CMV, VZV as well as HIV infections of the esophagus can have a similar presentation. Tissue culture is the most accurate means of distinguishing between the different viral causes. Caustic esophagitis, pill-induced esophagitis as well as yeast esophagitis can have a similar clinical presentation.

Herpes simplex virus is commonly found in humans, yet uncommonly results in systemic manifestations. Suppression of HIV with antiretroviral medications, careful monitoring of immunosuppressive medications are important means of prevention. Antiviral prophylaxis such as daily acyclovir in immunocompromised individuals may be considered.

Shingles can be confused with herpes simplex, dermatitis herpetiformis and impetigo, and skin reactions caused by contact dermatitis, candidiasis, certain drugs and insect bites.

Primary orofacial herpes is readily identified by clinical examination of persons with no previous history of lesions and contact with an individual with known HSV-1 infection. The appearance and distribution of sores in these individuals typically presents as multiple, round, superficial oral ulcers, accompanied by acute gingivitis. Adults with atypical presentation are more difficult to diagnose. Prodromal symptoms that occur before the appearance of herpetic lesions help differentiate HSV symptoms from the similar symptoms of other disorders, such as allergic stomatitis. When lesions do not appear inside the mouth, primary orofacial herpes is sometimes mistaken for impetigo, a bacterial infection. Common mouth ulcers (aphthous ulcer) also resemble intraoral herpes, but do not present a vesicular stage.

Genital herpes can be more difficult to diagnose than oral herpes, since most HSV-2-infected persons have no classical symptoms. Further confusing diagnosis, several other conditions resemble genital herpes, including fungal infection, lichen planus, atopic dermatitis, and urethritis. Laboratory testing is often used to confirm a diagnosis of genital herpes. Laboratory tests include culture of the virus, direct fluorescent antibody (DFA) studies to detect virus, skin biopsy, and polymerase chain reaction to test for presence of viral DNA. Although these procedures produce highly sensitive and specific diagnoses, their high costs and time constraints discourage their regular use in clinical practice.

Until the 1980s serological tests for antibodies to HSV were rarely useful to diagnosis and not routinely used in clinical practice. The older IgM serologic assay could not differentiate between antibodies generated in response to HSV-1 or HSV-2 infection. However, a glycoprotein G-specific (IgG) HSV test introduced in the 1980s is more than 98% specific at discriminating HSV-1 from HSV-2.

It should not be confused with conditions caused by other viruses in the "herpesviridae" family such as herpes zoster, which is caused by varicella zoster virus. The differential diagnosis includes hand, foot and mouth disease due to similar lesions on the skin.

As with almost all sexually transmitted infections, women are more susceptible to acquiring genital HSV-2 than men. On an annual basis, without the use of antivirals or condoms, the transmission risk of HSV-2 from infected male to female is about 8–11%.

This is believed to be due to the increased exposure of mucosal tissue to potential infection sites. Transmission risk from infected female to male is around 4–5% annually. Suppressive antiviral therapy reduces these risks by 50%. Antivirals also help prevent the development of symptomatic HSV in infection scenarios, meaning the infected partner will be seropositive but symptom-free by about 50%. Condom use also reduces the transmission risk significantly. Condom use is much more effective at preventing male-to-female transmission than "vice versa". Previous HSV-1 infection may reduce the risk for acquisition of HSV-2 infection among women by a factor of three, although the one study that states this has a small sample size of 14 transmissions out of 214 couples.

However, asymptomatic carriers of the HSV-2 virus are still contagious. In many infections, the first symptom people will have of their own infections is the horizontal transmission to a sexual partner or the vertical transmission of neonatal herpes to a newborn at term. Since most asymptomatic individuals are unaware of their infection, they are considered at high risk for spreading HSV.

In October 2011, the anti-HIV drug tenofovir, when used topically in a microbicidal vaginal gel, was reported to reduce herpes virus sexual transmission by 51%.

If the rash has appeared, identifying this disease (making a differential diagnosis) requires only a visual examination, since very few diseases produce a rash in a dermatomal pattern (see map). However, herpes simplex virus (HSV) can occasionally produce a rash in such a pattern (zosteriform herpes simplex). The Tzanck smear is helpful for diagnosing acute infection with a herpes virus, but does not distinguish between HSV and VZV.

When the rash is absent (early or late in the disease, or in the case of zoster sine herpete), shingles can be difficult to diagnose. Apart from the rash, most symptoms can occur also in other conditions.

Laboratory tests are available to diagnose shingles. The most popular test detects VZV-specific IgM antibody in blood; this appears only during chickenpox or shingles and not while the virus is dormant. In larger laboratories, lymph collected from a blister is tested by polymerase chain reaction for VZV DNA, or examined with an electron microscope for virus particles. Molecular biology tests based on in vitro nucleic acid amplification (PCR tests) are currently considered the most reliable. Nested PCR test has high sensitivity, but is susceptible to contamination leading to false positive results. The latest real-time PCR tests are rapid, easy to perform, and as sensitive as nested PCR, and have a lower risk of contamination. They also have more sensitivity than viral cultures.

Key measures to prevent outbreaks of the disease are maintaining hygiene standards and using screening to exclude persons with suspicious infections from engaging in contact sports. A skin check performed before practice or competition takes place can identify individuals who should be evaluated, and if necessary treated by a healthcare professional. In certain situations, i.e. participating in wrestling camps, consider placing participants on valacyclovir 1GM daily for the duration of camp. 10-year study has shown 89.5% reduction in outbreaks and probable prevention of contracting the virus. Medication must be started 5 days before participation to ensure proper concentrations exist.

A specific clinical diagnosis of HSV as the cause of dendritic keratitis can usually be made by ophthalmologists and optometrists based on the presence of characteristic clinical features. Diagnostic testing is seldom needed because of its classic clinical features and is not useful in stromal keratitis as there is usually no live virus. Laboratory tests are indicated in complicated cases when the clinical diagnosis is uncertain and in all cases of suspected neonatal herpes infection:

- Corneal smears or impression cytology specimens can be analyzed by culture, antigen detection, or fluorescent antibody testing. 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. However, its high cost limits its use to research centers.

- Demonstration of HSV is possible with viral culture.

- Serologic tests may show a rising antibody titer during primary infection but are of no diagnostic assistance during recurrent episodes.

The likelihood of the infection being spread can be reduced through behaviors such as avoiding touching an active outbreak site, washing hands frequently while the outbreak is occurring, not sharing items that come in contact with the mouth, and not coming into close contact with others (by avoiding kissing, oral sex, or contact sports).

Because the onset of an infection is difficult to predict, lasts a short period of time and heals rapidly, it is difficult to conduct research on cold sores. Though famciclovir improves lesion healing time, it is not effective in preventing lesions; valaciclovir and a mixture of acyclovir and hydrocortisone are similarly useful in treating outbreaks but may also help prevent them.

Acyclovir and valacyclovir by mouth are effective in preventing recurrent herpes labialis if taken prior to the onset of any symptoms or exposure to any triggers. Evidence does not support L-lysine.

In most cases the diagnosis is established based on response to therapy. Patients in whom esophageal candidiasis is suspected should receive a brief course of antifungal therapy with fluconazole. If the infection resolves after treatment with fluconazole, then the diagnosis of esophageal candidiasis is made and no further investigation is needed. However, if the infection persists or if there are other factors involved which may warrant further investigation, then patient will undergo an esophagogastroduodenoscopy if it is safe to do so. Endoscopy often reveals classic diffuse raised plaques that characteristically can be removed from the mucosa by the endsocope. Brushing or biopsy of the plaques shows yeast and pseudohyphae by histology that are characteristic of "Candida" species.

Treatment of herpes of the eye is different based on its presentation: epithelial keratitis is caused by live virus while stromal disease is an immune response and metaherpetic ulcer results from inability of the corneal epithelium to heal:

Treatment includes fluid intake, good oral hygiene and gentle debridement of the mouth, as well as oral acyclovir. In healthy individuals the lesions heal spontaneously in 7–14 days without scarring.

The majority of cases (85%) occur during birth when the baby comes in contact with infected genital secretions in the birth canal, most common with mothers that have newly been exposed to the virus (mothers that had the virus before pregnancy have a lower risk of transmission), an estimated 5% are infected in utero, and approximately 10% of cases are acquired postnatally. Detection and prevention is difficult because transmission is asymptomatic in 60% - 98% of cases.

Testing peoples blood, including those who are pregnant, who do not have symptoms for HSV is not recommended. This is due to concerns of greater harm than benefit such as relationship problems in the setting of a high rate of tests that may be falsely positive.

Docosanol, a saturated fatty alcohol, is a safe and effective topical application that has been approved by the United States Food and Drug Administration for herpes labialis in adults with properly functioning immune systems. It is comparable in effectiveness to prescription topical antiviral agents. Due to its mechanism of action, there is little risk of drug resistance. The duration of symptoms can be shortened a bit if an antiviral, anesthetic, zinc oxide or zinc sulfate cream is applied soon after it starts.

Effective antiviral medications include acyclovir and penciclovir, which can speed healing by as much as 10%. Famciclovir or valacyclovir, taken in pill form, can be effective using a single day, high-dose application and is more cost effective and convenient than the traditional treatment of lower doses for 5–7 days.

About 16 percent of Americans between the ages of 14 and 49 are infected with genital herpes, making it one of the most common sexually transmitted diseases. More than 80% of those infected are unaware of their infection. Annually, 776,000 people in the United States get new herpes infections.

Tests for herpes are not routinely included among STD screenings. Performers in the pornography industry are screened for HIV, chlamydia, and gonorrhea with an optional panel of tests for hepatitis B, hepatitis C and syphilis, but not herpes. Testing for herpes is controversial since the results are not always accurate or helpful. Most sex workers and performers will contract herpes at some point in their careers whether they use protection or not.

Herpes outbreaks should be treated with antiviral medications like Acyclovir, Valacyclovir, or Famcyclovir, each of which is available in tablet form.

Oral antiviral medication is often used as a prophylactic to suppress or prevent outbreaks from occurring. The recommended dosage for suppression therapy for recurrent outbreaks is 1,000 mg of valacyclovir once a day or 400 mg Acyclovir taken twice a day. In addition to preventing outbreaks, these medications greatly reduce the chance of infecting someone while the patient is not having an outbreak.

Often, people have regular outbreaks of anywhere from 1 to 10 times per year, but stress (because the virus lies next to the nerve cells), or a weakened immune system due to a temporary or permanent illness can also spark outbreaks. Some people become infected but fail to ever have a single outbreak, although they remain carriers of the virus and can pass the disease on to an uninfected person through asymptomatic shedding (when the virus is active on the skin but rashes or blisters do not appear).

The use of antiviral medications has been shown to be effective in preventing acquisition of the herpes virus. Specific usage of these agents focus on wrestling camps where intense contact between individuals occur on a daily basis over several weeks. They have also been used for large outbreaks during seasonal competition, but further research needs to be performed to verify efficacy.

Reductions in morbidity and mortality are due to the use of antiviral treatments such as vidarabine and acyclovir. However, morbidity and mortality still remain high due to diagnosis of DIS and CNS herpes coming too late for effective antiviral administration; early diagnosis is difficult in the 20-40% of infected neonates that have no visible lesions. A recent large scale retrospective study found disseminated NHSV patients least likely to get timely treatment, contributing to the high morbidity/mortality in that group.

Harrison's Principles of Internal Medicine, recommends that pregnant women with active genital herpes lesions at the time of labor be delivered by caesarean section. Women whose herpes is not active can be managed with acyclovir. The current practice is to deliver women with primary or first episode non primary infection via caesarean section, and those with recurrent infection vaginally, even in the presence of lesions because of the low risk (1-3%) of vertical transmission associated with recurrent herpes.

The current first-line treatment is fluconazole, 200 mg. on the first day, followed by daily dosing of 100 mg. for at least 21 days total. Treatment should continue for 14 days after relief of symptoms.

Other therapy options include:

- nystatin is not an effective treatment for esophageal candidiasis. It can be used as (swish, do not swallow) treatment for oral candidiasis that occurs with the use of asthma pumps.

- other oral triazoles, such as itraconazole

- caspofungin, used in refractory or systemic cases

- amphotericin, used in refractory or systemic cases

Although it is a self-limited illness, oral or intravenous antiviral treatments, particularly acyclovir, have been used in the management of immunocompromised or severely infected patients. Topical acyclovir has not been shown to be effective in management of herpetic whitlow. Famciclovir has been demonstrated to effectively treat and prevent recurrent episodes. Lancing or surgically debriding the lesion may make it worse by causing a superinfection or encephalitis.

It can be treated with systemic antiviral drugs, such as aciclovir or valganciclovir. Foscarnet may also be used for immunocompromised host with Herpes simplex and acyclovir-resistant Herpes simplex.

Gingivostomatitis symptoms in infants may wrongly be dismissed as teething. "Coincidentally, primary tooth eruption begins at about the time that infants are losing maternal antibody protection against the herpes virus. Also, reports on teething difficulties have recorded symptoms which are remarkably consistent with primary oral herpetic infection such as fever, irritability, sleeplessness, and difficulty with eating." "Younger infants with higher residual levels of antibodies would experience milder infections and these would be more likely to go unrecognized or be dismissed as teething difficulty."

Gingivostomatitis must also be differentiated from herpangina, another disease that also commonly causes ulcers in the oral cavity of children, but is caused by the Coxsackie A virus rather than a herpes virus. In herpangina, ulcers are usually isolated to the soft palate and anterior pillar of the mouth. In herpetic gingivostomatitis, lesions can be found in these locations, but they are almost always accompanied by ulcerations on the gums, lips, tongue or buccal mucosa and/or by hyperemia, hypertrophy or hemorrhage of the gums.

A gastroenterologist is a medical professional that can diagnose esophagitis. To diagnose esophagitis, the doctor will interview the patient regarding their signs and symptoms. If the doctor suspects esophagitis, tests can be ordered. Esophagitis can be diagnosed by an upper endoscopy, biopsy, upper GI series (or barium swallow), and laboratory tests.

An upper endoscopy is a procedure to look at the esophagus by using an endoscope. While looking at the esophagus, the doctor is able to take a small biopsy. The biopsy can be used to confirm inflammation of the esophagus.

An upper GI series uses a barium contrast, fluoroscopy, and an X-ray. During a barium X-ray, a solution with barium or pill is taken before getting an X-ray. The barium makes the organs more visible and can detect if there is any narrowing, inflammation, or other abnormalities that can be causing the disease. The upper GI series can be used to find the cause of GI symptoms. An esophagram is if only the throat and esophagus are looked at.

Laboratory tests can be done on biopsies removed from the esophagus and can help determine the cause of the esophagitis. Laboratory tests can help diagnose a fungal, viral, or bacterial infection. Scanning for white blood cells can help diagnose eosinophil esophagitis.

Some lifestyle indicators for this disease include: stress, unhealthy eating, smoking, drinking, family history, allergies, and an immunodeficiency. It is important for the doctor to review the patient's medical history before diagnosing with esophagitis. Specific subtypes and other causes should be taken into account when making the final diagnosis.

In children the primary source of infection is the orofacial area, and it is commonly inferred that the virus (in this case commonly HSV-1) is transferred by the cutting, chewing or sucking of fingernail or thumbnail.

In adults, it is more common for the primary source to be the genital region, with a corresponding preponderance of HSV-2. It is also seen in adult health care workers such as dentists because of increased exposure to the herpes virus.

Contact sports are also a potential source of infection with herpetic whitlows.

Reflux esophagitis

A backflow of stomach acids into the esophagus that causes irritation, chronic inflammation, and tissue damage in the esophagus.

Infectious esophagitis

Esophagitis that happens due to a viral, fungal, parasitic or bacterial infection. More likely to happen to people who have an immunodeficiency. Types include:

Fungal

- Candida (Esophageal candidiasis)

Viral

- Herpes simplex (Herpes esophagitis)

- Cytomegalovirus

Drug-induced esophagitis

Damage to the esophagus due to medications. If the esophagus is not coated or if the medicine is not taken with enough liquid, it can damage the tissues.

Eosinophilic esophagitis

This esophagitis is caused by a high concentration of eosinophils in the esophagus. The presence of eosinophils in the esophagus may be due to an allergen or acid reflux. This esophagitis can be triggered by allergies to food or to inhaled allergens. This type is still poorly understood.

Lymphocytic esophagitis

Lymphocytic esophagitis is when there is an increased amount of lymphocytes in the lining of the esophagus. It is a rare condition. It could be connected to eosinophilic esophagitis.