There are eight known herpes viruses that infect humans: herpes simplex virus (HSV)(types 1 and 2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and the recently described human herpes virus 6, human herpes virus 7, and human herpes virus 8.
Herpes viruses are enveloped, icosahedral viruses containing double stranded DNA. The fundamental distinguishing characteristic of herpes viruses is their establishment of latent infection with integration of viral genomic material into host chromosomes. Sites of latency are virus specific.
Herpes Simplex Virus (HSV)
The name herpes is derived from a Greek work meaning to creep. Herpes simplex virus type 1 (HSV1) usually causes cold sores and herpes simplex type 2 (HSV2) usually causes genital herpes infections though either can be associated with both symptom complexes.
The virus replicates initially in epithelial cells producing a characteristic vesicle on an erythematous base. It then ascends sensory nerves to the dorsal root ganglia where, after an initial period of replication, it establishes latency. During reactivation infection, the virus spreads distally from the ganglion to initiate new cutaneous and/or mucosal lesions.
Both HSV 1 and HSV 2 are common human pathogens and infections are characterized by their recurrent nature. The primary infection generally produces the worst clinical state.
Primary herpetic gingival stomatitis
Upon first encounter with HSV children often get a self-limiting but nasty infection of their mouth that is very painful. It often requires intravenous fluid therapy because of inability to eat or drink.
An infection of the cornea and can cause permanent corneal damage and visual impairment. Ulcers form in complex linear fashion referred to as “dendritic” for their resemblance to neural connections.
Infection of a finger that is very often misdiagnosed as a bacterial infection. This is a reasonably common condition especially among those that work with peoples mouths such as dentists and dental assistants.
This is usually sexually transmitted and, like all herpes simplex lesions, tends to recur.
A potentially devastating infection, most commonly caused by HSV 2 contracted during passage through the genital canal when the mother is shedding herpes virus at the time of delivery. Most obstetricians advocate C-section delivery if mother has active genital lesions. However, many affected babies are born to mothers with no known history of clinical HSV.
This is the most common cause of fatal sporadic encephalitis and is lethal in 50% of patients. It is usually caused by HSV 1.
HSV 1 and 2 are the easiest viruses to propagate in the laboratory and grow very quickly in many cell lines. They may also be identified by fluorescent antibody techniques and increasingly Nucleic Acid amplification techniques(NATS) are being employed. Vesicle fluid is the preferred specimen but samples of the base of ulcers may also yield virus.
The most successful antiviral agents are used in the therapy of Herpes virus infections. Acyclovir a nucleoside analogue was the first antiviral agent in widespread use. Therapy must be initiated early in the course of disease to be effective. Several similar agents are now in use.
Varicella zoster virus (VZV)
VZV causes varicella (chickenpox) and herpes zoster (shingles). The virus is transmitted via inhalation of virus particles suspended in air originating from disrupted vesicles. This route of spread, referred to as “airborne” is unusual and denotes a high level of infectivity. Most viruses are transmitted by more direct contact with secretions referred to as the “droplet” mode of transmission. After initial local replication in the respiratory tract viremia occurs leading to generalized vesicular lesions.
Varicella (chicken pox)
This is the condition that occurs after primary infection. Its highest incidence is in childhood and it is characterized by fever and very characteristic vesicular rash after an incubation period of 10 – 21 days.
The rash starts as crops of small red macules that soon develop a delicate single vesicle in the center. This lesion (the so-called dew drop on a rose petal) is the hallmark of varicella. Within hours the vesicle becomes pustular, breaks and begins to crust. Successive crops of lesions appear for three to five days and often all stages of skin lesions can be observed simultaneously.
While most often a benign illness in childhood, complications (e.g. secondary bacterial infection) do occur. Chicken Pox in adults is often much more severe.
Herpes zoster (shingles)
This condition occurs sporadically among those who have already had chicken pox. Reactivation of latent infection in sensory nerves analogous to HSV is responsible and is dermatomal in distribution. The appearance of chickenpox-like lesions is usually proceeded by pain in the area innovated by the nerve. Post-herpetic neuralgia, a chronic pain syndrome, is an infrequent but devastating complication. It is more common in elderly shingles patients and can persist for months or even years.
Usually the infection is clinically obvious. In uncertain cases culture can be attempted but is not a sensitive technique. Direct antigen detection with fluorescent antibody stains (DFA) are available. Serology is valuable in detecting individuals who have had past infection but who are unsure of their status. It is very important to know the sero-status of health care workers who may come into contact with immunocompromised patients.
Acyclovir and similar agents are active against VZV but are not routinely used for therapy of uncomplicated chicken pox in children. Chicken pox in adults patients is an indication for antiviral therapy as the complication rate is considerably higher than in children. Shingles is routinely treated as treatment has been shown to reduce the incidence of post-herpetic neuralgia which can be a devastating, very difficult to treat condition. As with all antiviral therapy, clinical effect is much greater if therapy is initiated early in the course of illness.
Varicella-zoster hyper-immunoglobulin (VZIG) is effective in aborting infection if administered soon after exposure. This approach is routinely used in immunocompromised patients such as bone marrow transplant recipients. VZV vaccine has recently become part of routine childhood immunization schedules. A shingles vaccine is now available in Canada to be administered to older adults. It is a higher dose of the infant vaccine that boosts immunity and prevents development of shingles quite effectively.
Epstein-Barr virus (EBV)
EBV was first seen in biopsies of an African Burkitt’s lymphoma patient and it was later determined to be the major cause of infectious mononucleosis. The virus is transmitted by direct contact, particularly via saliva. The period of infectivity is unpredictable and can be prolonged.
This common condition is characterized by extreme fatigue, fever, pharyngitis, lymphadenopathy and often hepatosplenomegaly. It most commonly affects older children and young adults. Infection in early childhood is common but often unrecognized.
EBV is causally associated with several malignancies. Most clear is its association with an unusual B-cell lymphoma called Burkitt’s lymphoma and with forms of nasopharyngeal carcinoma. Its role in the genesis of many other hematologic malignancies is an area of intense study.
Acute EBV infection is diagnosed clinically and confirmed serologically. Heterophile antibodies are antibodies that become elevated during infection with EBV but are not virus specific. They are easily tested for with simple agglutination tests e.g. Monospot®.
The measurement of specific antibodies to EBV is reserved for unusual circumstances and is complicated. There are several different types of antibody responses that can be measured including those directed against viral capsid antigen (VCA), Early Antigen (EA) and Nuclear Antigen (EBNA). For more information concerning these antibodies and their utility in diagnosis see CDC’s EBV page.
Another characteristic laboratory finding is unusual shaped lymphocytes referred to as “atypical” lymphocytes seen in peripheral blood smears.
While infection with CMV is very common (approximately 60% of the adult population in developed countries have CMV antibodies detectable in their serum) symptomatic infection occurs quite rarely. When it does, the manifestations vary with the age and immune status of the patient at the time or after the time of infection. It is a prominent cause of congenital infections, again many of which are unrecognized. As with other herpes viruses latent infection is established in all those infected with clinical disease potentially occurring after reactivation.
Approximately 1% of newborns in the North America are infected with CMV. Some of these infections are acquired in utero and some acquired at birth. Fortunately, less than 10% of those infected congenitally have symptoms.
Infections in immunocompetent adults
Infection in this group most is most often asymptomatic or results in minor nonspecific symptoms that go unrecognized. However, an illness indistinguishable from Infectious Mononucleosis caused by EBV occurs rarely i.e. CMV is a cause of “hetrophile antibody – negative” mononucleosis.
Infections in immunocompromised patients
CMV is a feared pathogen in the settings of immunoincompetence. Both new infections and reactivation of latent infections can cause severe disease, pneumonitis being the most worrisome manifestation. This is a particular problem in organ and bone marrow transplantation where all efforts are made to avoid the transplantation of CMV positive organs into CMV negative recipients.
Evidence of prior infection (and hence, ongoing latent infection) can be determined by measurement of antibodies in serum. Any “CMV positive” patient is at risk for development of disease when immunoincompetence ensues. The diagnosis of symptomatic infection is accomplished by culture, antigen detection or DNA amplification techniques on body fluids e.g. saliva, urine and respiratory secretions. However, it can be difficult to distinguish asymptomatic “shedding” of virus which occurs in a large proportion of latently infected immunocompromised patients free from overt disease. Often, pathologic confirmation is necessary. Active CMV replication in tissue is recognizable by the large cells with “owl’s eye” nuclei – the feature that is the origin of the virus’ name.
Human Herpes Virus 6
Identified recently, HHV-6 is the cause of the very common childhood illness roseola infantum or “baby measles”. It is also called exanthem subitum. This is generally a benign illness characterized by high fever and rash most commonly occurring in children aged 6 months to 2 years. Severe infections such as fulminant hepatitis and pneumonitis in immunocompromised patients have been described. Reactivation in immunosuppressed organ transplant recipients has been associated with severe disease and rejection.
Human Herpes Virus 7
Another recently identified and apparently very common, virus. It can be recovered from the majority of adults’ saliva. Alas, it is a virus without a disease, however.
Human Herpes Virus 8
The recently identified cause of Kaposi’s Sarcoma, HHV-8 is the subject of intense study in relation to potential roles in the genesis of several unusual conditions. Prevalence varies markedly geographically with a much higher incidence of antibody positivity in the Mediterranean and parts of Africa than in northern Europe and North America.
Herpes B Virus
Herpes B virus is the HSV equivalent of some non-human primates and causes little disease in its natural hosts. However, when primate handlers are accidentally infected, fulminant and often fatal infection occurs. For this reason, primates are screened for this virus before being admitted to research colonies in attempts to keep “B Virus free” conditions.