Herpes simplex viruses (HSV-1 and HSV-2) are double-stranded DNA viruses that cause numerous types of infections in humans. Apart from primary infections (when the individual is exposed to the virus for the first time), their recurrent ability to cause infections is possible because they establish a life-long latency in neuronal cells after their acquisition through direct contact with previously infected individuals [1]. Due to the loss of maternal antibodies, the initial infection by HSV-1 occurs in early childhood, either by direct contact with saliva and other secretions, whereas HSV-2 is principally transmitted through sexual intercourse [1] [2] [3]. It is estimated that antibodies to HSV-1 are present in up to 80% of adults, illustrating that many patients go through the initial encounter with HSV asymptomatically, while approximately 14% of adults have been exposed to HSV-2 and develop specific antibodies [1]. In the literature, the following clinical entities have been described [1] [2] [3] [4] [5] [6] [7]:

• Mucocutaneous infections - Acute herpetic gingivostomatitis and herpetic pharyngitis are two of the most common forms of primary HSV-1 infection, in which constitutional symptoms, irritability, and cervical lymphadenopathy appear and last up to 2 weeks, and are seen in the pediatric population [7]. Typical vesicular ulcerative lesions, the hallmark of herpes simplex infection, appear in the oral, gingival, labial, or buccal mucosa, and the surrounding skin [2] [7]. Herpes labialis (cold sores), on the other hand, denotes HSV-1 infection in adults as a result of its reactivation from a latent state in the proximal neuronal cells. Herpetic keratitis (infection of the eye presenting with a sudden onset of pain, conjunctivitis, and visual deficits), Herpetic whitlow (an infection of the finger), and Herpes gladiatorum (infection of the skin) are other less common forms [2] [3] [7]. On the other hand, genital herpes, predominantly caused by HSV-2 (although an increasing number of reports show an almost equal prevalence of HSV-1 and HSV-2 as causative agents), manifests with fever, myalgias, and a range of genital symptoms (vaginal/urethral discharge, dysuria, inguinal lymphadenopathy and pain) [1] [5]. Symptoms last for about 10-12 days in the setting of a primary infection, whereas recurrent forms usually have a milder clinical course [1] [5].
• Infections of the central nervous system (CNS) - Two main entities in this group are meningitis, principally occurring as a complication of genital HSV-2 infection, and encephalitis, with preexisting mucocutaneous HSV-1 infections being the probable cause of dissemination to the CNS [3]. The sudden onset of fever, neurological deficits, and altered consciousness must include herpes encephalitis in the differential diagnosis, as much higher mortality rates are seen if the diagnosis is delayed.
• Disseminated and systemic infections - The immunocompromised population (individuals suffering from malignant diseases, acquired immunodeficiency syndrome, or AIDS, prolonged corticosteroid therapy, etc) are at a particular risk for infections of the esophagus, lungs, the liver, and the CNS [3] [4] [7].
• Neonatal infection - Life-threatening herpes simplex infection in the neonatal period is usually acquired during delivery or postnatal contact with individuals who are shedding the virus. The neonate can develop any of the above-mentioned entities, particularly mucocutaneous and CNS forms [2] [6] [7].

• Cervical Lymphadenopathy

  lymphadenopathy appear and last up to 2 weeks, and are seen in the pediatric population. [symptoma.com]

  Initial infection Nonspecific symptoms: fever, headache, malaise myalgia, painful lymphadenopathy in the groin area Lesions in the anogenital area (see above) Urinary tract: dysuria, urethritis, cervicitis, urinary retention (rarely) White, thick, and [amboss.com]

  There may be associated fever, cervical lymphadenopathy, halitosis, lethargy, irritability and loss of appetite. [patient.info]

  Clinical Presentation In primary oral HSV-1, symptoms may include a prodrome of fever, followed by mouth lesions with submandibular and cervical lymphadenopathy. [aafp.org]

  Mononucleosis syndrome: pharyngitis, fever, cervical lymphadenopathy ; not uncommon primary infection of adolescents. Genital infection: see section below. [hopkinsguides.com]

• Pain

  Pain relievers may be taken for pain. [msdmanuals.com]

  The affected person may feel well or suffer from fever, pain and have enlarged local lymph nodes. [dermnetnz.org]

  Outbreaks are described as aches or pains in or around the genital area or burning, pain, or difficulty urinating. Some people experience discharge from the vagina or penis. [webmd.com]

• Fever

  The affected person may feel well or suffer from fever, pain and have enlarged local lymph nodes. [dermnetnz.org]

  Generalized symptoms such as fever and malaise may develop, and lymph nodes in the groin may enlarge. Lesions may persist in this stage for a week or more, and complete healing may take four to six weeks. [britannica.com]

  Fever Blister, Fever Blisters, Sore, Cold, Sores, Cold, herpes labialis, Fever sore, Cold sores lip, Cold sore (herpetic), Herpes on lip, fever blister, herpes febrilis, Herpes Labialis [Disease/Finding], fever sores, lip herpes, herpes lips, herpes [fpnotebook.com]

  The lip sore is called a cold sore or fever blister (so named because they are often triggered by colds or fevers). [msdmanuals.com]

• Malaise

  All players had a prodrome of fever, malaise, and anorexia with a weight loss of 3.6 to 9.0 kg. Two players experienced ocular lesions associated with cutaneous vesicular lesions of the face. [jamanetwork.com]

  Initial infection Nonspecific symptoms: fever, headache, malaise myalgia, painful lymphadenopathy in the groin area Lesions in the anogenital area (see above) Urinary tract: dysuria, urethritis, cervicitis, urinary retention (rarely) White, thick, and [amboss.com]

  No associated malaise, adenopathy or fever. – Carefully consider other sites: buccal (Stomatitis, Chapter 3), genital (Genital ulcers, Chapter 9), ophthalmic, and secondary bacterial infections. – Clean with soap and water 2 times daily until the lesions [medicalguidelines.msf.org]

  Fever, malaise, headache, and sore throat are presenting features. The vesicles rupture to form ulcerative lesions with grayish exudates on the tonsils and the posterior pharynx. [emedicine.medscape.com]

  […] most common primary symptomatic HSV-1 infection generally seen in children and young adults fever, malaise, irritability, headache, vomiting, lymphadenopathy, 1-2 days prior to lesions strikingly swollen and tender gums recurrent -- recurrent cold sores [quizlet.com]

• Constitutional Symptom

  Fever and constitutional symptoms are uncommon. The lesions heal in 8-10 days, and viral shedding lasts an average 5 days. The symptoms are more severe in women than men. [emedicine.medscape.com]

  In the literature, the following clinical entities have been described: Mucocutaneous infections - Acute herpetic gingivostomatitis and herpetic pharyngitis are two of the most common forms of primary HSV-1 infection, in which constitutional symptoms, [symptoma.com]

  Constitutional symptoms were common, including fever (25 percent), chills (27 percent), sore throat (40 percent), and headache (22 percent). [nejm.org]

  Primary infection may cause constitutional symptoms with fever, malaise, weight loss, and regional lymphadenopathy. Ocular involvement includes keratitis, conjunctivitis, and blepharitis. Transmission occurs primarily through skin-to-skin contact. [cdc.gov]

  Treatment on Primary Genital Herpes Symptom/sign Duration of symptoms/signs (days) Without acyclovir With acyclovir* Viral shedding 9 2 Time until all lesions are crusted 10 7 Time until all lesions are healed 16 10 Local pain 7 5 Constitutional symptoms [aafp.org]

• Military Personnel

  ABSTRACT | FULL TEXT Herpes simplex virus type 2 and HIV infection among US military personnel: implications for health prevention programmes Bautista et al. Int J STD AIDS 2009;20:634-637. [web.archive.org]

• Pharyngitis

  Postmortem examination revealed hepatic necrosis, tonsillitis, pharyngitis and uterine cervicitis caused by herpes simplex virus (HSV) together with microthrombosis in lungs and glomerular arterioles, suggesting the diagnosis of fulminant HSV disseminated [ncbi.nlm.nih.gov]

  If symptomatic, fever, sore throat, and pharyngeal oedema may occur. Painful ulcers can appear a few days later on the pharyngeal and oral mucosa, and fever and mouth pain may last for several days. [bestpractice.bmj.com]

  Acute herpetic pharyngotonsillitis In adults, oropharyngeal HSV-1 infection causes pharyngitis and tonsillitis more often than gingivostomatitis. Fever, malaise, headache, and sore throat are presenting features. [emedicine.medscape.com]

  pharyngitis and tonsillitis caused by HSV-1 Predominantly affects adults Severe pharyngitis; other clinical findings similar to herpetic gingivostomatitis Ulcerations on the tonsils and pharynx, fewer on the oral mucosa Diagnostics and treatment: See [amboss.com]

  Fever malaise and rash can appear if mistakenly treated with ampicillin War b/w infected B cells and the T cell response - pharyngitis due to respond to infected epithelial cells - fatigue due to energy needed to power robust T cell response so you are [brainscape.com]

• Dyspnea

  Fever, productive cough, dyspnea, bronchospasm and or chest pain are mentioned as the most frequent clinical manifestations of HSV lower respiratory tract infection, although none of these symptoms is specific. [dergipark.org.tr]

  The time from onset to dyspnea was 5.0 days, 7.0 days to hospital admission, and 8.0 days to ARDS. Common symptoms at onset of illness were fever, dry cough, myalgia, fatigue, dyspnea, and anorexia. [jamanetwork.com]

  A 41-year-old woman, with no significant history, attended the emergency room with a 4-day history of fever, cough, bloody sputum, and dyspnea at rest. Physical examination revealed a temperature of 39.3°C; BP 100/50mmHg; pulse 101bpm. [archbronconeumol.org]

  Tachypnea and dyspnea are also signs of lower respiratory involvement. Viral infection and resulting inflammation may make an individual susceptible to concomitant or sequential infection with a bacterial agent. [emedicine.medscape.com]

• Productive Cough

  Fever, productive cough, dyspnea, bronchospasm and or chest pain are mentioned as the most frequent clinical manifestations of HSV lower respiratory tract infection, although none of these symptoms is specific. [dergipark.org.tr]

• Nausea

  The manifestations of HSVE include low-grade pyrexia accompanied by severe headache, nausea, vomiting, and lethargy, followed by neurological features, which may include cognitive dysfunction (confusion, acute memory disturbances and disorientation), [orpha.net]

  […] sores), herpes zoster (a viral infection that causes chickenpox and shingles), leucopenia (low white blood cell counts), thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), vomiting, abdominal (tummy) pain, diarrhoea and nausea [et.glosbe.com]

  […] irritated gums with small, painful sores in and around the mouth – this is known as herpes simplex gingivostomatitis sore throat and swollen glands producing more saliva than normal high temperature (fever) of 38C (100.4F) or above dehydration feeling sick (nausea [nidirect.gov.uk]

  Primary HSV 1 Infection Clinical manifestations There is a 1 to 3 days viral prodromal of fever, loss of appetite, malaise and myalgia that may also be accompanied by headache and nausea. [myhealth.gov.my]

  Nausea Fever. Seizures Drowsiness. If left untreated, the symptoms tend to progress, become increasingly worse, and can ultimately lead to death. Diagnosis of HSE The rapid onset and development of HSE presents a dilemma to the clinician. [encephalitis.info]

• Vomiting

  A previously well 11-month-old infant presented with lethargy, a blanching rash, vomiting and diarrhoea. She was diagnosed with suspected gastroenteritis and discharged. [ncbi.nlm.nih.gov]

  The manifestations of HSVE include low-grade pyrexia accompanied by severe headache, nausea, vomiting, and lethargy, followed by neurological features, which may include cognitive dysfunction (confusion, acute memory disturbances and disorientation), [orpha.net]

  […] herpes simplex (a viral infection that causes cold sores), herpes zoster (a viral infection that causes chickenpox and shingles), leucopenia (low white blood cell counts), thrombocytopenia (low blood platelet counts), anaemia (low red blood cell counts), vomiting [et.glosbe.com]

  You get a headache, are nauseated, or vomit. Your eyes feel irritated or you feel like you have something in your eye. Your skin becomes itchy, swollen, or develops a rash after you take your medicine. [drugs.com]

• Diarrhea

  In this case report we stress that HSV infections of the colon and small intestine should be considered in the differential diagnosis of diarrhea and intestinal bleeding in the early post-transplantation period. [ncbi.nlm.nih.gov]

  It may lead to diarrhea, severe vision problems including blindness, infections of the stomach and intestines, and even death. [bodyandhealth.canada.com]

  Less common symptoms were headache, dizziness, abdominal pain, diarrhea, nausea, and vomiting (Table 1). A total of 14 patients (10.1%) initially presented with diarrhea and nausea 1 to 2 days prior to development of fever and dyspnea. [jamanetwork.com]

  Most travel travel-related illnesses include fever, diarrhea, and skin disease, which are relatively uncommon in returning travelers. [allmedx.com]

• Aphthous Stomatitis

  RIH may appear similar to traumatic lesions (mechanical/thermal/chemical) or other types of oral mucosal disorders, such as aphthous stomatitis. [jcda.ca]

  The differential diagnosis of primary herpetic gingivostomatitis includes acute necrotizing ulcerative gingivitis, herpangina, aphthous stomatitis, candidiasis of the mouth, Steven‐Johnson syndrome and hand, foot and mouth disease ( Amir 2001 ; Chauvin [doi.org]

• Exudative Pharyngitis

  pharyngitis Fever malaise and rash can appear if mistakenly treated with ampicillin War b/w infected B cells and the T cell response - pharyngitis due to respond to infected epithelial cells - fatigue due to energy needed to power robust T cell response [brainscape.com]

• Sore Mouth

  Symptoms of herpes simplex mouth infection Your child might say he has a sore mouth. His lips, gums and throat might also be sore. [raisingchildren.net.au]

• Eruptions

  In the female, vesicular eruptions usually involve the vulva, vagina, and cervix, and may extend to the perineum, inner thighs, and buttocks. [medical-dictionary.thefreedictionary.com]

  Mild uncomplicated eruptions of herpes simplex require no treatment. Blisters may be covered if desired, eg with a hydrocolloid patch. Severe infection may require treatment with an antiviral agent. [dermnetnz.org]

  The patient had herpes simplex before, and this was the second herpetic eruption. [ncbi.nlm.nih.gov]

• Skin Rash

  And although the skin rash and other symptoms go away, the infection, like all herpes infections, does not; it can reappear months or years later. [articles.chicagotribune.com]

  Knowing that the rash is from the herpes virus may help your provider treat you. How is it treated? The rash usually lasts 7 to 10 days. It’s important to not have skin contact with any uninfected person while you have the skin rash. [summitmedicalgroup.com]

  Knowing that the rash is from the herpes virus may help your provider treat you. How is it treated? The rash usually lasts 7 to 10 days. It is important that you do not have skin contact with any uninfected person while you have the skin rash. [kpjampang.com]

  These include low grade fever (100.4 degrees F., or more, rectally), poor feeding, irritability, and skin rash in the form of pimples or blisters, seizures or other similar symptoms that may develop within six weeks following birth. [health.ny.gov]

  It causes roseola (a viral disease causing high fever and a skin rash in small children) and a variety of other illnesses associated with fever in that age group. [bodyandhealth.canada.com]

• Vesicular Rash

  Reactivation causes the typical dermatomal pain and vesicular rash (fig 1). [bmj.com]

  1-2 d before rash and 4-5d after rash onset other symptoms of chicken pox prodrome, fever, malaise, pharyngitis; rash begins on chest, back, and face; spreads rapidly can spread to cerebellum and cause ataxia; pneumonia in older; hepatitis; immunocom [quizlet.com]

  Vesicular rash over the scrotum and penis was noted in all patients (Fig 1 ). [pediatrics.aappublications.org]

  […] in 24 hours Rash begins on chest back and face, spreads rapidly and lasts 3 - 5 days Rash starts out maculopapular and then small fluid filled vesicles with central dimple (umbilication) on a red base; rash is itchy All stages of rash present at any [brainscape.com]

  Although many wrestlers had typical vesicular skin lesions, there was great variability in the appearance of the rash. [nejm.org]

• Skin Ulcer

  Mouth, eye and genital skin ulceration may occur. It typically lasts 7 to 10 days. [doi.org]

  Individuals who participate in contact sports such as wrestling, rugby, and football (soccer), sometimes acquire a condition caused by HSV-1 known as herpes gladiatorum, scrumpox, wrestler's herpes, or mat herpes, which presents as skin ulceration on [en.wikipedia.org]

• Chancre

  […] vesicles that turn into painful ulcerations, also known as cold sores; (primarily affecting the oral mucosa and lip borders) Differential diagnoses [2] Shingles (Herpes zoster) Aphthous ulcers Herpangina Hand, foot, and mouth disease Candidiasis Syphilitic chancre [amboss.com]

  Primary oral chancre of syphilis. Signs of possible oral cancer include: Ulceration of the oral mucosa persisting for more than three weeks. Oral swellings persisting for more than three weeks. All red or red and white patches of the oral mucosa. [patient.info]

• Blepharitis

  Ocular involvement includes keratitis, conjunctivitis, and blepharitis. Transmission occurs primarily through skin-to-skin contact. Autoinoculation may lead to involvement of multiple sites. [cdc.gov]

  In addition, five had herpetic conjunctivitis or blepharitis; none had keratitis. [nejm.org]

  HSV infection may cause other ocular diseases, including blepharitis/dermatitis, conjunctivitis, dendritic epithelial keratitis, and corneal ulcerationFootnote 6. [canada.ca]

• Urinary Hesitancy

  She reported some urinary hesitancy although denied urinary or bowel incontinence, any sensory deficits of the lower extremities, or severe headaches. [karger.com]

The diagnosis of a herpes simplex infection starts with a meticulous patient history and a thorough physical examination that will identify the course of symptoms and the appearance of typical skin lesions, respectively. Physicians should carefully examine the skin and establish clinical suspicion based on the obtained signs and order a targeted laboratory investigation to confirm HSV as the underlying cause. In children, serology testing may be useful if a primary infection is suspected, as enzyme-linked immunosorbent assay (ELISA) can distinguish between antibody classes and confirm a high titer of immunoglobulin M (IgM) antibodies in serum [1] [2] [3]. Conversely, titers of IgG are not indicative of a recent or recurrent infection, which is why more advanced methods are necessary for adults. Detection of viral genetic material in serum, cerebrospinal fluid (in the setting of a CNS infection) or from biopsy samples through a polymerase chain reaction (PCR) testing are the methods of choice [1] [5] [6] [7]. Additionally, direct microscopic examination of the obtained biopsy samples is an equally effective method, and the Tzanck smear will show multinucleated giant cells and inclusion bodies in the nucleus, known as Cowdry type A acidophilic intranuclear inclusion bodies [2] [3] [7]. If frequent recurrences are observed, or if a disseminated infection is confirmed, the role of patient history is pivotal in assessing preexisting risk factors or underlying diseases, and a diagnosis of HIV infection must be excluded through appropriate serological testing.

• Colitis

  Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur. HSV outbreaks may be followed by erythema multiforme, possibly caused by an immune reaction to the virus. [merckmanuals.com]

• Intranuclear Inclusion Bodies

  Tzanck smear, i.e.Papanicolaou staining of corneal smears, show multinucleated giant cells and intranuclear inclusion bodies, however, the test is low in sensitivity and specificity. DNA testing is rapid, sensitive and specific. [en.wikipedia.org]

  Characteristic cytopathic effect -Perinuclear cytoplasmic inclusions form in addition to the intranuclear inclusions typical of herpesviruses(multinucleated cells are seen and become greatly enlarged. [es.slideshare.net]

• Viral Inclusion Body

  General Pathology Corneal scrapings of HSV keratitis prepared with Giemsa stain may reveal the presence of intranuclear viral inclusion bodies. Multinucleated giant cells may also be found. [eyewiki.aao.org]

Topical treatment has only marginal or no benefit in the treatment of orolabial or cutaneous diseases caused by HSV-1. Keratoconjunctivitis is treated with topical trifluridine or vidarabine. [clinicaladvisor.com]

The most common treatment is aciclovir cream which reduces healing time by just half a day compared with no specific treatment. [doi.org]

The documented change from HSV-2 towards HSV-1 in cases of genital HSV infection may have implications as to prognosis, future usefulness of vaccines, present and future usefulness of new type-specific serological tests. [ncbi.nlm.nih.gov]

Where dissemination occurs, infection carries a grave prognosis. Infection is particularly dangerous in premature infants. In mature infants, infection 10 days or more after birth carries a much improved prognosis. [virology-online.com]

Herpes Simplex Diagnosis Herpes Simplex Prognosis Herpes Simplex History Herpes Simplex Mechanism [news-medical.net]

The use of molecular diagnostic modalities in clinical practice may aid in determining infectious etiologies in patients with atypical clinical manifestations. [ncbi.nlm.nih.gov]

Epidemiology Fetal HSV infection much less common than neonatal HSV infection. The estimated incidence is at ~ 1 in 200,000 deliveries 3. Complications Overwhelming fetal sepsis might result in multi-organ failure, including fetal brain death. [radiopaedia.org]

HSV Infections Epidemiology Segmentation The disease epidemiology covered in the report provides historical as well as forecasted epidemiology [total prevalent cases, prevalent cases by types (Genital Herpes and Herpes Labialis), diagnosed prevalence] [giichinese.com.cn]

Using both clinical and molecular epidemiology, we sought to define the modes of transmission and the risk factors for infection. [nejm.org]

HSV: herpes simplex virus IV: intravenous PCR: polymerase chain reaction SEM: skin, eye, and mouth STI: sexually transmitted infection VZV: varicella-zoster virus Objectives After completing this article, readers should be able to: Characterize the epidemiology [dx.doi.org]

This model in humans should prove useful in evaluating the pathophysiology and prevention of viral reactivation. [ncbi.nlm.nih.gov]

Ocular herpes: the pathophysiology, management and treatment of herpetic eye diseases. Zhu L, et al. Virol Sin. 2014" 4. Harper DM, DeMars LR2. HPV vaccines-A review of the first decade. Gynecol Oncol. 2017;146(1):196-204. 5. [doctoranytime.gr]

Inside Clinical Pathology for Athletic Trainers, Second Edition, you will find an expanded discussion of the pathophysiology associated with general medical conditions, as well as case studies which facilitate the student's ability to formulate a differential [books.google.it]

Report Scope The report covers detailed overview of HSV infections explaining its causes, symptoms, classification, pathophysiology, diagnosis and treatment patterns The report provides the insight about the historical and forecasted patient pool of HSV [giichinese.com.cn]

Pathophysiology Add text here Primary prevention Prevention of herpetic infection includes avoidance of direct contact with known HSV. [eyewiki.aao.org]

The preventative effects of sunscreen were uncertain. Application of sunscreen prevented cold sores induced by experimental ultraviolet light, but did not prevent cold sores induced by sunlight. [doi.org]

OBJECTIVES: To assess the effects of interventions for the prevention of HSL in people of all ages. [ncbi.nlm.nih.gov]

Antiviral chemotherapy may be effective in preventing herpes-related cesarean sections, and its efficacy in preventing sexual transmission of HSV is under study. [dx.doi.org]

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3. Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology. Seventh edition. Philadelphia: Elsevier/Saunders; 2013.
4. Munawwar A, Singh S. Human Herpesviruses as Copathogens of HIV Infection, Their Role in HIV Transmission, and Disease Progression. J Lab Physicians. 2016;8(1):5-18.
5. Johnston C, Corey L. Current Concepts for Genital Herpes Simplex Virus Infection: Diagnostics and Pathogenesis of Genital Tract Shedding. Clin Microbiol Rev. 2016;29(1):149-161.
6. Corey L, Wald A. Maternal and Neonatal HSV Infections. The New England journal of medicine. 2009;361(14):1376-1385.
7. Mandell GL, Bennett JE, Dolin R. Mandel, Douglas and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, Pennsylvania: Churchill Livingstone; 2015