HSV-2 is the main trigger of genital herpes, which is characterized by the recurrent appearance of often painful lesions on the external genitalia, in the perianal region, or on the buttocks and upper thighs. The first onset of symptoms typically occurs within a week after the sexual acquisition of HSV-2, with affected individuals developing papules and vesicles that turn into ulcers before crusting and healing. Besides pain, patients frequently claim burning sensations and pruritus. Dysuria is commonly described by female patients. Local complaints may be accompanied by constitutional symptoms such as fever, malaise, headache, and myalgia. Because HSV-2 may spread to the local and regional lymph nodes, primary infections may be associated with inguinal and femoral lymphadenopathy. Neither constitutional symptoms nor lymphadenopathy tend to recur, but ulcerative blisters do: They initially reappear about four times a year, but relapses become less frequent as time goes by. Also, there is a general trend towards milder symptoms during relapses, and while the first symptoms may take weeks to resolve, lesions developing during recurrences typically heal within 5-10 days. More severe and persistent lesions, however, are observed in the immunocompromised and neonates [1].

Indeed, HSV-2 is the principal cause of congenital herpes simplex. Affected neonates may have acquired HSV-2 in utero, during delivery, or postnatally. The earlier the infection is established, the more detrimental consequences are to be expected. Congenital herpes simplex may cause abortion, stillbirth or perinatal death. In case of survival, growth retardation and developmental delays become apparent soon after birth. Microcephaly, encephalomalacia and intracranial calcifications are characteristic features of congenital herpes simplex and may be detected during the first days of life. The patients may suffer from fever, lethargy, and seizures, and present eye and skin lesions. Microphthalmia, cataract, chorioretinitis, and optic atrophy are common findings, and neonates often have a vesicular rash [2]. Pathogen dissemination is possible and may entail multiple organ failure and death [3].

Beyond that, immunodeficiency augments the risk of disseminated herpes simplex. There is a strong correlation between infections with HSV-2 and the human immunodeficiency virus (HIV) [4]. HSV-2 may reach the central nervous system, lungs, liver, and other organ systems, thereby inducing life-threatening HSV-2 encephalitis, pneumonia, or hepatitis, among others. These complications may result in the following clinical pictures:

• HSV-2 encephalitis may be diagnosed in neonates but is exceedingly rare in adults. Seizures, encephalopathy, and an altered mental state have been described as presenting symptoms [5]. HSV-2 may also induce meningitis, which usually manifests in fever, headache, photophobia, nausea, and vomiting [6].
• Similarly, Herpes simplex pneumonia is more commonly attributed to HSV-1. Affected individuals present with fever, cough, and dyspnea. HSV-2 has been identified as the causative agent, and the clinical presentation is identical [7] [8].
• Herpes simplex hepatitis tends to follow a fulminant course. Affected individuals may suffer from fever and upper abdominal pain. The results of blood sample analyses are most remarkable for severely increased levels of hepatic transaminases [9] [10].

Further manifestations of HSV-2 infections comprise herpetic whitlow and ocular infections. The latter may result in epithelial or stromal keratitis, kerato-uveitis or endothelitis, and retinitis [11] [12]. Herpetic whitlow is also referred to as herpetic paronychia and is characterized by an acute, often painful vesicular eruption on the fingers. It may be associated with lymphadenitis and is more commonly attributed to HSV-2 when acquired in adolescence or adulthood [13].

• Inguinal Lymphadenopathy

  Painful vesicles, ulcers, redness and swelling last for 2 to 3 weeks, if untreated, and are often accompanied by fever and tender inguinal lymphadenopathy. In males, herpes most often affects the glans, foreskin and shaft of the penis. [dermnetnz.org]

  She had no cervical, submandibular, axillary, or inguinal lymphadenopathy. Skin examination revealed no rashes and external genital exam did not reveal any vesicular lesions or discharge. [hindawi.com]

• Fever

  Local complaints may be accompanied by constitutional symptoms such as fever, malaise, headache, and myalgia. [symptoma.com]

  Cold sores (or fever blisters) are very common. They usually go away on their own within 1 to 2 weeks. What Are the Signs & Symptoms of Cold Sores? Cold sores first form blisters on the lips, around the mouth, and sometimes inside the mouth. [kidshealth.org]

  While similar to HSV-1 encephalitis in many respects, it may present without fever and with normal imaging or only very subtle imaging abnormalities. [n.neurology.org]

  The affected person may feel well or suffer from fever, pain and have enlarged local lymph nodes. [dermnetnz.org]

• Malaise

  Primary infections can range from subclinical to severe, with fever, headache, malaise, anorexia, pain, lymphadenopathy and edema. Secondary infections are usually milder. [clinicaladvisor.com]

  The symptoms can be quite severe and may include: blisters and ulceration on external genitalia, in the vagina, or on the cervix vaginal discharge pain and itching tender, enlarged lymph nodes pain when urinating high temperature (fever) malaise (feeling [medicalnewstoday.com]

  About 10 per cent of primary infections cause a more severe form of disease manifested by fever and malaise. [www2.health.vic.gov.au]

  Local complaints may be accompanied by constitutional symptoms such as fever, malaise, headache, and myalgia. [symptoma.com]

• Sepsis

  […] pacientēm ar recidivējošu olnīcu vēzi en Treatment with Protopic may be associated with an increased risk of herpes viral infections (herpes simplex dermatitis [ eczema herpeticum ], herpes simplex [ cold sores ], Kaposi s varicelliform eruption en Sepsis [lv.glosbe.com]

  Infants started on IV antibiotics for suspected sepsis who are found to have unexplained hepatitis. [cps.ca]

  Infection that spreads to the bloodstream and body-wide (sepsis) can also be a concern for children whose immune systems are weakened by certain diseases and medications. [healthychildren.org]

• Epilepsy

  […] societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association Disclosure: Serve(d) as a director, officer, partner, employee, advisor, [medscape.com]

  The role of HHV-6 as a viral predisposing cause of epilepsy due to mesial temporal sclerosis makes it plausible that early administration of efficacious antiviral therapy may prevent the development of epilepsy in affected children [49]. [ajronline.org]

• Perianal Ulcer

  Sexually Transmitted Disease Treatment Guidelines: Diseases Characterized by Genital, Anal, or Perianal Ulcers. Available online at http://www.cdc.gov/std/treatment/2010/genital-ulcers.htm#hsv. Page last reviewed January 28, 2011. [labtestsonline.it]

  Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur. HSV outbreaks may be followed by erythema multiforme, possibly caused by an immune reaction to the virus. [msdmanuals.com]

  Siegal F P, Lopez C, Hammer G S. et al Acquired immunodeficiency in male homosexuals manifested by chronic perianal ulcerative herpes simplex lesions. N Engl J Med 19813051439–1444. [PubMed] [Google Scholar] 51. [ncbi.nlm.nih.gov]

• Vesicular Rash

  Microphthalmia, cataract, chorioretinitis, and optic atrophy are common findings, and neonates often have a vesicular rash. Pathogen dissemination is possible and may entail multiple organ failure and death. [symptoma.com]

  This form of infection, which is a reactivation of latent virus, typically manifests as a localized vesicular rash with a dermatomal distribution. [ncbi.nlm.nih.gov]

  Reactivation of quiescent virus in the geniculate ganglion of the facial nerve (Ramsay Hunt syndrome, also known as herpes zoster oticus) is characterized clinically by intense pain in the ear and retroauricular region, erythematous vesicular rash in [ajronline.org]

• Suggestibility

  […] pathway analyses revealed that these T cells significantly upregulated antiviral genes such as GZMB, PRF1, INFG, IL-32, and LTA, carbohydrate and lipid metabolism-related genes such as GLUT-1, and chemotaxis and recruitment genes such as CCL5 and CCR1, suggesting [ncbi.nlm.nih.gov]

  Recent studies suggest that as much as 30% of neonatal HSE is due to HSV-1. The risk of acquisition during a primary infection with HSV-1 or HSV-2 is 50%. [jamanetwork.com]

• Meningism

  […] aseptic meningitis due to HSV-2 may occur with or without symptomatic herpetic mucocutaneous disorder. [jamanetwork.com]

  Infection may also occur year-round when the cause is exposure to infected pet hamsters. § Meningitis due to HIV usually begins early in the course of systemic infection—when seroconversion occurs. [msdmanuals.com]

  The meninges are the layers of thin tissue that cover your brain. If these tissues become infected, it’s called meningitis. When your brain becomes inflamed or infected, the problem is called encephalitis. [hopkinsmedicine.org]

• Burning Sensation

  This can last for approximately two weeks, and a burning sensation during urination and clear discharge from the penis is common. Symptoms include lymph node enlargement, fever, tiredness, headache, and muscle aches during the episode. [biology.kenyon.edu]

  sensation in the legs, buttocks or genital region Treatment for Herpes Simplex The sores caused by HSV-1 and HSV-2 usually disappear within a few weeks. [uclahealth.org]

  If you’re one of them, odds are you know this pattern: A tingling or burning sensation on your lip. A day later, an oozy, fluid-filled blister on your mouth, always at the most inopportune time. [health.clevelandclinic.org]

  People who do have symptoms may experience: an itching, tingling, or burning sensation around the lips and mouth or in the genital area painful red sores irritated skin small blisters that ooze or bleed Share on Pinterest Wearing condoms or dental dams [medicalnewstoday.com]

  Besides pain, patients frequently claim burning sensations and pruritus. Dysuria is commonly described by female patients. Local complaints may be accompanied by constitutional symptoms such as fever, malaise, headache, and myalgia. [symptoma.com]

• Stroke

  Kis et al. detected increased levels of HSV-1 antibodies in patients with acute ischemic stroke, suggesting an association of HSV-1 infection with the disease [14]. [hindawi.com]

  The major benefit from using best-contrast would be expected in the diagnosis of stroke. [ajronline.org]

  Chief Editor Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health Niranjan N Singh [medscape.com]

• Chorea

  Severe chorea with positive anti-basal ganglia antibodies after herpesencephalitis. J Neurol Neurosurg Psychiatry. 2007 Jan. 78(1):105-7. [Medline]. [Full Text]. Sköldenberg B, Aurelius E, Hjalmarsson A, Sabri F, Forsgren M, Andersson B, et al. [medscape.com]

• Aphasia

  Selective language aphasia from herpes simplex encephalitis. Pediatr Neurol. 1996 Sep. 15(2):169-71. [Medline]. McGrath NM, Anderson NE, Hope JK, Croxson MC, Powell KF. Anterior opercular syndrome, caused by herpes simplex encephalitis. [medscape.com]

• Genital Lesions

  Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose. Results: One hundred and thirty-four persons received all 3 doses. [ncbi.nlm.nih.gov]

  Correlation between the Recognition of Genital Herpes Lesions and Viral Shedding in 53 HSV-2– Seropositive Subjects with No Reported History of Genital Herpes. [nejm.org]

  Measurements: Women collected daily genital swabs of the vulvar, cervicovaginal, and perianal areas for HSV culture, maintained a diary of genital lesions, and were examined at the time of recurrences. [annals.org]

• Vaginal Discharge

  Symptoms include blisters, ulcers, pain when urinating, cold sores, and vaginal discharge. Although there is no cure for herpes, it can be treated using medications and home remedies. [medicalnewstoday.com]

  Other frequent symptoms are painful urination, urethral or vaginal discharge and swollen lymph nodes. The first exposure or primary episode consists of headache, fever, chills and muscular weakness. [health.ny.gov]

  In our study it was found that HSV-2 prevalence was higher among subjects with excessive vaginal discharge but was not significant statistically. [bmcinfectdis.biomedcentral.com]

  Symptoms such as weakness and fever, headache, nerve pain, itching, lower abdominal pain, urinary difficulties, and yeast infections and vaginal discharge (in women) are characteristics accompanying the eruptions on the skin--only a minority of patients [biology.kenyon.edu]

  Women can also present with vaginal discharge. Some people can be infected and remain asymptomatic; however, they can still spread the virus to other people. After the first episode, the virus can become latent and remain in sensory nerves. [policylab.us]

In the majority of cases, a tentative diagnosis of Herpes simplex infection may be made based on the patient's medical history and clinical findings. With regard to genital lesions, HSV-2 is the main cause of genital ulcers worldwide [1], so the intermittent course of the disease and the development of genital blisters are highly suspicious of a latent infection with HSV-2. Still, HSV-1 and other agents - namely Treponema pallidum (syphilis), Chlamydia trachomatis serotypes 1-3 (lymphogranuloma venereum), Haemophilus ducreyi (chancroid), Klebsiella granulomatis (granuloma inguinale), and distinct fungi - may cause similar lesions [14]. A more extensive workup may also be required to determine the involvement of HSV-2 in atypical disease or infections of the immunocompromised.

Serological tests assessing the presence of IgG antibodies against HSV-2 may shed light on the cause of genital and extragenital lesions. Alternatively, molecular biological assays may be carried out to confirm the suspicion [15] [16]. Polymerase chain reaction for HSV-2 is considered a highly sensitive method and does not depend on the presence of viable HSV-2 or appropriately infected cells - while the conventional isolation of HSV-2 in tissue cultures does. In those cultures, characteristic cytopathic effects are typically observed after 24-72 hours. Besides enlarged, rounded, and refractile cells subsequently undergoing necrosis, syncytia and multinucleated giant cells may be observed. Cytological changes may also be seen during the histological examination of specimens obtained with cotton swabs [17]. Syncytial giant cells and intranuclear inclusions may be detected [1].

Clinical suspicion merits the initiation of antiviral treatment before the confirmation of HSV-2 infection. Similarly, the administration of antivirals upon the notion of prodromal symptoms like tenderness, pain, or paresthesias in the lumbosacral dermatomes may prevent symptomatic recurrences [1].

Virostatics employed in the management of HSV-2 infections inhibit peripheral virus replication and lytic cycles. They are not generally administered with curative intent, but to alleviate complaints and to shorten symptomatic episodes, and thus, they are hardly used in asymptomatic individuals. Acyclovir is the best-known representative of this type of drugs, which may be applied topically or systemically. In the case of genital herpes, the systemic application of acyclovir has been shown to yield best results [1]. Besides acyclovir, nucleoside analogues valaciclovir and famciclovir are available for the management of genital herpes and other HSV-2 infections, while additional active substances are currently on trial. The decision in favor of or against the use of determined pharmaceuticals should consider the site and severity of infection, the pharmacokinetic properties of the drug, and possible antiviral drug resistance [18]. As implied above, dormant HSV-2 in the dorsal root ganglia and other sensory neurons are not affected by acyclovir and related compounds. They don't prevent recurrence and neither resolve the latent infection. To date, there is no cure for HSV-2 infections [19].

Morbidity associated with genital herpes is not limited to the mucocutaneous and extragenital lesions described above but also involves a strong psychological component. In this context, those diagnosed with genital herpes may benefit from psychological support [1].

Close to half a billion people are infected with HSV-2. Yet, periodic viral shedding may be asymptomatic, and the majority of affected individuals is unaware of their condition [17] [20]. But despite the fact that incident infections with HSV-1 tend to be more severe than those with HSV-2, recurrences and subclinical viral shedding are much more common in genital herpes due to HSV-2 [17]. Furthermore, HSV-2 is known to increase the susceptibility to infections with HIV. It is thus assumed to significantly contribute to the spread of this disease, and patients who are diagnosed with HSV-2 infections should not only be tested regarding possible co-infections but also informed about their belonging to a risk group [20].

Worst outcomes are seen in the immunocompromised and neonates. In the absence of therapy, mortality due to congenital herpes simplex exceeds 80% [2]. Disseminated HSV-2 infections of immunodeficient patients are similarly associated with high morbidity and mortality [5]. Even in immunocompetent individuals, ocular HSV-2 infections may result in blindness [21].

HSV-2 is a human pathogen that belongs to the family of herpesviridae and the subfamily of alphaherpesvirinae. It is transmitted almost exclusively via the sexual route. Because characteristic herpes blisters form near the primary site of infection, the sexual acquisition of HSV-2 usually results in genital herpes. The latter is associated with periodic but possibly asymptomatic viral shedding in genital secretions, which facilitates the spread of the disease [21]. Besides sexual partners, neonates are at risk of contracting the virus: The presence of HSV-2 in vaginal secretions is a major risk factor for congenital herpes simplex in children born to infected mothers. First infections during the third trimester of pregnancy are most likely to cause neonates to acquire the pathogen during delivery. The intrauterine transmission of HSV-2 is feasible but accounts for <5% of congenital cases [2].

Manifestations other than genital herpes or congenital herpes simplex are relatively rare, but HSV-2 may initiate infections at other mucosal or cutaneous surfaces. In this context, direct droplet spread of the virus may result in HSV-2 keratitis and related disorders [22], while herpetic whitlow usually affects the distal phalanx of one or more fingers [13].

Finally, the possibility of autoinoculation shall be mentioned. Indeed, herpetic whitlow is most frequently diagnosed in those with a history of typical Herpes simplex infections: Infectious droplets may originate from the patient's own genital secretions [13].

HSV-2 is highly prevalent all over the world. According to estimates, a total of 417 million people are infected with this virus, which results in a global prevalence of 11%. HSV-2 prevalence is highest in Africa, where almost one-third of the population is infected. Females are affected more frequently than males, and the global female-to-male ratio is close to 2. With regard to the age of people at the time of incident infections, the virus is most commonly acquired in adolescence or early adulthood, coincident with the initiation of sexual activity. Because HSV-2 establishes life-long infections, total prevalence rates increase with age [20].

HSV-2 is able to replicate within epithelial cells and neurons. Primary infections are usually established within the stratified squamous epithelium of the anogenital mucosa, where first lytic cycles are completed. The virus subsequently invades the local sensory nerve endings and is retrogradely transported along the axon to the neuronal cell body. Accordingly, HSV-2 is typically found in the lumbosacral ganglia [2]. While the axonal ascent of HSV-2 is critical for establishing life-long infections, the virus remains latent in neurons and barely replicates. Further lytic cycles are induced upon reactivation, when the pathogen undergoes anterograde transport towards peripheral nerve endings and surrounding epithelial cells. Even though HSV-2 tends to return to the primary site of infection, the virus may take alternative routes and exit at the nerve ending of any branch of the axon [1]. The reactivation of latent HSV-2 infections has been related to local stimuli such as exposure to ultraviolet light and trauma, and to systemic conditions resulting in fever or immunosuppression. In most cases, though, the precise cause of the current episode cannot be identified [1].

Furthermore, HSV-2 infections have been shown to increase the risk of HIV infections. On the one hand, genital lesions due to HSV-2 serve as a ready port of entry for HIV, and the Herpes simplex virus may accelerate HIV disease progression. While genital shedding of HIV is facilitated by HSV-2, the opposite is also true, and both the frequency and quantity of HSV-2 shedding are enhanced in those infected with HIV [1].

To date, there are no vaccines against HSV-2 infections. Due to the high prevalence of the pathogen, the general risk of infection is quite high. Nevertheless, seronegative people may adopt certain rules of conduct to reduce their individual risk of acquiring HSV-2, and such rules should be followed during periods of increased susceptibility. Pregnant women, for instance, should avoid primary infections to protect their unborn child. They should be encouraged not to change their sexual partners and to use condoms. If sexual partners are known to be infected with HSV-2 and abstinence is not an option, antiviral treatment of the infected partner may reduce the risk of sexual virus transmission [1]. Similarly, the prophylactic administration of antiviral drugs is recommended in seropositive patients undergoing immunosuppressive or chemotherapy [23].

Herpes simplex viruses belong to the family of herpesviridae. There are two types of Herpes simplex viruses, which are referred to as HSV-1 and HSV-2. Infections with either type of virus may trigger a variety of diseases. The majority of patients presents with characteristic lesions in the mouth and throat or external genitals, but systemic disease has been reported. In any case, mucocutaneous herpes simplex virus infections are most commonly attributed to HSV-1, while genital herpes is frequently caused by HSV-2 [21]. Clinical findings hardly allow for the differentiation between HSV-1 and HSV-2, which requires serological or molecular biological studies. In order to avoid duplications of content, though, this article focuses on genital herpes and summarizes less common manifestations of infections with HSV-2. For detailed information on orolabial herpes, the interested reader is referred to the respective entry on Herpes simplex virus 1 infection, available on this platform.

Herpes simplex virus 2 infection is most commonly associated with genital herpes, i.e., the recurrent appearance of ulcerative blisters on the external genitalia, in the perianal region, or on the buttocks and upper thighs. It is almost exclusively transmitted via the sexual route, and patients may shed the virus in the absence of symptoms. Besides sexual partners, the unborn child of infected women is at risk of contracting the disease. The transmission of HSV-2, as the causative agent is commonly called, during pregnancy or delivery may result in congenital herpes simplex, causing abortion, stillbirth or perinatal death. In case of survival, the child may experience growth retardation and developmental delays. Furthermore, immunodeficient patients must fear life-threatening complications of infections with HSV-2.

Due to the high prevalence of the virus, the life-long prevention of HSV-2 infection is a major challenge. Nevertheless, measures may be taken to prevent primary infection and to avoid recurrences during periods of increased susceptibility. The individual risk of contracting HSV-2 may be reduced by avoiding the direct or indirect contact with people suffering from symptomatic genital herpes, by limiting the number of sexual partners, and using condoms. Antiviral drugs may be administered to prevent symptomatic episodes, to alleviate complaints and to accelerate the healing of lesions.

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