Herpes Simplex Virus, Structure,Pathogenesis, Clinical Feature and Lab Diagnosis

Herpes Simplex viruses (HSV) are members of Herpes Virus family. HSV is a large virus (2nd only to Pox Virus) with a core containing double-stranded DNA within a coat, an icosahedron with 162 capsomeres.
Herpes Simplex Virus
Herpes Simplex Virus
The envelope which surrounds the ‘naked’ particle is partly nuclear membrane derived, partly virally coded, with glycoprotein spikes. The diameter of a complete particle is 120–200 nm. The ‘naked’ virion measures about 100 nm.
The virus enters the cells through cellular membrane fusion after being attached to specific receptors through an envelope glycoprotein. The capsid is transported to nuclear pores where DNA circularizes after uncoating, and enters the nucleus.

HSV-1 infections usually affect the oral cavity, lips or face and occasionally genital region, and HSV-2 infections are confined to genital region. In HSV 1, labial herpes (‘cold sore’) is the most common manifestation.
Primary infection The primary infection is symptomless in most cases, but may present as fever, enlarged submandibular lymph nodes, sore throat, gingivostomatitis with ulcers or vesicles, oedema, with associated anorexia, pain and malaise. This condition usually lasts for 10–21 days, and may be accompanied by inability to eat or drink. Dehydration may be a problem, especially in small children.
Symptomatic primary infection is most common in children of 1–5 years of age, with an incubation time of 2–12 days, mean about 4 days. There may be a prodrome of burning, itching or tingling pain for some hours followed by groups of vesicles usually on the external borders of the lips. Lesions may also be found in skin surrounding the lips; chin,  cheeks or nose. Within a few days the vesicles progress to pustules or ulcers with brownish-yellow crusts. Pain is most severe in the beginning and resolves during the next 4–5 days.
The Herpes 2 infection usually affects the genital regions. The primary genital infection may be severe, with illness usually lasting up to about 3 weeks (sometimes longer) with a shedding period of virus usually terminating shortly before or at the time of healing. The lesions are vesicles or ulcers localized to the cervix, vagina, vulva or perineum of the female, or the penis in the male. The lesions are painful, and may be associated with inguinal lymphadenopathy and dysuria. Systemic complaints, including fever and malaise, usually occur. Complicating extragenital affections, including aseptic meningitis, have been observed in about 10–20% of cases. Paraesthesia or dysesthesia may occur after the genital affection. Especially in women the severity of the primary infection may be associated with a high number of complications and frequent recurrences. Previous HSV1 infection reduces the severity and duration of primary HSV2 infection. The recurrent genital affection is usually milder, with fewer vesicles or ulcers and with duration of 7–10 days. The recurrent lesions seldom last more than 10 days, and the shedding of virus may terminate sooner. Sometimes, virus excretion can occur between active periods.
Neonatal herpes
Infection in the newborn may be acquired in utero, at or just after birth. The newborn has low resistance to this infection, and usually develops severe disease. The mortality rate of untreated disease is about 50%. Babies with neonatal herpes infection may develop:
  • A disseminated generalized form with many affected organs, including the central nervous system (CNS).
  • Encephalitis with or without herpetic lesions of the skin.
  • Herpetic lesions localized to skin, mouth and eyes.
The generalized form is especially serious, and is often combined with intravascular coagulopathy, hepatic and adrenal necrosis, pneumonitis and/or encephalitis followed by permanent neurological sequelae if the patient survives. The congenital infection may induce malformations such as microcephaly or microphthalmia, or other symptoms such as jaundice, hepatosplenomegaly, bleeding diathesis, seizures, irritability, chorioretinitisand herpetic vesicles of the skin.
HSV encephalitis.
In the USA HSV1 is considered the most common viral strain of fatal encephalitis.The lesion is usually a local process in the brain, consisting of haemorrhagic necrosis and oedema, mimicking a brain tumour. The localization is usually one of the temporal lobes. At later stages, however, the expansion retracts leaving scar tissue and midline structures deviating to the affecting side.
In immunocompromised patients the HSV infection may be severe, especially if the cellular immunity is reduced. This is true both in patients with a disease affecting the immune system, e.g. AIDS, and in patients under immunosuppressive treatment. Especially bone marrow, renal and cardiac transplant recipients are at risk for severe herpes infections. The lesions may be progressive, and involve unusual sites such as the respiratory tract, oesophagus, liver and intestinal mucosa, or occur as a disseminated infection in severely immunocompromised patients. The severity of the disease is directly related to the degree of immunosuppression, and will also last longer than usual, about 6 weeks. Malnourishment, especially in children, seems to aggravate symptoms. Even immunocompromised patients may discharge virus asymptomatically.
The initial infection with herpesvirus may be located in the eye, with severe keratoconjunctivitis as a result. Recurrent infections of the eye may appear as ulcers of the cornea, sometimes dendritic ulcers, or as vesicles on the eyelids. Later chorioretinitis may develop. The cornea may develop opacifications after recurrence, indicating a progressive involvement. Blindness may be the consequence. Even herpetic necrosis of the retina has been observed as a very rare consequence of the infection.
    – stain scrapings obtained from base of vesicle ( giemsa stain)
    – presence of multinucleated giant cells indicate HSV-1, HSV-2 or VZV.
  2. Isolation and identification of virus
    – isolated from lesions; also from throat washings, CSF and stool.
    – Inoculation of tissue cultures ( human diploid fibroblast).
    – Identification by Neutralization test or immunofluorescence staining with specific antiserum.
    – typing done by using monoclonal antibody or by RE analysis of viral DNA
  3. PCR: most sensitive / specific
    – detection of amplified viral DNA by PCR in CSF or other samples
    – typing done by using type- specific primers, or using common primers followed by RE analysis or hybridization probes.
  4. Serology
    -Serology is of no use in recurrences except in cases of encephalitis.
    – antibody appear in 4-7 days after infection, reach peak in 2-4 weeks.
    – CFT measures total antibody, not differentiating type- specific antibody.
    – EIA more efficient than CFT; type- specific antigen (gG) used to detect type – specific antibody.
    – diagnostic valve limited by multiple Ag shared by HSV-1 and HSV-2; also heterotypic anamnestic responses to VZV in HSV infection and vice- versa.
Interpretation of Diagnostic Test for Herpes Simplex Virus (HSV)
Test Result Interpretation Recommendation/Notes
Cultures of Vesicles or Ulcers Positive Active Infection Confirm by staining with specific monoclonal antibodies establishes the diagnosis. Culture from current late disease is much less sensitive
ELISA (Serology) Positive Prior exposure or active infection Distinguishes HSV-1 and HSV-2
Direct Cytologic exam Positive Active Infection Use Wright-Giemsa stain followed by Tzanck smear (See multinucleated giant cells. Negative test does not rule out diagnosis. Does not differentiate HSV-1 and HSV-2)
PCR Positive Active Infection Detects HSV in tissue, CSF or Cell Samples. Sensitive, specific and rapid. Distinguishes HSV-1 and HSV-2
Western Blot or
Prior Exposure
No prior exposure
Detects glycoprotein-G; distinguishes HSV-1 and HSV-2. Western blot is gold standard for antibody detection (IgM and IgG).


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