adequate. Barrier lip creams such as petroleum jelly have been suggested to prevent adhesions in patients with active herpetic gingivostomatitis. The most important component in the management of herpetic gingivostomatitis is hydration. Adequate hydration is often achieved with pain control; thus, analgesics such as oral acetaminophen and oral rinses are encouraged to make the patient more comfortable and promote fluid intake. It is important to note that patients who are unable to drink to maintain proper hydration should be hospitalized. Other indications for hospitalization include immunocompromised children, patients who develop eczema herpeticum, and HSV spread that results in encephalitis or pneumonitis. [11]

Several studies suggest the usage of acyclovir cream or oral suspension in a rinse and swallow technique. [7] Immunocompetent patients with significant pain or refusal to drink can be administered oral acyclovir if they present within the first 72 hours of disease onset. [12]

• Differential Diagnosis

Despite the largely based clinical diagnosis of herpetic gingivostomatitis, it is important first to rule out other diseases that present similarly, keeping in mind the age group and past medical history of the patient. Table 1 explains the differences in causation and clinical presentation of several childhood disorders that may be confused with herpes gingivostomatitis. Some of the differential diagnoses to keep in mind when considering herpetic gingivostomatitis include:

• Herpes zoster
• Primary chickenpox
• Behcet disease
• Herpetiform aphthae
• Erythema multiforme
• Acute necrotizing gingivostomatitis
• Reactive arthritis
• Cytomegalovirus ulceration
• Traumatic ulcers
• Burns, chemical and thermal
• Factitial injuries
• Vesiculobullous disease
• Complications

Complications of herpetic gingivostomatitis may include: [13]

• Dehydration
• Herpes labialis
• HSV encephalitis
• Herpetic whitlow
• Herpetic keratitis
• Eczema herpeticum [14]
• Deterrence and Patient Education

The patients and their families should be informed that the disease is generally mild and self-limited. They should be told about the appropriate management strategy that includes supportive care with pain control, adequate hydration, and a healthy diet. The patients should be managed at home but should be monitored closely for the development of any complications, such as difficulty in eating or drinking, or worsening of lesions. The patients and their families (especially in the case of young children) should be in regular contact with the primary treating physician. The patient should also be educated about the recurrence of the oral lesions (herpes labialis or cold sores) that may develop in one-third of the patients who develop primary herpetic gingivostomatitis.

• Enhancing Healthcare Team Outcomes

Herpes gingivostomatitis is a viral infection characterized by high-grade fever and painful oral lesions, occurring most commonly in children from ages 6 months to 5 years. Out-patient management is sufficient in most situations, but hospital admission may be warranted if the patient develops complications. The disease is best managed by an interprofessional team that includes a primary care provider, an internist, a pediatrician, a nurse practitioner, an emergency department physician, an infectious disease specialist, and a pharmacist. Coordination by different health care experts is necessary to improve patient outcomes and enhance patient care.

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Differential diagnosis of pediatric oral lesions Contributed by Rimsha Ali, MD

Disclosure: Minira Aslanova declares no relevant financial relationships with ineligible companies.

Disclosure: Rimsha Ali declares no relevant financial relationships with ineligible companies.

Disclosure: Patrick Zito declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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Interim Results from the ARTACUS Clinical Trial of RP1 Monotherapy in Solid Organ and Hematopoietic Cell Transplant Recipients with Skin Cancers Presented During Oral Presentation at the American Association of Cancer Research (AACR) 2024 Annual Meeting

SAN DIEGO, April 07, 2024 (GLOBE NEWSWIRE) — Replimune Group, Inc. , a clinical stage biotechnology company pioneering the development of a novel portfolio of oncolytic immunotherapies, today announced the presentation of interim results from ARTACUS, a Phase 1/2 clinical trial evaluating RP1 monotherapy for the treatment of skin cancers in patients who have had solid organ or hematopoietic cell transplants, by Michael R. Midgen, M.D., of the University of Texas MD Anderson Cancer Center during an oral session at the AACR 2024 Annual Meeting in San Diego. The results were initially presented late last year at the 38th Annual Meeting of the Society for Immunotherapy of Cancer (SITC).

In the study, treatment with RP1 as monotherapy, for up to 25 doses, resulted in an overall response rate (ORR) of 34.8 percent (8 of 23 evaluable patients, including 5 complete responses and 3 partial responses) with most responses ongoing as of the data cutoff date of September 18, 2023. In the evaluable patient population (n=23), 20 had cutaneous squamous cell carcinoma (CSCC) and three had merkel cell carcinoma. Of note, a patient treated with RP1 for CSCC also had a complete response of a new primary basal cell carcinoma which appeared post baseline. There was no evidence of allograft rejection including of hepatic and lung allografts. RP1 monotherapy was well tolerated, and the safety profile was similar to the profile in non-immunocompromised patients with advanced skin cancers. Additional biomarker data collected showed an increase in CD+8 T, a type of immune cell, and an increase in the expression of PD-L1, after treatment suggesting immune activation. The slides are available on the Replimune website under presentations.

“Organ transplant recipients are at a higher risk for skin cancer when compared to the broader population and have access to a limited number of treatment options given that systemic immunotherapy is typically contra-indicated,” said Sushil Patel, Ph.D., CEO of Replimune. “These data show RP1 as monotherapy has clear anti-tumor activity and may be a safe and effective treatment option for these patients with an overall response rate of nearly 35 percent with good durability of benefit to date.”

About ARTACUS

ARTACUS is a multicenter, open-label, two-part Phase 1b/2 study evaluating RP1 as monotherapy for the treatment of locally advanced or metastatic cutaneous malignancies in patients who underwent a kidney, liver, heart, lung, or other solid organ transplant, or hematopoietic cell transplantation, who are on chronic immunosuppressive treatment, in whom systemic immunotherapy is typically contra-indicated. Researchers will assess the safety of RP1 and also evaluate its ability to shrink tumors. ARTACUS is currently recruiting patients. To learn more, contact [email protected] or +1-781-222-9570.

RP1 is Replimune’s lead product candidate and is based on a proprietary new strain of herpes simplex virus engineered and genetically armed with a fusogenic protein (GALV-GP R-) and GM-CSF to maximize tumor killing potency, the immunogenicity of tumor cell death and the activation of a systemic anti-tumor immune response.

About Replimune  

Replimune Group, Inc., headquartered in Woburn, MA, was founded in 2015 with the mission to transform cancer treatment by pioneering the development of a novel portfolio of oncolytic immunotherapies. Replimune’s proprietary RPx platform is based on a potent HSV-1 backbone intended to maximize immunogenic cell death and the induction of a systemic anti-tumor immune response. The RPx platform is designed to have a unique dual local and systemic activity consisting of direct selective virus-mediated killing of the tumor resulting in the release of tumor derived antigens and altering of the tumor microenvironment to ignite a strong and durable systemic response. The RPx product candidates are expected to be synergistic with most established and experimental cancer treatment modalities, leading to the versatility to be developed alone or combined with a variety of other treatment options. For more information, please visit www.replimune.com.

Forward-Looking Statements

This press release contains forward looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, including statements regarding the design and advancement of our clinical trials, the timing and sufficiency of our clinical trial outcomes to support potential approval of any of our product candidates, our goals to develop and commercialize our product candidates, patient enrollments in our existing and planned clinical trials and the timing thereof, and other statements identified by words such as “could,” “expects,” “intends,” “may,” “plans,” “potential,” “should,” “will,” “would,” or similar expressions and the negatives of those terms. Forward-looking statements are not promises or guarantees of future performance and are subject to a variety of risks and uncertainties, many of which are beyond our control, and which could cause actual results to differ materially from those contemplated in such forward-looking statements. These factors include risks related to our limited operating history, our ability to generate positive clinical trial results for our product candidates, the costs and timing of operating our in-house manufacturing facility, the timing and scope of regulatory approvals, changes in laws and regulations to which we are subject, competitive pressures, our ability to identify additional product candidates, political and global macro factors including the impact of the coronavirus as a global pandemic and related public health issues, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and Quarterly Reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Our actual results could differ materially from the results described in or implied by such forward-looking statements. Forward-looking statements speak only as of the date hereof, and, except as required by law, we undertake no obligation to update or revise these forward-looking statements.

Investor Inquiries

Chris Brinzey

ICR Westwicke

339.970.2843

[email protected]

Media Inquiries

Arleen Goldenberg

917.548.1582

[email protected]

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