- Types of Herpes Simplex Infection
- Classification and Genomic structure of Herpes Simplex Virus
- Modes of Spread
- Symptoms and Signs of Herpes Simplex Infection
- Other Forms of Herpes Simplex Infection
- Long-term Course of Infection
- Lab Studies of Herpes Simplex Infection
- Diseases that Mimic Herpes Simplex Infection
- Treatment of Herpes Simplex Infection
- Prevention of Herpes Simplex Infection
Herpes simplex is an infection caused by HSV (herpes simplex virus). This virus can affect various organs including the external genitalia, anal region, mucosal surfaces, and skin in other parts of the body.
It is a contagious disease causing sores, painful blisters or ulcers at the site of infection.
The term herpes is derived from the Greek word “to creep or crawl” and refers to the spreading nature of herpetic skin lesions. The disease was known to people of early Greek civilization as far as 2000 years ago.
Types of Herpes Simplex Infection
There are two types of herpes simplex viruses, type 1 (HSV-1) and type 2 (HSV-2).
HSV-1 more commonly causes infections around the mouth but can also cause genital herpes
HSV-2 commonly causes genital infections.
Both of these are highly contagious infections and once acquired are lifelong.
Classification and Genomic structure of Herpes Simplex Virus
Both HSV-1 and HSV-2 are large double-stranded DNA viruses of the Herpetoviridae family and alpha-herpetovirinae sub-family.
Both of these share a similar genome structure, with 40% of sequence homologies reaching 83% homology of their protein-coding regions. This results in vast biological similarities and antigenic cross-reactivity between the two types.
HSV-1 and HSV-2 genomes each encode at least 80 different structural and non-structural polypeptides including at least 10 different viral glycoproteins.
Modes of Spread
Oral herpes caused by HSV-1 is mainly transmitted by oral to oral contact. Most HSV-1 infections are acquired during childhood, and infection is lifelong.
Genital herpes caused by HSV-2 is most commonly sexually transmitted, through contact with genital surfaces, skin, sores or fluids of someone infected with the virus.
HSV 2 can also cause vertical transmission from infected mother to the neonate during delivery leading to neonatal herpes.
Herpes infection is common and endemic throughout the world.
An estimated 3.7 billion people under the age of 50 (67%) have HSV-1 infection globally.
An estimated 417 million people aged 15-49 (11%) worldwide have HSV-2 infection.
Although many people infected with HSV develop oral or genital lesions, the majority are either undiagnosed or show no physical symptoms (asymptomatic or subclinical herpes)
Symptoms and Signs of Herpes Simplex Infection
HSV can cause either primary or reactivation (recurrent) infections
Primary infections are accompanied by systemic signs, longer duration of symptoms, and a higher rate of complications.
Recurrent infections are typically milder and shorter.
Oral herpes infection is mostly asymptomatic, and the majority of people with HSV-1 infection are unaware they are infected.
Acute infections usually present with non-specific flu-like symptoms including body aches, fever, sore throat, and malaise.
Acute Herpetic Gingivostomatitis
It is most commonly seen in children. It presents with swollen and erythematous gums. Vesicles develop on the oral mucosa, tongue, and lips which later rupture and coalesce, leaving ulcerated plaques.
Acute Herpetic Pharyngotonsillitis
In adults, acute HSV 1 infection more commonly involves the pharynx and tonsillar areas rather than causing gingivostomatitis.
This is the most common manifestation of recurrent HSV-1 infection.
- Initial symptoms of pain, burning, itching, and tingling often occurs at the affected site, commonly the face and the lips.
- painful vesicles or blisters or open sores develop in or around the mouth. Sores on the lips are called cold sores. Later these vesicles become pustular and ulcerate.
- After initial infection, the vesicles or ulcers can periodically recur. The frequency of recurrences varies from person to person. Usually, there are fewer than two recurrences each year, but some individuals experience monthly recurrences.
Maximum viral shedding is in the first 24 hours of the acute illness but may last for 5 days.
It is an HSV infection of the finger. It can occur following inoculation of the virus from primary orofacial or genital infections. Inoculation may occur from self or from other infected persons.
It is HSV infection of the face, arms, neck, and upper trunk. It is typically seen in wrestlers and people who play contact sports such as rugby. Trauma to the skin that occurs during matches promotes herpes infection. It is also called scrumpox, wrestler’s herpes, or mat herpes.
It is secondary HSV infection superimposed on an underlying damaged or diseased skin, as seen in uncontrolled atopic dermatitis. Extensive infection can occur and increases the risk of invasive disease, increased morbidity, and mortality.
Primary Genital Herpes
It can be caused by both HSV-1 and HSV-2.
HSV-2 has an affinity for genital mucosa and is usually more associated with genital infections.
However, HSV-1 is increasingly been associated with genital infection and causes more genital infections than HSV-2, especially in young people and homosexual males.
The symptoms and course of primary genital herpes caused by both HSV-1 and HSV-2 are the same, but recurrences are more common with HSV-2.
Prior oro-labial HSV-1 infection has a protective role against genital HSV-1 infection.
Primary genital herpes is characterized by severe and prolonged systemic and local symptoms. Both the symptoms as well as the complications are more severe in women.
The incubation period of primary genital herpes is usually 3-7 days. However, it may range from 1 day to 3 weeks.
Constitutional symptoms include fever, headache, malaise (generalized weakness), and myalgia.
Local symptoms include pain, itching, dysuria, vaginal and urethral discharge, and tender lymphadenopathy. The vesicles rupture to form ulcers or may progress to pustules. The ulcers persist for about 4 to15 days. After this encrusting and reepithelialization occur. The median duration of viral shedding is about 12 days.
In women, vesicles appear on the external genitalia. The vaginal mucosa is inflamed and edematous. The cervix is involved in the majority of the cases and is characterized by ulcers or necrotic mucosa.
In men, vesicles appear on the glans penis, the prepuce, the shaft of the penis, and sometimes on the scrotum, thighs, and buttocks.
Dysuria (pain on passing urine) and urethritis may be present. In some cases, it may cause urinary retention. HSV-1 infection causes urethritis more often than HSV-2 infection.
The perianal area and rectum may be involved in persons who engage in anal intercourse, resulting in herpetic proctitis.
Recurrent Genital Herpes
Genital herpes is characterized by frequent reactivation. However, the duration of symptoms is usually shorter in recurrent infection than in primary infection. Also, the frequency and severity of recurrences decrease with time.
There occurs tenderness, pain, and burning at the site of eruption that may last from 2 hours to 2 days. Fever and constitutional symptoms are uncommon. In some patients, severe ipsilateral sacral neuralgia occurs.
Vesicles are found on the external genitalia and can be very painful. These vesicles heal in 8-10 days, and viral shedding lasts for around 5 days.
Urethritis is uncommon.
Subclinical Genital Herpes
Majority of the cases of primary genital HSV infections are asymptomatic.
Around 80% of individuals who are seropositive for HSV are unaware of their infection. These asymptomatic individuals can, however, shed the virus in their genital tract and transmit the virus either sexually or perinatally (from mother to child).
Other Forms of Herpes Simplex Infection
Neonatal Herpes Simplex
It is caused by vertical transmission of HSV-1 or -2 from mother to newborn. It is a rare but serious condition. It manifests in the following ways:
- Localized form affecting skin, eyes, and mouth
- Disseminated form affecting the internal organs
- Central nervous system herpes which may lead to encephalitis
It is a recurrent or initial herpes simplex infection which affects mainly the hair follicles.
In patients with chronic atopic dermatitis, herpes infection may spread throughout the eczematous areas.
It a primary herpes infection, which causes swelling of the conjunctiva and eyelids (blepharoconjunctivitis). In addition, small white itchy lesions may be present on the surface of the cornea.
HSV infections in immunocompromised persons are usually more severe, prolonged, and widespread. There are also greater chances of recurrences.
HSV has also been implicated in certain neurological disorders including Alzheimer’s disease and bipolar disorder. However, direct causation has not been established. Also, it is acknowledged that genetic, as well as other environmental factors, play a significant role in the causation of these diseases.
It has been postulated that Bell’s palsy which causes facial paralysis may occur due to reactivation of HSV-1.
The association, however, is not very convincing. This is because Bell’s palsy does not occur in the majority of the individuals infected with the HSV Also the levels of antibodies for HSV are not found in greater quantity in HSV-infected individuals with Bell’s palsy compared to those without Bell’s palsy.
Nevertheless, antivirals, when used with corticosteroids, result in improvement in severe cases.
Herpes Viral Encephalitis and Herpes Viral Meningitis
HSV-1 can be transmitted to the temporal lobe of the brain from the nasal cavity. It can also travel from any site on the face through the trigeminal nerve up to the brainstem.
It is a rare but life-threatening condition.
Herpes infection can involve the esophagus resulting in painful swallowing (odynophagia) and difficulty in swallowing (dysphagia). It usually occurs in immunocompromised patients
Long-term Course of Infection
Once the herpes virus infects a person, it enters the nerves at the site of primary infection and remains latent inside the neurons of the ganglion throughout life. It is never removed from the body by the immune system. However, periodically, especially under conditions of emotional or physical stress, the virus may get reactivated causing recurrent infection.
The primary infection results in the production of antibodies against the specific type of HSV involved, thereby preventing a subsequent infection of that type at a different site. If a person is infected with HSV-1 resulting in oral infection, then the formation of antibodies will prevent other HSV-1 infections such as whitlow, genital herpes, and herpes of the eye. Also, it will reduce the symptoms of later HSV-2 infection, although HSV-2 can still be contracted.
Lab Studies of Herpes Simplex Infection
The gold standard method for confirming HSV infection is by isolation of the virus in tissue culture. Positive results can be obtained within 48 hours of inoculation.
Direct Fluorescent Antigen (Immunofluorescence)
Cells scraped from ulcer bases can be stained with a direct fluorescent antibody. This can be used to distinguish HSV-1 from HSV-2.
Similarly, viral particles isolated by tissue culture can also be stained to detect and distinguish HSV 1 and HSV 2. This procedure can usually be performed within 2-3 hours.
It helps in the diagnosis of cutaneous herpes virus infections.
An intact vesicle is selected from which the vesicular fluid is aspirated using a sterile tuberculin syringe. This fluid can be used for viral culture or PCR.
Since herpes vesicles are not multiloculated, aspiration usually results in the complete collapse of the vesicle. After aspiration, the vesicle should be unroofed aseptically. Using a sterile instrument, the floor of the newly produced ulcer is scraped and the material obtained is spread on a glass slide, dried, fixed and stained. The slide is then examined under a microscope.
HSV induces characteristic changes in the cells which can be demonstrated in Tzank smears. Multinucleated giant cells and epithelial cells containing eosinophilic intranuclear inclusion bodies are indicators of herpes virus infection.
It allows for a quick diagnosis (usually within an hour). However, smear preparation requires expertise and trained personnel. Moreover, it does not distinguish HSV-1, HSV-2, and varicella-zoster virus.
Punch biopsy from the involved site provides reliable material for histological examination. However, the results take slightly longer (around 1 week) than cytological tzank smear testing.
Polymerase Chain Reaction (PCR)
HSV can be detected by polymerase chain reaction (PCR) techniques. It is more sensitive than culture and is the preferred test for CNS and ocular infections.
Vesicular fluid can be used in the case of cutaneous lesions. In HSV encephalitis, PCR can be performed on Cerebrospinal fluid (CSF) which is a rapid, less-invasive and equally sensitive technique as compared to brain biopsy.
PCR can be used to detect HSV-2 as the cause of recurrent meningitis(Mollaret) and has shown a strong association between HSV-1 and Bell’s palsy.
PCR can be used to detect asymptomatic viral shedding.
Indirect Serological Diagnosis of Herpetic Infections
Antibody titer increases generally do not occur during recurrences of HSV infection. Therefore, the test is generally not used for the diagnosis of mucocutaneous HSV relapse.
HSV-specific IgG antibodies can be detected by several immunological methods. Their presence indicates a seroconversion. Negative serology result and a positive viral culture result indicate a primary infection in which antibodies have not yet formed against the virus.
Testing for HSV-specific immunoglobulin M (IgM) antibodies is not available.
Antibody testing has been the mainstay of large-scale epidemiologic studies. Because of sero–cross-reactivity, IgG antibodies cannot distinguish between HSV-1 and HSV-2. Type-specific serology based on glycoprotein G antibody assay is available that can help to distinguish between the two IgG1 for HSV1 and IgG 2 for HSV2.
Diseases that Mimic Herpes Simplex Infection
Varicella-zoster virus infection: Lesions of varicella-zoster caused by herpes zoster may be similar to herpes simplex. Both may show clustered vesicles or ulcers on an erythematous base. However, varicella-zoster usually follows a dermatomal distribution which is the main distinguishing point from herpes simplex. Disseminated forms of both cannot be distinguished clinically.
Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): Similar to herpes simplex, it can also present with oral and/or genital ulcerative lesions. Presence of subepidermal blisters, full-thickness epidermal sloughing, and involvement of the palms and soles are features exclusively seen in SJS/ TEN.
Aphthous ulcers: These usually occur in the mouth but can also involve the genitals, such as in Behcet disease. Large aphthous ulcers are associated with immunocompromised states such as HIV infection. They present as small round ulcers with a yellow or grey ulcer floor. They may be single or multiple occurring in a linear pattern and usually heal within 1 week.
Syphilis: It usually presents as a single painless ulcer. Also, it does not recur usually.
Chancroid: It presents as painful ulcers having a shaggy border and yellow/grey exudate.
Lymphogranuloma venereum: It usually presents as a painful papule that may ulcerate. It may be associated with buboes, draining sinuses, and/or lymphedema.
Treatment of Herpes Simplex Infection
There is no cure for herpes. Aim of the treatment is to relieve the symptoms, reduce pain and shorten the healing time.
Symptomatic treatment is required for constitutional features like fever.
Ulcerative lesions require appropriate wound care. Prevention and treatment of secondary bacterial skin infections may be required.
Warm baths may relieve the pain associated with genital sores.
Antiviral drugs including acyclovir, famciclovir, and valacyclovir are used to treat the symptoms of herpes. Besides reducing the intensity and frequency of outbreaks, these drugs also reduce the chances of the virus being transmitted to other individuals.
Prevention of Herpes Simplex Infection
Since the herpes simplex virus is ubiquitously present in the environment, it is difficult to avoid contact with individuals who excrete the virus in saliva or genital secretions. Moreover, the majority of the individuals infected with the virus are asymptomatic and may themselves be unaware of their infection.
Antiviral therapy can reduce viral shedding and the risk of transmission.
Genital HSV infections can be prevented from being transmitted by using barrier contraceptives like condoms.
Vertical transmission from mother to new-born child can be prevented by opting for a cesarean mode of delivery rather than vaginal birth.
Arduino PG, Porter SR. Oral and perioral herpes simplex virus type 1 (HSV-1) infection: review of its management. Oral Dis. 2006 May. 12(3):254-70.
Corey L, Adams HG, Brown ZA, Holmes KK. Genital herpes simplex virus infections: clinical manifestations, course, and complications. Ann Intern Med. 1983 Jun. 98(6):958-72.
Schiffer J, Corey L. Herpes Simplex Virus. Mandell Gl, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 8th ed. Pennsylvania: Elsevier; 2015. Vol 2: 1713-30.
Gnann JW, Salvaggio MR. Drugs for Herpesvirus Infections. Cohen J, Powderly W, eds. Infectious Diseases. 2nd ed. New York: Mosby; 2004. Vol 2: 1895-909.
Mark KE, Wald A, Magaret AS, Selke S, Olin L, Huang ML. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis. 2008 Oct 15. 198(8):1141-9.
Fleming DT, McQuillan GM, Johnson RE, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med. 1997 Oct 16. 337(16):1105-11.