Deterrence/Prevention
Because of the ubiquitous and cosmopolitan nature of herpes simplex virus (HSV), avoiding contact with individuals who (often asymptomatically) are excreting the virus in saliva or genital secretions is difficult. Daily antiviral therapy can be given to reduce episodes of asymptomatic genital shedding and to further reduce the risk of transmission; however, it is unclear how long this should be administered.
Although not easily applicable to oral-oral contact, barrier protection using latex condoms is recommended to minimize exposure to genital HSV infections.
Because HSV genital ulcers may occur outside of areas covered by the condom, transmission can occur in those areas.
Herpetic whitlow can be avoided with latex gloves when health care workers insert their hands into the oral cavity of patients. Transmission of genital virus to the hand can occur during unprotected finger-genital contact during sexual activities.
Preventing acquisition of a new genital herpes infection is particularly important for women in late pregnancy, as this is when the risk for neonatal herpes is greatest.
Suppressive antiviral therapy can be used in individuals with frequent and/or particularly symptomatic relapses, but clinical trials have shown variable results.
Dual target microbicides which are topically applied to the vaginal tract or rectum are being studied in prevention of both HIV and HSV through various antiviral mechanisms and proven safe and effective specially in genital herpes. [33]
Some benefit, especially in terms of shortened duration of episodes, has been attributed to suppressive antiviral treatment compared with no treatment. Suppressive therapy reduces the frequency of genital herpes recurrences by 70%–80% in patients who have frequent recurrences. However, high-dose antiviral therapy, as opposed to standard dosing, has shown mixed results. In three randomized open-label crossover trials, high-dose valacyclovir (1 g tid) significantly improved symptom duration over standard-dose valacyclovir (500 mg bid), but similar benefits were not observed with high-dose acyclovir (800 mg tid) versus standard-dose valacyclovir. The study also noted that short bursts of subclinical genital HSV reactivation were frequent and that transmission can still occur during standard-dose or high-dose suppressive antiviral therapy. [34]
Prophylactic antiviral agents are typically given to recipients of solid organ transplants and hematopoietic stem cell transplants during the pre-engraftment phase to minimize risk of infection.
Preventative vaccines might also preclude symptoms of disease induced by wild-type virus and reduce or prevent virus shedding. Despite many attempts, neither a therapeutic nor preventive vaccine exists for HSV-1 or -2. Although all vaccines that have been investigated thus far stimulate virus-specific immune responses and reduce mortality and virus shedding in animals, they have ultimately yielded disappointing results in human trials. [35]
Specific cleavage or an induced lethal mutation of latent viral DNA would potentially preclude recurrent infections, thus curing patients of HSV infection. Although still in the early stages, use of endonuclease systems such as CRISPR/Cas9 to target herpesvirus genomes in infected cells is ongoing and represents a promising approach. [35, 36]
There are also ongoing intriguing studies on antiviral agents repressing cellular targets that can play a role in recurrent infections.
Complications
Bacterial and fungal superinfections
Bacterial and fungal superinfections are not uncommon.
Balanitis can occur in an uncircumcised male as a result of bacterial infection of the herpetic ulcers.
Candidal vaginitis has been described in as many as 10% of women with primary genital herpes, particularly in women with diabetes. Care should be taken to confirm the diagnosis of candidiasis, as ulcerative herpetic disease can have whitish mucosal lesions that can be confused with yeast infection.
Ocular infections
This complication is not uncommon in children as a result of autoinoculation during acute herpetic gingivostomatosis or asymptomatic oropharyngeal HSV infection.
Ocular infection is caused primarily by HSV-1, except in neonates, in whom it may be caused by HSV-2, and manifests as unilateral follicular conjunctivitis or as acute herpetic keratoconjuctivitis with dendritic corneal ulcers. [37, 38]
Other ocular complications attributable to HSV include keratitis, retinal necrosis, and chorioretinitis.
Recurrences occur in as many as 25% of patients and can be associated with progressive scarring of the cornea. HSV has been the leading infectious cause of blindness in the United States.
Skin infections
Various cutaneous complications related to HSV can occur.
Eczema herpeticum: This occurs in individuals with underlying dermatitis and may be localized (which can be confused with herpes zoster) or disseminated. The process can also occur in patients with extensive skin breakdown as with burns, pemphigus, or Sézary syndrome.
Herpetic whitlow: HSV infections of the fingers occur at or near the cuticle or at other sites associated with trauma. When involving the nail area, it has been confused with a bacterial felon and been subjected, inappropriately, to incision and drainage. Herpetic whitlow is associated with HSV-1 in health care workers and children related to saliva exposure and with HSV-2 related to digital-genital exposure.
Herpes gladiatorum: Scattered cutaneous HSV-1 lesions have been observed in wrestlers who have had viral contact through exposure to infectious saliva during a match.
Visceral infections
HSV infection of the visceral organs usually results from viremia, and multiple organ involvement is common. This may occur during otherwise asymptomatic primary infections and sometimes in seemingly immunocompetent hosts but more often in immunocompromised hosts. Visceral infections also tend to be more common in neonates. In fact, neonates have the highest number of visceral infections than any HSV-infected populations.
In most cases of disseminated herpes, the lesions are confined to the skin; however, fatal visceral dissemination can occur with or without vesicular skin lesions. Multiple organs are involved, but fulminant HSV hepatitis is usually clinically prominent. HSV-1 and HSV-2 are both implicated in fulminant hepatitis.
Disseminated disease is often associated with leukopenia, thrombocytopenia, and disseminated intravascular coagulation.
Disseminated HSV-1 and HSV-2 infections can also result in herpetic esophagitis, adrenal necrosis, interstitial HSV pneumonitis, HSV cystitis, HSV arthritis, HSV meningitis, and HSV encephalitis.
Respiratory tract infections
Herpes infection of the upper airway is fairly common in children and can involve the epiglottitis, laryngitis, and tracheobronchitis. Symptoms usually last about 2 weeks and are typically self-limiting. Lower respiratory tract infections, including pneumonias, are rare and could follow disease extension from an upper airway herpetic infection. Cases have been described in immunocompromised hosts, including patients with HIV infection, recipients of solid organ and bone marrow transplants, individuals with malignancies, and patients with burns. [39, 40, 41] Herpes simplex virus excretion in lower respiratory tract secretions is not infrequent in ventilator associated pneumonia and it is associated with greater severity and worse prognosis. [42]
Central nervous system complications
Aseptic meningitis is an acute, generally benign lymphocytic meningitis. It is recurrent and self-limiting (also known as benign lymphocytic recurrent meningitis [Mollaret meningitis]) and is typically more common with HSV-2 infection. Meningeal symptoms usually start 3-12 days after the onset of genital lesions; they reach a maximum 2-4 days into the illness and recede over 2-4 days. However, a history of clinical genital herpes is not always reported. Typically, there are more than two recurrences of fever and meningeal signs with spontaneous recovery. Signs and symptoms of encephalitis are unusual, and neurological sequelae are rare. HSV-2 has been identified by PCR in the CSF of patients with benign lymphocytic recurrent meningitis, suggesting that HSV may be the cause of this so-called idiopathic syndrome. [20, 23]
Ganglionitis and myelitis
Genital and anorectal HSV infections may be complicated by urinary retention, sacral neuralgia, and sacral anesthesia. This is due to associated ganglionitis and radiculitis. The symptoms usually resolve in 1-2 weeks. Transverse myelitis is rarely reported.
Herpes simplex encephalitis
This is an acute necrotizing viral encephalitis that, beyond the neonatal period, is nearly always caused by HSV-1. It accounts for 10%-20% of all cases of encephalitis and is the most common cause of sporadic acute necrotizing encephalitis in the United States. Herpes simplex encephalitis occurs as a primary infection in about 50% of cases and may be due to recurrent infection or to reinfection with a different strain of HSV-1 in the remainder.
HSV encephalitis; coronal T2-weighted MRI showing increased intensity in the temporal lobes (arrow) in a 33-year-old female who presented with fever, confusion, agitation, and mutism and was diagnosed with HSV encephalitis. Courtesy of Wikimedia Commons [Dr Laughlin Dawes] (https://commons.wikimedia.org/wiki/File:Hsv_encephalitis.jpg).
Clinical features include the following:
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Nonspecific findings common to all forms of encephalitis, which include headache, signs of meningeal irritation, altered mental status, and generalized seizures
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Changes referable to focal necrosis of the orbitofrontal and temporal cortex and the limbic system, including anosmia, memory loss, olfactory and gustatory hallucinations, and focal seizures
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Rapid development of hemiparesis and coma may occur. In some patients, the clinical picture is protracted, mimicking acute psychosis or delirium tremens.
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The CSF has moderate pleocytosis with mixed mononuclear cells and polymorphonuclear cells, moderate RBC counts, and mildly elevated protein levels with normal glucose levels.
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Brain imaging options include CT and MRI. MRI is the most sensitive imaging procedure.
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The most sensitive method of diagnosis is the demonstration of HSV DNA by PCR.
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The mortality rate is high (70%) in untreated patients. Even with treatment, a high incidence of neurological sequelae remains
Other neurologic complications attributable to HSV include transverse myelitis and Bell palsy.
Genital herpes and pregnancy
Maternal acquisition of HSV in the third trimester of pregnancy carries the highest risk of neonatal transmission.
A primary outbreak in the first trimester of pregnancy has been associated with neonatal chorioretinitis, microcephaly, and skin lesions in some cases. [43] Although HSV has been associated with an increased risk of spontaneous abortion, recent studies do not support such a risk. [44] Women with a primary or nonprimary first-episode outbreak in pregnancy, as well as women with a clinical history of genital herpes, should be offered suppressive therapy beginning at 36 weeks of gestation. Alternatively, for primary outbreaks that occur in the third trimester, continuing antiviral therapy until delivery may be considered. Because of enhanced renal clearance, the doses of antiviral medication used for suppressive therapy for recurrent HSV infection in pregnancy are higher than the corresponding doses in nonpregnant women. Cesarean delivery is indicated in women with active genital lesions or prodromal symptoms, such as vulvar pain or burning at delivery, because these symptoms may indicate viral shedding. [45]
There are no documented increases in adverse fetal or neonatal effects because of acyclovir exposure. [46, 47, 48]
Neonatal HSV disease
Neonatal intrauterine HSV exposure presents with 3 classic manifestation: dermatologic, neurologic, and ocular. Cutaneous presentation may include aplastic cutis, hyperpigmentation, hypopigmentation, or lesions. Neurologic findings may include calcifications, hydranencephaly, or microcephaly. Ocular presentation may include chorioretinitis, microphthalmia, or optic atrophy. [49, 50]
A conclusive neonatal HSV infection is best diagnosed using viral cultures. Acyclovir is the standard therapy for congenital HSV infection. Length of treatment varies depending on disease classification. Infants with skin, eyes, or mouth disease should be treated for 14 days. Infants with CNS or disseminated disease should be treated for a minimum of 21 days. Infants treated for CNS disease should have a repeat CSF HSV PCR near the end of the treatment course. If the CSF HSV PCR result continues to be positive, then treatment should be extended past 21 days in 7-day increments until the CSF HSV PCR result is negative.
This neonate displayed a maculopapular outbreak on his feet due to congenitally acquired herpes simplex virus infection. Courtesy of the CDC/Judith Faulk.
Copathogenesis with HIV
HSV and HIV can probably be best described as co-partners in disease, with the presence of one aiding the establishment of the other. In 2017, a systematic review and meta-analysis of 55 prospective studies found that the risk of becoming infected with HIV was at least tripled in people with HSV-2 infection compared with people without HSV-2, after controlling for sexual behaviour and other factors. [51] Advanced HIV disease causing loss of cellular immunity generally predisposes to more severe and possibly widespread HSV disease, while genital ulcers and chronic genital inflammation due to herpes infection (especially HSV-2) has been shown to promote the acquisition of HIV. [52] Multiple studies have also shown that the presence of antibodies to HSV-2 increases the risk of becoming infected with HIV, independent of the presence of genital ulcers. [53] While early studies in Africa have demonstrated a reduction of HIV viral load in patients with HIV infection receiving therapy directed toward HSV infection, the mechanism is unclear. [54, 55] T here are only a few studies about the effect of ART on HSV reactivation, but available data suggest that ART decreases symptomatic HSV disease but may not reduce asymptomatic HSV shedding. [56]
Patient Education
For patient education resources, see the Sexual Health Center and the Oral Health Center. Also, see the patient education articles Genital Herpes, Oral Herpes, Birth Control Overview, and Birth Control Methods.
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Herpes simplex virus type 1. Primary herpes can affect the lips, and the ruptured vesicles may appear as bleeding of the lips. Courtesy of A.K. ElGeneidy, DDS.
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Herpes simplex virus type 1. Recurrent herpes is most often noted clinically as herpes labialis, with clustered vesicles (often coalescing) on the lip vermilion and often on the perioral skin. Recurrences generally occur in the same area each time, although their severity may vary. Courtesy of Sara Gordon, DDS.
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This neonate displayed a maculopapular outbreak on his feet due to congenitally acquired herpes simplex virus infection. Courtesy of the CDC/Judith Faulk.
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Herpes simplex virus type 1. Recurrent herpes is occasionally observed intraorally. Inside the oral cavity, recurrent herpes typically affects only keratinized tissues, such as the gingiva or the hard palate. Vesicles often break quickly, so the clinician may observe small clustered ulcers. Courtesy of Sheldon Mintz, DDS.
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Herpetic whitlow in a young child who earlier had developed herpes gingivostomatitis. Courtesy of Wikimedia Commons [James Heilman, MD] (https://commons.wikimedia.org/w/index.php?search=Herpetic+whitlow+in+a+young+child&title=Special:MediaSearch&go=Go&type=image).
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Eczema herpeticum; cluster of blisters and punched out erosions of HSV in a child. Courtesy of Wikimedia Commons [Mohammad2018] (https://commons.wikimedia.org/wiki/File:Eczema_herpitcum.jpg).
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HSV encephalitis; coronal T2-weighted MRI showing increased intensity in the temporal lobes (arrow) in a 33-year-old female who presented with fever, confusion, agitation, and mutism and was diagnosed with HSV encephalitis. Courtesy of Wikimedia Commons [Dr Laughlin Dawes] (https://commons.wikimedia.org/wiki/File:Hsv_encephalitis.jpg).
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Genital herpes (female); outbreak of genital herpes affecting the vulva. Courtesy of Wikimedia Commons [SOA-AIDS Amsterdam] (https://commons.wikimedia.org/wiki/File:SOA-Herpes-genitalis-female.jpg).
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Genital herpes (male); vesicular lesions of HSV affecting the penis. Courtesy of Wikimedia Commons [SOA-AIDS Amsterdam] (https://commons.wikimedia.org/wiki/File:SOA-Herpes-genitalis-male.jpg).
