Genital herpes 1. Pathogenesis Herpes simplex virus (HSV) was the first human herpes virus to be discovered. HS is a double-stranded linear DNA virus that exists in a cyclic form and belongs to the alpha subfamily of human herpesviruses, the only known hosts of which are humans. It has a diameter of about 150 nm and is structurally divided into three parts: a 150-kb long genome, a 162-peptide capsid, and a lipid periplasm containing multiple virus-specific glycoproteins from the host cell membrane. The viral particles contain more than 10 envelope proteins, named gB to M, which are related to virus adsorption, invasion and stimulation of the body’s immune response. gG is a type-specific protein that induces antibodies that distinguish HSV from HSV-I and HSV-2. HSV-I and HSV-2 can both cause genital herpes, with HSV-2 predominating at about 90%. The genital herpes is caused by HSV-2, almost always through sexual contact and latent in the sacral nerve roots. 2, epidemiology In the last 20 years, the incidence of genital herpes has increased rapidly and has become the leading cause of genital ulcers in many countries and regions. The vast majority of HS2 infections are subclinical, manifesting as clinical latent and occult infections. Patients with genital herpes are the main source of infection. The age of prevalence is 20 to 30 years, with more males than females. The recurrent type is common, with most recurrences occurring more than 5 times per year. The recurrent symptoms are mild, the duration of the disease is short, and there are generally no systemic symptoms, and most of them have triggers and prodromal symptoms before the onset of the disease. HSV-1 infection can be co-infected with HSV-2, while HSV-2 infection is rarely co-infected with HSV-1. HSV serologic studies have confirmed that the prevalence of HSV infection is significantly higher in developing countries than in developed countries. In some parts of Africa, the prevalence of HSV-2 infection in adults is about 30% to 80% in women and 10% to 50% in men. In developing countries in Asia, the prevalence of HSV-2 infection in the general population is 10% to 30%, while in Japan the prevalence is less than 7%. The annual incidence of genital herpes in North America and Europe is between 4% and 25%. 3, pathogenesis During sexual intercourse, the virus enters the normal cells through direct contact between the normal skin mucous membrane surface and the patient’s skin fast mucous membrane surface or secretions, and the virus multiplies and expands within the cells, this process is the acute infection period, there can be no conscious symptoms. Local multiplication of the virus leads to infection of the sensory nerve endings, and then the virus runs through the sensory nerves against the axon to the neuronal cells and enters the dorsal root ganglion, where it enters the latent infection state after a short replication (2-3 days). At this point, the infected cells do not die, the viral genes exist in a suppressed state in the infected cells, and cell survival and function are not affected. It can last for several years or even a lifetime. Under the right conditions, such as host trauma, menstruation and immunosuppression, the virus can be activated and released from the dorsal root ganglion, infecting and destroying skin or mucosal cells to form ulcers. Since the virus is infected through intercellular infection and can be latent in the dorsal root ganglion, it can evade the body’s immune response to a large extent, thus causing recurrent lesions. The pattern of latent HSV infection may be that, upon entry of HSV into neurons, the expression of alpha genes, which are important for transcriptional regulation, is suppressed; multiple stimuli can activate the latent viral genome to enter the replication cycle. In addition to an increase in viral DNA copy number, the involvement of host transcription factors is required to fully activate the viral genome, and the ability of viral replication activation to lead to infection depends on whether the strain has all the genes necessary for replication and whether these genes are adequately expressed. The replication of DNA is a decisive factor in the activation of latent viruses. 4. Clinical manifestations Herpes simplex virus can cause a variety of skin and mucous membrane infections, with clinical manifestations of primary and recurrent infections, and primary infections of HSV often have severe symptoms. Genital herpes can be divided into eight types: primary genital herpes, first episode of non-primary HSV-2 genital herpes (previous HSV-1 infection), first episode of reactive genital herpes (original latent HSV infection), recurrent genital herpes, genital herpes in immunodeficient or immunosuppressed individuals, subclinical and asymptomatic genital herpes, genital herpes in pregnant women, and neonatal HSV infection. Also, genital herpes can produce a series of complications such as disseminated HSV infection, viral meningitis, spinal cord radiculopathy, and pelvic inflammatory syndrome; genital herpes in pregnant women can also cause in utero HSV infection and neonatal HSV infection; in addition, herpes is closely related to the occurrence of cervical cancer and may also be an important causative factor in post-abortion infertility and male infertility. This article focuses on primary and recurrent genital herpes. (1) Primary genital herpes 10%-20% of patients will show signs of primary infection after initial infection, with an incubation period of 3-14 days on average, and prominent clinical manifestations of local symptoms. The rash starts as a maculopapular rash, papules, and then localized clusters of small blisters, which break down after 2-4 days to form superficial ulcers with significant pain, and last 2-3 weeks before localized crusting and healing. It is often accompanied by painful enlarged inguinal lymph nodes, which subside only after 1 to 2 months, and palpation shows movable tenderness nodules. Antibodies to HSV-2 in the blood often appear after 1 week of primary infection and peak at 3 to 4 weeks; early detection of antibodies in the blood can be negative. Most patients with primary infection do not show primary infection and go directly to the latent infection phase, which is clinically manifested as an insidious infection. A small number of patients may present with symptoms of aseptic meningitis, manifested as fever, neck tonicity, photophobia, headache, etc. Cerebrospinal fluid examination may reveal cell and protein abnormalities, which are more common in women. (2) Recurrent genital herpes Recurrent genital herpes is an important source of infection for genital herpes. Patients should avoid sexual intercourse until they have symptoms and the lesions have completely healed about 4 months after the recurrence of latent infection, the lesions often occur in the same area of the primary infection, and there can be local discomfort and mild symptoms a few hours before the rash develops. The area of recurrent lesions is small, new lesions are few, and systemic symptoms such as fever and pain are less manifest. The lesion section lasts from one week to 10 days and does not leave a scar after self-healing. Recurrent genital herpes occurs in about 50% of male patients within about 4 months after the initial genital herpes outbreak; in women, it is only at 8 months that 50% of cases recur. -The frequency of recurrence is generally faster in men than in women, and the pain is worse in women when they have a recurrence. The average number of recurrent genital herpes is 3-4 times a year, and up to 8 times or more in 15% of patients. (3) 3HSV I2 and carcinogenic effects When HSV I2 infects the cervix, it manifests as cervical redness, ulceration and vaginal discharge. In primary genital infections, HSV virus can be isolated from the cervical area in 59% of patients, while the detection rate of recurrent genital herpes in the cervix is only 8%. Acute herpes simplex cervicitis may also be the only clinical manifestation of primary genital herpes infection. In patients with cervical cancer, the antibody positivity rate of HSV-2 is significantly higher than that of normal control population. HSV-2 may be related to the occurrence of cervical cancer, but there is not enough evidence to confirm the inevitable link between the two. (4) Relationship between HSV-2 and HIV Since HSV infection leads to skin mucosal rupture in the genital area, and at the same time there is an accumulation of inflammatory T cells in the ulcerated area, these create favorable conditions for the transmission of HIV. HSV infection is prone to recurrence, which also makes patients more likely to be infected by HIV. serum HSV I2 antibodies in H IV positive patients are much more frequent than in HIV negative patients, and Serum antibodies to HSV I-2 in the gay male population also correlate positively with HIV antibodies, and the positive rate of HSV infection in the genital area with H IV infection is higher than that of other sexually transmitted diseases with HIV infection. Conversely, the suppression of the body’s immunity due to HIV infection also promotes the process of HSV infection. Clinical manifestations of genital herpes are frequent recurrences, prolonged disease duration and increased symptoms. Progressive aggravation of deep sores in the genital and oral mucosa with secondary bacterial and fungal infections may occur. (5) HSV-2 infection in newborns Genital herpes infection in pregnant women is uncommon, but pregnant women are prone to serious lesions such as necrotizing hepatitis, platelet and leukopenia after infection; the virus can be transmitted through the cervix or placenta, which can involve the fetus, and infection within 20 weeks of pregnancy can cause spontaneous abortion, and infection after 20 weeks can cause fetal growth retardation; HS can be transmitted to the newborn through the birth canal during delivery. HS can be transmitted to the newborn through the birth canal during delivery. If a pregnant woman is infected with primary genital herpes, the mother’s vaginal secretions can cause primary infection in approximately 50% of newborns during delivery. The first manifestation is the appearance of characteristic herpetic lesions 4 to 7 days after birth. Infection often occurs at sites of trauma to the body, such as the location of scalp electrodes used to monitor the fetus after delivery; HSV infection in neonates may involve the central nervous system and internal organs such as the liver directly without skin damage. Primary neonatal HSV infection is often difficult to diagnose in the absence of cutaneous manifestations of infection. When recurrent genital herpes occurs during delivery, the fetus is at relatively less risk of infection because it may have received maternal antibodies. 5. Laboratory tests (1) Isolation and identification of the virus: Isolation to HSV is a reliable method to confirm the diagnosis and can be inoculated in cells, chick embryo chorioallantoic membrane. After 24-48 hours of culture, the cells can be enlarged and rounded, with giant cells or fused cells appearing, and small raised white spots can be seen on the chick embryo chorioallantoic membrane; it can also be isolated by inoculation in the brain of mammary rats or mice, and if it is positive, the animals – usually die after 4-6 days due to encephalitis. The positive rate of virus culture is 85%-95%, which is higher than other methods for specific diagnosis of HSV infection. (2) Serological diagnosis: Commonly used serological diagnostic methods include complement binding test, indirect hemagglutination and hemagglutination inhibition test, neutralization test and enzyme-linked immunosorbent assay. Serological results are not significant for clinical diagnosis. (3) Direct immunofluorescence: mucous membrane and skin cells at the lesion site are smeared, fixed with specific antibodies and tested by direct immunofluorescence. The diagnosis can be made by finding bright green fluorescence in the cells, but the positive rate is not high. (4) Wright-Giemsa staining of mucous membrane and skin cell smear at the lesion site, and the finding of intranuclear inclusion bodies and multinucleated giant cells should be considered as HSV I-2 infection. (5) Molecular biology methods: molecular hybridization and polymerase chain reaction can directly detect HSVDNA in lesion tissues, which is one of the methods for rapid, sensitive and specific diagnosis of HSV infection. 6.Histopathology: Histopathology shows intracellular and intercellular edema, blister formation in the epidermis, and balloon degeneration. Multinucleated giant cells and eosinophilic inclusions in the nucleus can be seen. 7, diagnosis and differential diagnosis According to the history of unclean sexual contact or other close contact history, typical symptoms and signs, a clear diagnosis can be made. If necessary, isolate and culture the virus, stain the cell smear or test the virus serum, etc. The diagnosis is based on the history of sexual contact or other close contact, typical symptoms and signs. The syphilis hard chancre is mostly a single hard ulcer with no symptoms, and there may be hard and enlarged inguinal lymph nodes with positive syphilis seropositivity. 8.Treatment and prevention There is no cure for genital herpes. The aim of treatment is to shorten the course of the disease and inhibit the frequency of HSV reanimation. Acyclic guanosine (ACV), a derivative of guanine, specifically inhibits the replication of the virus by acting on the replication link of HSV, and is the drug of choice for the clinical treatment of genital herpes, which can shorten the local detoxification time and accelerate the healing of the lesion. Active and adequate use of the drug can shorten the course of genital herpes and reduce the recurrence of HSV infection. It is effective when prodromal symptoms appear or within 2 days of onset, and can be administered orally or intravenously, with the latter – route being more effective in patients with primary infection. Famciclovir and valacyclovir are analogues of ACV with long intracellular half-lives and extended dosing intervals. These drugs have low cytotoxicity and generally no significant adverse effects; when administered intravenously, AC can crystallize in the renal parenchyma and cause temporary renal insufficiency, so attention should be paid to slow sedation and adequate rehydration. (1) Acyclic guanosine drugs (2) Immunotherapy: interferon and GM-CSF can help enhance the immune function of patients and relieve clinical symptoms. (3) Non-steroidal anti-inflammatory drugs: anti-inflammatory pain can inhibit the synthesis of prostaglandins and strengthen the killing ability of NK cells, which can reduce the recurrence of genital herpes and be used for the treatment of recurrent genital herpes. It can be applied with ACV, 25mg, taken orally 3 times a day. (4) Local treatment: Patients should wear loose clothing and keep the affected area clean and dry to prevent secondary infection. Avoid contact with the skin lesions as much as possible and wash hands as soon as possible after contact. Topical acyclovir cream, phthalimide cream, imiquimod, etc. can be applied to the lesions 4-6 times a day for 7 days. (5) Prevention: The use of condoms can largely reduce the incidence in women, but has little effect on men; preventive and therapeutic effects of HSV vaccine: The ideal method to prevent viral infection is vaccination. Evidence that HSV vaccine can prevent viral infection has been obtained in animal models; it is not clear whether it can have the effect of preventing genital recurrence. HSV vaccine has also entered the era of genetically engineered vaccines from the initial research on inactivated viral vaccines, with more research on live vector vaccines, live attenuated vaccines. Vaccines, subunit vaccines, DNA vaccines, etc.