Version July 2025
INTRODUCTION —
Esophagitis is most often caused by noninfectious conditions, such as gastroesophageal reflux disease, whereas esophageal infection occurs predominantly in hosts with impaired immunity resulting from chemotherapy, transplantation, or HIV infection. The most common causes of infectious esophagitis include Candida, cytomegalovirus (CMV), and herpes simplex virus (HSV).
This topic will address the epidemiology, clinical manifestations, diagnosis, and treatment of HSV esophagitis. Topics on candidal and CMV esophagitis are found elsewhere. (See "Esophageal candidiasis in adults" and "AIDS-related cytomegalovirus gastrointestinal disease" and "Oropharyngeal candidiasis in adults".)
EPIDEMIOLOGY —
Herpes simplex virus (HSV) infection of the esophagus is usually observed in patients who are immunocompromised, but can occasionally be seen in patients who are immunocompetent. The vast majority of infections are related to HSV type 1, although HSV-2 has occasionally been reported [1,2].
HSV esophagitis may result from reactivation of HSV with spread of virus to the esophageal mucosa by way of the vagus nerve or by direct extension of oral–pharyngeal infection into the esophagus [3]. It may also occur during primary herpes infection; in a cohort study of healthy adults and adolescents with herpes esophagitis, 11 of 25 evaluable cases (44 percent) had primary infection based upon serology [1].
Immunocompromised hosts — HSV esophagitis occurs most frequently in solid organ and bone marrow transplant recipients [4-8]. HSV and cytomegalovirus (CMV) were the most commonly identified pathogens in a study of 21 patients with endoscopically proven esophagitis who had undergone bone marrow transplantation [9]. HSV esophagitis has also been reported in organ transplant recipients in the setting of acute rejection and intensive immunosuppression [5,10]. As an example, in a series of renal transplant recipients at a single institution in Pakistan, 97 patients with esophagitis underwent a biopsy during endoscopy, and esophageal candidiasis, CMV, and herpes virus were found in 33, 8, and 5 patients, respectively [10]. Simultaneous infection with multiple pathogens has also been reported in this population [11,12]. The etiology of the esophagitis is likely to be significantly influenced by the type of prophylaxis the patient is receiving at the time of diagnosis (ie, acyclovir, valganciclovir, fluconazole, or other antifungal agents). (See "Prophylaxis of infections in solid organ transplantation".)
HSV is a less common cause of esophagitis in patients with HIV infection than in transplant recipients. In three illustrative reports, esophagitis from HSV-1 infection was identified in only 3 to 5 percent of HIV-infected patients with esophagitis [9,13,14]. In most reports, the most common cause of esophagitis in patients with advanced acquired immunodeficiency syndrome (AIDS) was Candida, whereas the most common viral cause was CMV [14]. Both infections coexist in some patients. However, the incidence of infectious esophagitis from any cause has declined since the introduction of potent antiretroviral therapy. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection" and "Esophageal candidiasis in adults" and "The natural history and clinical features of HIV infection in adults and adolescents", section on 'Impact of treatment'.)
HSV esophagitis has also been reported in the setting of extreme malnutrition as the cause of immunosuppression [15] as well as uncontrolled diabetes mellitus and chronic alcohol use [16].
Immunocompetent patients — Esophagitis due to HSV-1 has been described in otherwise healthy patients in case reports [1,17-28]. In a review of 56 patients (39 men and 17 women), the mean age at presentation was 35 years with cases among men predominating in those under 40 years of age [1]. Atypical presentations can occur in the elderly with anorexia and weakness [29]. In one report, HSV esophagitis was described after COVID-19 infection, which may augment risk [30]. Cases of HSV-1 esophagitis have also been reported in immunocompetent children [18,19]. HSV-2 is also a rare but reported cause of HSV esophagitis in immunocompetent patients [2,31].
CLINICAL MANIFESTATIONS —
Patients usually present with odynophagia and/or dysphagia [1,12,32]. In one report of 46 patients with herpes simplex esophagitis, odynophagia and dysphagia occurred in 35 and 30 percent, respectively [12]. Fever and retrosternal chest pain can also occur, and in a review of 56 immunocompetent patients, these symptoms were present in about half [1]. These latter symptoms are also a feature of herpes simplex virus (HSV) esophagitis in immunocompromised individuals. Abdominal pain and anorexia can also occur, and in the elderly may be presenting symptoms [29,33].
Patients with HSV esophagitis can have coexistent herpes labialis, glossitis, or oropharyngeal ulcers [34,35]. Complications that have been described in older case reports include bleeding [36], the development of a tracheoesophageal fistula [37,38], esophageal perforation with mediastinal collection [39], and food impaction [40]. Intractable hiccups in association with HSV esophagitis has also been described [41,42]. A few reports have described an association with eosinophilic esophagitis [43-49].
DIAGNOSIS —
The diagnosis of herpes simplex virus (HSV) esophagitis is usually based on endoscopic findings confirmed by histopathological examination of the observed lesions. Suggestive findings may sometimes be seen during a barium swallow (image 1).
Lesions usually affect the squamous mucosa of the distal esophagus where the earliest manifestation is a vesicle, although this early stage is rarely seen on endoscopy. The lesions coalesce to form ulcers (usually less than 2 cm), frequently with normal-appearing intervening mucosa (picture 1). The ulcers are well circumscribed and have a "volcano-like" appearance, distinguishing them from the ulcers seen in cytomegalovirus (CMV) infection, which tend to be linear or longitudinal and deeper [4,50]. Exudates, plaques, refractory ulcers, or diffuse erosive esophagitis may also be present [51,52].
Biopsies or brushing should be taken from the edge of an ulcer where viral cytopathic effects are most likely to be present. Histologic findings include multinucleated giant cells, with ground-glass nuclei and eosinophilic inclusions (Cowdry type A inclusion bodies) that occupy up to one-half of the nuclear volume (picture 2) [53]. Immunohistochemical stains for HSV glycoproteins may also be helpful [51,54]. In patients who do not respond to acyclovir, viral culture of suspicious lesions should be performed during endoscopy, if possible, to confirm the diagnosis and to identify resistant viral isolates.
Qualitative and quantitative polymerase chain reaction (PCR) testing has been investigated to detect HSV DNA from biopsy samples [55,56]. Efforts are also being made to assess whether determining a tissue viral load using PCR testing could improve specificity and positive predictive values [56].
DIFFERENTIAL DIAGNOSIS —
The differential diagnosis includes other infectious causes of esophagitis (mainly cytomegalovirus [CMV] and Candida). Although Candida is the most common fungal cause of esophagitis, other fungal infections, including cryptococcosis, histoplasmosis, blastomycosis, and aspergillosis have rarely been described [57]. Other pathogens, such as mycobacteria and Nocardia, have occasionally been reported [57,58]. In patients with advanced HIV infection, idiopathic aphthous ulcers have been described in up to one-fourth of patients with esophageal symptoms who did not respond to empiric antifungal therapy [14]. (See "Esophageal candidiasis in adults".)
Other diagnostic considerations include noninfectious causes of esophagitis, particularly pill esophagitis (eg, from doxycycline), autoimmune inflammatory diseases such as Crohn’s disease or lichen planus, or malignancy [59]. (See "Pill esophagitis".)
TREATMENT —
The management of herpes simplex virus (HSV) esophagitis depends upon the host's underlying immune status. Treatment recommendations are based on the approach to treatment of other herpes simplex infections since data evaluating treatment of herpes esophagitis are lacking.
Indications — Immunocompromised patients with HSV esophagitis should receive antiviral therapy. Although data supporting the treatment of HSV esophagitis are limited, immunocompromised patients can develop severe HSV infections, and the risks of antiviral therapy are generally minimal, especially when oral therapy is used.
In patients who are not immunocompromised, we suggest antiviral therapy unless symptoms already appear to be abating. In untreated immunocompetent patients, spontaneous resolution usually occurs after one to two weeks, although patients may respond more quickly if treated with a short course of antiviral therapy. In a case report of a patient with HSV-2 esophagitis, acyclovir appeared to hasten resolution of lesions [2].
Regimen selection
Patients able to tolerate oral therapy — There are limited data to guide the dose and duration of antiviral therapy for patients with HSV esophagitis.
For immunocompromised patients able to take oral medications, acyclovir (400 mg five times daily), valacyclovir (1 g two times daily), or famciclovir (500 mg two times daily) can be used. Doses should be adjusted in those with reduced kidney function, as described in the drug information topics within UpToDate. For such patients, we administer antiviral therapy for 14 to 21 days.
For patients who are not immunocompromised, the duration of therapy can be shorter (eg, 7 to 10 days). In addition, if acyclovir is used, a lower dose (eg, 400 mg orally three times daily) is reasonable [1,60].
Acyclovir, valacyclovir, and famciclovir are comparable in terms of their efficacy for the treatment of HSV. Valacyclovir and famciclovir have the advantage of decreased pill burden; however, they are generally more expensive than acyclovir. (See "Famciclovir: An overview" and "Valacyclovir: An overview".)
Patients with severe odynophagia or dysphagia — Patients with severe odynophagia may require hospitalization for parenteral antiviral therapy, pain management, and hydration or alimentation.
●Intravenous (IV) acyclovir (5 mg/kg IV every eight hours for 7 to 14 days) should be administered to those who are unable to swallow. Patients who improve can be switched to oral therapy to complete their therapeutic course. (See 'Patients able to tolerate oral therapy' above.)
●Swallowed viscous lidocaine oral topical solution (15 mL of a 2% formulation) with or without an antacid can be tried to relieve pain [61], but in our experience is usually only of modest benefit. About 35 percent of the dose is absorbed; thus ingestion should be limited to no more than 300 mg lidocaine (viscous) per dose for patients weighing greater than 65 kg and 4.5 mg/kg lidocaine (viscous) per dose for patients weighing 65 kg or less, and no more than eight doses per day [62].
Patients with drug-resistant HSV — Patients who do not respond to therapy may have virus resistant to acyclovir resulting from mutations within the thymidine kinase (TK) or, less commonly, the DNA polymerase gene of HSV [63]. Viruses with TK mutations are generally cross-resistant to other drugs in this class, including valacyclovir and famciclovir, but remain susceptible to antiviral agents that act directly on DNA polymerase (eg, foscarnet) [64,65].
Most experience with acyclovir resistance is related to HSV oral mucositis or genital infection. Although rare, acyclovir resistance is more commonly seen in immunocompromised patients, those who have undergone chemotherapy, transplantation, or who have HIV infection [66-68]. Many of these patients will have received multiple courses of acyclovir in the past. Resistant HSV can also arise spontaneously from natural variations within the viral population; this is evident from studies that have demonstrated acyclovir resistance in treatment-naive patients [67]. However, in extensive surveys conducted in the United States and the United Kingdom of immunocompetent hosts, isolation of drug-resistant HSV remains low (approximately 0.1 to 0.7 percent of isolates). Low levels of drug resistance have been attributed to rapid clearing of HSV infection by an intact immune system [69].
Cases of severe persistent infection with acyclovir-resistant HSV occur rarely and almost exclusively in immunocompromised hosts [69]; in immunocompetent hosts, rare cases of drug-resistant virus have cleared without adverse clinical outcome [69].
Treatment with foscarnet can be effective for immunosuppressed patients with HSV strains known to be resistant to acyclovir or for those who do not respond to acyclovir, although foscarnet must be given parenterally and is associated with considerable toxicity [70,71]. (See "Foscarnet: An overview".)
The use of the investigational agent pritelivir, a helicase-primase inhibitor, is being evaluated for the treatment of acyclovir-resistant mucocutaneous HSV in immunocompromised adults [72]. Information about this phase 3 trial can be found at clinicaltrials.gov.
PREVENTION —
For immunocompromised patients, antiviral therapy may reduce the risk of developing herpes simplex virus (HSV) esophagitis. As examples:
Primary prophylaxis — Many transplant patients receive antiviral prophylaxis for a period of time after transplant to reduce the risk of developing disease caused by cytomegalovirus and varicella zoster virus. These agents (eg, valganciclovir and acyclovir) also reduce the risk of developing clinical disease due to HSV. However, clinicians should be aware that some of the newer antiviral prophylaxis agents, such as letermovir or maribavir, do not prevent HSV (or varicella-zoster virus), and additional antiviral prophylaxis is required to prevent those infections when these agents are used. (See "Prevention of viral infections in hematopoietic cell transplant recipients" and "Prophylaxis of infections in solid organ transplantation".)
Secondary prophylaxis — Some immunocompromised patients who had moderate to severe esophagitis remain at risk for recurrent infection after treatment (eg, those being treated for organ rejection). For such patients, we suggest secondary prophylaxis with an antiviral agent. We typically use acyclovir or valacyclovir since there is the most experience with these agents. The doses are the same as those used for standard prophylaxis (eg, oral acyclovir 400 or 800 mg twice daily; oral valacyclovir 500 mg twice daily). (See "Prophylaxis of infections in solid organ transplantation" and "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Herpes simplex virus'.)
When antiviral therapy is used for secondary prophylaxis, the duration of treatment is determined on a case-by-case basis depending upon the patient's degree of immunocompromise and risk of recurrent infection. The duration is typically measured in months; secondary prophylaxis to prevent recurrent HSV esophagitis is almost never administered indefinitely.
SUMMARY AND RECOMMENDATIONS
●Epidemiology - Herpes simplex virus (HSV) infection of the esophagus is usually observed in patients who are immunocompromised and occurs most frequently in those receiving immunosuppressive agents, such as solid organ and bone marrow transplant recipients. However, it has also been described in otherwise healthy patients. (See 'Epidemiology' above.)
●Clinical manifestations - Patients with HSV esophagitis usually present with odynophagia and dysphagia. Fever, epigastric pain, nausea, vomiting, and heartburn are less frequent. Occasional patients have coexistent herpes labialis or oropharyngeal ulcers. (See 'Clinical manifestations' above.)
●Diagnosis – The diagnosis of HSV esophagitis is usually established with an upper endoscopy. Biopsies or brushing should be taken from the edge of an ulcer where viral cytopathic effects are most likely to be present. (See 'Diagnosis' above.)
●Differential diagnosis - The differential diagnosis includes other forms of infectious esophagitis and pill esophagitis. (See 'Differential diagnosis' above.)
●Treatment
•Indications - Antiviral therapy should be administered to immunocompromised patients with HSV esophagitis as infection is likely to progress rather than abate without treatment. (See 'Indications' above.)
For immunocompetent patients with persistent symptoms, we also suggest antiviral therapy (Grade 2C).
Data on the efficacy of antiviral therapy for treating HSV esophagitis are limited; however, based on the experience treating other HSV infections, antiviral therapy likely hastens the resolution of lesions.
•Regimen selection
-Patients able to take oral therapy - For patients who are able to take oral therapy, treatment options include acyclovir, valacyclovir, or famciclovir. The efficacy of all three agents is similar for the treatment of herpes simplex infections. Valacyclovir and famciclovir have the advantage of decreased pill burden; however, acyclovir may be preferred in some settings as it is typically a less expensive alternative. (See 'Patients able to tolerate oral therapy' above.)
Treatment should be administered for 7 to 10 days in immunocompetent persons. We extend the duration to 14 to 21 days for immunocompromised patients.
-Patients with severe odynophagia or dysphagia - Patients with severe odynophagia typically require hospitalization for parenteral antiviral therapy (intravenous acyclovir; 5 mg/kg IV every eight hours), pain management, and hydration or alimentation. Once the patient improves, they can be switched to oral therapy to complete the course of treatment. (See 'Patients with severe odynophagia or dysphagia' above.)
●Response to therapy – Most patients respond to antiviral therapy within approximately five to seven days. Drug-resistant virus should be suspected in patients who do not respond during this time frame. Viruses with thymidine kinase mutations are generally cross-resistant to other drugs in this class, including valacyclovir and famciclovir, but remain susceptible to antiviral agents that act directly on DNA polymerase (eg, foscarnet). (See 'Patients with drug-resistant HSV' above.)
●Prevention
•Primary prevention - Most transplant patients receive antiviral prophylaxis for a period of time after transplant to reduce the risk of developing certain viral infections. These agents (eg, valganciclovir and acyclovir) also reduce the risk of developing clinical disease due to HSV. (See 'Primary prophylaxis' above.)
•Secondary prevention - Some immunocompromised patients who had moderate to severe HSV esophagitis remain at risk for recurrent infection after treatment (eg, those being treated for organ rejection). For such patients, we suggest secondary prophylaxis with an antiviral agent (Grade 2C). Acyclovir or valacyclovir are typically used for prophylaxis since there is the most experience with these agents.(See 'Secondary prophylaxis' above.)
ACKNOWLEDGMENT —
The editorial staff at UpToDate would like to acknowledge Dori F Zaleznik, MD, who contributed to an earlier version of this topic review.
