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Image of herpes labialis (cold sores) caused by reactivation of herpes simplex virus type 1 (HSV-1) from Wikimedia Commons | Speifensender.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpes Simplex Virus 1 and 2

HSV types 1 and 2 (HSV-1, HSV-2, respectively) are double-stranded DNA viruses of the family Herpesviridae. Primary infection occurs via direct contact with infected skin and subsequent inoculation of mucous membranes or defects in the skin's surface. The virus then reaches sensory and autonomic nerve endings and remains latent in the nerve cell bodies of ganglion neurons. This allows for reactivation, explaining the recurrent signs and symptoms characteristic of HSV infection.[1]

HSV-1 is traditionally associated with orofacial disease; it causes vesicular lesions commonly referred to as cold sores when present in the oral cavity (shown). HSV-1 is typically acquired in childhood, but reactivation can occur in adolescence and later.

HSV-2, however, is most commonly associated with genital herpes, a well-known sexually transmitted infection (STI). Note that in rare cases, HSV-2 can be isolated from oral lesions, just as HSV-1 can be isolated from genital lesions.

Colonoscopy images of the rectal mucosa showing Herpes simplex proctitis, from Sandgren KE, Price NB, Bishop WP, McCarthy PJ. Case Rep Pediatr. 2017;2017:3547230. [Open access.] PMID: 28473937, PMCID: PMC5394410.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Many HSV infections may be subclinical or mild, and up to 88.1% of HSV-2-infected individuals between ages 14 and 49 years have never received a clinical diagnosis.[2] However, symptomatic infections can be severe and present with a sudden onset of systemic signs, including fevers, regional lymphadenopathy, and painful vesicular lesions. Recurrent infections manifest similarly, although they are typically less severe and have a shorter duration; they also tend to lack systemic signs such as fevers. In immunocompromised hosts, infections can cause life-threatening complications.

The worldwide prevalence of HSV infection, particularly HSV-2–related genital disease, has increased over the last several decades, making HSV infection a major global public health problem.[3-5] Prompt recognition of herpes simplex infection and early initiation of therapy are crucial in the management of infection.

Image courtesy of Medscape.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Genital herpes

Genital herpes lesions typically appear as one or more vesicles in the genital and/or rectal area. They can look similar to the lesions associated with chancroid or syphilis (other STIs), so further workup may be necessary to confirm the diagnosis.

Primary genital HSV infection can have a highly variable presentation. The most common symptoms include painful genital ulcers (shown), dysuria, fever, tender lymphadenopathy, and headache. Men who have sex with men are also at risk for proctitis secondary to HSV infection.[3] Note that in a majority of cases, the presentation may be much less severe or entirely subclinical, and thus the infection may be misdiagnosed or go unrecognized. The typical incubation period following exposure is 2-12 days (average: 4 days). Ulcers from primary genital infections typically resolve after an average of 19 days.[3]

Following a primary outbreak, intermittent asymptomatic viral shedding occurs and is associated with an increased risk of viral transmission to sexual partners. The risk is greater when the male partner has been initially infected and the female is susceptible (ie, not previously infected).[3] Primary genital HSV-2 infections tend to shed from the genital tract for a more prolonged period than HSV-1 infections do.[3]

Image of primary vesiculopapular penile herpes lesions, from the Centers for Disease Control and Prevention (CDC).

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Recurrent genital herpes infections are common, with most cases caused by HSV-2. However, HSV-1 has been associated with an increasing prevalence of genital outbreaks.[2] Global estimates from the World Health Organization (WHO) indicate about 3.7 billion people younger than 50 years (67%) are infected with HSV-1, and about 417 million people aged 15-49 years have HSV-2 infection.[4] In the United States, approximately 776,000 people are infected with genital herpes annually.[2]

Recurrent genital herpes infections are typically less severe and have a shorter duration than primary infections (average of 10 days vs 19 days, respectively). Prodromal tingling or pain in the area of outbreak may occur prior to a vesicular eruption; however systemic symptoms are uncommon with recurrent herpes outbreaks.[3]

Image from Wikimedia Commons | Kapitainekavern.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Neonatal herpes simplex infection

A complication of genital herpes infection in females is vertical transmission to infants during childbirth. Neonatal HSV infection develops in 1 of every 3,200-10,000 live births, with approximately 1,500 new cases occurring annually in the United States.[6] Factors that influence perinatal transmission include maternal HSV antibody status, type of infection (primary vs recurrent), duration of ruptured membranes, and mode of delivery (cesarean vs vaginal). The risk of neonatal transmission rises if vaginal delivery occurs during an active HSV outbreak; thus, cesarean delivery is preferred in this setting. The highest risk for transmission occurs when a primary genital HSV infection is acquired close to the time of delivery.[7]

Neonatal HSV can be classified into three main categories: 1) skin, eye, and mouth (SEM) disease (shown); 2) central nervous system (CNS) disease, with or without SEM disease; and 3) disseminated disease.

Image of herpes skins lesions on the face, torso, arm, and legs of an infant, from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

SEM disease usually presents within the first 2 weeks of life and is characterized by localized vesicular eruptions at the site of infection. Left untreated, SEM disease has a high risk of progression to CNS or disseminated disease. Neonates with HSV CNS disease may present with seizures, lethargy, tremors, poor feeding, temperature instability, and/or a full anterior fontanelle. Although these symptoms typically occur in the second or third week of life, they can manifest any time within the first 6 postnatal weeks.

Disseminated disease generally presents in the first week of life with nonspecific signs and symptoms of neonatal sepsis and multisystem organ failure. Mortality exceeds 80% if disseminated disease is not promptly addressed and treated.[8] Of note, SEM symptoms may not be present in neonates who present with later stage CNS or disseminated disease.

As a general entity, neonatal HSV infection can often be difficult to diagnose, because all of its variants can closely mimic other conditions. Furthermore, it may be difficult to identify neonates at high risk for acquiring infection, because many women have subclinical disease and lack specific symptoms.[7] A high degree of suspicion is needed to expeditiously diagnose and treat neonatal HSV.

Image courtesy of Medscape.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpes simplex meningitis

Neural penetration of HSV along nerve roots, where it lies dormant, can lead to CNS infections, namely meningitis and encephalitis.[9]

HSV-related aseptic viral meningitis is generally caused by HSV-2; patients present with photophobia, meningismus, and headache. About 13-36% of patients with primary genital herpes present with clinical findings of meningeal involvement. In approximately 85% of patients with HSV-2 meningitis, genital lesions precede the onset of CNS symptoms by approximately 1 week.[10]

Cerebrospinal fluid (CSF) studies are paramount in making the diagnosis; viral meningitis shows a characteristic pleocytosis with lymphocytic predominance, slightly elevated protein levels, and normal glucose levels. CSF polymerase chain reaction (PCR) assay is the gold standard in the diagnosis of herpes meningitis.[9] Magnetic resonance imaging (MRI) of the brain typically shows diffuse enhancement of the meninges in herpes meningitis (shown).

Image from MedPix | James G Smirniotopoulos, MD, Uniformed Services University.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpes simplex encephalitis

In contrast to HSV meningitis, which is generally caused by HSV-2, herpes simplex encephalitis (HSE) is caused by HSV-1. HSV encephalitis is the most common cause of sporadic fatal encephalitis in the world.[11] Encephalitis manifests with abnormal cerebral function, and common presenting symptoms include fever, headache, psychiatric symptoms, seizures, vomiting, focal weakness and neurologic deficits, and/or memory loss.[10] MRI abnormalities involving the temporal lobe (shown) are found in 90% of patients with HSE.

The neuronal damage evident in HSE is poorly understood, but it is thought to be due to the ability of HSV-1 to induce cell death, a property not characteristic of HSV-2.[12,13] The diagnosis of HSV encephalitis can be confirmed only by PCR assay of the CSF or by brain biopsy.

Image from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

This hematoxylin-and-eosin–stained micrograph shows the histopathologic changes in brain tissue associated with HSE. Prior to the onset of extensive necrosis, histopathologic examination shows perivascular mononuclear cells, activated microglia with microglial nodules, and intranuclear inclusions. Brain biopsy was considered the gold standard for diagnosing HSE prior to the development of PCR assay detection of HSV in the CSF. The advent of empiric treatment with antiviral agents for patients who present with symptoms suggestive of encephalitis has further decreased the necessity of biopsy as a diagnostic study.[14]

Treatment of HSE often involves admission to an intensive care unit to manage increased intracranial pressure and seizures, as well as early administration of intravenous (IV) acyclovir.[11] HSE is a neurologic emergency, and nearly two thirds of survivors will have significant neurologic deficits, including cognitive deficits, recurrent seizures, amnesia, dysnomia, and behavioral abnormalities.[11]

Images courtesy of Medscape.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpetic gingivostomatitis

HSV-1–associated gingivostomatitis is the most common manifestation of primary HSV infection in childhood. It is frequently seen in children after their levels of passively acquired maternal antibodies have diminished. Less commonly, HSV gingivostomatitis may also occur in adults.

Transmission occurs via infected saliva from other children or adults who may be asymptomatic. After an incubation period of approximately 6-8 days, a syndrome consisting of fevers, listlessness, gingivitis, pharyngitis, and painful vesicular lesions on the oral mucosa develops (left image). The lesions can interfere with eating, drinking, and swallowing.[15] Vesicles appear in the oral mucosa and eventually crust and reepithelialize (right image).[15] The healing process may last 1-3 weeks in more severe cases.

Recurrences are common; most patients will experience a repeat of painful lesions with the absence of systemic signs.[15] As with other herpes infections, the virus remains latent after resolution of the clinical syndrome and may reactivate with various stimuli. In herpetic gingivostomatitis, the virus typically remains dormant in the trigeminal ganglion; reactivation can cause recurrent stomatitis or herpes labialis.[15]

Left image courtesy of Medscape; right image from Wikimedia Commons | James Heilman, MD.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpetic whitlow

Herpetic whitlow (shown) develops when HSV infection (usually HSV-1) occurs in breaks in the skin on the nail bed or finger. Typically, lesions present with acute onset of edema, erythema, and localized burning pain and tenderness. Systemic symptoms, such as flulike symptoms and lymphadenopathy, can occur and may be associated with primary infection as a prodrome to the outbreak; subsequent outbreaks are less likely to be associated with systemic symptoms.

Herpetic whitlow can be a complication of primary HSV gingivostomatitis, often occurring in infected children as a result of finger or thumb sucking. It can, however, arise in anyone exposed to HSV, such as healthcare workers who have unprotected contact with infected oropharyngeal secretions.[16]

Image from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpes labialis

Reactivation of HSV-1 causes herpes labialis (shown), otherwise known as cold sores or fever blisters. These lesions commonly erupt in response to stressful stimuli such as fevers, infection, or menstruation. They are typically confined to the mucosa of the hard palate and the lips, in contrast to the lesions of primary HSV-1 infection. Most patients develop prodromal symptoms about 1 day prior to the appearance of active lesions.

The condition is harmless, but it is contagious to those who are HSV-1 naïve or who are immunocompromised. HSV-1 can also be transmitted from the oral cavity to the genitals through direct contact.[17]

Image courtesy of Medscape.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Herpes gladiatorum

Herpes gladiatorum is another presentation of HSV-1 infection (shown). First described in the mid-1960s, it is strongly associated with contact sports such as wrestling and rugby, as skin-to-skin contact is the main mode of transmission.[18] Outbreaks have been reported across the United States.

Vesicular, fluid-filled blisters most commonly occur around the head, neck, and ears. Primary infection may lead to a constellation of symptoms, including fever, lymphadenopathy, headache, and malaise,[18] similar to other primary HSV outbreaks.

Images courtesy of DermNet New Zealand.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Eczema herpeticum

Eczema herpeticum, or Kaposi varicelliform eruption, is usually caused by HSV-1 but can also result from HSV-2. It is typically associated with a primary infection, and repeated episodes are unusual.[19] Patients with atopic dermatitis (eczema) are at particularly high risk for developing this condition, thus the name eczema herpeticum.

As shown in the image above, eczema herpeticum presents with clusters of painful blisters and erosions, most commonly on the face and the neck. Associated symptoms include fever, malaise, and irritability. As with many other herpes infections, recurrence is less severe. Secondary infection with Staphylococcus aureus or Streptococcus pyogenes commonly occurs and may complicate the condition.[20]

Image courtesy of Medscape.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

HSV diagnosis

Historically, Tzanck smear (shown) has been used for the diagnosis of HSV-1 and -2 infections. In patients with active genital lesions, a positive result reveals multinucleate giant cells. However, owing to its low sensitivity and specificity, Tzanck smear has been widely replaced by newer tests that can produce more sensitive and specific results as well as differentiate HSV strains.

Viral culture may assist with the diagnosis in those with active lesions. Vesicular fluid can be sampled in early stages of the disease, although sensitivity of the culture is only approximately 75% for the first occurrence and 50% for recurrences.[21,22] The diagnostic yield is highest during the early stages of a breakout before the vesicles have begun to crust over and heal. Immunofluorescent staining for antibodies in growing viral cultures can help identify a particular strain of the virus.[23]

Adapted image of gel electrophoresis of PCR products extracted from HSV-1-infected human epithelial cells, from Cantatore A, Randall SD, Traum D, Adams SD. BMC Complement Altern Med. 2013;13:139. [Open access.] PMID: 23777309, PMCID: PMC3698045.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

PCR assay has emerged as a more sensitive test than viral culture, and it is also useful in the detection of asymptomatic HSV shedding. PCR assay can differentiate between HSV-1 and -2 in specimens obtained from genital ulcers, as well as from other mucocutaneous sites. It has also become the test of choice for CNS infections with HSV.[23,24]

Asymptomatic carriers have type-specific antibodies to HSV-1 and/or HSV-2; this has facilitated the emergence of rapid serologic testing, which has a sensitivity and specificity of 97% and 98%, respectively.[25] Antibody testing can confirm the diagnosis in a patient with a history of lesions who may previously have had a negative HSV culture or PCR assay.

Adapted image from the CDC | Debora Cartagena.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

HSV treatment

Treatment for herpes infection is multifaceted. An important consideration is primary prevention. Avoiding skin-to-skin contact during outbreaks is essential for preventing spread from person to person. Counsel those with genital herpes that they may have asymptomatic shedding in between outbreaks and they therefore should avoid unprotected intercourse even in the absence of symptoms. Barrier methods can reduce the risk of transmission (eg, condom, shown). Furthermore, educate patients that the use of antiviral agents can prevent the transmission of genital herpes in discordant couples.[26]

Topical antiviral therapy has minimal therapeutic efficacy, but penciclovir 1% cream can be applied every 2 hours for some improvement in orolabial infection. Over-the-counter docosanol 10% cream has been shown to reduce the median time to healing by 18 hours as well as reduce the pain, itching, and burning associated with herpes labialis.[27]

Adapted image from Wikimedia Commons | Ragesoss.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Oral antiviral therapies, including acyclovir (shown), valacyclovir, and famciclovir, are all options for treatment of HSV infections. Acyclovir therapy is beneficial if treatment is initiated early (within 72 hours) in primary HSV infections, but it does not reduce the risk of recurrent HSV-1 infections. Chronic treatment with acyclovir or valacyclovir helps to reduce the number of clinical episodes of HSV infection in persons with recurrent outbreaks that are frequent or bothersome.[28]

Although primary episodes of genital HSV infection can be treated with single-time courses of acyclovir, valacyclovir, or famciclovir, treatment options for recurrent outbreaks include episodic therapy and chronic suppressive therapy. Generally, patients with six or more reoccurrences per year should be offered chronic suppressive therapy (CST) rather than episodic treatment.[29] About 70-80% of patients on CST have a significant reduction in recurrent outbreaks, and 50% remain recurrence-free. Moreover, CST reduces the risk of transmission to an uninfected partner.

Administer IV acyclovir for treatment of HSE as soon as possible to prevent catastrophic CNS damage. The definition of early treatment includes the following criteria: before loss of consciousness, within 24 hours of symptomatic onset, and when the patient has a Glasgow coma scale score of 9-15.[30] The therapy for herpes meningitis also should include IV acyclovir.[31] Any patient presenting with signs suspicious for meningoencephalitis should receive acyclovir early to empirically cover encephalitis before CSF studies confirm the diagnosis.[9]

Electron micrographs of different viruses from the Herpesviridae family, from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human Herpesvirus Types 3-8

Other forms of herpesviruses include human herpesvirus 3 (HHV-3, varicella-zoster virus), HHV-4 (Epstein-Barr virus [EBV]), HHV-5 (cytomegalovirus [CMV]), HHV-6 (causes roseola infantum), HHV-7, and HHV-8 (Kaposi sarcoma–associated herpesvirus). These viruses belong to the family Herpesviridae, just as HSV-1 and -2 do. HHV-3 through -8 have differing presentations from the more familiar constellation of symptoms characteristic of HSV-1 and -2.

Image from Wikimedia Commons | F malan.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Chickenpox rash (above) is seen in a 30-year-old male 5 days after the lesions first developed.

Human herpesvirus 3: Varicella

HHV-3, or VZV, causes chickenpox (or varicella). Chickenpox is transmitted via inhalation of infected air droplets or through direct contact with an infected host. Over 90% of these infections occur in children younger than 10 years. However, since the introduction of the varicella vaccine in 1995, the incidence of chickenpox has declined significantly.

Within 10-21 days of contact with, or exposure to, an infected host, a characteristic rash forms, with lesions in different stages of development. Erythematous macules begin to erupt and later develop into vesicles and papules that rupture, crust, and reepithelialize. The rash is characteristically pruritic and can become secondarily infected, causing cellulitis, impetigo, erysipelas, and scarring.[32]

Varicella is generally a clinical diagnosis based on the appearance of the eruption, although real-time PCR assay, viral culture, and direct fluorescent antibody testing are available if the diagnosis is uncertain.[33] The condition is usually self-limited, and antiviral therapy is not recommended for immunocompetent children and adolescents. Immunocompetent adults typically present with a more severe form of the syndrome and therefore should be provided with oral antiviral therapy, as well as supportive care, for the duration of the infection. Immunocompromised patients are particularly susceptible to infection and also require antiviral therapy, along with more aggressive supportive care.[34]

Image from Wikimedia Commons | Fisle.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human herpesvirus 3: Shingles

As with other herpesviruses, varicella remains latent in the dorsal ganglion cells of sensory nerves and therefore can reactivate. Reactivation of the infection is referred to as herpes zoster (shingles). Reactivation typically occurs in ganglia in which the varicella virus has achieved a higher density in comparison to others and can be triggered by environmental factors such as trauma or irradiation, as well as by immunosuppression.

Prodromal pain, tenderness, and paresthesias commonly occur prior to the outbreak. The resulting rash evolves from papules to vesicles and bullae within 48 hours and then to pustules, eventually crusting over. The eruption is typically extremely painful and characteristically spans a particular dermatome (shown). The mucous membranes, including the conjunctiva of the eyes (herpes zoster ophthalmicus), may be involved.[20] Postherpetic neuralgia may occur as a sequela of herpes zoster and involves severe stabbing and burning pain in the affected area that may last months to years after the eruption resolves.[35]

Image from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Oral antiviral therapy is indicated for patients with uncomplicated zoster who present within 72 hours. If new lesions are still occurring after that time frame, antiviral therapy may still have some benefit; however, earlier treatment is ideal. Analgesics may also be necessary to control pain.[36] For individuals who suffer from postherpetic neuralgia, gabapentin has been shown to provide pain relief and is generally well tolerated.[37,38]

Herpes zoster vaccine is available for individuals aged 50 years or older to reduce the risk of herpes zoster and postherpetic neuralgia. Vaccination is indicated for all individuals in this age group regardless of their history of varicella infection. Vaccination can reduce the risk of developing zoster by up to an estimated 97.2% (with administration of the non-live, recombinant glycoprotein E vaccine known as Shingrix).[39]

Left image from Wikimedia Commons | James Heilman, MD; right image from Flickr | Ed Uthman, MD.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

The images depict exudative pharyngitis (left) and reactive lymphocytes (right), in infectious mononucleosis.

Human herpesvirus 4: Epstein-Barr virus

HHV-4, or EBV, is the primary agent causing infectious mononucleosis, a common condition in young adults. The virus infects B lymphocytes, where it remains latent once active infection has resolved. In contrast to other herpesviruses, reactivation is not a common sequela of EBV; however, it can be associated with lymphoproliferative disorders and malignancies years after the initial primary infection has occurred,[40] including Burkitt lymphoma, Hodgkin lymphoma, nasopharyngeal carcinoma, and T-cell lymphoma.

Primary infection leads to infectious mononucleosis, a syndrome characterized by severe malaise, pharyngitis, tonsillitis, cervical lymphadenopathy, splenomegaly, and fever. Palatal petechiae, periorbital and/or palpebral edema, and rashes may also be observed. Less common presentations involving the central and peripheral nervous systems, as well as acute blood abnormalities, have also been described.[40,41]

Image showing splenomegaly due to mononucleosis resulting in a subcapsular hematoma, from Wikimedia Commons | James Heilman, MD.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Patients with suspected mononucleosis should have a heterophile test performed for diagnostic confirmation. Antiviral treatment has not proven to have any curative benefit or effect on latent EBV infection. Therefore, symptomatic therapy is the main approach, and acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are recommended to control the pain associated with severe pharyngitis, as well as fever.

Airway obstruction is an emergency complication of EBV-associated pharyngitis, and high-dose corticosteroids may be warranted if this occurs. A minimum of 4 weeks' avoidance of contact sports after illness onset must be enforced to lower the risk of splenic rupture, as splenomegaly is common in EBV mononucleosis (shown).[42]

Image from Wikimedia Commons | James Heilman, MD.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human herpesvirus 5: Cytomegalovirus

HHV-5, or CMV, is most commonly associated with mononucleosis, but it can also be linked to pneumonia and other organ-specific complications in immunocompetent people. In those who are immunocompromised, significant morbidity and mortality are likely to occur from CMV. The infection is also particularly dangerous for pregnant women whose fetuses can experience deleterious effects from neonatal CMV exposure.

CMV transmission can occur through sexual exposure, close contact, blood or tissue exposure, and perinatal exposure. Infection frequently results in CMV mononucleosis, a condition resembling EBV mononucleosis, characterized by flulike symptoms, lymphadenopathy, and fever. Cervical lymphadenopathy (shown) and pharyngitis are typically more prominent in mononucleosis caused by EBV.

Image from the CDC.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

CMV infection should be suspected when an EBV heterophile antibody test is negative in a patient displaying signs of CMV mononucleosis. Further workup will reveal lymphocytosis with over 50% mononuclear cells and more than 10% atypical lymphocytes on blood smear.[43] Fibroblast culture, serology, antigen assays, PCR assay, and cytopathology are all available to confirm the diagnosis of CMV. The "owl eye" appearance is a classic finding on cytopathology, secondary to a clear halo surrounding intranuclear inclusions of infected cells (shown).[44]

Symptomatic CMV infection, especially the mononucleosis variant, is generally self-limited and does not require treatment with antivirals. Severe CMV infections, such as those that occur in immunocompromised patients, require treatment with antiviral medications, typically ganciclovir, valganciclovir, foscarnet, or cidofovir.[43]

Image from Wikimedia Commons | Emiliano Burzagli.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human herpesvirus 6

There are two different species of HHV-6: HHV-6A and HHV-6B. HHV-6B causes roseola infantum; HHV-6A is found in immunocompromised hosts, but the exact syndrome caused by the infection is still largely unknown.[45,46] Hepatitis, pneumonitis, encephalitis, and bone marrow suppression have been observed in association with HHV-6 infection in transplant patients.

Roseola most commonly presents in children between the ages of 6 months and 3 years. It is spread from person to person via saliva from infected hosts, usually asymptomatic adults. If an infected child becomes symptomatic, he or she will develop 3-5 days of a high fever, nasal congestion, pharyngitis, irritability, and a characteristic rash consisting of small pink papules that mainly affect the trunk.[47] The rash often occurs after abrupt resolution of the fever.

The diagnosis of roseola is usually made clinically based on the characteristic rash and constellation of symptoms. In patients who are immunocompromised or who have atypical presentations, real-time PCR assay, qualitative PCR assay, viral culture, antigen detection, and serologic testing are available to confirm the diagnosis.[48]

Treatment for roseola is supportive, and there is no current indication for antiviral therapy. The condition is self-limited and resolves without curative treatment.

Image courtesy of DermNet New Zealand.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human herpesvirus 7

HHV-7, although poorly understood, has been implicated in a range of illnesses, including psoriasis, pityriasis rosea (shown), febrile seizures, lichen planus, and Kaposi sarcoma.[49,50] HHV-7 has also been shown to cause roseola, but HHV-6 is the more common etiology.

Despite the association between HHV-7 and the above conditions, cause and effect have yet to be understood and definitively accepted. Consequently, there are few clinical indications to test for HHV-7, and although antiviral medications have been shown to be effective against it in vitro, there are no clear indications for initiating treatment.[51]

Image from the National Cancer Institute.

Herpesviruses: Test Your Knowledge

Lars Grimm, MD, MHS; Michael J. Payette, MD, MBA; Kristen Russomanno, MD | December 20, 2018 | Contributor Information

Human herpesvirus 8 and Kapsoi sarcoma

Kaposi sarcoma (shown in a patient with acquired immunodeficiency syndrome [AIDS]) is an angioproliferative disorder that is associated with HHV-8. It is classified into four distinct types based on the clinical scenario in which it occurs: 1) classic, 2) AIDS-related, 3) iatrogenic, and 4) endemic.

Classic Kaposi sarcoma is indolent and most commonly occurs in older men of Mediterranean descent. Lesions of classic Kaposi sarcoma occur on the lower legs and feet. AIDS-related Kaposi sarcoma is the most common tumor associated with human immunodeficiency virus (HIV)-infected patients, and it is considered an AIDS-defining illness. Iatrogenic Kaposi sarcoma is associated with immunosuppression, and persons who have undergone solid organ transplantation are at particular risk. Endemic/African Kaposi sarcoma occurred in Africa prior to the HIV epidemic.[52-54]

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31 Signs of Sexually Transmitted Infections

Sexually transmitted infections are a common occurrence, but many lesions can be readily mistaken for other diseases. Can you make an accurate diagnosis in these cases?Slideshows, October 2018
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Herpes Simplex

Herpes simplex viruses are ubiquitous, host-adapted pathogens that cause a wide variety of disease states. Two types exist: herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). Both are closely related but differ in epidemiology. HSV-1 is traditionally associated with orofacial disease, while HSV-2 is traditionally associated with genital disease.Diseases/Conditions, March 2018
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References