Version April 2023
INTRODUCTION — Worldwide, an estimated 66 percent of the population has herpes simplex virus type 1 (HSV-1) infection. HSV-1 is typically transmitted from person to person via infected oral secretions during close contact. After initial infection, HSV-1 establishes chronic infection in sensory ganglia and reactivates on mucosa and skin. Although infections are frequently asymptomatic, they can produce a variety of signs and symptoms. These include recurrent oral or perioral lesions ("cold sores"), skin and mucous membrane lesions, including genital lesions, ocular infections (eg, herpetic keratitis), and serious systemic illnesses such as encephalitis and neonatal disease involving multiple organs.
This topic will review the epidemiology, clinical manifestations, and diagnosis of HSV-1 infection. Other topic reviews related to herpes simplex type 1 include:
●(See "Herpes simplex keratitis".)
●(See "Herpes simplex virus type 1 encephalitis".)
●(See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)
EPIDEMIOLOGY — Herpes simplex virus type 1 (HSV-1) infection occurs worldwide. Infection occurs equally between the sexes and without seasonal variation [1].
Seroepidemiology — Globally, an estimated 3.7 billion people under the age of 50 years have HSV-1 infection [2]. The prevalence is highest in low- and middle-income countries. In sub-Saharan Africa and Latin America, the seroprevalence is over 90 percent in many populations [1,3].
By contrast, the prevalence rate for people in high-income countries has been declining [4-8]. Although the rates of seropositivity remain high (93 percent) in patients with a known history of cold sores [9], a cross-sectional seroprevalence survey of 9165 individuals in the United States reported a decline in the seroprevalence of HSV-1 from 62 percent during the period from 1988 to 1994 to 47.5 percent during the period from 2015 to 2016 [4,7].
The decrease in seroprevalence includes adolescents, as demonstrated in a National Health and Nutrition Examination Survey (NHANES) study that reported a 23 percent decline in HSV-1 seroprevalence among those 14 to 19 years of age, from 39 percent during the period from 1999 to 2004 to 30 percent during the period from 2005 to 2010 [5]. Thus, young adults may be at increased risk for primary oral or genital HSV infection, which can be clinically severe [10]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Primary infection' and 'Oral infections' below.)
Among younger children in the United States, an NHANES study reported an HSV-1 seroprevalence of 31.1 percent between 1999 and 2002 [11]. The seroprevalence increased with age from 26.3 percent at 6 to 7 years to 36.1 percent at 12 to 13 years. The prevalence was similar among boys and girls, but was higher in those living below the poverty level (52 percent seroprevalence compared with 24 percent among those living at or above poverty level).
Transmission — Transmission of HSV-1 occurs when someone with no prior infection with HSV-1 comes in contact with herpetic lesions, mucosal secretions, or skin that contain HSV-1 [12]. HSV-1 transmission typically occurs via oral-oral, oral-genital, or genital-genital contact, as well as contamination of skin abrasions with infected oral secretions.
Primary genital HSV-1 infection is thought to be transmitted most frequently through oral-genital contact. Although definitive data are lacking, persons who have prior oral HSV-1 infection are not thought to be susceptible to HSV-1 reinfection in the genital region. In addition, HSV-1 acquisition in HSV-2-infected persons is unusual. By contrast, most epidemiologic studies indicate scant, if any, protection against HSV-2 acquisition in patients with a history of HSV-1 infection. However, prior seropositivity to HSV-1 decreases the likelihood of symptoms in the setting of HSV-2 acquisition [13,14]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Nonprimary'.)
Transmission can occur if the source is asymptomatic or symptomatic when contact occurs; however, transmission is more likely if the source is symptomatic since the viral titer is much greater when lesions are present [15]. In various series, HSV has been recovered in culture from 81 to 88 percent of vesicles and 34 percent of ulcers or crusts; detection by polymerase chain reaction (PCR) is substantially higher. However, HSV-1 can also be transmitted during episodes of asymptomatic shedding. Asymptomatic shedding in the saliva occurs on 3.6 to 25 percent of saliva specimens from patients with evidence of HSV-1 infection only by clinical history or serology [12,16]. (See 'Diagnosis' below.)
In patients with herpes keratitis (which is due to reactivation of latent disease), the risk of transmitting HSV to others from the infected eye is thought to be extremely low. However, transmission of ocular HSV-1 has been documented in a case of corneal transplantation into an HSV-1-seronegative patient with glaucoma [17]. This infection resulted in the loss of sight. (See "Herpes simplex keratitis", section on 'Risk of transmission to others'.)
Populations at risk — Most HSV-1 infections are acquired during intimate (but not necessarily sexual) contact. Under such circumstances, family members are the most likely source, but children are also at risk in day care centers where saliva sharing behavior can occur [18,19].
Other populations who may be at increased risk for HSV-1 include:
●Sexually active adolescents – As adolescents initiate sexual activity, they are at risk for acquiring either oral or genital HSV-1 infection. Transmission via oral-genital or genital-genital contact has resulted in an increasing number of cases of HSV-1 genital herpes infection, especially among young women and men who have sex with men [4,5,20-23]. In a study that prospectively followed 3438 HSV-seronegative women between the ages of 18 and 30 years in the United States and Canada between 2003 and 2007, 183 became infected with HSV: 127 (3.7 percent) with HSV-1 and 56 (1.6 percent) with HSV-2 [20]. The rate of infection for HSV-1 was more than twice the rate for HSV-2 (2.5 versus 1.1 per 100 person-years, respectively).
●Athletes involved in contact sports – For athletes involved in contact sports (especially wrestlers), cutaneous and ocular HSV-1 infections have been recognized as a health risk. In wrestlers, transmission likely involves contamination of skin abrasions with infected oral secretions during close contact, resulting in "herpes gladiatorum." (See 'Herpes gladiatorum' below.)
In one study that evaluated students at a high school wrestling camp, 34 percent had active herpetic infection, which commonly involved the head (73 percent), extremities (42 percent), and trunk (28 percent) [24]. A large outbreak was described in 2007, in which 54 athletes from 23 teams had symptomatic disease within 38 days of a large team tournament. This outbreak was halted after initiating an eight-day statewide wrestling shutdown [25]. Skin checks and prophylactic/suppressive antivirals have been used to decrease the risk of herpes gladiatorum outbreaks [26]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Cutaneous disease'.)
●Neonates – Neonatal HSV-1 is transmitted from the maternal genital tract during delivery, often in the absence of history of genital herpes or lesions evident during labor. The risk of HSV-1 transmission from maternal genital secretions to neonates during birth is substantial if the woman acquired genital HSV-1 during pregnancy or if HSV-1 reactivation occurs in the genital tract at the time of delivery [27,28]. Maternal HSV-1 gingivostomatitis in late pregnancy is also a risk factor for transmission to the neonate [29]; however, it is not clear whether this is due to concurrent infection in the genital area or contact with the maternal saliva after birth. Approximately 10 percent of neonatal HSV-1 is acquired postnatally from parental or other contacts with oral HSV-1 infection. A more detailed discussion of neonatal HSV-1 is found elsewhere. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)
●Health care workers – Occasional nosocomial outbreaks of HSV-1 have been reported [30,31]. However, health care workers are not typically at increased risk for HSV-1 acquisition compared with the general population given the widespread use of standard infection control precautions. (See "Infection prevention: Precautions for preventing transmission of infection".)
PATHOGENESIS OF INFECTION
Primary infection and establishment of latency — Infection with HSV-1 begins with an acute phase, during which virus rapidly replicates at the site of contact. Dermal keratinocytes and other epithelial sites are the principal sites of viral replication in the skin [32,33]. The virus attaches to epithelial cells through interactions between HSV-1 surface glycoproteins and cellular HSV receptors, such as nectin-1 [34], subsequently entering the cell. The virus then enters the sensory nerve ending and is transported to sensory ganglia via retrograde transport [35]. HSV-1 establishes lifelong latent infection in the trigeminal or sacral ganglia, depending on the initial site of infection. Latency is characterized by a restricted transcriptional profile, with the latency-associated transcripts (LATs) the only gene product produced [36-38]. The mechanisms of lytic versus latent infections have been traced to epigenetic regulation, with viral lytic genes associated with heterochromatin, preventing transcription, during latency [39].
Reactivation — During the cycle of HSV recurrences, the virus undergoes reactivation from latent to lytic replication in trigeminal or sacral ganglia neurons with anterograde axonal transport to epithelial cells. The virus replicates in epithelial cells and may be shed asymptomatically or may be associated with clinically apparent ulcerations.
Immunocompromised hosts are at risk for an increased frequency of reactivation since HSV requires intact cellular immunity to be contained. However, even with a vigorous host humoral and cellular immune response, HSV evades eradication by multiple immune evasion mechanisms. Human studies have shown active surveillance by T cells both in the mucosa and in the ganglia [40,41].
CLINICAL MANIFESTATIONS — The clinical manifestations of herpes simplex virus type 1 (HSV-1) infection depend upon the anatomic site involved and whether the clinical episode is due to primary infection or reactivation disease. While infection is lifelong, it is rarely fatal in the immunocompetent host.
Asymptomatic infection — Many patients with primary HSV-1 infections are asymptomatic. Retrospective studies demonstrate that only 20 to 25 percent of patients with HSV-1 antibodies have a clinical history of oral-labial or genital infections [42,43]. However, asymptomatic viral shedding can lead to transmission to others via contact with secretions or mucous membranes [15]. (See 'Transmission' above.)
Oral infections — Inoculation of HSV-1 at mucosal surfaces or the skin results in viral replication at the epidermis and the dermis and infection of sensory and autonomic nerve endings. The virus then travels to sensory ganglia, where it establishes a latent reservoir that cannot be eliminated by the immune system. Once HSV-1 infection is established, the virus persists in a latent state in the trigeminal ganglia and reactivates intermittently. (See 'Primary infection and establishment of latency' above.)
Gingivostomatitis and pharyngitis are the most frequent clinical manifestations of primary HSV-1 infection, whereas herpes labialis is the most frequent sign of reactivation disease. (See 'Primary infection' below and 'Recurrent infection' below.)
Primary infection — In primary infection, clinical illness typically occurs 2 to 12 days after exposure [44,45] and may be characterized by the appearance of multiple painful oral lesions (herpetic gingivostomatitis) with local lymphadenopathy. Systemic symptoms can include fever, malaise, and headache. In the absence of antiviral therapy, the lesions associated with primary HSV-1 infection last for approximately 12 days (range 7 to 18 days) [46,47].
The presentation can differ in children and adults:
●Children – Primary HSV-1 oral infection usually presents as gingivostomatitis in children [48,49]. After a brief incubation period, fever, pharyngitis, and painful vesicular lesions develop suddenly [16]. Lesions can occur anywhere on the pharyngeal and oral mucosa and progress over several days, eventually involving the soft palate, buccal mucosa, tongue, and the floor of the mouth (picture 1). The intraoral vesicles ulcerate rapidly. Gingivitis and extensions to lips and cheeks can be seen, with consequent difficulties in eating, drinking, and swallowing. Children may require hospitalization for pain control and/or dehydration. Common systemic symptoms and signs include fever, malaise, myalgias, irritability, and cervical lymphadenopathy, which can last up to two weeks. A more detailed discussion of herpetic gingivostomatitis in young children is presented in a separate topic review. (See "Herpetic gingivostomatitis in young children".)
●Adults – Primary oral HSV-1 infection in adults often presents as severe pharyngitis. In one study of 613 college students, clinical pharyngitis was due to HSV-1 in 5.7 percent of cases [49]. Presenting signs of pharyngeal HSV-1 included pharyngeal edema (71 percent), tonsillar exudate (40 percent), and oral exudative and ulcerative lesions (34 percent). Other associated symptoms and signs can include fever, malaise, myalgia and cervical lymphadenopathy [48,49]. Severe mouth pain and fever usually persist for two to eight days, until the ulcers reepithelialize; in comparison, cervical lymphadenopathy may persist for weeks [49].
Other diseases that present with oral lesions and/or severe pharyngitis include aphthous stomatitis, syphilis, bacterial pharyngitis, enteroviruses (eg, herpangina), mononucleosis, and Stevens-Johnson syndrome. (See "Evaluation of acute pharyngitis in adults" and "Evaluation of sore throat in children" and "Oral lesions".)
Recurrent infection — Recurrent HSV-1 infections of the lips and perioral area are estimated to occur in 20 to 40 percent of the infected population [16]. (See 'Reactivation' above.)
In contrast to primary HSV-1, recurrent HSV-1 is rarely associated with systemic symptoms. Precipitating factors for HSV-1 recurrence include immunodeficiency, stress, exposure to sunlight, and fever [16,50]. Trauma to the area of primary infection, such as trigeminal nerve manipulation or dental procedures, may also trigger a recurrence [51].
Most patients (>85 percent) develop prodromal symptoms about 24 hours before the appearance of painful lesions at the lip borders [15,16]. These symptoms can include pain, burning, tingling, and pruritus and may last from 6 to 53 hours prior to the appearance of the first vesicles [16].
When recurrent lesions develop, they typically present as localized oral-labial ulceration (herpes labialis or cold sores/fever blisters) (picture 2 and picture 3). Recurrences typically present at the vermillion border (where the colored portion of the lips meets the skin), although they can also occur on the buccal intraoral surface. Recurrent aphthous ulcers are often confused with HSV-1 infection; however aphthous ulcers are rarely preceded by vesicles and occur exclusively on nonkeratinized mucosal surfaces, such as the inner surfaces of lips, buccal mucosa, ventral tongue, and mucobuccal fold in the anterior part of the oral cavity [52-54]. (See "Recurrent aphthous stomatitis".)
Recurrent HSV-1 lesions progress from vesicle to crust in five to eight days in the absence of antiviral therapy (picture 4), with significant diminution of pain after the first 24 hours [16]. While most lesions are small, larger lesions can take longer to heal [16].
The location, frequency, and severity of recurrences over time are highly variable between patients [16,55] but may have a typical pattern within individual patients. In one report, recurrences occurred as frequently as once per month (24 percent) or as infrequently as twice per year (19 percent) [16]. No differences in the frequency of recurrences between the sexes have been observed.
Genital HSV-1 infections — Patients with primary genital HSV-1 typically present with bilateral genital ulcerations and tender lymphadenopathy. Systemic symptoms such as fevers, headache, and myalgias can also occur. Autonomic dysfunction with hyperesthesia or anesthesia of the perineal region with concomitant urinary retention or constipation may develop in some patients, and in this setting, physical examination may be notable for increased bladder size on percussion, decreased sacral sensation, and poor rectal tone. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Extragenital complications'.)
Genital HSV-1 lesions may recur, particularly in the first year after infection; however, multiple recurrences are rare. In an observational study that followed the natural history of HSV-1 genital infection in 77 patients, there was a median of one recurrence per year in the first year after infection [56]. This is in contrast to HSV-2, which recurs more often in the genital area [37,57]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Recurrent infection'.)
For women with genital HSV-1, transmission of HSV-1 to infants can occur at delivery, especially in the setting of primary infection of the mother. This is discussed in greater detail elsewhere. (See "Genital herpes simplex virus infection and pregnancy" and "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)
Cutaneous manifestations — There are a variety of manifestations associated with HSV-1 infection of the skin, as discussed below.
Herpetic whitlow — HSV infection of the finger, known as herpetic whitlow, can occur by inoculation of the virus through a break in the skin barrier (picture 5 and picture 6). Untreated, these infections gradually heal over two to three weeks, but similar to oral HSV-1 infection, they can recur [58]. Herpetic whitlow is often misdiagnosed as a bacterial infection [59]. The distinction is important, since antibiotics and drainage are not necessary.
In children, herpetic whitlow can occur at the time of primary oral infection through autoinoculation. In one study, 80 percent of children with herpetic whitlows also had history of oral lesions [58]. Herpetic whitlow can also be an occupational hazard among dental workers and others whose hands are exposed to infected oral secretions, although these have become rare with universal use of barriers for mucosal exposures [60].
An additional discussion of herpetic whitlow is presented elsewhere. (See "Overview of hand infections", section on 'Herpetic whitlow'.)
Herpes gladiatorum — Herpes gladiatorum is a skin infection that classically occurs on the face, neck, and arms of wrestlers. Similar to HSV in other areas, it presents initially with a vesiculopustular rash on an erythematous base that progresses to ulceration and may be misdiagnosed as folliculitis or impetigo. Outbreaks of HSV-1 skin infections have occurred among wrestlers and rugby players in the context of close contact to skin, likely exposure to saliva, and superficial skin abrasions, which can occur during matches [61,62]. (See 'Populations at risk' above.)
Erythema multiforme — HSV-1 infection may be associated with the onset of erythema multiforme [63], which is an uncommon immune-mediated disorder that presents with cutaneous and/or mucosal lesions. HSV DNA may be detected from erythema multiforme lesions (picture 7) [64,65]. (See "Erythema multiforme: Pathogenesis, clinical features, and diagnosis".)
Eczema herpeticum — Patients with atopic dermatitis are at risk for developing an HSV-related skin complication called "eczema herpeticum" (also known as Kaposi's varicelliform eruption), particularly if they are taking immunosuppressive agents for control of their primary dermatologic condition. Eczema herpeticum is characterized by cutaneous pain and vesicular new skin lesions secondary to a viral infection (usually HSV-1) (picture 8); in some cases, the rash may be difficult to distinguish from the patient's baseline eczema if the latter is poorly controlled (picture 9) [66]. This eruption can also occur in burn patients. Eczema herpeticum can spread rapidly, leading to severe morbidity and mortality in the absence of antiviral therapy [67]; thus, prompt antiviral therapy is indicated while awaiting diagnostic testing for HSV, including administration of intravenous acyclovir in severe cases [68]. (See "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults", section on 'Cutaneous disease'.)
Ocular manifestations — Ocular HSV infections occur in less than 5 percent of patients but can cause significant morbidity, leading to vision loss and blindness. The most common ophthalmologic complications of HSV-1 are keratitis and acute retinal necrosis.
Keratitis — Recurrent HSV-1 keratitis continues to be a leading cause of corneal blindness in high-income countries [69,70]. HSV keratitis has an acute onset with symptoms of pain, visual blurring, and discharge. Physical examination is notable for chemosis, conjunctivitis, decreased corneal sensation, and characteristic dendritic lesions of the cornea (picture 10) [71]. Recurrent ocular HSV-1 infections are also common. Approximately 25 to 50 percent of patients with herpetic keratitis will have a recurrence within two years [69]. Recurrent bouts can lead to stromal involvement and scarring. A detailed discussion of HSV keratitis is presented in a separate topic review. (See "Herpes simplex keratitis".)
Acute retinal necrosis — Acute retinal necrosis (ARN) is a rare, potentially blinding, retinal disease resulting from ocular infection with HSV or varicella zoster virus (VZV). ARN is characterized by decreased vision and has been reported in immunocompetent hosts, pregnant people, and persons with HIV infection [72-75]. Bilateral ARN has been reported in children [76].
Conjunctivitis and blepharitis — HSV-1 can present as a unilateral conjunctivitis and/or blepharitis with the development of vesicles on the lid margin (picture 11). Associated symptoms include chemosis, edema of the eyelids, and tearing [69].
Chorioretinitis — Chorioretinitis, also known as posterior uveitis, is a manifestation of disseminated HSV infection that can be seen in neonates [48,77]. (See "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Skin, eye, and mouth disease'.)
Severe manifestations — HSV-1 can be associated with severe disease. When patients present with these clinical manifestations, typical oral or genital lesions are often not present, since these manifestations are usually reactivation events. Risk factors for severe disease include HIV infection, malignancy, organ and hematopoietic stem cell transplantation, malnutrition, burn and skin disorders, pregnancy, and advanced age [78-85]. More detailed discussions of HSV-1 infection in immunocompromised hosts and those with burn or skin disorders are found below. (See 'Special populations' below.)
Neurologic syndromes — A variety of neurologic syndromes have been linked to infection with HSV-1. These include:
●Encephalitis – HSV-1 causes sporadic cases of encephalitis with high rates of morbidity and mortality. The clinical syndrome is often characterized by the rapid onset of fever, headache, seizures, focal neurologic signs, and impaired consciousness [86]. Approximately one-third of cases occur in children and adolescents, with another peak among the elderly, likely reflecting primary HSV-1 infection in the former and reactivation in the latter. Several rare genetic deficiencies in the immune signaling pathways have been identified that result in recurrent HSV-1 encephalitis in children. This topic is discussed in great detail elsewhere. (See "Herpes simplex virus type 1 encephalitis".)
●Bell's palsy – HSV reactivation has become accepted as a cause of Bell's palsy. In one study, HSV-1 genomes were identified in facial nerve endoneurial fluid and auricular muscle in 11 of 14 patients undergoing decompression surgery for Bell's palsy but in none of the controls [87]. (See "Bell's palsy: Pathogenesis, clinical features, and diagnosis in adults".)
●Aseptic meningitis – HSV infection can be associated with aseptic meningitis in the setting of primary genital HSV infection, as well as a form of benign recurrent aseptic meningitis (Mollaret's meningitis). However, both are more common with genital HSV-2 rather than HSV-1 infection. (See "Aseptic meningitis in adults", section on 'Viral meningitis'.)
Other neurologic syndromes rarely associated with HSV-1 infection include autonomic dysfunction, usually manifesting as urinary retention in the setting of primary genital herpes infection, and transverse myelitis.
Hepatitis — Disseminated disease with fulminant hepatitis is a rare complication of HSV infection. Both HSV-1 and HSV-2 have been implicated as etiologic agents [88]. Typical oral and/or genital lesions occur in only 30 percent of patients, although sometimes scattered skin lesions can be identified [89]. Due to the lack of specific findings associated with HSV hepatitis, HSV should be on the differential of all cases of idiopathic fulminant hepatitis, especially during pregnancy [88]. Treatment with acyclovir has sometimes been life-saving [78,88]. (See "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis".)
Those at risk for HSV hepatitis include neonates, patients taking steroids, persons with HIV infection, those with cancer or myelodysplastic syndromes, and pregnant people [78,88-90]. HSV hepatitis has also been reported as an early cause of death after liver transplantation with concomitant lung and gastrointestinal involvement [78]. HSV-related hepatitis can be seen in immunocompetent hosts; however, this occurs rarely and is usually in the setting of new acquisition [88].
Respiratory tract infections — Children may develop epiglottitis or laryngitis (herpetic croup) with nonproductive cough and stridor [60]. In most patients, the illness is self-limited, lasting 10 to 14 days without complications. (See "Epiglottitis (supraglottitis): Clinical features and diagnosis".)
HSV-1 pneumonitis is very uncommon but can be seen in immunocompromised patients and may be due to direct extension from the upper airways secondary to tracheobronchitis. Cases have been reported in burn patients, solid organ and hematopoietic cell transplant recipients, patients with malignancy, pregnant patients, and patients with HIV infection [85,91-94]. HSV pneumonitis has been observed rarely in immunocompetent patients [95].
Sometimes it is hard to distinguish HSV colonization from HSV pneumonitis. As an example, although HSV detection from respiratory secretions in mechanically ventilated immunocompetent hosts has been reported [96,97], it is most often thought to represent viral contamination of the lower tract (eg, through instrumentation from the oropharynx or from local tracheobronchial viral reactivation without parenchymal involvement) rather than true bronchopneumonitis [98]. However, true infection (rather than contamination) should be suspected in patients who have a clinical syndrome consistent with viral pneumonitis when diffuse ground glass opacities are seen on imaging, intranuclear inclusions are identified from cytologic examination of bronchoalveolar lavage fluid, and HSV-1 is isolated from culture.
HSV esophagitis — HSV esophagitis can develop in both immunocompetent and immunocompromised hosts, although immunocompromised patients are at much greater risk. HSV esophagitis usually presents with odynophagia, dysphagia, or retrosternal chest pain. It can result from direct extension from the oropharynx or through reactivation and spread through the vagus nerve to the mucosa. This topic is discussed in detail elsewhere. (See "Herpes simplex virus infection of the esophagus".)
SPECIAL POPULATIONS
Immunocompromised hosts — Certain immunocompromised patients are at risk for increased frequency and severity of recurrent herpes simplex virus (HSV) infections compared with the general population, since intact cellular immunity is required to contain primary infection, prevent HSV reactivation, and minimize severity of disease. In patients with impaired cellular immunity, chronic mucocutaneous herpes simplex infection may extend into deeper cutaneous layers, leading to easy friability and tissue necrosis. This can be associated with severe pain and atypical-appearing lesions on examination [99]. Such patients are also at increased risk for viral shedding as well as dissemination of infection to sites that are rarely involved in immunocompetent hosts, such as the lungs or gastrointestinal tract. (See 'Severe manifestations' above.)
Examples of HSV-1 in specific immunocompromised populations include:
●HIV infection – Patients with advanced HIV infection (CD4 count <200 cells/microL) are at increased risk for recurrent and extensive HSV infections. HSV infections can occur anywhere on the skin or mucosal surfaces, often presenting as extensive perianal or oral ulcers (picture 12 and picture 13). Patients with advanced HIV infection can also develop esophagitis, colitis, chorioretinitis, acute retinal necrosis, tracheobronchitis, and pneumonia [83]. (See 'Severe manifestations' above.)
●Transplant recipients – Transplant recipients who have been previously infected with HSV-1 have been reported to have reactivation rates of 60 to 80 percent in the absence of suppressive antiviral therapy [78]. Suppressive acyclovir therapy reduces the risk of developing symptomatic HSV infection [100,101]. Detailed discussions of how to prevent HSV-1 reactivation in transplant recipients are presented elsewhere. (See "Prophylaxis of infections in solid organ transplantation", section on 'Herpes simplex and varicella-zoster' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus'.)
Immunocompromised hosts are also more likely to develop acyclovir-resistant infections compared with immunocompetent patients. Thus, persistence of HSV-1 ulcers despite several days of appropriately dosed antiviral therapy should raise suspicion of acyclovir resistance [102]. (See "Acyclovir: An overview", section on 'Mechanism of resistance'.)
Patients with burns and other skin disorders — Patients who have disrupted skin integrity secondary to severe burns or primary dermatologic disorders, such as eczema and pemphigus vulgaris, are at risk for severe HSV infection [103]. (See 'Eczema herpeticum' above.)
HSV-1 should be suspected at the site of burn wounds if the lesions appear discolored and ulcerated. Reactivation of HSV-1 infection can also lead to dissemination to the respiratory tract or visceral organs [82,91]. Necrotizing tracheobronchitis following intubation in burn patients has been described [104]. (See 'Severe manifestations' above.)
Pregnant persons — Pregnant persons who acquire HSV-1 during pregnancy are at risk for developing disseminated infection and fulminant hepatitis [88,105,106], as discussed above. (See 'Hepatitis' above.)
In addition, babies may be at increased risk of neonatal HSV infection. The epidemiology, clinical features, and diagnosis of neonatal HSV infection are presented separately. (See "Genital herpes simplex virus infection and pregnancy", section on 'Vertical transmission' and "Neonatal herpes simplex virus infection: Clinical features and diagnosis".)
DIAGNOSIS
Approach to testing — The approach to testing depends upon the site of disease.
●Mucosal or cutaneous disease – We obtain testing to confirm the diagnosis of herpes simplex virus (HSV) in patients who present with new mucosal or cutaneous lesions or recurrent mucosal or cutaneous lesions of unclear etiology.
•The diagnosis of HSV infection is generally based upon virologic confirmation through DNA detection via polymerase chain reaction (PCR) or culture of the virus. Real-time HSV PCR assays have emerged as the most sensitive method to confirm HSV infection in clinical specimens obtained from mucocutaneous sites. Other tests, such as direct fluorescent antibody testing or Tzank smears, are less sensitive and less specific. (See 'Tests to confirm the diagnosis' below.)
•To obtain an adequate specimen for PCR or culture, the vesicle should be "unroofed" with a sterile swab. The base of the ulcer should be swabbed to isolate epidermal cells, which contain HSV.
Serologic testing has limited application in confirming the diagnosis of acute HSV-1 infection. In addition, antibody titers have not been found to correlate with positive cultures or the presence of lesions [12]. (See 'Role of serologic testing' below.)
●Ocular disease – The diagnosis of ocular HSV-1 infection is often clinical and should be made in conjunction with an experienced ophthalmologist. However, detection of viral DNA via PCR testing from intraocular fluid may be helpful to confirm the diagnosis of acute retinal necrosis. (See 'Polymerase chain reaction' below.)
A detailed discussion of the diagnosis of HSV-1 keratitis is presented in a separate topic review. (See "Herpes simplex keratitis", section on 'Clinical manifestations'.)
●Visceral and neurologic infection – When neurologic or visceral infection is suspected, HSV is often diagnosed by detecting HSV DNA from a sterile site (eg, cerebrospinal fluid), by identifying the organisms in a tissue biopsy (eg, lung, liver, or esophagus) based on pathologic findings (intranuclear inclusions and immunocytochemistry), or through culture. Histologic findings may be particularly helpful to confirm the diagnosis when it is unclear if detection of HSV by PCR reflects true infection or contamination from oral secretions. (See 'Respiratory tract infections' above and 'HSV esophagitis' above.)
HSV PCR from blood may be helpful for diagnostic and clinical management purposes in cases of disseminated multi-organ neonatal herpes or fulminant HSV hepatitis [107]. While low-level viremia may be present in persons with severe mucosal disease, high copy number in a neonate or a patient with hepatitis indicates dissemination.
More detailed discussions of how to diagnose visceral and neurologic disease are found in separate topic reviews. (See "Herpes simplex virus type 1 encephalitis", section on 'Diagnosis' and "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis" and "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Liver biopsy' and "Neonatal herpes simplex virus infection: Clinical features and diagnosis", section on 'Evaluation and diagnosis'.)
Tests to confirm the diagnosis — In patients with suspected HSV-1 infection, the most commonly used tests to confirm the diagnosis are HSV PCR and culture.
Polymerase chain reaction — Real-time HSV polymerase chain reaction (PCR) assays have emerged as the most sensitive method to confirm HSV infection in clinical specimens obtained from mucocutaneous sites, including oral and genital ulcers. Detection of HSV with PCR is more sensitive than culture; in one study, the rate of HSV-1 detection in self-collected samples from the mouth, nasal mucosa, and tears was three times higher with PCR [108]. However, the sensitivity of the PCR assay is dependent on the amount of virus present; as an example, the sensitivity has been reported to be >95 percent with ≥3 log10 copies/mL of HSV present [109]. The sensitivity can also vary depending upon the assay that is used, and multiple different PCR assays are available in clinical laboratories.
In addition to mucocutaneous disease, detection of HSV DNA in cerebrospinal fluid (CSF) by PCR has become the standard for the diagnosis of HSV meningitis and encephalitis. In patients with encephalitis, PCR testing on CSF offers rapid results with high sensitivity and specificity compared with brain biopsy specimens. (See "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis".)
PCR may also be utilized to test vitreous fluid for HSV in the setting of acute retinal necrosis [75,110]. The use of quantitative PCR to determine if HSV quantity is prognostic for improved visual acuity is being explored [111,112].
Viral culture — When viral cultures are obtained, viral medium should be immediately transported to the appropriate laboratory, but it may be stored at 4°C for up to nine hours [16]. The characteristic cytopathic effects appear in the selected cell line within 24 to 48 hours, especially if the initial inoculum is high [113].
Viral culture is less sensitive than PCR for detection of HSV, as described above. In addition, the quantity of HSV present in the specimen directly correlates with the sensitivity of viral culture. As an example, in a study comparing PCR and culture positivity, 45 percent of samples were positive by viral culture when HSV DNA was detected by PCR when ≥4 log10 copies/mL of HSV DNA were present; however, only 6 percent of samples with <4 log10 copies/mL HSV DNA were positive by viral culture [114].
Other tests — In addition to PCR and culture, other types of tests are available; however these are not recommended because of their poor sensitivity compared with PCR and culture.
Such tests include:
●The direct fluorescent antibody assay, which is an antigen detection test that can be performed in patients with active mucocutaneous lesions. Although this test provides rapid results, its sensitivity is 50 and 70 percent compared with PCR and culture, respectively [115,116]. The sensitivity can be impacted by multiple factors, including the quality of the sample and the skill of the microscopist.
●The Tzanck smear is performed by smearing material scraped from the base of a vesicle onto a slide and staining it with Wright's stain. A positive smear demonstrates the characteristic cytopathic effect of herpesviruses (multinucleate cells with or without intranuclear inclusions). This test has limited utility because of its poor sensitivity and specificity.
Role of serologic testing — Type-specific antibodies to HSV develop during the first several weeks after primary infection and persist indefinitely. Serologic assays can distinguish between HSV-1 and HSV-2 but do not differentiate between sites of infection (eg, oral versus genital HSV-1). Various assays have been used to detect antibodies, these include virus neutralization, complement fixation, passive hemagglutination, enzyme-linked immunosorbent assay (ELISA), complement-mediated cytolysis, antibody-dependent cellular lysis, and radioimmunoassays [117-119].
In general, serologic testing has a limited role in the diagnosis of HSV-1 infection, since primary infection may be diagnosed in patients who are HSV antibody negative but who have positive viral cultures and evidence of acute infection. In addition, many of the commercially available antibody assays for HSV are insufficiently accurate, often providing false-negative results for HSV-1 and false-positive results for HSV-2 [120]. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection", section on 'Serologic testing'.)
However, obtaining serologies may be reasonable to help determine prognosis and prevention. As an example, in a patient with a clinical history of herpes symptoms who does not have any active lesions at the time of the patient encounter, distinguishing between HSV-1 and HSV-2 infection via serologic testing may be useful. In addition, negative serologic testing would indicate that an individual is at risk for acquiring HSV infection. (See "Epidemiology, clinical manifestations, and diagnosis of genital herpes simplex virus infection" and "Treatment and prevention of herpes simplex virus type 1 in immunocompetent adolescents and adults".)
Serologic testing can also be useful to determine the need for prophylaxis in certain immunocompromised hosts, such as solid organ and hematopoietic cell transplant recipients, since those who are seropositive for HSV should initiate antiviral prophylaxis prior to transplant. However, type-specific antibody assays are not required, as both HSV-1 and HSV-2 are managed with antiviral prophylaxis. (See "Prophylaxis of infections in solid organ transplantation", section on 'Herpes simplex and varicella-zoster' and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Cold sores (oral herpes) (The Basics)")
●Beyond the Basics topic (see "Patient education: Genital herpes (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Epidemiology – Herpes simplex virus type 1 (HSV-1) infection occurs worldwide. Infection occurs equally between the sexes and without seasonal variation. The prevalence is highest in low- and middle-income countries, whereas the prevalence rate in high-income countries has been declining. (See 'Epidemiology' above.)
●Transmission – Transmission of HSV-1 occurs when someone with no prior infection with HSV-1 comes in contact with herpetic lesions or oral secretions that contain HSV-1.
HSV-1 transmission typically occurs via oral-oral, oral-genital, or genital-genital contact. It can also occur via contamination of skin abrasions with infected oral secretions. (See 'Transmission' above.)
Transmission via oral-genital or genital-genital contact has resulted in an increasing number of cases of HSV-1 genital herpes infection, especially among young women and men who have sex with men. (See 'Populations at risk' above.)
●Clinical manifestation – The clinical manifestations of HSV-1 infection depend upon the anatomic site involved and whether the clinical episode is due to primary infection or reactivation disease. While infection is lifelong, it is rarely fatal in the immunocompetent host. (See 'Clinical manifestations' above.)
•Gingivostomatitis and pharyngitis are the most frequent clinical manifestations of primary HSV-1 infection, whereas herpes labialis is the most frequent sign of reactivation disease. (See 'Oral infections' above and 'Genital HSV-1 infections' above.)
•Patients with primary genital HSV-1 typically present with bilateral genital ulcerations and tender lymphadenopathy. Genital HSV-1 lesions may recur, particularly during the first year after infection; however, multiple recurrences are rare. (See 'Genital HSV-1 infections' above.)
•There are a variety of cutaneous manifestations associated with HSV-1 infection of the skin. These include herpetic whitlow, herpes gladiatorum, erythema multiforme, and eczema herpeticum. (See 'Cutaneous manifestations' above.)
•Ocular HSV infections occur in less than 5 percent of patients but can cause significant morbidity, leading to vision loss and blindness. The most common ophthalmologic complications of HSV-1 are keratitis and acute retinal necrosis. (See 'Ocular manifestations' above.)
•HSV-1 can be associated with severe disease (eg, encephalitis, meningitis, hepatitis, respiratory tract infections, esophagitis). Risk factors for severe disease include HIV infection, malignancy, organ transplantation, malnutrition, burn and skin disorders, and pregnancy. (See 'Severe manifestations' above and 'Special populations' above.)
●Diagnosis – The approach to diagnosis depends upon the site of disease (eg, mucocutaneous, ocular, neurologic or visceral). Polymerase chain reaction assays have emerged as the most sensitive method to confirm the diagnosis. (See 'Approach to testing' above and 'Tests to confirm the diagnosis' above.)
Type-specific antibodies to HSV develop during the first several weeks after primary infection and persist indefinitely. However, serologic testing has a limited role in the diagnosis of HSV-1 infection, since patients with acute infection who are HSV antibody negative may have virologic evidence of acute infection. Serologies may be most helpful in determining prognosis and the need for prevention. (See 'Role of serologic testing' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robyn S Klein, MD, PhD, who contributed to an earlier version of this topic review.
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