Herpes simplex virus esophagitis in immunocompetent patients: a case report and updated literature review

Abstract

Introduction:

Herpes simplex virus (HSV) esophagitis in immunocompetent individuals is a rare occurrence, albeit it being a self-limiting disease.

Case presentation:

We describe a case of HSV esophagitis in a 49-year-old female immunocompetent patient who presented with dysphagia, odynophagia, and fever. Upper gastrointestinal endoscopy revealed ulcerative esophagitis in the mid to distal esophagus. Histopathology and immunohistochemistry were positive for HSV, and the patient was treated with intravenous acyclovir and a high-dose proton pump inhibitor. Repeat endoscopy at 2 months showed marked improvement in esophageal ulceration.

Discussion:

The incidence of HSV esophagitis still remains poorly documented in the literature, given its self-limiting nature and postulated pathogenesis. We performed a comprehensive literature review aiming to identify clinical and endoscopic features, diagnostic methods, treatment, and outcomes of HSV esophagitis spanning over the last decade, from 2009 to the present. Histopathology was predominantly used in 34/41 (82.9%) of cases for diagnostic confirmation and was often employed in conjunction with immunohistochemistry or polymerase chain reaction. There is limited evidence regarding the use of antivirals in this setting, yet 34/41 (82.9%) of patients still received antiviral therapy. No complications were reported in the majority of cases; however, there were two cases of esophgeal perforation, three cases of eosinophilic esophagitis, and two cases of recurrence documented.

Conclusion:

Despite HSV esophagitis being a self-limiting disease, early endoscopic examination and biopsy may be beneficial in assisting the early initiation of antivirals where indicated, thereby preventing serious complications.

Introduction

Herpes simplex virus (HSV) is an infrequent cause of esophagitis in immunocompetent individuals. It is commonly recognized in patients who are immunocompromised, including those with human immunodeficiency virus (HIV) infection, malignancy, burns, a history of solid organ or bone marrow transplantation, and those undergoing immunosuppressive treatment^[1,2^]. In an immunocompetent adult, HSV esophagitis often represents a self-limiting primary infection or reactivation of disease[3]. We present a case of an immunocompetent female with HSV esophagitis and a history of prior gastric banding. The incidence of HSV esophagitis remains poorly documented in recent literature, with the last comprehensive review conducted over 15 years ago[1]. This prompted an updated review of published cases from 2009 to the present.

HIGHLIGHTS

• HSV esophagitis is a rare cause of esophagitis in immunocompetent individuals and often has a self-limiting disease course.

• We present a case of HSV esophagitis in an immunocompetent 49-year-old female who presented with progressive odynophagia. Clinical, endoscopic, and radiological findings were disproportionate to the histopathological diagnosis.

• Despite its self-limiting nature, complications such as bleeding, recurrence, and esophageal perforation have been documented in the literature; early endoscopic examination and biopsy may be beneficial in preventing serious complications.

• The efficacy of antivirals in immunocompetent HSV esophagitis remains unknown.

Methods

We report a single case of HSV esophagitis and performed a comprehensive literature review. This case report has been prepared in line with the SCARE checklist[4]. A literature search was conducted on MEDLINE and PubMed databases for all relevant articles published in English from 2009 to the present using the key words “immunocompetent,” “herpes simplex” or “HSV” or “herpes simplex virus” or “herpes virus,” and “oesophag*” or “esophag*.” All cases of HSV esophagitis in individuals aged ≥18 years without any obvious cause of immunosuppression were included. The diagnosis of HSV was established by one or more of the following: characteristic cytopathological microscopic findings on esophageal biopsy or brushings, immunohistochemistry indicative of HSV in esophageal tissue, or HSV detection in esophageal tissue via polymerase chain reaction (PCR). We excluded all cases of patients with other concomitant infectious causes of esophagitis, evidence of Helicobacter pylori infection, and a diagnosis of HSV esophagitis based on serology alone.

Case presentation

A 49-year-old female presented with a 3-day history of progressively worsening dysphagia and severe odynophagia. She also experienced associated nausea and vomiting. She denied any symptoms of an upper respiratory tract infection. She had no known history of immunosuppression, HSV or candida infections, or recent sick contacts. She had known gastroesophageal reflux disease (GORD) managed on oral pantoprazole 40 mg daily and a history of previous gastric banding 12 years prior. She also had a normal endoscopy and colonoscopy the year prior for surveillance as a familial adenomatous polyposis gene carrier. All vital signs were within normal ranges, except for a temperature of 39.0°C. On examination, she had a soft abdomen with epigastric tenderness. She had no oral or perioral vesicular lesions. She had an elevated C-reactive protein (CRP) of 118 mg/L and a normal white cell count at 9.95 × 10⁹/L. Serology for HSV was not performed routinely. The history of severe and persistent odynophagia on admission prompted concern for esophageal perforation. Hence, computed tomography (CT) of the upper abdomen with both intravenous and oral contrast was performed. Imaging revealed circumferential thickening of the distal thoracic esophagus and gastro-esophageal junction (GOJ) with submucosal edema, consistent with esophagitis. There was associated esophageal, right para-esophageal, and gastric lymph node enlargement. A known small hiatus hernia was visualized with no evidence of gastric outlet obstruction or perforation. Four milliliters of water was drained from the gastric band at the bedside; however, there was no effect on her symptoms. She proceeded to an upper gastrointestinal endoscopy, which demonstrated a long 10 cm segment of ulcerative esophagitis from 28 to 38 cm from the incisors (Fig. 1). There was no evidence of erosion or slippage of the gastric band. Differential diagnoses for the endoscopic findings include reflux esophagitis, pill-induced esophagitis, and infectious causes of esophagitis including candida, cytomegalovirus, and herpes simplex virus[5].

Figure 1.

Image from initial upper gastrointestinal endoscopy showing severe esophagitis and ulceration.

Biopsies of the esophagus and GOJ revealed evidence of ulceration, along with appearances of herpetic viral cytopathic effect, evident by squamous cell nuclei with basophilic homogenization. Immunohistochemistry was positive for HSV-1 and combined HSV-1/2 for all esophageal biopsies taken. No fungal organisms were identified.

The patient was commenced on intravenous acyclovir for 4 days, along with maximal IV proton pump inhibitor therapy. Despite treatment, she experienced ongoing odynophagia and maintained poor oral intake, hence requiring enteral feeds via a previously placed nasogastric tube. She was discharged home on day 8 post-admission with enteral nutrition and a 10-day course of oral famciclovir. At 1 week post-discharge, she reported improvement with oral intake, and her feeding tube was removed. Screening for immunosuppression was not formally performed. Repeat endoscopy at 2 months revealed marked improvement of esophagitis from Los Angeles Grade D to Grade A (Fig. 2) and laparoscopic gastric band removal was performed concurrently due to longstanding reflux.

Figure 2.

Image from repeat upper gastrointestinal endoscopy at 2 months with evidence of healing of ulceration.

Discussion

HSV esophagitis in immunocompetent individuals may be underrepresented^[6,7^]. This may be due to its self-limiting nature, uncomplicated clinical course, or misattribution to GORD. Nevertheless, complications such as bleeding, recurrence, and esophageal perforation have been documented^[8–10^].

We identified and reviewed 35 articles reporting 41 cases of HSV esophagitis in immunocompetent individuals (Table 1). The mean age was 37.8 years, with over half under 40 years of age. The most frequent presenting symptoms were odynophagia (25/41 61.0%)^[1,8,11–29^], fever (20/41 48.8%)^[1,10–13,16–18,20,23,28–33^], and dysphagia (15/41 36.6%)^[8,10,11,13–17,19,28,29,32–34^]. Less commonly, sore throat, fatigue, and myalgia were reported. In two cases, patients presented with oral or labial lesions ^[1,13^].

Table 1.

Clinical characteristics of 41 immunocompetent patients with herpes simplex esophagitis.

Study	Patient	Clinical presentation	Endoscopic findings	Diagnosis	Treatment	Clinical outcome	Complications
Sbeih et al[25]	77 M	Odynophagia, epigastric pain, nausea, vomiting	Ulcerations in esophagus + second part of duodenum	H	IV + PO Acyclovir	Complete resolution at 1 month repeat endoscopy	Duodenitis
Bresler et al[36]	19 F	Nausea, vomiting	Shallow mid-esophageal ulcers	I + P	IV + PO Acyclovir	Resolution of symptoms with PO intake	Recurrence of symptoms
O’Neill et al[20]	21 M	Odynophagia, myalgia, fever, and retrosternal discomfort	Multiple punched-out/confluent mid-distal esophageal ulcers	H + I	IV Acyclovir + PO Valaciclovir	Return of oral intake at 3 days	Nil documented
Padwale et al[21]	68 F	Severe odynophagia, hematemesis	“Volcano-like” ulcers	H + I + S	PO Acyclovir, PPI, Sucralfate	Complete resolution at 3 month repeat endoscopy	Nil documented
Deen et al[31]	18 M	Fever, vomiting, epigastric pain	Severe mid-distal ulcerative esophagitis	I	IV + PO Acyclovir, PPI	7 days symptom resolution	Nil documented
Vougiouklakis et al[43]	35 M	Nausea, vomiting, epigastric pain	Solitary distal esophageal ulceration with exudate along with second-grade esophagitis	H + I + P	PO Valacyclovir	14 days symptom resolution	Nil documented
Shah et al[26]	27 M	Odynophagia, epigastric pain, nausea, vomiting	Multiple cratered, punched-out esophageal ulcers at 35–43 cm from the incisors	H + I	PO Acyclovir, PPI, Sucralfate	3 months symptom resolution	Nil documented
Sousa et al[34]	65 M	Dysphagia	Gastroesophageal junction stenosis	H + I + P	IV Acyclovir + PO Acyclovir	Complications from aspiration	Aspiration + Nosocomial infection -> Death
Mohamed et al[44]	57 M	Epigastric chest pain	Multiple esophageal and gastric ulcers	H + S	IV Acyclovir, PPI	Not specified	Nil documented
Bhattarai et al[8]	68 F	Progressive odynophagia and dysphagia, epigastric pain	Friable nodular growth above squamocolumnar junction with distal ulceration	H	Acyclovir	Not specified	Iron deficiency anemia
Ohta et al[45]	91 F	Loss of appetite	Multiple round esophageal ulcers and erosions	H	IV Acyclovir	7 days symptom resolution	Nil documented
Upadhaya Regmi et al[28]	55 F	Dysphagia, Marked odynophagia, fever	Multiple mid-distal ulcers with hemorrhage	H	IV + PO Acyclovir	14 days symptom resolution	Nil documented
Haider et al[46]	63 F	Coffee ground emesis, abdominal distention	Severe erosive esophagitis, multiple punched out ulcers	I	PO Valacyclovir	10 days symptom resolution	Nil documented
Naqvi et al[47]	31 F	Hematemesis, sore throat	Multiple nonbleeding linear ulcers involving proximal-distal esophagus	I	Ganciclovir + Valacyclovir	Not specified	Nil documented
Moore et al[9]	78 M	Retrosternal chest pain	Florid esophagitis, healed mucosal scar within a shallow pseudo-diverticulum from a healed mid-esophageal perforation at 30 cm	H	PPI only	Few weeks symptom resolution	Perforated esophageal diverticulum, with posterior mediastinal collection.
Patel et al[22]	20s M	Severe odynophagia, sore throat, nausea, vomiting	Diffuse ulcerative esophagitis with areas of hemorrhage, multiple annular white-colored erosions with exudate	H	PO Acyclovir	Symptom resolution	Eosinophilic esophagitis 8 months endoscopy
Quera et al[33]	26 M	Dysphagia, fever, retrosternal pain	Diffuse ulcerative esophagitis with areas of hemorrhage, multiple annular white-colored erosions with exudate	H + I	PPI + Sucralfate + Gaviscon	5 days symptom resolution	Eosinophilic esophagitis 3 months endoscopy
Ahmed et al[10]	71 F	Dysphagia, chest pain, fevers, dyspnea	Chronic/subacute perforations at 25–27 cm from incisors, communicating with mediastinum	H	IV Acyclovir	Partial resolution at 6 weeks repeat endoscopy	Esophageal perforation with penetration into vertebral space, with formation of esophago-bronchial fistula
Diezma-Martin et al[13]	22 F	Severe odynophagia, retrosternal pain, nausea, fever	Small confluent white distal ulcers with exudate	H + P	PO Acyclovir	Symptom resolution	Nil documented
Diezma-Martin et al[13]	21 M	Odynophagia, chest pain, fever, oropharyngeal lesions	Multiple linear ulcers in the upper third of the esophagus	H + P	PO Acyclovir	Symptom resolution	Nil documented
Diezma-Martin et al[13]	23 M	Epigastric pain, reflux, regurgitation, fever, dysphagia	Longitudinal superficial ulcers along entire length	H + P	PO Acyclovir + PPI	Not specified	Nil documented
Ullah et al[27]	35 M	Severe odynophagia, chest pain	Diffuse esophagitis with shallow ulcers	H + S	IV + PO Acyclovir	Few days symptom improvement	Nil documented
Davis et al[11]	62 F	Severe odynophagia, dysphagia, sore throat, night sweats, fever	Severe hemorrhagic necrotic ulcerative esophagitis, entire length	H	IV + PO Acyclovir	5 days symptom resolution	Nil documented
Jette-Cote et al[15]	72 F	Odynophagia, dysphagia	Mid-esophageal stenosis at 25 cm	H	PO Valacyclovir	6 days symptom improvement	Nil documented
Czako et al[30]	55 M	Fever, dark stools	Multiple circumscribed raised-edge ulcers	H + I + P	IV Acyclovir	Few days symptom improvement	Nil documented
Kadayakkara et al[16]	28 M	Progressive dysphagia, odynophagia, epigastric pain, fever	Small distal/mid ulcers with exudate, some confluent	H + I	IV + PO Acyclovir	Not specified	Nil documented
Marinho et al[17]	22 F	Dysphagia, odynophagia, epigastric pain, fever	Distal third pleomorphic yellow-white plaques with central erosion	H + I	PO Acyclovir	7 days symptom resolution	Nil documented
Koubaa et al[32]	36 F*	Dysphagia, epigastric pain, fever	Diffuse white patches/exudates, edematous friable mucosa	H	PPI only	5 days symptom resolution, complete resolution 1 month endoscopy	Nil documented
Saravanan et al[24]	45 F	Odynophagia, chest discomfort	Near-circumferential mid-esophageal ulcerations, circumferential scarring	H	PPI, Domperidone, Gaviscon	Few days symptom improvement	Nil documented
Ng et al[19]	50 M	Severe dysphagia, odynophagia, husky voice	Longitudinal, whitish ulcer at 20 cm	H	Nil antivirals	1 month symptom resolution	Nil documented
Geraci et al[14]	58 M	Dysphagia, odynophagia, retrosternal chest pain	Small distal erosion	H	PO Acyclovir, PPI, Sucralfate	5 days symptom resolution, complete resolution 1 year endoscopy	Nil documented
Remmelts et al[23]	25 F*	Fever, epigastric pain, odynophagia, vomiting	Diffuse mucosal erythema and fibrin exudates, becoming partially confluent	H + I	IV Acyclovir	2 days symptom improvement	Nil documented
Canalejo et al[1]	20 M	Fever, severe odynophagia, vomiting, diarrhea, painful oral aphthae	Multiple mid-distal esophageal ulcerations with friable mucosa	P	IV + PO Acyclovir	7 days symptom resolution	Nil documented
Canalejo et al[1]	23 F	Fever, epigastric pain, heartburn, vomiting, weight loss, lower lip vesicles	Multiple rounded mid-esophageal ulcers with a fibrinous base	H	IV + PO Acyclovir	14 days symptom resolution + repeat endoscopy resolution	Nil documented
Bando et al[48]	82 F	Fever, epigastric discomfort	Mid-distal exudative shallow circumscribed ulcers	H + P	Acyclovir	Not specified	Nil documented
Puente et al[29]	38 F	Odynophagia	Diffuse longitudinal ulceration	P	PO Acyclovir, PPI, Ziverel	5 days symptom resolution	Nil documented
Puente et al[29]	45 M	Odynophagia, dysphagia, fever	Distal superficial confluent ulcers	H	PPI only	14 days symptom resolution	Nil documented
Puente et al[29]	29 M	Odynophagia, tonsilitis	Distal superficial, raised, rounded ulcers	H + S	PO Acyclovir	7 days symptom resolution	Recurrence of symptoms
Puente et al[29]	22 M	Odynophagia, dysphagia, chest pain, reflux, vomiting	Diffuse superficial longitudinal ulcers	P + S	IV + PO Acyclovir, Ziverel, PPI	10 days symptom resolution	Nil documented
Monsanto et al[18]	20 M	Retrosternal pain, odynophagia, fever, myalgia	Friable distal 2/3rds with longitudinal erosions, whitish exudates	H	IV Acyclovir, PPI	6 days symptom resolution	Eosinophilic esophagitis at 6 week repeat endoscopy
de Boer et al[12]	45 F	Severe odynophagia, nausea, vomiting, fever, retrosternal pain	Mid-distal ulcerative esophagitis with whitish exudates	H + I + S	Nil antivirals	2 days symptoms resolution, complete resolution at 6 week endoscopy	Perianal herpetic lesions

H, histopathology; I, immunohistochemistry; S, serology; P, polymerase chain reaction; IV, intravenous; PO, oral; PPI, proton pump inhibitor

Immunocompetent denotes aged ≥18 years without any obvious cause of immunosuppression

*Pregnant

There have been only three cases of spontaneous esophageal perforation secondary to HSV esophagitis in immunocompetent individuals^[9,10,35^]. The first case was described in 1992 with esophageal perforation leading to a mediastinal abscess, pericarditis, and pleural effusion[35]. Ahmed et al reported a 4-week history of dysphagia, retrosternal chest pain, and fevers, while Moore et al reported a 6-month history of episodic retrosternal chest pain. In both cases, endoscopic findings were most consistent with an unrecognized chronic HSV infection that had progressed to spontaneous esophageal perforation in an immunocompetent individual^[9,10^]. Patients who present with clinically suspicious symptoms should be evaluated with an upper gastrointestinal endoscopy, which enables timely recognition and may aid early initiation of antiviral therapy.

The efficacy and role of antivirals in preventing complications in immunocompetent patients have not been established due to the rare incidence and self-limiting nature of the disease[3]. However, the majority of the reviewed cases received intravenous and/or oral antivirals, commonly Acyclovir. Valacyclovir and Famciclovir were less commonly used. A study by Hoversten et al found that residual symptoms were uncommon regardless of antiviral use in both immunocompromised and immunocompetent individuals, although immunocompromised patients were more likely to require prolonged treatment[2]. Hence, the duration and the decision to use antivirals may be guided by the patient’s immune status and clinical severity.

HSV esophagitis is most often caused by HSV-1 and occasionally HSV-2, arising from primary infection or reactivation of a latent infection^[1,36^]. Transmission of infection may occur due to the disrupted mucosa being exposed to swallowed saliva containing the virus[1]. Theories of pathogenesis in an immunocompetent host include trauma and disruption of esophageal mucosal integrity, such as GORD or esophageal instrumentation. The history of both prior surgery and GORD in the reported case may suggest disruption to the esophageal mucosal integrity. Limited literature has suggested an association of HSV esophagitis with eosinophilic esophagitis; however, causation cannot be determined^[22,33^]. In our review, three cases have reported findings of eosinophilic esophagitis on repeat endoscopy. A postulated hypothesis is that HSV injury to esophageal mucosa triggers viral antigens and T-cells to produce a reaction with a Th-2 cytokine profile that induces eosinophilic inflammation^[18,37^]. The chronic inflammatory state that HSV-1 induces may also be weakly associated with the development of esophageal cancer, but this is not well studied[38]. Although several pathogenic associations have been proposed in immunocompetent individuals, risk factors for HSV esophagitis remain unidentified.

Typical endoscopic findings of HSV esophagitis can vary from non-specific erosive appearances to linear, multiple, or coalescent ulcers varying in depth. Macroscopic appearances have been classified by Itoh et al. Types I and II are small punched-out lesions, with or without raised margins, respectively. Type III describes multiple confluent ulcers, appearing like a map^[39,40^]. Ulcer appearances are often described as “punched-out” or “volcano-like,” predominantly affecting the mid to distal esophagus. The mucosa is often described as friable, and hemorrhagic changes may be present[3]. Associated features of fibrin exudate or plaque may also be present^[3,39^].

Histopathological diagnosis is the predominant and gold standard in the etiological diagnosis of esophagitis and is frequently supported by immunohistochemistry or PCR[41]. Histological features of HSV esophagitis include intranuclear inclusion bodies (Cowdry type A), ballooning degeneration of squamous epithelial cells, and multinucleated giant cells^[39,42^]. Immunohistochemistry and PCR do not routinely provide any diagnostic benefit and may only be beneficial when the diagnosis is unclear[41]. Serology is often of limited value, given that 90% of the healthy population may have been exposed to HSV and carry antibodies[3]. In our case report, immunohistochemistry for HSV-1 and HSV-1/2 was also positive; however, it was difficult to differentiate if this simply reflected HSV type I positivity.

Conclusion

In summary, HSV esophagitis, though typically associated with immunocompromised individuals, should be considered in immunocompetent individuals presenting with persistent odynophagia or dysphagia. The characteristic endoscopic appearances are ulcerative esophagitis affecting the mid to distal esophagus. Biopsies should be obtained for histopathological diagnosis. While the role of antiviral therapy in immunocompetent individuals remains uncertain, most reported cases demonstrate rapid clinical improvement with short-course antivirals used in conjunction with acid suppression.

Ethical approval

The subject of the case report provided informed, written consent to publish the included information.

Consent

The subject of the case report provided informed, written consent to publish the included information.

Sources of funding

None.

Author contributions

H.H.Y.: Data collection, data analysis, writing of manuscript, and conceptualization. J.P.: Data analysis, writing of manuscript, reviewing of manuscript, and conceptualization. S.T.: Data analysis and reviewing of manuscript. N.B.: Data analysis and reviewing of manuscript. A.A.: Data analysis and reviewing of manuscript. M.T.: Data analysis, reviewing of manuscript, and conceptualization.

Conflicts of interest disclosure

All authors have no conflicts of interest to declare.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Markus Trochsler.

Provenance and peer review

Not commissioned; externally peer-reviewed.

Data availability statement

None.

Assistance with the study

None.

Use of artificial intelligence

The authors declare that no artificial intelligence (AI) was used in the research or manuscript development.