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].

• Pain

  Secondary endpoints include total healing time stratified by stage of the lesion at onset of treatment, highest pain severity and time to pain resolution. ETHICS AND DISSEMINATION: New Zealand Ethics Registration 15/NTB/93. [ncbi.nlm.nih.gov]

  […] to pain resolution (days), defined as time from first experiencing pain to total resolution of pain. (5) Time to stage 4 from randomisation. (6) Time to stage 7 from stage 4. (7) Acceptability of treatments. [doi.org]

• Fever

  A 6 months old female infant presented with history of fever, cough and severe respiratory distress. There was past history of recurrent attacks of pneumonia. She succumbed to the illness after a hospital stay of 7 days. [ncbi.nlm.nih.gov]

  Herpes simplex virus, the causative agent of fever blisters. Thin section of virions as they leave the nucleus of an infected cell. [utmb.edu]

  Picture of Herpes Simplex Virus Type 1 Herpes simplex type 1: A herpes virus that causes cold sores and fever blisters in and around the mouth. [medicinenet.com]

  The herpes simplex virus type 1 (HSV-1) mainly causes infections in the mouth and facial area ("fever blisters"), whereas the type 2 virus (HSV-2) is predominantly found in the genital region (Herpes genitalis). [bag.admin.ch]

  – Recurrent herpes labialis: tingling feeling followed by an eruption of vesicles on an erythematous base, located on the lips (‘fever blisters’) and around the mouth, they may extend onto the face. [medicalguidelines.msf.org]

• Malaise

  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]

  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]

  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]

  This includes fever, loss of appetite, muscle aches and a general feeling of being unwell (malaise). These symptoms do not usually appear with recurrences. HSV-2 infections are more likely than HSV-1 to recur. [healthhype.com]

  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]

• Cervical Lymphadenopathy

  Generalised muscle pains and often rigors occur, with cervical lymphadenopathy and sometimes splenomegaly. Recurrent infections can occur and typically recurrences are in the same site. [bestpractice.bmj.com]

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

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

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

  These are accompanied by tender cervical lymphadenopathy, and a vesicular eruption on the lips, tongue and buccal mucosa. It may occur more commonly in those with HIV infection. [aids.gov.hk]

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

  While herpetic gingivostomatitis is characterized by painful lesions of the oral and pharyngeal mucosa, herpetic whitlow causes blisters on the fingers with pronounced regional lymphadenopathy. [amboss.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]

• 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]

  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]

  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]

  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]

• Stridor

  We present a case of acute neonatal stridor secondary to such localized disease and discuss its management. [ncbi.nlm.nih.gov]

• 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]

• 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]

  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]

  […] responsible for Mollaret meningitis, and some authorities have suggested that the term be restricted to recurrent aseptic meningitis without an identifiable cause.7 A woman aged 33 years presented with a 4-day history of intractable headache, photophobia, nausea [jamanetwork.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. [medbroadcast.com]

  These consisted of rash (one case in each group), diarrhea (one in the vidarabine group), tremulousness (two in the vidarabine group and one in the acyclovir group), and vomiting (one in the acyclovir group). Laboratory Data Figure 2. Figure 2. [doi.org]

• Acute Abdomen

  A 77-yr-old man who had received systemic steroids for more than 6 yr presented with an acute abdomen. Laparotomy revealed an ulcerative jejunitis with purulent peritonitis. [ncbi.nlm.nih.gov]

• 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 frequently absent - lymphadenopathy less common Heterophile antibody negative - IgM class antibody that agglutinate RBC from certain species like sheep Infects and transforms B lymphocytes - binds to cd21 on B cells, some become latently [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

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

  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]

  – Recurrent herpes labialis: tingling feeling followed by an eruption of vesicles on an erythematous base, located on the lips (‘fever blisters’) and around the mouth, they may extend onto the face. [medicalguidelines.msf.org]

• Skin Rash

  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]

  You may also notice a blistery skin rash around the eyelids (but not in all cases). It is usually one eye that is affected. This photo shows someone with herpes simplex eye infection. [patient.info]

  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]

  It’s important to not have skin contact with any uninfected person while you have the skin rash. Your healthcare provider may prescribe a medicine called acyclovir in a pill or an ointment form or oral valacyclovir to speed your recovery. [summitmedicalgroup.com]

• Vesicular Rash

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

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

  rash that follows a deermatomal distribution; does not cross midline when tip of nose is involved, eye is often infected; herpes zoster oticus affects facial nerve near infected ear herpes zoster oticus is a viral infection of the inner middle and external [quizlet.com]

  Any vesicular rash in an infant up to eight weeks of age should be cultured and the infant immediately started on antiviral therapy with acyclovir (Zovirax) pending culture results. [aafp.org]

  rash that follows a dermatome distribution following reaction of VZV in a single dorsal root ganglion Rarely crosses midline Rash involves thoracic and lumbar distribution; ophthalmic distribution can lead to serious eye infection Post herpetic neuralgia [brainscape.com]

• Skin Ulcer

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

• 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]

  Each year, about 50,000 new and recurring cases of ocular HSV (predominantly type 1) are diagnosed in the United States.2 HSV can cause disease in any layer of the eye, and common manifestations include blepharitis, follicular conjunctivitis, keratitis [aao.org]

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

• 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. [msdmanuals.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]

  inclusion bodies, margination of chromatin and formation of multinucleated giant cells Cell fusion provides an efficient method for cell-to-cell spread of HSV A. [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]

1. Sauerbrei A. Herpes Genitalis: Diagnosis, Treatment and Prevention. Geburtshilfe Frauenheilkd. 2016;76(12):1310-1317.
2. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
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