In the general population the term “Herpes” is used almost exclusively to describe genital herpes simplex. However, there are actually 8 members of the family Herpesviridae (AKA Herpesviruses). These viruses have a linear double stranded DNA genome and an envelope.
Human Herpes Viruses:
- Herpes Simplex 1 (HSV-1 or HHV-1)
- Herpes Simplex 2 (HSV-2 or HHV-2)
- Varicella-Zoster Virus (VZV or HHV-3)
- Epstein Bar Virus (EBV or HHV-4)
- Cytomegalovirus (CMV or HHV-5)
- Herpesvirus 6 (HHV-6 or Roseola)
- Herpesvirus 7 (HHV-7)
- Herpesvirus 8 (HHV-8 or Kaposi Sarcoma)
We will not discuss all 8 of these viruses in this video. Human Herpesvirus 6 (HHV-6) and Human Herpesvirus 7 (HHV-7) are very low yield for the exam so we will skip them. We also will hold off on discussing Human Herpesvirus 8 (HHV-8 or Kaposi Sarcoma) until a later video that will discuss HIV & AIDs in depth.
This family includes some of the most common and contagious infections in the general population. Over 90% of people have 1 or more of the above viruses. However, for a huge majority of the time these infections are not active. After primary infection they have prolonged latent phases where the inactive viruses hide from the immune system. In some cases there are sporadic periods of reactivation (AKA secondary infection) where the patient again becomes symptomatic for a period. The symptomatic periods of these infections are usually self-limited, but there is no cure to eliminate the virus or complete prevent reoccurrences. Some patients don’t even know they have the infection as even the primary infection can be asymptomatic or very mild.
The diagnosis of these viruses is usually made clinically. However, there are tests that can aid in the diagnosis. A Tzanck Test (AKA Tzanck Smear) is a rapid test that can be performed when HSV-1, HSV-2, CMV or Varicella is suspected. A skin vesicle is broken open and smeared on a slide with a stain. Microscopically if multinucleated giant cells with intranuclear inclusions is visible it is a positive results. We will discuss the Monospot test later in the video that can identify EBV.
There are 2 types of Herpes Simplex, HSV-1 & HSV-2. HSV-1 presents primarily on the lips/mouth (AKA “Cold Sores” or Orolabial Herpes) while HSV-2 presents primarily on the genitalia. HSV-2 is most often an STD while HSV-1 is mostly spread by saliva. However, there is significant overlap between types and you can get both viruses via either route and in either area. In both cases Herpes Simplex can be asymptomatic or cause painful fluid filled blisters on the skin or mucous membrane that can progress to ulcerations. The vesicles usually transition into a crusting scab before healing. Genital herpes typically has multiple lesions while orolabial herpes more commonly has a single lesion. There may also be non-specific symptoms before the lesions occur called a Viral Prodrome. The prodrome can include fever, malaise, and tingling the area that later shows lesions. HSV-1 & HSV-2 are lifelong infections with asymptomatic periods where the virus lays dormant in sensory neurons. The virus mostly lays dormant in the trigeminal ganglia after Orolabial Herpes while Genital Herpes usually results in the virus laying dormant in the sacral ganglia. There is currently no cure for the virus, but treatment usually involves antiviral drugs to reduce the severity, duration and risk of transmission. Oral antivirals such as acyclovir are usually the treatment of choice.
HSV-1 is the most common cause of Viral Encephalitis and most often affects temporal lobe. This presents clinically with AMS, fever and in some cases seizures. Immunosuppressed indivudals are at greater risk for herpes encephalitis. Lumbar puncture shows high lymphocytes in the CSF and imaging may show changes in the temporal lobe. This topic will be discussed in more detail in the neuro section.
Varicella-Zoster Virus (VZV or HHV-3) is more commonly referred to as Chickenpox (primary infection) or Shingles (secondary infection). Both of these present clinically with an erythematous (red) vesicular (fluid filled) rash that progressed to scabs. VZV is primarily spread by respiratory secretions, but can also be spread via direct contact with a lesion.
Chickenpox (AKA Chicken Pox or Varicella) presents primarily in children when they are first exposed to the varicella virus. It affects non-immune hosts, meaning you can only get chickenpox once in your life if you have an intact immune system. Chickenpox is usually benign and primarily characterized by severe itchiness over the entire body as the virus has spread through the blood. The lesions start on the trunk and head and then spread to the extremities. Sometimes they describe the rash as being in a variety of stages at once which means you can see red bumps, fluid filled vesicles, pustules and scabs at the same time. The symptoms usually resolve over a couple weeks without any treatment. However, calamine lotion, trimming finger nails, wearing gloves, and/or acetaminophen are often used for symptomatic relief. The individual also needs to be isolated to prevent spread of the contagious disease. In recent years the Varicella Vaccine (AKA Chickenpox Vaccine) has been developed. The vaccine drastically reduces the risk of getting the disease while also decreasing the severity of the disease for those that still get it.
After chickenpox, the body is not able to completely remove the virus. A small number of virus particles survive for decades in the sensory ganglia (primarily the cranial and thoracic ganglia). As the patient becomes elderly their immune system becomes weakened and the same varicella-zoster virus can become reactivated to cause Shingles.
The skin lesions of Shingles (AKA Zoster) only occur in a single dermatome. Therefore, the rash appears in “stripes” cross the skin that do not cross the midline. This localized and well demarcated area of skin represents the specific area of skin that is innervated by the sensory nerve that the virus has been reactivated in. Shingles can occur anywhere on the body, but the chest & back are the most common areas affected. The rash is a grouped erythematous maculopapular lesions. Shingles is primarily characterized by burning pain and fever, but there can also be a tingling sensation in the dermatome even before the lesions arise. The prodrome can also include non-specific symptoms like malaise, headache, and nausea.
The symptoms usually resolve spontaneously over a couple weeks. However, antivirals can be used if shingles is diagnosed early on early as it can lessen the severity and duration. Pain medications and antipyretics can be used for symptom control. Postherpetic Neuralgia is when patient’s pain persists for months even after the rash has resolved. There is also a vaccine for shingles called the Zoster Vaccine (Trade Name Zostavax). It is a live attenuated vaccine that can be thought of as just a stronger version of the Varicella Vaccine. A onetime dose is recommended for adults starting at age 60.
Epstein Bar Virus (EBV or HHV-4) is the primary cause of Infectious Mononucleosis (AKA “Mono” or “The Kissing Disease”). The virus can be transmitted in saliva, hence the name “Kissing Disease.” It should be noted while sexual activity increases the risk of getting EBV, this is not an STD/STI. EBV infection is usually asymptomatic, but causes Mono in some individuals. Mono primarily presents with flu like symptoms of fatigue, pharyngitis (sore throat), headache, and lymphadenopathy (enlarged lymph nodes). The lymphadenopathy may be accompanied by an exudative pharyngitis similar to strep throat. The symptoms last for a few weeks and are most commonly seen in teenage patients. Mono is usually self-limited and no specific treatment is needed. However, infected individuals should avoid contact sports (football, cheerleading etc.) for about 1 month, because splenomegaly increases the risk of splenic rupture. EBV is also associated with Nasopharygeal Carcinoma, Burkitt’s lymphoma and other cancers.
EBV infects the B lymphocytes mainly in the pharynx and signals these B-cells to proliferate. In response to these infected B-cells, cytotoxic CD-8 T-cells become activated and proliferate. The white blood cell count for infected individuals is high and there is a high number of lymphocytes/T Cells (>50%). However, B-cells on the CBC are near normal as most of the B-Cells are in the lymph nodes and cannot be seen in the test of peripheral blood. In EBV infections the CD8 T-cells take on a characteristic appearance with abundant cytoplasm called “Atypical Lymphocyte”. These atypical lymphocytes can be seen on microscopy.
Cytomegalovirus (CMV or HHV-5) infects B cells and can be transmitted via saliva similar to EBV. CMV can also be transmitted sexually or through blood transfusions or organ transplants. HHV-5 infection is primarily asymptomatic, but can cause Mono just like EBV. Immunosuppression is a key risk factor for becoming symptomatic and symptoms are more often seen in AIDs patients or following a transplant. Immunosuppressed individuals may also have invasive Cytomegalovirus that most often presents with interstitial pneumonia. Histologically CMV usually presents with “Owl Eyes” which is tough to distinguish from the Reed Sternberg Cells of Hodgkins Lymphoma. This appearance is caused by infected lymphocytes accumulating basophilic inclusions.
Both EBV and CMV can cause mono. Therefore, differentiating between the two based solely on clinical scenario is difficult. For cases of mono, a Monospot Test (AKA Mononucleousis Test or Heterophile Antibody Test) is used to determine the causal virus. This test is used to detect heterophile antibodies, a type of antibody that reacts with proteins from other animals. A sample of the patient’s serum is added to sheep or horse blood and if the heterophile antibody is present in the patient’s blood it will cause the animal blood to agglutinate (clump up). A positive monospot test means the symptoms are caused by EBV and a negative means something else (probably CMV) is.
Thank you to Geoff Paterson from the UK for his generous donation!
- “Tzanck test” by NIH available at https://commons.wikimedia.org/wiki/File:Tzanck_test.png via Public Domain
- “Herpes(PHIL 1573 lores)” by CDC available at https://commons.wikimedia.org/wiki/File:Herpes(PHIL_1573_lores).jpg via Public Domain
- “Vannkopper chickenpox” by Øyvind Holmstad available at https://commons.wikimedia.org/wiki/File:Vannkopper_chickenpox.JPG via Creative Commons 4.0 International Attribution Share Alike License
- “Grant 1962 663” by John Charles Boilea available at https://commons.wikimedia.org/wiki/File:Grant_1962_663.png via Public Domain
- Derivative of “Shingles” by James Heilman available at https://commons.wikimedia.org/wiki/File:Shingles.JPG via Creative Commons 3.0 Unported Attribution Share Alike
- Derivative of “Herpes zoster neck” by Gentgeen available at https://commons.wikimedia.org/wiki/File:Herpes_zoster_neck.png via Creative Commons 3.0 Unported Attribution Share Alike
- Derivative “Infectious Mononucleosis 3” by Ed Uthman available at https://commons.wikimedia.org/wiki/File:Infectious_Mononucleosis_3.jpg via Public Domain
- Derivative of “CMV encephalitis owl eye inclusions HE stain” by Jensflorian available at https://commons.wikimedia.org/wiki/File:CMV_encephalitis_owl_eye_inclusions_HE_stain.jpg via Creative Commons 4.0 International Attribution Share Alike License
- Derivative of “Cytomegalovirus 01” by CDC/Dr. Edwin P. Ewing available at https://commons.wikimedia.org/wiki/File:Cytomegalovirus_01.jpg via Public Domain