Herpes Simplex Virus: Type 1 and Type 2

Herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2) infect specific anatomical sites. HSV-1 usually infects mouth or pharynx, and HSV-2 infects the genitals. The primary locations for latency are the trigeminal nerve (orofacial herpes) and the sacral ganglia (genital herpes). HSV-1 reactivation occurs most frequently above the waist, compared to HSV-2 reactivation, which typically occurs below the waist. Both viruses can reactivate at or near the site of the initial infection. The skin lesions produced by HSV-1 and HSV-2 infection initially look similar. Both start with a clear vesicle containing infectious herpesvirus with red lesions at the base of the vesicle. The lesion may become encrusted and an ulcer may develop. HSV-2 is associated with sexual transmission, whereas HSV-1 is usually associated with infections in children.

HSV-1 can cause a number of herpetic diseases, including cold sores of the mouth; lesions on the lip; herpes keratitis of the eye (which is the leading cause of corneal blindness in the United States); herpes gladiatorum, or “mat herpes” (transmitted during frequent contact in wrestling); and herpes rugbeiorum, or “scrum pox” (seen in contact sports like rugby). The majority of HSV-1 infections are unrecognized, and therefore undiagnosed. HSV-1 causes genital herpes in about 10% of cases. HSV-1 reactivation is associated with the following factors:

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  Immune suppression by cytotoxic drugs

  
  
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  Sexual contact

  
  
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  Physical and emotional stress

  
  
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  Temperature changes (hot or cold, such as burning the mouth with hot coffee)

  
  
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  Too much ultraviolet light (e.g., sunburn)

  
  
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  Menstruation

  
  
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  Pregnancy

  
  
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  Lactation

  
  
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  Malnutrition

  
  
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  Excessive fatigue

HSV-2 is responsible for 90% of genital herpes cases. Approximately 45 million people in the United States suffer from genital herpes infections (FIGURE 11-2). New HSV-2 infections occur at a rate of about 1 million new cases every year. Individuals with HSV-2 infections can shed virus during asymptomatic periods. Safe-sex practices such as the use of condoms in combination with valacyclovir reduce the spread of HSV-2 infection during heterosexual intercourse by 75%. A pregnant woman who has an active case of genital herpesvirus infection should deliver the infant by caesarean section because HSV-2 can be transmitted to the infant during a vaginal delivery.

Varicella Zoster Virus

Varicella zoster virus (VZV) causes two different infectious diseases: chickenpox and shingles. Chickenpox is a highly contagious but mild disease that usually afflicts children, but it can be severe in infants, adults, and individuals with impaired immune systems.

Chickenpox is the only herpesvirus that spreads person to person by coughing or sneezing (airborne mode of transmission), making it highly contagious. Like other herpesviruses, it is also spread by close contact. Symptoms develop 10–21 days after contact with an infected person. When a person is initially infected with VZV, the herpesvirus infects the skin or mucosa of the respiratory tract and progresses through the blood and lymphatic system to the cells of the reticuloendothelial system. The reticuloendothelial system is a part of the immune system that consists of phagocytic cells (mainly monocytes and macrophages) located in reticular connective tissue. Their primary role is phagocytosis. The first sign of disease is often the itchy exanthematous rash that is characteristic of chickenpox (FIGURE 11-3). Some people experience a fever and malaise. The blisters dry and form scabs in 4–5 days. On average, an individual with chickenpox has 300–400 blister-like lesions on the body during an attack. Adults are more susceptible to complications, such as bacterial infection of the skin, swelling of the brain (encephalitis), and pneumonia. The Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices recommends that all children be routinely vaccinated to prevent chickenpox with the MMRV or Varivax vaccines (see chapter opener figure) at 12–18 months of age and that all susceptible children receive the vaccine before their 13th birthday (see Section 11.6).

After a primary VZV infection, the herpesvirus remains dormant or latent in the dorsal root ganglia (neurons of the nerve roots) of anyone who has had chickenpox. VZV can be reactivated later in life to cause an illness referred to as shingles or herpes zoster. VZV is most commonly reactivated after the age of 60, and the risk of reactivation increases with age. It is also more common and severe in people with compromised immune systems, such as those suffering from acquired immune deficiency syndrome (AIDS).

The onset of shingles is characterized by severe pain, headache, chills, numbness, and itching, followed by a vesicular rash that forms over 3–5 days. The rash follows a nerve on one side of the body (FIGURE 11-4). In an otherwise healthy individual, the disease lasts 10–15 days, but it may take a month for the skin to return to normal. For about one person in five, severe pain can continue long after the rash clears up. This is called postherpetic neuralgia. In an immunocompromised patient, lesion formation can take up to 2 weeks, and scabbing may not take place until 3–4 weeks into the course of the disease. Chronic shingles may also occur in people with AIDS, in which case new lesions form in the absence of healing of existing lesions, which is particularly debilitating.

An individual suffering from shingles is contagious to individuals who have not had chickenpox; thus, people who have not had chickenpox can be infected with VZV and contract chicken-pox if they have close contact with the person who has shingles. One cannot, however, get shingles from someone afflicted with shingles. Shingles is caused only by VZV that has been dormant since an individual acquired chickenpox. The shingles vaccine, Zostavax, was licensed by the U.S. Food and Drug Administration (FDA) in 2006. In clinical trials it reduced the reactivation of VZV by 50%. A single dose of shingles vaccine is recommended for adults 60 years or older (see Section 11.6).

Cytomegalovirus

Cytomegalovirus (CMV) infections are common in all human populations, affecting 40–70% of adults in the United States and nearly 40–80% in developing countries. CMV is transmitted in utero during the first 6 months of life from exposure to the mother’s genital secretions and breast milk and among preschoolers through oral and respiratory secretions. Healthy individuals who become infected with CMV after birth experience few or no symptoms of the disease and no long-term health consequences. Once a person is infected, CMV is dormant within the person’s body for life. For the majority of people, CMV is not a serious disease.

CMV is, however, the most common opportunistic pathogen in immunocompromised patients, such as older adults, persons chronically infected with HIV, and organ transplant recipients. CMV is the most common and single most important viral infection in all solid organ transplant recipients. Approximately 20–60% of transplant recipients develop symptomatic CMV infection during the first year following transplantation. CMV infection in transplant recipients includes latent reactivation of CMV in a seropositive transplant recipient, donor-transmitted CMV infection, and CMV present in donor blood through transfusions. The patient at highest risk for serious CMV disease is the CMV-seronegative recipient/CMV-seropositive donor who develops a primary infection after transplant. CMV can cause a variety of diseases, including the following:

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  Congenital CMV syndrome in neonates (infants younger than 4 weeks old)

  
  
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  Infectious mononucleosis with prolonged fever and hepatitis in young adults

  
  
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  Pneumonia in bone marrow transplant recipients

  
  
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  Disease syndromes such as fever, pneumonia, gastrointestinal ulcers (colitis), and hepatitis in lung, liver, kidney, and heart transplant recipients

  
  
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  Acute and/or chronic transplant rejection and organ failure in transplant recipients

  
  
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  Retinitis in AIDS patients

CMV is transmitted from person to person through close, intimate contact with a person excreting the virus in his or her saliva, urine, or other bodily fluids. It can be transmitted from the mothers’ vaginal secretions during birth, through breast milk, through semen (sexual transmission), from transplanted organs from a seropositive donor, and rarely by blood transfusions. CMV is the most important cause of congenital viral infection (infection during pregnancy through the time of delivery/childbirth) in the United States, where approximately 1–3% of women are infected during pregnancy. Developing unborn babies are at highest risk for developing complications of CMV infection. Complications include hearing loss, visual impairment, varying degrees of intellectual and developmental disabilities, and motor problems. If a woman who has never been infected by CMV becomes infected during pregnancy, there is the potential risk that after birth the infant may have CMV-related complications. In contrast, infants and children who contract CMV after birth experience few, if any, symptoms or complications.

An effective CMV vaccine could prevent the majority of birth defects caused by congenital CMV infections. CMV is also the most common pathogen among transplant patients, affecting up to 75% of all solid organ transplant recipients. CMV infection usually develops during the first few months after transplantation and is associated with clinical infectious disease symptoms and acute and/or chronic organ rejection or dysfunction. A CMV vaccine would significantly lower costs associated with long-term special needs associated with congenital CMV infections and healthcare costs incurred by transplant recipients suffering from severe CMV disease. During 40 years of research, vaccine development was unsuccessful. However, two vaccines have shown promise in trials on healthy adults and transplant recipients. The two vaccines are gB/MF59 and a DNA-based vaccine known as TransVax.

Epstein-Barr Virus

It is estimated that Epstein-Barr virus (EBV) causes 79% of infectious mononucleosis cases and that CMV causes the remaining 21%. The term infectious mononucleosis is used because the white blood cells, or mononuclear cells, increase dramatically within an infected individual. Infection by EBV is common throughout the world. The vast majority of EBV infections occur in young children and are asymptomatic. Individuals infected with EBV during their teens or 20s become symptomatic. Adults older than age 35 are less likely to become infected with EBV, but those who do often become very ill. In developing countries, particularly those in Africa, EBV infection is associated with Burkitt’s lymphoma, a type of B cell cancer in children.

EBV is transmitted through intimate contact with saliva of an infected person (e.g., kissing or sharing beverages or eating utensils). Mononucleosis is sometimes referred to as the “kissing disease” and has an incubation period of 4–6 weeks. Infectious mononucleosis features the following symptoms:

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  Sore throat

  
  
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  Fever

  
  
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  Swollen lymph glands

  
  
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  Malaise

  
  
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  Exhaustion

  
  
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  Enlarged spleen (sometimes)

  
  
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  Enlarged liver (sometimes)

  
  
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  Heart problems (rare)

  
  
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  Central nervous system (Cns) problems (rare)

Symptoms usually resolve within 1–2 months. EBV remains latent in the throat and blood for the rest of the infected person’s life. EBV may also play a role in multiple sclerosis (MS). EBV reactivation may have the potential to trigger autoimmunity and tissue damage associated with MS lesion development (VIRUS FILE 11-2).

Human Herpesviruses 6 and 7

Human herpesvirus 6 (HHV-6) was isolated from T lymphocyte cultures derived from the blood of AIDS patients. Human herpesvirus 7 (HHV-7) was isolated from CD4+ T lymphocytes of a healthy person. Like human immuno-deficiency virus (HIV), both viruses can infect and kill CD4+ T cells. HHV-6 infects nearly all humans by 2 years of age. There are two distinctly different HHV-6 viruses: HHV-6A and HHV-6B. HHV-6A has rarely been associated with disease. HHV-6B causes sixth disease, which is also called exanthema subitum (meaning “sudden rash”) and roseola infantum. Sixth disease is a mild disease of children. It begins with a sudden fever followed by a red rash. The name “sixth disease” comes from the fact that when childhood rash diseases were enumerated, it was the sixth one listed. The six childhood rash diseases are:

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   Measles

   
   
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   Scarlet fever

   
   
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   Rubella (German measles)

   
   
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   Duke’s disease

   
   
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   Fifth disease (caused by parvovirus B19)

   
   
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   Sixth disease

Both HHV-6 and HHV-7 have been associated with sixth disease, infantile fever, and seizures. However, most cases are attributed to infection by HHV-6. It is estimated that 5–25% of visits to emergency rooms for fever in infants are due to HHV-6. HHV-6 also causes approximately one-third of fever seizures in children up to 2 years of age. HHV-7 shares 20–75% amino acid identity with HHV-6 in many of their viral proteins.

Kaposi’s Sarcoma–Associated Herpesvirus (Human Herpesvirus 8)

In 1872, Hungarian dermatologist Moritz Kaposi (1837–1902) described five cases of a pigmented sarcoma of the skin in men aged 40–68 years. He used the term “idiopathic multiple pigmented sarcoma of the skin,” which were present primarily on the feet of the men. He described the skin sarcomas as follows:

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